Drug Evaluation

Drugs 35: 373-447 (1988)

0012-6667/88/0004-0373/$37.50/0
© ADIS Press Limited
All rights reserved.

Ciprofloxacin
A Review of its Antibacterial Activity, Pharmacokinetic
Properties and Therapeutic Use

Deborah M. Campoli-Richards, Jon P. Monk, Allan Price,

Paul Benfield, Peter A. Todd and Alan Ward
ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: A.P. Ball, Infectious Disease Unit, Cam-
eron Hospital, Fife, Scotland; A.L. Barry, Clinical Microbiology Institute, Tualatin, Or-
egon, USA; T. Bergan, Department of Microbiology, Institute of Pharmacy, University
of Oslo, Oslo , Norway; A. Digranes, Department of Microbiology and Immunology, The
Gade Institute, Haukeland Hospital, Bergen, Norway; G.L Drusano, Department ofMed-
icine, University of Maryland School of Medicine, Baltimore, Maryland, USA; R. Jank-
negt, K1inische Pharmacie, Hospital Sittard, Sittard, The Netherlands; J. Kumazawa, De-
partment of Urology, Faculty of Medicine, Kyushu University, Fukuoka, Japan; M. LeBel,
Universite Laval and Service d'Infectiologie, Centre Hospitalier de L'Universite Laval,
Quebec, Canada; L.A. Mandell, McMaster University, Henderson General Hospital,
Hamilton, Ontario, Canada; S. W. Newsom, Hospital Infection Society, Papworth Hos-
pital, Cambridge, England; S.R. Norrby, Department of Infectious Diseases, University
of Umea, Umea University Hospital, Umea, Sweden; D. Pastel, Cedars-Sinai Medical
Center, Department of Pharmacy, Los Angeles, California, USA; S.M. Smith, Microbio-
logy Section, Veterans Administration Medical Center, East Orange, New Jersey, USA;
D.J. Winston, Los Angeles, California, USA; JS. Wolfson, Infectious Disease Unit, Mas-
sachusetts General Hospital, Boston, Massachusetts, USA.

Contents Summary 375

I. Antibacterial Activity 379
1.1 In Vitro Inhibitory Antibacterial Activity 380
1.1.1 Gram-Negative Bacteria 380
1.1.2 Gram-Positive Bacteria 385
1.1.3 Anaerobic Bacteria 387
1.1.4 Chlamydia and Mycoplasma 387
1.2 Activity Against Resistant Bacteria 389
1.3 Factors Influencing In Vitro Activity 389
1.3.1 Inoculum Size 389
1.3.2 Medium 391
1.3.3 Cations, pH and Urine 391
1.3.4 Serum 391
1.3.5 Peritoneal Dialysis Fluid and Effluent , 391
1.4 Bactericidal Activity 392
1.4.1 In Vitro 392
1.4.2 Serum Bactericidal Activity Ex Vivo 392
1.5 Post-Antibiotic Effect 392
1.6 Antibacterial Synergy and Antagonism : 393
1.7 Mechanism of Action 394
Ciprofloxacin: A Review 374

1.8 Development of Resistance 394

1.9 Efficacy in Animal Models of Infection 395
2. Pharmacological Effects 397
2.1 Effects on Immune Function 397
2.2 Effects on Faecal and Oropharyngeal Flora 398
2.3 Toxicity 400
3. Pharmacokinetics 400
3.1 Absorption and Serum Concentrations 400
3.1.1 Oral Administration 400
3.1:2 Intravenous Administration 402
3.2 Distribution 402
3.3 Metabolism and Elimination 404
3.3.1 Elimination Half-Life 406
3.4 Influence of Disease on the Pharmacokinetics of Ciprofloxacin 406
3.4.1 Renal Dysfunction 406
3.4.2 Continuous Ambulatory Peritoneal Dialysis 407
3.4.3 Cystic Fibrosis 407
3.5 Influence of Age on the Pharmacokinetics of Ciprofloxacin 407
4. Therapeutic Trials 408
4.1 Worldwide Cumulated Efficacy Data 408
4.1.1 Clinical Efficacy 408
4.1.2 Bacteriological Efficacy 410
4.1.3 Superinfections and the Development of Resistance .411
4.2 Urinary Tract Infections 412
4.2.1 Non-Comparative and Dose Response Studies .412
4.2.2 Comparative Studies 413
4.3 Sexually Transmitted Diseases 416
4.3.1 Gonorrhoea ..: 416
4.3.2 Non-Gonococcal Urethritis 416
4.3.3 Other Sexually Transmitted Diseases .417
4.4 Gastrointestinal Infections 417
4.4.1 Non-Comparative Studies 417
4.4.2 Comparative Studies 417
4.5 Respiratory Tract Infections 417
4.5.1 Non-Comparative Studies 418
4.5.2 Comparative Studies 419
4.6 Respiratory Tract Infections in Patients with Cystic Fibrosis 419
4.6.1 Non-Comparative and Dose Response Studies 421
4.6.2 Comparative Studies 421
4.7 Skin and Soft Tissue Infections 422
4.7.1 Non-Comparative Studies 423
4.7.2 Comparative Studies , 423
4.8 OSteomyelitis 423
4.9 Prophylaxis in Immunocompetent Patients 425
4.9.1 Surgical Prophylaxis 425
4.9.2 Prophylaxis for Recurrent Cholangitis .425
4.10 Immunologically Compromised Patients 425
4.10.1 Fever and Documented Infections 426
4.10.2 Prophylaxis 426
4.11 Decontamination of Pathogen 'Carriers' 427
4.11.1 Neisseria meningitidis 427
4.11.2 Methicillin-Resistant Staphylococcus aureus (MRSA) 427
4.11.3 Nosocomial Klebsiella Species 428
4.11.4 Salmonella species 428
4.12 Other Infections 428
Ciprofloxacin: A Review 375

5. Side Effects 428

5.1 Clinical Symptoms 428
5.2 Effects on Laboratory Indices 431
6. Drug Interactions 431
6.1 Xanthine Derivatives 431
6.2 Antacids and Other Drugs Affecting Absorption 432
7. Dosage and Administration 432
8. Place of Ciprofloxacin in Therapy .433

Summary
Synopsis Ciprojloxacin is one ofa new generation ofjluorinated quinolonesstructurally related
to nalidixic acid. The primary mechanism ofaction of ciprofloxacin is inhibition ofbac-
terial DNA gyrase. It is a broadspectrum antibacterialdrug to which most Gram-negative
bacteria are highly susceptible in vitro and many Gram-positive bacteria are susceptible
or moderately susceptible. Unlike most broad spectrum antibacteriald!J.lgs, ciprojloxacin
is effective after oral or intravenous administration.
Ciprojloxacin has been most extensively studied following oral administration. It at-
tains concentrations in most tissues and body fluids which are at least equivalent to the
minimum inhibitory concentration designatedas the breakpointfor bacterialsusceptibility
in vitro. The results of clinical trials with orally and intravenously administered cipro-
floxacin have confirmed the potentialfor its use in a wide range ofinfections, which was
suggested by its in vitro antibacterial and pharmacokinetic profiles. It has proven an
effective treatment for many types of systemic infections as well as for both acute and
chronic infections of the urinary tract.
Ciprofloxacin generally appeared to be at least as effective as alternative orally ad-
ministered antibacterial drugs in the indications in which they were compared, and in
some indications, to parenterally administered antibacterial therapy. However, further
studies are needed to fully clarify the comparative efficacyof ciprofloxacin and standard
antibacterialtherapies.
Bacterialresistance to ciprojloxacin develops infrequently. both in vitro and clinically,
except in the setting ofpseudomonal respiratory tract infections in cysticfibrosis patients.
The drug is also well tolerated. Thus. as an orally active, broad spectrum and potent
antibacterialdrug. ciprofloxacin offersa .valuablealternative to broad spectrum parenter-
ally administered antibacterial drugs for use in a wide range of clinical infections. in-
cluding difficult infections due to multiresistant pathogens.

Antibacterial Activity Ciprofloxacin is a fluorinated quinolone, with the most potent in vitro antibacterial
activity against most bacterial species of all the newer quinolones marketed to date. The
primary mechanism of action of ciprofloxacin and other quinolones involves inhibition
of bacterial DNA gyrase. Ciprofloxacin has an MIC 90 of ~ 1 mg/L (indicating suscep-
tibility) against all species of Enterobacteriaceae, except some species of Providencia.
Acinetobacter species, Neisseria gonorrhoeae, Neisseria meningitidis, Branhamella catar-
rhalis and Haemophilus species (including (j-lactamase negative and positive strains) were
also highly susceptible to ciprofloxacin. Pseudomonasaeruginosa was susceptible (MIC 9o
range 0.12-1 mg/L), but ciprofloxacin was less active against other Pseudomonas species
(MIC 90 range 0.25-16 mg/L), Other Gram-negative organisms susceptible to ciprofloxacin
include Campylobacter jejuni, Vibrio species and Legionella species, while Gardnerella
vaginalis was only moderately susceptible. In general, against Gram-negative aerobes in
vitro. ciprofloxacin has equivalent activity, or was more potent by I or 21iilutions than
ofloxacin, and was consistently more potent than other quinolones such as norfioxacin,
enoxacin or pefloxacin.
Staphylococcus species, such as S. epidermidis, S. saprophyticus and S. aureus (in-
Ciprofloxacin: A Review 376

eluding penicillin-resistant and methicillin-resistant strains) were susceptible to cipro-

floxacin (MIC 9o range 0.12-1 mg/L). Streptococcus species, including penicillin-resistant
strains of S. pneumoniae, were moderately susceptible to ciprofloxacin (MIC 9o range 0.5-
6.3 mg/L), Among the marketed quinolones only ofloxacin has similar activity to cip-
rofloxacin in vitroagainst Gram-positive organisms. Among the non-quinolones reviewed
only cefotaxime and mezlocillin show greater activity against non-enterococcal strepto-
cocci and only imipenem shows greater activity against S. aureus.
Mycobacterium tuberculosis. Mycobacterium fortuitum, Mycobacterium intracellulare
and Listeria monocytogenes were susceptible or moderately susceptible to ciprofloxacin,
but other Mycobacterium species and Nocardia asteroides tended to be resistant (MIC 9o
range ~ 4 mg/L).
Ciprofloxacin has a broad range of reported MIC9Q values against Bacteroides species
(0.06-32 mgfL); B. oralis and B. ureolyticus tended to be susceptible while B. fragilis
tended to be resistant. Peptococcus species were moderately susceptible to ciprofloxacin,
but Peptostreptococcus species and Clostridium species were resistant. Chlamydia tracho-
matis proved moderately susceptible (MIC range 0.5-2 mg/L),
The antibacterial activity of ciprofloxacin is influenced little, if at all, by inoculum
size, growth medium or the presence of serum. However, both bacteriostatic and bac-
tericidal activities (which are achieved at similar concentrations for ciprofloxacin) are
reduced by magnesium ions and acidity, which may account for the drug's reduced ac-
tivity in urine.
Mutants having reduced susceptibility to ciprofloxacin emerge at a relatively low in-
cidence in vitro. Moreover, strains which become less susceptible to ciprofloxacin rarely
become resistant (i.e. MIC values generally remain < 4 mg/L). Cross-resistance with
nalidixic acid or other quinolones occurs, but it is rare with non-quinolone antibacterial
drugs. The mechanisms of resistance to quinolones are unclear. Plasmid-mediated re-
sistance does not occur, but chromosomal mutation influencing DNA gyrase and/or the
cell membrane may confer resistance.

Pharmacological Effects Ciprofloxacin has little, if any, effect on chemotaxis of - and may increase phago-
cytosis and killing by - polymorphonuclear leucocytes. At concentrations up to 125 mgf
L it has no effect on human mitogen-stimulated mononuclear cell proliferation.
In the gastrointestinal tract ciprofloxacin markedly reduces or eradicates Enterobac-
teriaceae, with a less dramatic effect against staphylococci and enterococci and little effect
on the anaerobic microflora. There is little evidence of overgrowth or superinfection.
Preclinical toxicology studies, including ophthalmological examination, in various
animal species reveal no significant evidence of toxicity. In young rats and dogs cipro-
floxacin does cause articular damage, but the clinical implications, if any, are unknown.

Pharmacokinetics After oral administration of single doses (50 to 1000mg) of ciprofloxacin, peak serum
concentrations of 0.28 to 5.92 mg/L were reached within 0.5 to 2 hours. Mean peak
concentrations increased in proportion to the dose within the normal therapeutic range.
Multiple dose administration for up to 8 days in healthy volunteers, either orally (500mg
bid) or intravenously (200mg bid), did not produce significant drug accumulation. Food
had no significant effect on the pharmacokinetics of ciprofloxacin, except to delay ab-
sorption, but simultaneous administration of antacids containing magnesium hydroxide
and/or aluminium hydroxide with ciprofloxacin reduced the bioavailability of the latter.
Following intravenous administration, the plasma concentration profile of ciprofloxacin
is best characterised by a 3-conipartment open model. The absolute bioavailability of
oral ciprofloxacin averages between 69 and 85%.
The apparent volume of distribution of ciprofloxacin was calculated to be approxi-
mately 2 to 3 L'kg. The volume of the central compartment was between 0.16 and 0.63
L'kg, which approximately represents the total volume of extracellular water. The tissue
concentrations achieved are at least as high as the serum concentrations for most tissues.
Ciprofloxacin was approximately 16 to 40% bound to plasma proteins.
Ciprofloxacin: A Review 377

After administration of a single oral dose (259mg) of 14C-labelled ciprofloxacin to

healthy volunteers, approximately 94% of the dose was recovered in urine and faeces
over 5 days, with most radioactivity being recovered in the urine (55.4%). This study
demonstrates that unchanged ciprofloxacin is the major moiety in both urine (45%)and
faeces (25%). After a single intravenous dose (107mg) of 14C-Iabelled ciprofloxacin to
healthy volunteers, approximately 89% of the dose was recovered in urine and faeces
over 5 days with about 75% of radioactivity being recovered in the urine. As with oral
dosage, unchanged ciprofloxacin is also the major moiety in urine (62%)and faeces(15%).
Small amounts of 4 metabolites are present in urine and faeces, all with some antibac-
terial activity, but less than that of ciprofloxacin.
Total serum clearance of ciprofloxacin in healthy volunteers ranged from 23 to 43 L/
h/1.73m 2• Renal clearance accounts for approximately 60 to 70%of total serum clearance,
and was approximately 3 times higher than creatinine clearance. Active tubular secretion
of ciprofloxacin is confirmed by the observation that coadministration of probenecid
decreases the ciprofloxacin renal clearance.
The elimination half-life of ciprofloxacin after single and multiple doses ranged from
3.4 to 6.9 hours following oral administration (50 to 1000mg) and from 3 to 4.4 hours
following intravenous administration (50 to 200mg).
The pharmacokinetics of ciprofloxacin are altered in patients with renal dysfunction.
After single doses, peak serum concentration, area under the serum concentration-time
curve (AVC) and elimination half-life are substantially increased depending on the degree
of renal impairment. Thus, dosage adjustment may be required in such subjects. Cip-
rofloxacin is poorly removed from the body by haemodialysis. The pharmacokinetics of
ciprofloxacin are generally not affected to a clinically significant extent by age or the
presence of cystic fibrosis. However, serum concentrations tend to be higher in elderly
subjects, possibly due to diminished renal function or changes in volume of distribution.

Therapeutic Trials With its broad spectrum of antibacterial activity and widespread distribution to most
tissues and body fluids, ciprofloxacin should have potential therapeutic application in
many types of infection. Cumulated European and VS clinical trial data revealed that
ciprofloxacin (in most cases administered orally in a daily dosage of 500 to 1500mg
divided into two 12-hourly doses, for 7 to 14 days) was clinically effective in greater than
88%of patients with infections of the urinary tract, respiratory tract, skin and skin struc-
ture, bones or joints, gastrointestinal tract, blood and gynaecological organs. In Japanese
patients (most of whom received 200mg of oral ciprofloxacin 3 times daily) cumulated
clinical trial data revealed clinical efficacy rates of greater than 80% in most infection
types and of approximately 75% in lower respiratory tract infections, and ear, nose and
throat infections. High rates of clinical efficacy were achieved in infections due to most
Gram-positive and Gram-negative pathogens, including multiresistant but ciprofloxacin-
susceptible nosocomial pathogens. However, only 43.2% of patients in Japan with infec-
tions of various sites due to P. aeruginosa responded versus approximately 75% of non-
Japanese patients, a difference which may be a consequence of the lower dosages used
in Japan as compared with the rest of the world. Bacterial eradication rates for most
species of pathogens reported in data cumulated worldwide are generally 75% or greater,
with the majority being 85% or greater. P. aeruginosa is again an exception in the Jap-
anese data, being eradicated from only 22.7% of infections.
As with many broad spectrum antibacterial drugs, superinfection due to Candida
species or bacterial pathogens occurs with ciprofloxacin, in some cases requiring addi-
tional antimicrobial therapy. Development of resistance or reduced susceptibility to cip-
rofloxacin generally occurs infrequently. However, transitory, or in a few cases persistent,
resistance to P. aeruginosa is commonly encountered among cystic fibrosis patients. In
addition, among debilitated patients or in those suffering chronic and/or complicated
infections, emergence of reisistance to P. aeruginosa or other bacteria occurs occasionally
and has resulted in clinical treatment failures. Cross-resistance has been reported rarely
in Pseudomonas species between ciprofloxacin and aminoglycosides, ureidopenicillins
Ciprofloxacin: A Review 378

and cephalosporins, and cross-resistance has also been reported between ciprofloxacin
and aminoglycosides in S. aureus.
Several small randomised studies have compared the clinical efficacy of ciprofloxacin
and alternative antibacterial drugs in the treatment of urinary tract infections (UTI).
While none of these trials provided statistical analyses of the results, oral ciprofloxacin
appeared to be similar in clinical and bacteriological efficacy to orally administered co-
trimoxazole (trimethoprim/sulpharnethoxazole) [complicated and uncomplicated infec-
tions], trimethoprim (uncomplicated infections), norfloxacin (complicated infections) and
cinoxacin (uncomplicated infections). Intravenous ciprofloxacin appeared to be similar
in clinical and bacteriological efficacy to intravenous mezlocillin (complicated infections).
In addition, in a large Japanese study, oral ciprofloxacin 200mg 3 times daily was re-
ported to be statistically superior to oral norfloxacin 200mg 4 times daily in both clinical
efficacy and bacterial eradication rates in the treatment of complicated UTI. Of note, in
the above studies the incidence of side effects was lower with ciprofloxacin than with
co-trimoxazole.
Results of several comparative and non-comparative studies indicated that single oral
doses of ciprofloxacin 100 to 2000mg (usually 100 to 500mg) produced 100% bacterio-
logical cure rates in gonococcal urethritis. Comparative rates for single doses of ampicillin
2 to 3.5g plus probenecid Ig were 90 to 92%. Ciprofloxacin was consistently effective
against penicillinase-producing strains of N. gonorrhoeae, and was often effective in cur-
ing oropharyngeal or rectal infections. In contrast, ciprofloxacin lacks a reliable degree
of clinical efficacy in non-gonococcal urethritis due to Chlamydia trachomatis or Urea-
plasma urealyticum.
Ciprofloxacin appears to be similar to or, in the studies which analysed the results
statistically, was not significantly different in clinical efficacy from doxycycline, cepha-
lexin, amoxycillin, bacampicillin or co-trimoxazole in various lower respiratory tract in-
fections. Randomised comparative studies showed oral ciprofloxacin to be statistically
(p < 0.001) superior to cefaclor. in clinical efficacy in the treatment of infectious exac-
erbations of chronic bronchitis and other chronic lung diseases, and statistically (p <
0.05) superior to ampicillin in clinical efficacy in outpatients with acute bronchitis.
Several randomised comparative studies documented the efficacy of oral ciprofloxacin
in young adult patients with cystic fibrosis who were suffering from lower respiratory
tract infections due, in most instances, to colonising P. aeruginosa. Statistical analyses
in 2 separate studies demonstrated that ciprofloxacin 500 or 750mg twice daily was gen-
erally no different in clinical efficacy 10 the combination of intravenous azlocillin plus
an aminoglycoside, although in one of these two studies oral ciprofloxacin produced a
superior improvement in 2 parameters of lung function (p < 0.05). Two crossover studies
showed no statistically significant difference in clinical efficacy between twice daily oral
administration of ciprofloxacin (500 or 750mg) and ofloxacin (400mg). Because of the
potential for the development of resistant P. aeruginosa, ciprofloxacin is not recom-
mended for long term prophylaxis or multiple sequential courses oftreatment in recurrent
lung infections in cystic fibrosis patients.
Three double-blind randomised studies revealed oral ciprofloxacin 750mg twice daily
to be not statistically different in clinical efficacy from intravenous cefotaxime 2g 3 times
daily in skin and soft tissue infections. A fourth study, involving mild to moderate in-
fections, reported significantly (p < 0.05) more failures among the cefotaxime-treated
patients (21% vs 3%).
Several case studies reported the successful treatment with ciprofloxacin of systemic
Salmonella infections in immunocompromised patients. Encouraging preliminary results
were also noted in other immunocompromised patients with fever or doeumented in-
fection. Prophylaxis of remission induction therapy with oral ciprofloxacin 500mg twice
daily resulted in a significantly (p < 0.05) lower infection rate (18%) than prophylaxis
with the combination of co-trimoxazole 160/800mg plus colistin 200mg orally 3 times
daily (50%). However, results of both prophylaxis and treatment in immunocompromised
Ciprofloxacin: A Review 379

patients suggest that streptococci and staphylococci may not be adequately inhibited by
ciprofloxacin alone.
Treatment with ciprofloxacin eliminates nasopharyngeal carriage of Neisseria men-
ingitidis and gastrointestinal carriage of Salmonella species and nosocomial Klebsiella
species.

Side Effects Significant adverse effects associated with ciprofloxacin therapy are uncommon. The
overall worldwide incidence of side effects in patients treated with the drug was reported
to be from 5 to 10%, and therapy had to be discontinued in less than 2% of patients.
Gastrointestinal symptoms, mainly nausea, vomiting, abdominal pain, diarrhoea, and
anorexia, were reported most frequently (in up to 10% of patients receiving higher oral
dosages), followed by central nervous system events such as anxiety, nervousness, in-
sommia, euphoria, tremor and, very rarely, seizures and hallucinations (1 to 4%), and
hypersensitivity reactions of a dermatological nature (I %). Other untoward effects that
have been reported rarely (incidence less than I%) include eye disorders and chest pain.
Mild, transient alterations in laboratory values were sometimes observed [eosinophilia,
elevated serum creatinine, blood urea nitrogen, AST (SGOT) and ALT (SGPT»), although
their clinical significance is unknown. Isolated cases of haematuria, interstitial nephritis
and arthropathy have also been reported.

Dosage and Administration Ciprofloxacin is usually administered orally as a twice daily regimen in a total daily
dosage of 500 to 1500mg depending on the nature and severity of the infection. For mild
to moderate urinary tract infections a total daily dosage of 500mg is usually appropriate,
while 1000mg daily is recommended for severe or complicated urinary tract infections,
and mild to moderate respiratory tract, bone and joint, or skin and skin structure infec-
tions. For severe or complicated respiratory tract infections a dosage of 1500mg daily is
recommended. In Japan the standard recommended oral dosage is 200mg 3 times daily.
The recommended dosage ofciprofloxacin administered intravenously is lOOmg twice
daily in urinary tract infections and 200mg twice daily in other infections. In patients
with pseudomonal or staphylococcal infections, or in immunocompromised patients, a
dosage of 300mg twice daily may be used.
Dosage adjustments for altered renal function are usually not required except in patients
with severe renal impairment (creatinine clearance .:s;; 20 ml/min) in whom the total daily
dose may be reduced by one-half.
Elevated plasma concentrations of theophylline and a prolongation of its elimination
half-life may result from the concurrent administration of ciprofloxacin with theophyl-
line. If concomitant use cannot be avoided, plasma concentrations of theophylline should
be monitored and dosage adjustments made as appropriate.
Antacids containing magnesium and/or aluminium hydroxide interfere with the ab-
sorption of ciprofloxacin, resulting in subtherapeutic serum and urine concentrations.
Thus, concurrent administration of these antacids with ciprofloxacin should be avoided.

1. Antibacterial Activity tributes to the potent antimicrobial activity. The

Ciprofloxacin is a 4-quinolone antibacterial drug.
Figure I presents the chemical structure of cipro-
floxacin and shows how it has been modified from
the basic quinolone ring. At position 1 ciproflox-
acin includes a cyclopropane ring, which replaces
an ethyl group in most other quinolones and con-
fluorinated carbon at position 6 is common to cip-
rofloxacin, enoxacin, norfloxacin and ofloxacin,and
considerably increases the activity of these drugs
in comparison with nalidixic acid. The early quin-
olones were characterised by a low ratio of peak
tissue concentration to minimum inhibitory con-
centration (MIC) -limiting their use to urinary tract
infections - and by central nervous system side ef-
Ciprofloxacin: A Review
Rs 0
R~R3
R7~N)lR2
I 8
R1
Quinolone ring
o obtained worldwide. For most bacterial speciesonly
r~aJC02H
HN~ A been considered as indicative of differences in sus-
CiprofloX8cin
Fig. 1. Structural formula of ciprofloxacin in comparison with
the basic quinolone ring.
fects. Modification of the quinolone ring structure
at positions 6, 7 and 8 has overcome these prob-
lems in the new quinolones. In ciprofloxacin the
fluorination at position 6 and the piperazine ring
at position 7 have greatly enhanced the activity of
this compound (Schentag & Domagala 1985;Smith
1984a,b).
Clinical efficacy of an antibacterial drug derives
from a combination of several factors, including
antibacterial activity, mechanism of action and
achievable serum and tissue concentrations. Im-
portantly, the differences in achievable serum and
tissue concentrations between antibacterial drugs,
as reflected in susceptibility cutoff points, should
be considered when extrapolating comparative po-
tency measured in vitro. Ciprofloxacin achieves a
maximum serum concentration of about 2 to 3 mg/
L with the oral dosage schedule of 500mg twice
daily.Moreover, its tissue penetration is good and
drug concentrations achieved in most tissues are
of the order of those in serum (see section 3). Thus,
as a guide in the following review of antibacterial
activity, an individual organism may be consid-
ered susceptible to ciprofloxacin if the minimum
concentration required to inhibit it in vitro is ~ 1
mgjL.
380
1.1 In Vitro Inhibitory Antibacterial
Activity
In this review in vitro activity is (unless other-
wise stated) based on minimum inhibitory concen-
trations (MIC) determined using agar or broth di-
lution techniques and an inoculum of 104 to 106
colony-forming units (cfu) against clinical isolates
studies including 20 or more strains are discussed.
Differences in the concentrations inhibitory to 90%
of tested strains (MIC90) of ~ 2 dilutions have
ceptibility (i.e. activity or potency of the antibac-
terial drugs in vitro).
References to information in text may be iden-
tified in the accompanying tables unless otherwise
specified.
1.1.1 Gram-Negative Bacteria
Enterobacteriaceae
The ciprofloxacin MIC90 for Enterobacteriaceae
is ~ 1 mg/L for all species reviewed, except some
species of Providencia (see table I). For most spe-
cies the ciprofloxacin MIC90 is much lower than 1
mg!L.
Ciprofloxacin and ofloxacin are consistently
more potent inhibitors of Enterobacteriaceae than
norfloxacin or enoxacin, except against Salmonella
and Shigella species and Yersinia enterocolitica
which are equally susceptible to all four quino-
lones. Moreover, for most species ciprofloxacin is
more potent than ofloxacin by 1 or 2 dilutions.
In comparison with non-quinolone antibacterial
drugs, ciprofloxacin is considerably more potent in
vitro than gentamicin, mezlocillin or ampicillin
against all Enterobacteriaceae (see table II). In vitro
it is at least as potent as cefotaxime against Kleb-
siella pneumoniae, Proteus mirabilis, Providencia
species, Shigella species and Y. enterocolitica, and
as potent as aztreonam against Escherichia coli, K.
pneumoniae and Klebsiella, Proteus, Providencia,
Salmonella and Serratia species. Against all other
species in vitro ciprofloxacin is the most potent of
the drugs reviewed.
Ciprofloxacin: A Review
Neisseriaceae
Neisseria species, including N. meningitidis and
both penicillin-susceptible and penicillin-resistant
(penicillinase-producing and chromosomally me-
diated) N. gonorrhoeae are highly susceptible to
ciprofloxacin (MIC 9o ~ 0.03 mg/L), as they are to
other quinolones (see table I). Cefotaxime and cef-
tazidime have equivalent or slightly less activity
against these species than ciprofloxacin in vitro (see
table II).
Against 34 strains of Moraxella species cipro-
floxacin showed greater inhibitory activity than
norfloxacin in vitro (MIC9o values of 0.5 and 2 mg/
L, respectively) [Appelbaum et at. 1986]. Against
Branhamella catarrhalis (20 strains per study) cip-
rofloxacin had an MIC 90 of 0.03 mg/L, which was
lower than those of norfloxacin, pefloxacin, enox-
acin, ofloxacin or nalidixic acid (MIC 9o values in
the range 0.12-8 mg/L) [Cornaglia et at. 1987; King
& Phillips 1986].
Against Acinetobacter calcoaceticus, ciprofloxa-
cin had an MIC90 in the range 0.25 to 1 mg/L,
showing similar activity to ofloxacin and imipe-
nem, and greater activity than norfloxacin, nali-
dixic acid, cefotaxime, ceftazidime, gentamicin or
aztreonam in vitro (see tables I and II). A. eal-
coaceticus var. anitratus, lwoffii, haemolyticus and
alcaligenes are all susceptible to ciprofloxacin (Ap-
pelbaum et at. 1986), while var. lwoffii is more sus-
ceptible than var. anitratus (Fass 1983; Joly-Guil-
lou & Bergogne-Berezin 1986).
Haemophilus species
All the newer quinolones are potent inhibitors
of H aemophilus species in vitro, with ciprofloxacin
being the most potent of those reviewed in table I.
Among the non-quinolones reviewed, only cefo-
taxi me shows a similar degree of inhibitory activity
against Haemophilus influenzae in vitro; ceftazid-
ime, mezlocillin and ampicillin are less potent (see
table II). Ciprofloxacin is equally active against {3-
lactamase negative and positive strains of H. influ-
enzae (Chau et at. 1986; Weber et at. 1985). Against
100 strains of Haemophilus ducreyi ciprofloxacin
was a more potent inhibitor in vitro (MIC 9o 0.001
mg/L) than 9 other antibacterial drugs including
381
ceftriaxone, erythromycin and rosoxacin (Taylor et
at. 1985); against 23 multiresistant, {3-lactamase
positive strains it was a more potent inhibitor
(MIC 9o 0.016 mg/L) than 13 other drugs and was
at least as potent as ofloxacin or erythromycin
(MIC9o 0.03 mg/L) [Sanson-Le Pors et at. 1986].
Pseudomonadaceae
The quinolones as a group are less active against
Pseudomonas species than they are against other
Gram-negative organisms. However, most strains
of Pseudomonas species are susceptible to cipro-
floxacin in vitro (see table I), which tends to be
more potent than norfloxacin, enoxacin or oflox-
acin. Appelbaum et at. (1986) demonstrated greater
activity of ciprofloxacin for Pseudomonas aerugin-
osa, fluoreseens and stutzeri (MIC9o 0.25-0.5 mg/
L) than for Pseudomonas maltophilia and cepacia
(MIC9o 1-4 mg/L), However, Comaglia et at. (1987)
reported similar activity of ciprofloxacin (MIC9o 1-
2 rng/L) against P. aeruginosa, maltophilia, eepa-
cia, jluorescens and putrefaciens. Among the non-
-quinolone antibacterial drugs reviewed, none is as
potent an inhibitor of Pseudomonas species in vitro
as ciprofloxacin (see table II).
Aeromonas hydrophila is highly susceptible to
ciprofloxacin (MIC9o 0.008-0.097 mg/L) [Fass 1983;
Felmingham et al. 1985; Goosens et al. 1985; Rein-
hardt & George 1985], which proved more active
in vitro than norfloxacin, aztreonam, amikacin or
thienamycin in one study (Fass 1983), and tetra-
cycline, chloramphenicol or gentamicin in another
(Reinhardt & George 1985). Ciprofloxacin had
equivalent in vitro inhibitory activity against Aero-
monas caviae and A. sobria as against A. hydro-
phila (Reinhardt & George 1985).
Studies including ~ 16 strains of Plesiomonas
species have shown this organism to be susceptible
to ciprofloxacin (MIC 9o 0.008-0.063 mg/L) [Fel-
mingham et al. 1985; Reinhardt & George 1985;
Van Caekenberghe & Pattyn 1984].
Other Gram-Negative Organisms
MIC 90 values for ciprofloxacin against Cam-
pylobaeter jejuni have been reported in the range
0.12 to 0.62 mg/L (MIC range ~ 0.008-2 mg/L)
[Auckenthaler et al. 1986; Chau et al. 1986; Fel-
mingham et at. 1985; Fliegelrnan et al. 1985; Goos-
ens et al. 1985; Turgeon et al. 1987; Van der Au-
Table I. In vitro activity of ciprofloxacin and other quinolones against Gram-negative organisms. All studies used broth or agar dilution techniques, at least 20 strains of
clinical isolates and an inoculum size of 1()4 to 106 cfu 1°a :::::!2
0
Organism MICrange (reported range of MIC 90 values) [mg/L] References b I ~
~
clprofloxacln ofloxacin norfloxacin enoxacin nalidixic acid ?'
(~ 1 mg/L)a (~ 1 mg/L)a (~4 mg/L)a (~4 mg/L)a (~ 16 mg/L)8 ~
I :-0
~
Enterobacteriaceae <
(p'
Citrobacter spp. 0.004-8 (~0.03-0.39) ~0.03-2 (0.12) ~0.008-32 ~0.03-1 (0.125-0.5) 1->200 (4-200) 3,6-10,12,14,15, I ~
(0.125-0.78) 16a,17,18a,20
Enterobacter
aerogenes ~0.OO8-4 (0.03-0.12) 0.03-0.25 (0.12) 0.03-4 (0.12-1) 0.06-8 (0.25) 2-;J!:64 (4-;J!:64) 6,10,12,15
cloacae 0.005-1 (0.05-0.125) 0.03-4 (1) 0.02-16 (0.4-1) 0.06-8 (1) 1->512 (4-128) 5,6,10,12,15,16a,18a
spp. 0.004-8 (~0.03-0.25) ~0.03-2 (0.06-0.5) ~0.03-32 (0.25-2) ~0.03-4 (0.25-0.5) 0.25-1024 (2-32) 2,3,7-10,13a,14,17,20,22
Escherichia coli 0.004-1 (0.015-0.25) 0.015-2 (0.06-0.125) ~0.015-4 (~0.097-1) ~0.008-8 (0.25-1) 0.5->512 (4-256) 2,3,5-9,12-15,16a,17,
18a,20,22,23,25,26
Klebsiella
oxytoca ~0.OO8-4 (0.03-0.125) 0.06-0.25 (0.25) 0.05-2 (0.12-1) 1-8 (8) 5,6,12
pneumoniae 0.005-0.5 (0.05-0.25) 0.015-0.5 (0.25) 0.03-8 (0.125-2) 0.06-1 (0.5) 1->32 (4->32) 2,3,5,6,10,12,16a
spp, 0.008-2 (~0.03-0.5) ~0.03-4 (0.06-1) ~0.03-16 (0.1-2) ~0.03-4 (0.1-2) 1-512 (16-128) 7-9,13a,14,15,17,
18a,20,22,26
Morganella morganii ~0.002-0.12 ~0.03-0.5 (0.06-0.12) 0.01-0.5 (0.02-0.25) ~0.008-1 (0.25) 1-256 (4-8) 5,6,8,9,12,15
(0.15-0.03)
Proteus
mirabilis ~0.008-1 (~0.03-0.2) 0.03-2 (0.12-0.5) ~0.03-8 (0.12-0.78) 0.12-1 (0.5) 1-256 (4-100) 3,6,8-10,12,14,15,
17,18a,22,26
vulgaris 0.004-1 (~0.03-0.06) ~0.03-1 (~0.03-0.25) ~0.03-1 (~0.03-0.5) ~0.03-0.25 1-16 (4-8) 6,9,13a,15
(0.125-0.25)
spp.s 0.008-4 (0.03-1) 0.03-0.5 (0.25) 0.03-2 (~0.06-1.56) 0.05-4 (0.2-2) 2->256 (4-100) 2,13a,14,16a,17,18a,
20,26
Providencia
rettgeri 0.008-1 (~0.03-0.25) ~0.03-2 (0.25-0.5) ~0.03-4 (0.25-4) 0.05-4 (0.5) 1-128 (8-16) 6,8,9,15
stuartii 0.005-8 (~0.03-8) ~0.03-8 (0.25-2) 0.02-16 (0.06-16) 0.12-32 (2) 1->512 (32-256) 3,5,6,8,9,15
spp, ~0.015-6.25 0.06-6.25 (0.5-3.12) 0.12-2 (1) 1->200 (;J!:64-100) 12,14,18a
(0.25-3.12)
Salmonella
typhi 0.03-0.25 (0.06-0.25) 0.03-0.097 0.03-0.097 0.06-0.25 (0.12-0.25) 2 (2) 11,13b,23
(0.06-0.097) (0.06-0.097)
spp. 0.002-0.5 (0.015-0.25) 0.015-0.25 ~0.01-2 (0.097-1) 0.06-0.25 (0.12-0.25) 1-64 (4-32) 2,5,6,11 ,13b,21,25
(0.06-0.097)

I w
00
IV
Serratia o
marcescens 0.015-2 (0.06-1) "0.03-2 (0.25-2) "0.03-8 (0.25-4) "0.03-4 (0.25-2) 0.5-1024 (4-~256) 2.3.5-7,10.12,13a a
~
spp. "0.015-2 (0.12-1) 0.12-1 (0.5) 0.03-6.25 (0.5-3.12) "0.06-8 (0.25-2) 1->512 (8-50) 15,18a,20,25 o
Shigella spp. "0.002-0.25 0.03-1 ("0.097-0.12) 0.01-1 (0.03-0.25) "0.06-0.5 (0.12-0.25) 2-8 (2-8) 2.4-6,11.13b,23.25
~~.
("0.015-0.25)
Yersinia enterocolitica 0.008-0.25(0.015-0.25) 0.06-0.12 "0.015-1 (0.03-0.5) 0.12-0.25 (0.12-0.25) 0.5-4 (2-4) 6,11.13b,23.25 >
("0.097-0.12)
~
<
Neisseriaceae ~.
Acinetobacter
calcoaceticus "0.03-0.5 (0.25-0.5) "0.03-0.5 (0.5) 0.06-16 (2-8) 2-32 (32) 6,8,9
Neisseria
gonorrhoeae d 0.005-0.12(0.002-0.03) 0.0015-0.5(0.007-0.06) "0.007-0.5 0.01-0.06 (0.05-0.06) 0.2-2 (1-2) 3,4,8,15.16b,18b,
(0.015-0.12) 20,26
meningitidis "0.0005-0.015 0.015 (0.015) 0.015-0.5 (0.03-0.5) 0.015-0.03 (0.03) "0.12-2 (0.5-2) 3.6,11
(0.004-0.015)

Other Gram-negative bacterial species

Hemophilus
ducreyi 0.004-0.03(0.016-0.03) 0.015-0.06 (0.03) 0.03-0.12 (0.12) 0.12 (0.12) 4-6 (>4-16) 19,24
influenzae d 0.004-0.05(0.008-0.05) 0.015-0.06 (0.03) 0.015-0.12 (0.03-0.12)0.03-0.25 (0.06-0.2) "0.25-4 (0.5-4) 3,4,6,11.14,15
20.25,26
Pseudomonas
aeruginosa "0.015-8 (0.12-1) "0.03-8 (1-4) "0.03-50 (1-25) "0.06-8 (1-4) 8->1024 (8->1024) 1,3-12,13a,14,15,16a,
17,18a,20,22,25,26
maltophilia 0.015-8 (1-8) 0.125-128 (4->16) 0.25-16 (4-16) 1-16 (16) 1,3,4,6.8,12,15,20
spp. 0.004-16 (0.25-16) "0.03-32 (1-32) 0.03-32 (0.5-16) 0.03->16 (4-16) 0.5->256 (16->256) 1,6,12.25

Referencesb 1-26 2,4,7-9,11,12,13a, 1-7,9-22,24-26 2,7,11,12,15.20, 2.3.6,7,10.11,13a,

13b.15,16b,18b,19, 23-25 14,15.16a,17,18a
22,24 1.9-22,24,26

a Cutoff point for susceptibility. Values for norfloxacin and nalidixic acid apply only to organisms isolated from urinary tract infections (after Monk & Campoli-Richards
1987; NCClS 1985; Rudrik et al. 1985).
b References are presented both by drug and by organism. References to the antibacterial activity of a specific drug against a particular organism are those which
appear in the lists for both the relevant drug and organism.
c Mostly indole-positive Proteus spp.
d Including p-Iactamase positive strains.
References: 1 Appelbaum et al. (1986); 2 Auckenthaler et al. (1986); 3 Barry et al. (1984); 4 Chau et al. (1986); 5 Chin & Neu (1984); 6 Cornaglia et al. (1987);
7 Cullmann et al. (1985); 8 Digranes (1987); 9 Digranes et al. (1985); 10 Eliopoulos et al. (1984); 11 Felmingham et at, (1985); 12 Floyd-Reising et at, (1987);
13a Forsgren (1985); 13b Goosens et al. (1985); 14 Hoogkamp-Korstanje (1984); 15 King & Phillips (1986); 16a Klietmann et al. (1987); 16b Liebowitz et al.
(1986); 17 Muytjens et al. (1983); 18a Piccolomini & Ravagnan (1986); 18b Peeters et al. (1984); 19 Sanson-le Pors et al. (1986); 20 Selwyn & Bakhtiar (1984);
21 Turgeon et at (1987); 22 Van Caekenberghe & Pattyn (1984); 23 Vanhoof et al. (1986); 24 Wall et at (1985); 25 Weber et al. (1985); 26 Wise et al. (1983). w
00
w
Table II. Range of reported MICgo values for ciprofloxacin against Gram-negative organisms compared with non-quinolone antibacterial drugs. All studies used broth or o
agar dilution techniques, at least 20 strains of clinical isolates and an inoculum size of 10" to 106 cfu ~.
:::::!3
Organism MICso range References8 o
ciprofloxacin cefotaxime ceftazidime gentamicin aztreonam mezlocillin ampicillin imipenem
~
(~ 1 mg/L)b (~ 8 mg/L) (~8 mg/L) (~4 mg/L) (~8 mg/L) (~16 mg/L) (~8 mg/L) (~ 4 mg/L) ~r
>
Enterobacteriaceae
Citrobacter diversus 0.02-0.03 ~0.01-0.13 0.1 2 8 2,5a
~
<
Citrobacter freundii ~0.06-0.39 1-100 2-128 1-8 2·32 128 64-100 0.5 2,4,5a,6,7,9,12 ~.
Enterobacter 0.03-0.12 4-50 8-25 ~0.5->15 16-32 >128->200 >200 1 2,4,5a,6,9,ll
cloacae
Enterobacter spp. 0.03-0.4 4-128 4-16 16 64->1024 >1024 0.5 1,3,4,11
Escherichia coli ~0.Q16-0.25 0.06-2 0.2-4 1->8 ~0.125·0. 78 128->1024 7.4->1024 0.25-0.5 1-6,9,11,15,16,18
Klebsiella 0.03-1 0.06-0.72 0.2-1 ~0.5-32 0.13-0.25 >128-~256 0.5 l,2,4,5a,6,7,ll
pneumoniae
Klebsiella spp. 0.06-0.25 0.5-~128 ~0.5-2 0.25-128 ~0.5 >1024 >1024 ~0.5 3,8,9,16,18
Morganella morganii 0.015-0.02 2-4 0.5 32-64 2,5a,13
Proteus mirabilis 0.03-0.2 0.03-0.5 0.1-0.5 0.5-~128 ~0.Q16-0.5 1 2 l,4,5a,8,9,16,18
Proteus vulgaris ~0.03-0.06 0.25-32 2 0.03 4->1024 >1024 3,5a
Proteus spp. 0.032-1 0.5-4 0.5-1.56 0.5-15 ~0.125 4 2 1,6,9,11,18
Providencia spp. 0.12-3.12 0.2-1 0.39 4 0.125-0.25 8->128 2 l,2,5a,9,13
Salmonella spp. ~0.015-0.3 ~0.097-0.5 4 0.9->128 ~0.097-0.25 1.2->128 2,5b,7,11,15-17
Serratia marcescens 0.06-1 ~0.25-128 ~0.5-3.1 ~0.5·2 ~0.5·1 128->1024 >1024 2-5a,7 ,8,10
Serratia spp. 0.125-0.78 12.5-64 12.5 8-128 0.5 ~256 1,9,16
Shigella spp. ~0.008-0.25 ~0.03·0.25 1 0.39 1.8>128 2,5b,15,16,17
Yersinia ~0.015-0.25 ~0.097-0.25 1-1.56 4 18-256 5b,14,15,17
enterocolitica

Neissenaceae
Aceinetobacter spp. 0.25-1 >4-256 4 1-128 32-64 64->1024 256->1024 0.5-1 1,3,5,8,11
Neisseria spp. 0.004-0.015 ~0.007-0.06 0.03 0.06-4 13,18
Other Gram-negative bacterial species
Haemophilus ~0.007 -0.015 0.03 0.25 16 0.25-16 13,16-18
influenzae
Pseudomonas 0.12-1 12.5->128 2-50 2-64 4-16 32->256 4 1-6,8-10,13,17,18
aeruginosa
Pseudomonas spp. 4 >32 >32-64 >6 >32 >128 >32 5,8,17

References 8 1-18 2,3,5,7-9,11, 2,6-10,12 1-3,6-9,11, 1,5,7,8,10, 1,3,5,11, 2,3,9,12-18 1,8,12

13-16,18 14,17,18 12,16,18 12,14 13,14

a References are presented both by drug and by organism. References to the antibacterial activity of a specific drug against a particular organism are those which
appear in the lists for both the relevant drug and organism.
b Values in parentheses are cutoff points for suceptibility (after NCClS 1985).
References: 1 Aldridge et al. (1985b); 2 Chin & Neu (1984); 3 Cullmann et al. (1985); 4 Eliopoulos et al. (1984); 5a Fass (1983); 5b Goosens et al. (1985); 6 Klietmann
at al. (1987); 7 lefrock et al. (1986); 8 Parry et al. (1985); 9 Piccolomini & Ravagnan (1986); 10 Righter (1984); 11 Rubinstein et al. (1986); 12 Samonis et al.
(1987); 13 Sanders et al. (1987); 14 Stille et al. (1983); 15 Vanhoof et al, (1986); 16 Verbist (1986); 17 Weber et al. (1985); 18 Wise et al. (1983). w
00
,J:o.
Ciprofloxacin: A Review
wera & Scorneaux 1985; Vanhoof et al. 1986].
Ciprofloxacin was slightly more potent an inhibi-
tor of C. jejuni in vitro than ofloxacin, enoxacin or
norfloxacin, and was at least 10 times more potent
than cefotaxime, ceftazidime, ampicillin or amoxy-
cillin. Campylobacter pyloridis was less susceptible
in vitro to ciprofloxacin (MIC90 0.25 mg/L) than
to penicillin (MIC 90 0.03 mg/L), but was no more
susceptible to erythromycin, gentamicin or cefox-
itin (MIC90 0.12-0.25 mg/L) than to ciprofloxacin
(McNulty et al. 1985).
Vibrio species, including V. parahaemolyticus
and V. cholerae (10 to 20 strains per study), are
susceptible to ciprofloxacin and to other quino-
lones, such as ofloxacin, pefloxacin and amifloxa-
cin, with MIC 90 values in the range 0.008 to 0.5
mg/L (Chau et al. 1986; Felmingham et al. 1985;
Vanhoof et al. 1986). In individual studies, differ-
ences in MIC 90s between these quinolones have
been small.
Against 37 clinical strains of Legionella species
ciprofloxacin proved of similar activity in vitro to
ofloxacin (MIC range ~ 0.002-0.06 mg/L), was
more active than enoxacin, norfloxacin or eryth-
romycin, but was considerably less active than rif-
ampicin (Saito et al. 1986). Ruckdeschel et al.
(1984) reported higher MIC values for ciprofloxa-
cin in 38 mixed clinical and reference strains (MIC
range 0.25-0.5 mg/L), with similar susceptibility of
Legionella pneumophila and other Legionella
species.
Gardnerella vaginalis may be considered mod-
erately susceptible to ciprofloxacin in vitro, since
MIC 90 values have been reported in the range of
1 to 8 mg/L (Felmingham et al. 1985;· Hart et al.
1984; King & Phillips 1986; Liebowitz et al. 1986).
In vitro, ampicillin, penicillin and tetracycline are
more potent inhibitors of this organism than cip-
rofloxacin, but only ofloxacin, among the quino-
lones, has equivalent activity.
Ciprofloxacin also inhibits the growth of Bru-
cella melitensis (68 and 95 clinical strains per study)
at concentrations of ~ 1 mg/L (MIC 90 0.5-1 mg/
L) [Bosch et al. 1986; Gobernado et al. 1984]. The
activity of ciprofloxacin was less than that of doxy-
cycline (MIC 90 0.12 mg/L) and equivalent to that
385
of tetracycline, ceftriaxone and streptomycin (Bosch
et al. 1986).
1.1.2 Gram-Positive Bacteria
Staphylococci
Staphylococci are susceptible to ciprofloxacin,
which has equivalent activity in vitro to ofloxacin
and is more potent than norfloxacin, enoxacin or
nalidixic acid (see table III). Cornaglia et al. (1987)
reported similar activity of ciprofloxacin against all
Staphylococcus species, including S. aureus, S. si-
mulans, S. capitis, S. saprophyticus, S. epidermidis,
S. hominis and S. haemolyticus (MIC90 0.5-1 mg/
L). Among the non-quinolone antibacterial drugs
reviewed only imipenem was a more potent inhib-
itor of S. aureus in vitro than ciprofloxacin, al-
though some of the comparative drugs exhibited a
moderate degree of activity (see table IV).
The MIC 90 of ciprofloxacin against S. aureus is
similar for strains susceptible or resistant to pen-
icillin (Auckenthaler et al. 1986), methicillin and
oxacillin (Auckenthaler et al. 1986; Barry et al. 1984;
Chau et al. 1986; Chin & Neu 1984; Floyd-Reising
et al. 1987; Lefrock et al. 1986; Stratton et al. 1987;
Verbist 1986; Weber et al. 1985), and gentamicin
(Chau et al. 1986).
Streptococci
Streptococcus faecalis and other enterococci
(group D), Streptococcus pneumoniae, Streptococ-
cus pyogenes (Group A) and Streptococcus agalac-
tiae (Group B) are all moderately susceptible to
ciprofloxacin in vitro (MIC9o 0.5-6.3 mgfL), with
only ofloxacin among the quinolones in table III
showing similar activity. Among non-quinolones,
cefotaxime and mezlocillin both show consider-
ably greater activity than ciprofloxacin against
nonenterococcal streptococci (see table IV). The
potency of ciprofloxacin in vitro is equivalent to
that of co-trimoxazole (trimethoprim plus sulpha-
methoxazole) against S. pneumoniae, and imipe-
nem against Group D Streptococcus.
Mycobacteria
Studies involving Mycobacterium species have
generally employed Lowenstein-Jensen medium
and an inoculum size in the range 102 to 105 cfu.
Table III. In vitro activity of ciprofloxacin and other quinolones against Gram-positive organisms. All studies used broth or agar dilution techniques, at least 20 strains
of clinical isolates, and an inoculum size of 1()4 to 106 cfu I~a
~
0
Organism MIC range (reported range of MICgo values) [mg/L] Referen~esb I ~
~
clprofloxacln ofloxacin norfloxacin enoxacin nalidixic acid ?'
(~ 1 mg/L)a (~ 1 mg/L)a (~4 mg/L)a (~4 mg/L)a (~ 16 mg/L)a >
::tl
n
Staphylococcus <
(D'
aureus c 0.06-8 (0.12-1) 0.06-8 (0:5-1) 0.03->32 (1-3.12) 0.2-32 (1-4) 2->200 (16->200) 1-14,16,17,19,20 ~
epidermidis 0.05-1 (0.25-0.5) 0.125-1 (0.25-0.5) 0.1-8 (1-4) 0.1-4 (1) 16->256 (64->256) 1,3,5,7,8,17
saprophyticus ~0.03-1 (0.25-0.5) 0.12-1 (0.5-1) 0.12-4 (2-4) 1-4 (2) >512 (>512) 8,9
spp. ~0.015-1 (0.25-1) 0.25-1 (0.5) 0.03-8 (1-8) 0.25-8 (2) 16->128 (32-128) 2,5,9,19

Streptococcus
pneumoniae 0.06-4 (1-4) 0.015-4 (1-2) 2-32 (8-16) 4-32 (16) 32->512 (>128.;.>512) 1,2,5,9,12,13,19
Group A 0.25-8 (1-4) 0.5-2 (1) 0.25->64 (2~2) 2-32 (16) >64->256 (>64->256) 2,5,11,17,19
Group B 0.25-4 (1-2) 0.25-2 (1-2) 1-16 (4-16) 2-32 (8-32) 64->q12 (>64->512) 1,2,4,5,9,13
Group 0 0.25-32 (0.5-6.3) 0.5-32 (2-4) 0.2-50 (4-25) 0.2-32 (4-16) >32-1024 (>32-1024) 1,2,5-19

Referencesb 1-20 1,3,6-9,11,13,18 1,2,4-6,8-13,15-20 1,6,9,10,13,17,19 1,2,5,6,9,12-18,20

a Cutoff point for susceptibility. Values for norfloxacin and nalidixic acid apply only to organisms isolated from urinary tract infections (after Monk & Campoli-Richards
1987; ""CCLS 1985; Rudrik et al. 1985).
b References are presented both by drug and by organism. References to the antibacterial activity of a specific drug against a particular organism are those which
appear in the list for both the relevant drug and organism.
c Including some strains resistant to pencillin and/or oxacillin, methicillin and gentamicin.

References: 1 Auckenthaler et al. (1986); 2 Barry et al. (1984); 3 Chau et al. (1986); 4 Chin & Neu (1984); 5 Cornaglia et al. (1987); 6 Cullmann et al. (1985);
7 Digranes (1987); 8 Digranes et al. (1985); 9 Felmingham et al. (1985); 10 Floyd-Reising et al. (1987); 11 Forsgren (1985}; 12 Hoogkamp-Korstanje (1984); 13 King
& Phillips (1986); 14 Klietmann et al. (1987); 15 Muytjens et al. (1983); 16 Piccolomini & Ravagnan (1986); 17 Selwyn & Bakhtiar (1984); 18 Van Caekenberghe &
Pattyn (1984); 19 Weber et al. (1985); 20 Wise et al. (1983). w
00
0'1
Ciprofloxacin: A Review
An MIC 90 of 0.5 to 1.56 mg/L has been reported
for ciprofloxacin against Mycobacterium tubercu-
losis (Collins & Uttley 1985; Fenlon & Cynamon
1986; Gay et al. 1984). There was no difference in
activity between strains susceptibile or resistant to
antituberculous drugs (Collins & Uttley 1985).
Against Mycobacterium fortuitum the MIC 90 for
ciprofloxacin has ranged from 0.25 to 1.56 mg/L
(Casal et al. 1987; Collins & Uttley 1985; Gay et
al. 1984; Swenson et al. 1985). Among a wide range
of comparative antibacterial drugs, including cef-
triaxone, cefotetan, aztreonam, imipenem, mezlo-
cillin and netilmicin, only amikacin (MIC9o ~ 1
mg/L) had an MIC90 within 5 dilutions of that for
ciprofloxacin (Swenson et al. 1985). Against other
mycobacteria the following MIC90 values have been
recorded for ciprofloxacin: M. intracellulare 2 mg/
L (Fenlon & Cynamon 1986), M. chelonei 8 to 12.5
mg/L, M. kansasii 4 to 6.25 mg/L, M. avium 12.5
to 16 mg/L, M. xenopi 1.56 mg/L (Collins & Uttley
1985; Gay et al. 1984; Swenson et al. 1985) and
Mycobacterium spp. 1.2to 3.2 mg/L (Davies et al.
1987; Marinis & Legakis 1985).
Other Gram-Positive Organisms
Listeria monocytogenes is susceptible to cipro-
floxacin (MIC 9o 0.4-1 mg/L) [Auckenthaler et al.
1986; Chin & Neu 1984; Comaglia et al. 1987],
which is more active in vitro than other quinolones
(MIC 9o ~ 2 mg/L), Nocardia asteroides is less sus-
ceptible, with an MIC 90 of8 to 16 mg/L (MIC 0.12-
32 mg/L) [Auckenthaler et al. 1986; Felmingham
et al. 1985]; other quinolones studied were again
less active than ciprofloxacin in vitro.
1.1.3 Anaerobic Bacteria
Bacteroides species
Among the Bacteroides species, B. oralis [MIC 9o
0.5 mg/L against 17 strains (Klietmann et al. 1987)]
and B. ureolyticus [MIC 9o 0.06 mg/L against 10
strains (King & Phillips 1986)] have been reported
to be susceptible to ciprofloxacin, while B. melan-
inogenicus (MIC 9o 1-4 mg/L; see table V) may be
considered moderately susceptible. In most studies
ciprofloxacin had an MIC 90 against Bacteroides
387
fragilis of ~ 8 mg/L, It has greater activity than
most other quinolones but is less active than
metronidazole, clindamycin or imipenem.
Clostridium species
Clostridium difficile and other Clostridium spe-
cies are generally resistant to ciprofloxacin and
other quinolones, with MIC values ~ 4 mg/L (see
table V), although C. perfringens [35·strains (Hof-
fler 1986); 50 strains (Felmingham et al. 1985)] has
been reported to be susceptible (MIC9o 1 and 0.5
mg/L, respectively).
Other Anaerobic Organisms
Fusobacterium fusiforme proved moderately
susceptible to ciprofloxacin in vitro in some stud-
ies, but was consistently more susceptible to clin-
damycin or metronidazole (see table V). A few
strains of Fusobacterium nucleatum and Fusobac-
terium necrophorum have been assessed and found
to be moderately susceptible to ciprofloxacin
(MIC9o 4 mg/L) [King & Phillips 1986]. Against
Peptococcus species the activity ofciprofloxacin was
equivalent to that of clindamycin or metronidazole
(MIC 9o 1-8 mg/L). Peptostreptococcus species are
less susceptible to ciprofloxacin (MIC9o 8 mg/L).
Two other species of anaerobic organisms have
been reported to be susceptible to ciprofloxacin:
Propionibacterium species [MIC9o 0.5 mg/L against
36 strains (Hoffler 1986)] and Corynebacterium
species [MIC9o 1 mg/L against 113 strains (Fer-
nandez-Roblas et al. 1987)].
1.1.4 Chlamydia and Mycoplasma
The activity of ciprofloxacin against clinical
strains of Chlamydia trachomatis (10 strains per
study) was investigated using an inoculum of 102
to 103 inclusion-forming units on cycloheximide-
treated McCoy cells. The MIC for ciprofloxacin
against all strains ranged from 0.5 to 2 mg/L (Az-
nar et al. 1985; Ridgway et al. 1984); rosoxacin
(MIC 4-8 mg/L), norfloxacin (16 mg/L), enoxacin
(8-16 mg/L) and ofloxacin (1 to 8 mg/L) were less
active.
Ridgway et al. (1984) reported MIC values in
the range 0.5 to 2 mg/L against 10 strains of Urea-
Table IV. Range of reported ~IC90 values for ciprofloxacin against Gram-positive organisms compared with non-quinolone antibacterial drugs. All studies used broth or
agar dilution techniques, at least 20 strains of clinical isolates and an inoculum size of 1()4 to 106 cfu "0
I 0a~
Organism MICgo range 0
References 8 I
~
ciJirrfloxacln cefotaxime gentamicin mezlocillin trimethoprim/ imipenem F!"
(~ 1 'llg/l)b (~4 mg/l) (~8 mg/l) (~ 16 mg/l) sulphamethoxazole (~4 mg/l) >
(~ 2/38 mg/l) ~
<:
Staphylococcus aureus 0.25-1 2-256 0.25-50 8->128 1-160 0.032-0.5 1-9,11-14 ~"

Staphylococcus epidermidis 0.12-0.5 2-16 >6->32 4-32 >128 1 5,8,11,12

Streptococcus pneumoniae 2-8 ~0.016-0.12 ~0.06-0.25 4 5,11,13

Streptococcus Group A 1-2 ~0.016-0.03 ~0.06-0"12 32 5,11

Streptococcus Group B 1 0.06 0.13 4 5

Streptococcus Group 0 1-6.3 ~32->256 1-16 2 1-1280 2-4 1-9,11,13

References 8 1-14 5,7-9,11,13 1,3,6-10,12-14 1,3,5,11 3,5-7 1,8

a References are presented both by drug and by organism. Reference to the antibacterial activity of a specific drug against a particular organism are those which
appear in the list for both the relevant drug and organism.
b Values in parentheses are cutoff points for susceptibility (NCClS 1985).

References: 1 Aldridge et a!. (1985b); 2 Chin & Neu (1984); 3 Cullmann et al. (1985); 4 Eliopoulos et at, (1984); 5 Fass (1983); 6 Klietmann et at, (1987); 7 lafrock
at al. (1986); 8 Parry et al, (1985); 9 Piccolomini & Ravagnan (1986);10 Rubinstein et al. (1986); 11 Sanders et al. (1987); 12 Verbist (1986); 13 Weber at al, (1985);
14 Wise at a!. (1983). w
00
00
Ciprofloxacin: A Review
plasma urealyticum, and of0.25 to 0.5 mg/L against
10 strains of Mycoplasma hominis. In contrast, Es-
calante et a1. (1985) reported ~lIC90 values for cip-
rofloxacin of 32 mg/L and 4 mg/L, respectively,
against these two species (32 and 12 strains, re-
spectively). The different results most likely reflect
the different inoculum sizes used in each study; 105
colour-changing units in the study by Ridgway et
a1. (1984) and 106 to 107 colour-changing units in
the study by Escalante et a1. (1985).
1.2 Activity Against Resistant Bacteria
Enterobacteriaceae which were selected for re-
sistance to cefotaxime and/or ceftazidime re-
mained susceptible to ciprofloxacin (all strains in-
hibited by ~ 2 mg/L) [Kelley et a1. 1986; Simberkoff
& Rahal 1986], although cross-resistance has been
reported between ciprofloxacin and cephalosporins
(see section 1.8). Reductions in the inhibitory ac-
tivity of ciprofloxacin against Enterobacteriaceae
resistant to ampicillin (Roy et a1. 1983), amikacin
(Simberkoff & Rahal 1986) or norfloxacin (Kelley
et a1. 1986) are small, and the drug remains a po-
tent inhibitor of such organisms. Ciprofloxacin re-
tains at least moderate inhibitory activity (MIC9o
0.5-2 mg/L) against P. aeruginosa strains resistant
to aminoglycosides (Kelley et a1. 1986; Piccolomini
& Ravagnan 1986; Roy et a1. 1983; Weinstein et
a1. 1987), cefotaxime and/or ceftazidime (Kelley et
a1. 1986), and those multiply-resistant to penicil-
lins, aminoglycosides and cefotaxime (Venezio et
a1. 1986). However, P. aeruginosa strains resistant
to norfloxacin also proved resistant to ciprofloxa-
cin (Kelley et a1. 1986).
Among Gram-positive bacteria, the inhibitory
activity of ciprofloxacin has been investigated
against resistant strains of S. aureus, S. epidermi-
dis, S. pneumoniae and S. faecalis. Many studies
have investigated the drug's activity against meth-
icillin-resistant S. aureus. In those including over
50 resistant strains the MIC for ciprofloxacin ranged
from 0.064 to 1 mg/L (MIC 9o 0.25-0.5 mg/L) [Ald-
ridge et a1. 1985a; Moorhouse et a1. 1985; Smith
1986b; Smith & Eng 1985]. Vancomycin, teico-
planin and ofloxacin had equivalent activity to cip-
389
rofloxacin in vitro, rifampicin and coumermycin
were more potent inhibitors, and norfloxacin, en-
oxacin, amifloxacin, doxycycline, amikacin and
clindamycin were less potent. Methicillin-resistant
S. epidermidis (Simberkoff & Rahal 1986; Venezio
et a1. 1986), and oxacillin-resistant S. aureus (Kel-
ley et a1. 1986; Weinstein et a1. 1987) and coagu-
lase-negative staphylococci (Weinstein et a1. 1987)
are also susceptible to ciprofloxacin (MIC 9o 0.25-
1 mg/L),
Ciprofloxacin inhibited all strains of penicillin-
resistant S. pneumoniae [n = 13 (Simberkoff & Ra-
hal 1986) n = 10 (Gombert & Aulicino 1984)] at
concentrations of 0.125 to 2 mg/L, Cefotaxime and/
or ceftazidime-resistant S. faecalis is also suscep-
tible to ciprofloxacin, although norfloxacin-resist-
ant S. faecalis is not (Kelley et a1. 1986).
Thus, although there is some increase in MIC
values for ciprofloxacin against strains of both
Gram-negative and Gram-positive bacterial spe-
cies which are resistant to non-quinolone antibac-
terial drugs, these organisms usually remain sus-
ceptible to ciprofloxacin. However, in strains
resistant to other quinolones, increases in MIC val-
ues may be larger and the strains may prove re-
sistant to ciprofloxacin. Cross-resistance between
the quinolones has been reported in several studies
(Barry & Jones 1984; Courvalin et a1. 1984; Cull-
mann et a1. 1985; Piddock et a1. 1986).
1.3 Factors Influencing In Vitro Activity
1.3.1 Inoculum Size
Antibacterial activity of the fluorinated qui no-
lones is influenced little by inoculum size (up to
100-fold increases) [Janknegt 1986]. For ciproflox-
acin, inhibitory and bactericidal activity is reduced
to some extent against most species at an inoculum
size of 107 or 108 cfu (Aldridge et a1. 1985b; Auck-
enthaler et a1. 1986; Blaser et a1. 1986; Chin & Neu
1984; Fass 1983; Lefrock et a1. 1986; Piccolomini
& Ravagnan 1986; Rubinstein et a1. 1986; Weber
et a1. 1985). More notable reductions in activity
[up to 8-fold increases in MIC or minimum bac-
tericidal concentration (MBC)] were reported in
some studies for S. aureus (Aldridge et a1. 1985b;
Table V. In vitro activity of ciprofloxacin compared with other antibacterial drugs against anaerobic organisms. All studies used broth or agar dilution techniques, at least
20 strains of clinical Isolates (except where otherwise stated), and an inoculum size of 1()4 to 1()6 cfu. I~a
~
Organism MIC range (reported range of MICgo values) [mg/l] Referencesa 0
I ~
Q)
o
elprofloxaeln ofloxacin cefoxltin cllndamycln imipenem metronidazole meziocillln 1=!"
(~ 1 mg/L)b (~ 1 mg/l)b (~8 mg/l)b (~ 0.5 mg/l)b (~4 mg/l)b (~ 16 mg/l)b ~
~
~
Bacteroides fragilis ~0.01-256 1-16 (4-8) 0.25-256 (8-64) 0.031->128 (1-2) 0.031-2 (0.5) 0.12-4 (0.5-1) 1->256 (16->128) 1,4,5,7-12 <:
(;j'
(0.8-32) ~
Bacteroides 0.25-16 (1-4) 0.5-4 (2) 0.5-4 (2) 0.25-2 (1) 5,8,9
me/anlnogenlcus
Bacteroides spp. 0.016->128 0.06-32 ~0.03->128 >0.03->128 0.063-2 (0.25) ~0.03-4 (0.25-4) ~0.125->256 5,7-11
(0.06-32) (0.12-32) (4-32) (0.5->32) (16-32)
Clostridium difficile 4-32 (8-32) 4-16 (8-16) 32-256 (128) 4->128 (8->128) 2-8 (8) 0.125-0.5 (0.5) 1-8 (8) 2-5,11
Clostridium spp. 0.12-64 (16-64) 0.25-64 (1-32) 0.125->128 0.031->128 (4-8) 0.008-0.25 (0.25) 0.125-4 (1) ~0.008-32 (0.5-4) 5,7,8,10,11
(2-64)
Fusobacterium spp.c 0.06->32 (2-32) 0.5-4 (4) ~0.03-128 (2-64) ~0.03-8 (0.5-2) ~0.03-2 ~0.125->256 (32) 5,8-11
(0.25-0.5)
Peptococcus spp. 0.03-32 (1-2) 1-32 (8) 0.25-128 (32) 0.25->128 (4-8) 0.25->32 (2) 8-10
Peptostreptococcus 0.25->32 (8) 0.25-2 (2) ~0.03-8 (1-4) ~0.03->128 (2-16) 0.06->128 (1) ~0.125-16 (1) 8-11
spp.

Referenees a 1-12 3-5,10 2,7,10,11 2,7,9-11 2,7 2,7,9,11 7,11

a References are presented both by drug and by organism. Reference to the antibacterial activity of a specific drug against a particular organism are those which
appear in the list for both the relevant drug and organism.
b Cutoff point for susceptibility (NCClS 1985).
c At least 10 strains per stUdy.

References: 1 Chin & Neu (1984); 2 Chow et al. (1985); 3 Delmee & Avesani (1986); 4 Edlund & Nord (1986); 5 Felmingham et al. (1985); 6 Fernandez-Roblas et
al. (1987); 7 Hoffler (1986); 8 King & Phillips (1986); 9 Klletmann et al. (1987); 10 Prabhala et al. (1984); 11 Sutter et al. (1985); 12 Wise et al. (1983). ~
'C
o
Ciprofloxacin: A Review
Fass 1983), S. faecalis, Enterobacter species (Auck-
enthaler et al. 1986; Fass 1983), Serratia marces-
cens and P. aeruginosa (Auckenthaler et al. 1986;
Piccolomini & Ravagnan 1986). Against anaerobic
organisms, MIC values for ciprofloxacin were re-
duced up to 4-fold by 1000-fold decreases of the
inoculum (Watt & Brown 1986).
1.3.2 Medium
The activity of ciprofloxacin against Enterobac-
teriaceae, P. aeruginosa and S. aureus was similar
when tested on Mueller-Hinton, brain-heart infu-
sion, tryptic soy digest, Columbia or nutrient me-
dia (Chin & Neu 1984). Comparison of the drug's
activity when determined on Mueller-Hinton agar
versus Mueller-Hinton broth revealed identical re-
sults (Gombert & Aulicino 1985; Piccolomini &
Ravagnan 1986; Rubinstein et al. 1986) or MIC
values only 2-fold different (Blaser et al. 1986). Watt
and Brown (1986) reported no influence of me-
dium on the activity of ciprofloxacin against an-
aerobic organisms, but Borobio and Perea (1984)
reported MICs for ciprofloxacin against B. fragilis
3 times higher on brucella agar than Wilkins Chal-
gren agar.
1.3.3 Cations, pH and Urine
The activity of ciprofloxacin in urine is de-
creased and is dependent on pH and magnesium
concentration (Ratcliffe & Smith 1984b). Thus, at
acidic pH (5.5 to 5.8) there is a marked reduction
in both the inhibitory and bactericidal activity of
ciprofloxacin in urine, compared with the activity
in urine at higher pH, which is lower than the ac-
tivity in normal agar or broth (Chin & Neu 1984;
Efstratiou et al. 1983; Piccolomini & Ravagnan
1986; Ratcliffe & Smith 1984b; Reeves et al. 1984;
Zeiler 1985). This is consistent with the results of
studies assessing the influence of pH on antibac-
terial activity in agar or broth. MIC and MBC val-
ues for ciprofloxacin against aerobic and anaerobic
organisms tend to be relatively unchanged at a pH
between 6 and 8 (Borobio & Perea 1984; Piccolom-
ini & Ravagnan 1986; Reeves et al. 1984; Watt &
Brown 1986; Weber et al. 1985). Activity decreases
progressively as pH is reduced, with increases in
391
MIC and MBC values of 4- to 16-fold at pH 5 or
5.5 compared with pH 7 or 7.5 (Chin & Neu 1984;
Lefrock et al. 1986; Rubinstein et al. 1986; Weber
et al. 1985; Zeiler 1985).
Several authors have demonstrated that increas-
ing the concentration of magnesium in the me-
dium used for in vitro testing reduces the antibac-
terial activity of ciprofloxacin (Auckenthaler et al.
1986; Blaser et al. 1986; Ratcliffe & Smith 1983).
Neither zinc nor calcium supplementation had the
same effect (Auckenthaler et al. 1986). The mech-
anism by which magnesium antagonises the ac-
tivity of ciprofloxacin and other quinolones is
unclear. In urine, magnesium has a greater antag-
onistic effect against the bactericidal activity than
the inhibitory activity of ciprofloxacin (Ratcliffe &
Smith 1984b).
1.3.4 Serum
The supplementation of Mueller-Hinton broth
with serum from healthy volunteers, by 50 to 70%,
has no influence, or produces small increases, in
the antibacterial activity of ciprofloxacin (Chin &
Neu 1984; Piccolomini & Ravagnan 1986; Reeves
et al. 1984; Wise et al. 1983).
1.3.5 Peritoneal Dialysis Fluid and Eflluent
MIC values for ciprofloxacin against 100 iso-
lates of staphylococci were unchanged or increased
by only 2 dilutions (in particular for coagulase-
negative staphylococci) in the presence of perito-
neal dialysis effluent in the medium (Guay et al.
1986). Against 3 strains of P. aeruginosa (1 clinical,
2 laboratory), the MBC for ciprofloxacin was in-
creased by 3 dilutions in recovered peritoneal fluid
at pH 7.4, but not in peritoneal fluid itself at this
pH (Shalit et al. 1985). In this study the MBC for
ciprofloxacin was 2· mg/L even in the recovered
peritoneal fluid, indicating that the drug could still
be an effective treatment for pseudomonal infec-
tion in continuous ambulatory peritoneal dialysis
patients. Moreover, McCormick and Echols (987)
reported no influence of dialysis effluent on the
bactericidal activity of ciprofloxacin against clinical
or laboratory strains of E. coli, P. aeruginosa or
staphylococci. Weissauer-Condon et al. (1987) re-
Ciprofloxacin: A Review
ported that the bactericidal activity of ciprofloxa-
cin against E. coli, K. pneumoniae, P. aeruginosa,
S. aureus and S. epidermidis was greatly decreased
(increase in MBC of;;?; 4 dilutions) in peritoneal
dialysis fluid to 0.5, 2, 16, 64 and 4 mg/L, respec-
tively. In peritoneal dialysis fluid recovered from
patients the decrease in activity was also large for
S. aureus and S. epidermidis (MBC 1 and 4 mg/L,
respectively) but was only minor (~ 2 dilutions)
for the Gram-negative species (MBC 4, 0.015 and
0.008 for P. aeruginosa, K. pneumoniae and E. coli,
respectively).
1.4 Bactericidal Activity
1.4.1 In Vitro
Ciprofloxacin is rapidly bactericidal at concen-
trations close to the MIC (Reeves et al. 1984). In
most studies the MBC has been within 2 dilutions
of the MIC against all Gram-negative and Gram-
positive aerobes tested (Auckenthaler et al. 1986;
Aznar et al. 1985; Lagast et al. 1985; Parry et al.
1985; Piccolomini & Ravagnan 1986; Rubinstein
et al. 1986; Weber et al. 1985; Wise et al. 1983).
Higher MBC to MIC ratios (2 to 4) have been re-
ported against P. aeruginosa and staphylococci
(Auckenthaler et al. 1986; Lagast et al. 1985; Pic-
colomini & Ravagnan 1986), and also against some
Proteus and Providencia species (Piccolomini &
Ravagnan 1986). Chin and Neu (1984) reported an
MBC within 4 dilutions of the MIC for ciproflox-
acin in 75% of isolates, including aerobes and an-
aerobes. However, in no case was the MBC above
1.5 mg/L,
The MBC to MIC ratio for ciprofloxacin, com-
pared with those for norfloxacin, enoxacin or pe-
floxacin, was higher against Pseudomonas species
and staphylococci (1.5 to 4.5) but lower against S.
agalactiae. S. faecalis and Enterobacteriaceae (about
1 to 2) [Auckenthaler et al. 1986].
1.4.2 Serum Bactericidal Activity Ex Vivo
Several authors have investigated the serum
bactericidal activity of ciprofloxacin following oral
or intravenous administration to healthy volun-
teers. One hour after a 15 to 30 minute intravenous
392
infusion of 200mg, mean serum concentrations of
ciprofloxacin in 3 separate studies were in the range
0.61 to 0.96 mg/L (Standiford et al. 1987; Van der
Auwera & Klastersky 1986; Weiss et al. 1986). At
the same time geometric mean bactericidal titres
in serum samples were in the range 1 : 20 to 1 : 64
against Enterobacteriaceae, but were < 1 : 3 against
P. aeruginosa (Standiford et al. 1987; Weiss et al.
1986); this activity of ciprofloxacin against Enter-
obacteriaceae (1 : 20 to 1 : 64) was less than that
after a single dose of ceftazidime (2g IV) or cefo-
taxi me (2g IV) but greater than that after pipera-
cillin (4g IV) or gentamicin (80mg IV). Against
Gram-positive organisms (including S. aureus, S.
epidermidis, L. monocytogenes and M. fortuitum)
ciprofloxacin showed very poor activity (titre
<1 : 2) at 1 hour (Standiford et al. 1987; Van der
Auwera & Klastersky 1986).
Following oral administration of ciprofloxacin
500mg the mean serum concentration 1 to 2 hours
after a single dose was 1.3 to 2.6 mg/L (Machka &
Milatovic 1987; Trautmann et al. 1986), and 1 hour
after the last of three 500mg doses at 12-hour in-
tervals was 2.4 mg/L (Lagast et al. 1985). Again
ciprofloxacin proved very active against Entero-
bacteriaceae at 1 hour (mean or median bacteri-
cidal titres in the range 1 : 30 to 1 : 256), while bac-
tericidal titres were much lower against P.
aeruginosa, staphylococci and streptococci (titres
in the range < 1 : 2 to 1: 4) [Lagast et al. 1985;
Machka & Milatovic 1987]. Ofloxacin 200mg given
orally resulted in markedly lower bactericidal titres
against Enterobacteriaceae, and had equally poor
activity against P. aeruginosa and Gram-positive
organisms (Machka & Milatovic 1987). Against
Salmonella typhi ciprofloxacin had greater serum
bactericidal activity than ofloxacin (1 : 119 to 1: 388
vs 1 : 30 to 1 : 84, respectively), and both drugs had
markedly greater activity than chloramphenicol, co-
trimoxazole or amoxycillin (Trautmann et al. 1986).
1.5 Post-Antibiotic Effect
Persisting suppression of bacterial growth after
only limited exposure to an antibacterial drug (i.e,
continued antibacterial effect in the absence of the
Ciprofloxacin: A Review
drug) is described as a post-antibiotic effect (PAE).
Exposure of E. coli, S. marcescens, K. pneumoniae,
P. mirabilis, Citrobacter freundii, P. aeruginosa and
S. aureus to ciprofloxacin, at concentrations sev-
eral times the MIC, for a period of 1 to 2 hours in
Mueller-Hinton broth revealed a PAE with a re-
covery period in the range of about 1 to 6 hours
(Chin & Neu 1987a; Fuursted 1987; Lagast et al.
1985; Neu et al. 1987; Smith et al. 1986c). The ex-
tent of the PAE increased with increasing duration
of exposure to ciprofloxacin (Chin & Neu 1987a),
but was not dependent on the drug concentration
(Chin & Neu 1987a; Smith et al. 1986c). A PAE
was also apparent for ciprofloxacin against these
organisms in broth supplemented with magnesium
or adjusted to an acidic pH, in urine and in serum
(Chin & Neu 1987a). It is unclear whether cipro-
floxacin has a PAE against S. faecalis: Lagast et al.
(1985) reported a PAE in 8 of 9 strains of S. fae-
calis.. with a mean duration of recovery of 1.66
hours, but there have been other reports of no PAE
against this species (Chin & Neu 1987a; Neu et al.
1987).
1.6 Antibacterial Synergy and Antagonism
The in vitro activity of ciprofloxacin in com-
bination with various other antibacterial drugs has
been investigated using the checkerboard micro-
dilution technique and groups of 10 or more strains
per species. The clinical relevance of these findings
has yet to be established.
Synergy was defined as a 4-fold or greater de-
crease in MIC or MBC of each antibiotic, or a frac-
tional inhibitory index of s 0.5. Several groups have
shown a synergistic effect against P. aeruginosa
when ciprofloxacin was combined with azlocillin.
Synergy against 6 of 10 ciprofloxacin-susceptible
strains was reported by Rudin et al. (1984). In other
studies synergy against 30% (Chin et al. 1986), 53%
(Muszynski et al. 1985a) and 56% (Moody et al.
1987) of P. aeruginosa isolates was seen, although
other groups found no consistent effects (Davies &
Cohen 1985; Overbeek et al. 1985).
Combinations of ciprofloxacin with various
aminoglycosides did not produce synergistic or
393
antagonistic effects against 10 species of Entero-
bacteriaceae or P. aeruginosa, although an in-
creased rate of kill against S. marcescens and E.
coli was noted when ciprofloxacin was combined
with gentamicin (Haller 1985). Moody et aL (1987)
showed that ciprofloxacin combined with tobra-
mycin or gentamicin produced only low rates of
synergy against several species of Enterobacteri-
aceae, while synergy occurred against 57% and 67%
of tested strains of S. marcescens and S. aureus,
respectively, when ciprofloxacin was combined with
amikacin. This group also showed that a combin-
ation of ciprofloxacin and ceftizoxime produced
synergy against 40% of P. aeruginosa and 50% of
S. marcescens strains. Some synergy has been re-
ported between ciprofloxacin and imipenem against
P. aeruginosa (Chin & Neu 1987b; Giamarellou &
Petrikkos 1987). Against S. aureus there was nei-
ther synergy nor antagonism between ciprofloxacin
and vancomycin (Van der Auwera & Klastersky
1986). The low ratio of synergy between ciproflox-
acin plus aminoglycosides or (j-Iactam antibacterial
drugs against Enterobacteriaceae may be explained
by the high susceptibility of these organisms to cip-
rofloxacin.
There have been fewer studies of combined
antimicrobial effects against anaerobes. From 598
isolates of various species, Whiting et aL (1987)
selected 41 with reduced susceptibility or resist-
ance to ciprofloxacin. Combining ciprofloxacin with
clindamycin, cefoxitin, cefotaxime 'or mezlocillin
produced low rates of synergy against several spe-
cies. The most effective combinations were cipro-
floxacin plus cefotaxime against B. fragilis group
isolates (44% synergy) and ciprofloxacin plus clin-
damycin against Peptostreptococcus species (37%
synergy). In a study involving 30 clinical isolates
of B. fragilis not selected for resistance or suscep-
tibility to the antibacterial drugs tested, ciproflox-
acin was synergistic with clindamycin against 38%
of the strains, whereas ciprofloxacin plus mezlo-
cillin or cefoxitin exhibited synergy against ap-
proximately 30% of the strains (Esposito et al.
1987b).
Antagonism (fractional inhibitory index ~ 4) has
been reported only rarely, such as against all 30
Ciprofloxacin: A Review
isolates of P. aeruginosa obtained from sputum of
patients with cystic fibrosis when ciprofloxacin was
combined with polymyxin B (Muszynski et al.
1985b). Scribner et al. (1984) found no antagonism
between quinolones (including ciprofloxacin) and
chloramphenicol, rifampicin or tetracycline, but
Smith (1984a) showed chloramphenicol and rif-
ampicin to be serious antagonists of the bacteri-
cidal activity of 4-quinolones against E. coli.
1.7 Mechanism of Action
The primary antibacterial activity of quinolones
is believed to involve the inhibition of bacterial
DNA gyrase (topoisomerase II), the enzyme re-
sponsible for introducing negative supercoils into
bacterial DNA (for reviews see Hooper et al. 1987;
Kayser 1985; Smith 1984a,b, 1986a). DNA gyrase
is composed of 2 A and 2 B subunits. It is pos-
tulated that the A subunits introduce staggered
single-strand DNA incisions on the bacterial chro-
mosome and then reseal the DNA following intro-
duction of negative supercoils into the DNA
double-strand helix by the B subunits. The quin-
olones are believed to inhibit resealing of the DNA
double-strand by the A subunits. This leaves single-
strand DNA exposed to exonucleolytic degrada-
tion. At clinically achievable concentrations quin-
olones would not seem to inhibit human topoiso-
merase II.
Some authors have shown a correlation be-
tween inhibition of gyrase-dependent supercoiling
and MIC values for various quinolones (Ronnlund
et al. 1985; Sato et al. 1985). However, such a cor-
relation was not always found (Domagala et al.
1986; Manning et al. 1984; Zweerink & Edison
1986). Thus, mechanisms other than DNA gyrase
inhibition may also be involved in determining the
potency of these drugs. Differences in the ability
of quinolones to permeate bacteria may be im-
portant. It has been suggested that the most potent
quinolones, such as ciprofloxacin, exhibit an ad-
ditional bactericidal activity (Lewin & Smith 1986;
Ratcliffe & Smith 1984a; Smith 1984a,b, 1986a).
Several in vitro studies have shown that cipro-
floxacin causes significant endotoxin release from
394
dying bacteria compared with aminoglycosides at
comparable bactericidal concentrations (Cohen &
McConnell 1985, 1986; McConnell & Cohen 1986).
However, there is no evidence to suggest that this
endotoxin release might lead to septic shock in vivo.
1.8 Development of Resistance
For many bacterial species, small increases in
resistance can be selected in a single-step exposure
to an antibacterial drug, while larger increases in
resistance are selected for in most bacterial species
by serial selection involving exposure to increasing
drug concentrations. The small increases resulting
from single-step exposure may be of clinical sig-
nificance for bacterial strains of only moderate sus-
ceptibility. The incidence of resistant mutants
emerging during single or serial passage of organ-
isms through agar containing concentrations of
antibacterial drugs is comparable among the 4-
quinolones (Auckenthaleret al. 1986; Cullmann et
al. 1985). In studies employing a single passage of
Enterobacteriaceae, P. aeruginosa or S. faecalis
through drug concentrations ~ 8-times the MIC,
the frequency of mutation with ciprofloxacin was
low (10- 7 to 10- 9) [Chin & Neu 1984; Cullmann
et al. 1985; Sanders et al. 1984]. This incidence was
lower than that for nalidixic acid and no greater
than that for amikacin (Sanders et al. 1984). Mu-
tants selected by growth on a medium containing
a specific quinolone tended to have increased MIC
values for all quinolones, indicating cross-resist-
ance within this drug class (Sanders et al. 1984).
This has been confirmed in studies involving En-
terobacteriaceae and P. aeruginosa strains resistant
to various 4-quinolones and nalidixic acid (Barry
& Jones 1984; Chin & Neu 1984; Courvalin et al.
1984; Cullmann et al. 1985; Piddock et al. 1986).
Serial passage of clinical isolates of K. pneumoniae,
Enterobacter aerogenes, E. cloacae and P. aerugin-
osa through broth containing subinhibitory con-
centrations of ciprofloxacin for 7 days resulted in
reduced activity of ciprofloxacin and all other
quinolones tested, although MIC values for cip-
rofloxacin still remained ~ 1 mg/L (Barry & Jones
1984). However, a strain of P. aeruginosa with an
Ciprofloxacin: A Review
MIC of 2 mg/L was selected for by Sanders et al.
(1984).
The development of resistance during clinical
experience with ciprofloxacin therapy has been re-
ported uncommonly, to date. Resistance has de-
veloped in various bacterial species including S.
marcescens, K. pneumoniae and most frequently P.
aeruginosa (section 4.1.3). However, in some of
these reports the development of resistance was de-
fined as a significant decrease in the susceptibility
to ciprofloxacin (increased MIC value). The MIC
value may have remained below the breakpoint of
resistance « 4 mg/L) with the infection still re-
sponding favourably to ciprofloxacin therapy.
Cross-resistance with ciprofloxacin (also some-
times defined as decreased susceptibility) has been
reported with ureidopenicillins, cephalosporins and
aminoglycosides (Greenberg et al. 1987a; Parry
1985; Piddock et al. 1987; Preheim et al. 1987).
On the basis of this limited number of reports
it is difficult to ascertain the potential clinical sig-
nificance of the development of resistance to cip-
rofloxacin or of cross-resistance with other anti-
microbial agents. With respect to the mechanism(s)
involved in the development of resistance to cip-
rofloxacin and other quinolones, there are a num-
ber of encouraging findings. Firstly, plasmid-me-
diated resistance to quinolones does not occur
(Hooper et al. 1987; Kayser 1985; Smith 1984c).
In fact, ciprofloxacin can induce plasmid elimin-
ation from bacteria (Mehtar et al. 1987; Michel-
Briand et al. 1986; Weisser & Wiedemann 1987).
There is also no known mechanism whereby re-
sistance can develop from bacterial degradation of
the quinolone (Hooper et al. 1987). Chromosomal
mutation appears to confer resistance by at least 2
mechanisms. The first involves mutations which
affect DNA gyrase (Hooper et al. 1987; Kayser
1985; Smith 1984c). This mechanism may confer
resistance to quinolones as a group. The second
mechanism appears to involve changes to the cell
membrane, in particular to porin channels, which
inhibit antimicrobial drug penetration into the bac-
terial cells (Hooper et al. 1987; Piddock et al. 1987;
Preheim et al. 1987; Suerbaum et al. 1987). This
latter mechanism may prevent cellular penetration
395
of other antimicrobial agents besides the quino-
lones and thus confer cross-resistance.
L9 Efficacy in Animal Models of Infection
Whilst there are limitations associated with the
extrapolation of results of treatment in animal
models of infection to the clinical situation in
patients, properly performed studies provide useful
information about relative antibacterial activities.
A large number of studies have been conducted in
a wide variety of such animal models examining
the anti-infective potential of ciprofloxacin.
Many studies have examined the effects of cip-
rofloxacin therapy in animal models (usually rab-
bits) of infective left- and right-sided endocarditis
caused by S. aureus or P. aeruginosa - models that
are usually associated with 100% mortality if left
untreated (Bayer et al. 1986a,c; Bayer & Kim 1986;
Carpenter et al. 1986; Fernandez-Guerrero et al.
1985; Kaatz et al. 1987a,b; Levison et al. 1985;Per-
rone et al. 1987; Strunk et al. 1985). Ciprofloxacin
doses of 60 to 150 rug/kg/day, usually admini-
stered intramuscularly, have uniformly decreased
bacterial vegetation titres, improved bacterial cure
rates, decreased mortality, and prevented relapses.
In addition, ciprofloxacin has reduced renal ab-
scesses (Bayer et al. 1986a), pulmonary infarction
(Bayer & Kim 1986), renal, splenic and cardiac
bacterial counts (Kaatz et al. 1987a,b; Strunk et al.
1985) and bacteraemia (Kaatz et al. 1987a,b; Per-
rone et al. 1987), where measured. Serum cipro-
floxacin concentrations have been recorded at
greater than the MBC values for both P. aerugin-
osa (Bayer et al. 1986c) and S. aureus (Carpenter
et al. 1986) at 1 hour after administration. Com-
parisons with other antibacterial agents in the stud-
ies described above have shown ciprofloxacin to
have superior efficacy to ceftazidime, gentamicin,
BMY 028142 and the combination of netilmicin
plus azlocillin in P. aeruginosa models of endo-
carditis, and to coumeramycin A1 and nafcillin in
S. aureus models - ciprofloxacin was shown to be
equal in efficacy to vancomycin (methicillin-re-
sistant and methicillin-susceptible S. aureus
models), nafcillin, nafcillin plus gentamicin and
Ciprofloxacin: A Review
cloxacillin plus gentamicin (s. aureus model) and
to amikacin plus azlocillin and to azlocillin plus
tobramycin (P. aeruginosa models). Addition of
amikacin or gentamicin conferred no significant
improvement to ciprofloxacin therapy.
Ciprofloxacin has also been studied in several
other experimental models of infection. In P. aeru-
ginosa osteomyelitis in rabbits, ciprofloxacin 120
mg/kg subcutaneously for 28 days significantly re-
duced disease severity and sterilised 94% of bone
cultures, and was more effective than tobramycin
20 mg/kg (Norden & Shinners 1984, 1985). In
methicillin-resistant S. aureus osteomyelitis in rats,
subcutaneous administration of ciprofloxacin 100
rug/kg/day for 28 days produced only a slow de-
crease in bone bacterial counts, which was aug-
mented by the addition of rifampicin. This com-
bination was more effective than vancomycin plus
rifampicin at 4 weeks but not thereafter (Henry et
al. 1987). Two studies of septic arthritis in rabbits
caused by E. coli have shown ciprofloxacin 10 to
20 rug/kg/day to produce sterilised joints and syn-
ovial samples in 53% of animals (Bayer et al.
1986b), which was increased to almost 100% at a
dose of 80 rug/kg/day for 17 days (Bayer et al.
1985). In these studies ciprofloxacin was more ef-
fective than ceftriaxone 50 mg/kg/day or genta-
micin 5 rug/kg/day, respectively, although none of
the treatments was effective in preventing postin-
fection synovitis.
In neutropenic guinea-pigs with P. aeruginosa
pneumonias, intramuscular ciprofloxacin 50 to 80
rug/kg/day significantly decreased bacterial counts
and increased survival in acute infections, and was
more effective than ticarcillin, equally as effective
as pefloxacin, ofloxacin or enoxacin, but less ef-
fective than tobramycin (Gordin et al. 1985; Kem-
merich et al. 1986; Schiff et al. 1984). In chronic
infections, doses of 30 to 60 rug/kg/day were more
effective than tobramycin and ticarcillin, but less
effective than ofloxacin (Kemmerich et al. 1986;
Schiff et al. 1984). In leucopenic rats with experi-
mental K. pneumoniae pneumonia, the dose of cip-
rofloxacin which protected 50% of the animals from
death (3.3 rug/kg/day) was significantly (p < 0.001)
lower than that of ceftazidime (24.4 rug/kg/day)
396
[Roosendaal et al. 1987]. Importantly, in the latter
study ciprofloxacin was shown to kill both actively
growing bacteria and bacteria in the stationary or
slow phase of growth, whereas ceftazidime was
bactericidal only against actively growing bacteria.
In mice with pneumonia caused by H. influenzae,
bacteria were successfully eradicated, and survival
rates increased by ciprofloxacin 40 rug/kg/day
compared with chloramphenicol or ampicillin
treatment (Kemmerich et al. 1987), whereas in My-
coplasma pneumoniae infection in hamsters, al-
though there was a decreased pulmonary lesion
score, organisms were not eradicated (Brunner et
al. 1984). In experimental (L. pneumophilai Le-
gionnaires disease in guinea-pigs, intramuscular
ciprofloxacin 2 and 6 rug/kg/day, and to a lesser
extent oral doses of 5 and 15 rug/kg/day, prevented
pyrexia, reduced lung bacterial numbers and sig-
nificantly decreased mortality (Fitzgeorge et al.
1985). At the higher intramuscular dose, and in a
subsequent study using a 1% aerosol solution in-
haled for 7 hours, mortality was reduced to 0%,
which was equal to the efficacy of rifampicin and
greater than that of erythromycin (Fitzgeorge et al.
1985).
Some investigations have evaluated the efficacy
of ciprofloxacin against P. aeruginosa sepsis in
neutropenic mice and rats. In mice, a variety of
doses of ciprofloxacin significantly improved sur-
vival rates, with ciprofloxacin being more effective
than enoxacin, ofloxacin or gentamicin (Jules &
Neu 1984), imipenem, ceftazidime, azlocillin or
tobramycin (Ulrich et al. 1986), azlocillin (Chin et
al. 1986) or norfloxacin (Hof et al. 1985). In rats,
ciprofloxacin was more effective than ceftazidime,
azlocillin or tobramycin (Robson 1985). In ex-
perimental P. aeruginosa burn sepsis in mice, sur-
vival was observed in about 40% of animals treated
with ciprofloxacin 2.5 to 15 mg/kg 6 times daily.
This rate was further improved by the addition of
Pseudomonas immune globulin - derived from
plasma of persons with high concentrations of IgG
to lipopolysaccharide antigens of P. aeruginosa
(Collins et al. 1987).
In models of infected abscess in mice and rats,
involving E. coli and/or S. aureus, B. fragilis or S.
Ciprofloxacin: A Review
marcescens, treatment with ciprofloxacin generally
produced rapid decreases in bacterial counts and
marked improvements in mortality and abscess
cure rates. In comparison with other antibacterial
drugs, ciprofloxacin was more effective than nor-
floxacin, vancomycin, cephalexin or methicillin
(Rolin et al. 1986; Zeiler & Voigt 1987), and at
least as active as cefotaxime (Thadepalli et al. 1985),
ofloxacin and pefloxacin (Rolin et al. 1986; Zeiler
& Voigt 1987). However, ciprofloxacin neither re-
duced the incidence of B. fragilis abscess nor erad-
icated B. fragilis from abscesses, while rifampicin
both prevented B. fragilis abscess formation and
eradicated bacterial abscess (Fu et al. 1987).
In rabbit models of bacterial meningitis, intra-
venous infusion of ciprofloxacin 1 to 30 mg/kg/h
for 7 hours proved equally effective as infusions of
ceftazidime 25 mg/kg/h or tobramycin 2.5 mg/kg/
h in reducing bacterial counts of P. aeruginosa
(Hackbarth et al. 1986). A single intravenous dose
of 50 mg/kg reduced bacterial counts of ampicillin-
resistant H. influenzae to a similar extent to oflox-
acin 30 mg/kg and to a greater extent than chlor-
amphenicol 30 mg/kg/h infused over 8 hours (So-
bieski & ScheId 1985).
Decreased bacterial counts of E. coli were seen
following ciprofloxacin 5 to 150 rug/kg/day in a rat
model of acute and chronic pyelonephritis. Cip-
rofloxacin was more effective than cefotaxime 25
rug/kg/day in chronic infections (Tietgen et al.
1986). Similarly, in the treatment of experimental
P. mirabilis pyelonephritis in mice, ciprofloxacin
was superior to ticarcillin, piperacillin, aztreonam
and gentamicin with respect to the percentage of
sterile kidneys and the mean numbers of bacteria
per kidney (Peerbooms & Maclaren 1987).
Ciprofloxacin has also proven of use in mark-
edly reducing blood, spleen and liver bacterial titres,
and increasing the survival of mice with dissemi-
nated M. avium complex when combined with
amikacin and imipenem/cilastin (Inderlied et al.
1985), and in S. typhimurium typhoid infection
(Easmon & Blowers 1985; Easmon 1987). How-
ever, ciprofloxacin has proven ineffective against
S. aureus sinusitis in rabbits (Ogawa et al. 1985),
Mycobacterium leprae leprosy in mice (Banerjee
397
1986; Guelpa-Lauras et al. 1987), and L. mono-
cytogenes infection in mice (Hof et al. 1985).
Resistance to ciprofloxacin has generally not
been a feature of the bacteria studied in these ani-
mal models. However, the emergence of resistance
has been demonstrated by P. aeruginosa (Bamber-
ger et al. 1986; Michea-Hamzepour et al. 1987), S.
aureus (Kaatz et al. 1987b) and an enteric bacteria
(Bamberger et al. 1986).
2. Pharmacological Effects
2.1 Effects on Immune Function
It is currently accepted that many antimicrobial
agents interfere with some aspects of immune
function; for instance, the {j-lactams, tetracyclines,
gentamicin, ampicillin and cefoperazone have all
been shown to reduce chemotaxis, phagocytosis
and/or killing by human polymorphonuclear leu-
cocytes (Fietta et al. 1983; Forsgren et al. 1974;
Iannello et al. 1983). The clinical significance of
these effects observed in vitro is unclear.
Preincubation of human polymorphonuclear
leucocytes and mononuclear cells with ciproflox-
acin 5 to 100 mg/L had no effect on the chemotaxis
to Escherichia coli or the phagocytosis or killing
activities against Candida albicans (Delfino et al.
1985). Similarly, preincubation of human poly-
morphonuclear leucocytes with ciprofloxacin did
not affect chemotaxis, phagocytosis or bactericidal
activity against Providencia stuartii or Staphylo-
coccus aureus, although killing of S. aureus was en-
hanced (Forsgren & Bergkvist 1985). Using a
chemiluminescence assay, subinhibitory concen-
trations of ciprofloxacin facilitated opsonin-de-
pendent phagocytosis of S. aureus and coagulase-
negative staphylococci by human neutrophilic
granulocytes (Roszkowski et al. 1985), but had no
effect on zymosan phagocytosis by human poly-
morphonuclear granulocytes (Duncker & Ullmann
1986), or zymosan or formyl-methionyl-leucyl-
phenylalanine phagocytosis by human polymor-
phonuclear leucocytes (Forsgren & Bergkvist 1985).
The uptake of ciprofloxacin by human neutro-
phils to levels greater than extracellular concentra-
tions has been shown to reduce in vitro survival of
Ciprofloxacin: A Review
S. aureus and Mycobacterium fortuitum and in vivo
survival of Salmonella typhimurium. However,
ciprofloxacin does not appear to be firmly bound
within the cell, and its uptake is not dependent on
an active transport mechanism (Easmon & Crane
1985; Easmon et al. 1986).
Ciprofloxacin 1.6 to 6.25 mg/L has been shown,
along with other 4-quinolone compounds, to in-
crease the uptake of pyrimidines (but not purines)
into the DNA of mitogen-stimulated human
lymphocytes. However, de novo pyrimidine bio-
synthesis, the growth of some cell lines, cell cycle
progression and immunoglobulin secretion were all
inhibited. Genetic alterations were not detected at
concentrations up to 25 mg/L (Forsgren et al.
1987a,b).
At concentrations up to 125 mg/L, ciprofloxa-
cin did not affect human mitogen-stimulated
mononuclear cell proliferation (Gollapudi et al.
1986).
Subinhibitory concentrations of ciprofloxacin
have been shown to 'unmask' previously encap-
sulated cell envelope components of Klebsiella
pneumoniae making them more accessible to com-
plement and immunoglobulins (Williams 1987).
2.2 Effects on Faecal and Oropharyngeal
Flora
The administration of antibacterial agents in the
treatment of infection can have a variety of effects
on the gastrointestinal flora of patients, some of
which may not be desirable. For example, most al-
imentary tract infections in immunocompromised
patients are caused by opportunistic aerobic Gram-
negative bacilli and yeasts from the endogenous
orointestinal flora. Anaerobes rarely cause infec-
tion and, indeed, these impart protection to the
patient by competitively preventing colonisation
by potentially pathogenic aerobic micro-organisms
(van der Waaij 1982). Thus, the aim of selective
decontamination of the gastrointestinal system is
to eliminate or reduce all potential aerobic patho-
gens without affecting anaerobic organisms.
The 4-quinolones, including ciprofloxacin, have
a broad spectrum of antibacterial activity against
398
aerobic Gram-positive and Gram-negative bacte-
ria, but little if any activity against most anaerobes.
Although substantial concentrations of these quin-
olones do appear in the lower gastrointestinal tract
after oral administration, exceeding the MICs of
even obligate anaerobic bacteria, it would appear
either that they are bound to intestinal contents
(data on file, Bayer; Van Saene et al. 1986) or that
anaerobic strains rapidly develop resistance in the
faeces (Brumfitt et al. 1984).
The effect of ciprofloxacin on the faecal flora
composition has been studied extensively in healthy
volunteers and, to a lesser extent, in patients with
infections other than those of the gastrointestinal
system. The usual dosage regimens were 600 to
1000 rug/day for upwards of 5 days (table VI).
These studies clearly demonstrate the marked re-
duction or complete eradication of Enterobacteri-
aceae. This occurs rapidly (i.e. usually within 3 days
of commencing therapy), and has not been asso-
ciated with the emergence of resistant strains. Fol-
lowing discontinuation of therapy, these bacteria
return to pretreatment concentrations within 3 to
4 weeks, if not much sooner. The effects of cip-
rofloxacin on staphylococci and enterococci are not
as dramatic or consistent as with the Enterobac-
teriaceae, although many studies report significant
reduction in one or both of these groups. Where
reported as separate entities, aerobic Gram-posi-
tive bacilli were unaffected (table VI).
Generally, ciprofloxacin does not affect levels of
anaerobic flora. However, where anaerobic cocci,
Fusobacterium and Bacteroides species have been
analysed separately, some studies have demon-
strated decreases in faecal levels (table VI). Inter-
estingly, although anaerobic bacteria were not sig-
nificantly affected by ciprofloxacin overall, the
number of susceptible strains after therapy was re-
duced from 75 to 12% (Brumfitt et al. 1984).
In most studies, there was an absence of over-
growth or superinfection by resistant bacteria (see
table VI). There have been no reports of over-
growth with Pseudomonas aeruginosa, one report
of 4 patients with transiently detectable .levels of
Clostridium difficile but little detectable toxin and
no clinical effects, and only one report of 5 patients
Table VI. Effects of ciprofloxacin on the composition of faecal flora in healthy volunteers and patients. o
>6'
Reference Subjects Dosage Entero- Staph. Anae- Over~rowth/colonisation Emergence Time till return a
(no.) bacteri- entero- robes of resistant of 0
=
aceae cocci P. C. C. others strains pretreatment ~
Ilo'
aeruginosa difficile albicans ()
flora
;:f
Aoki et al, Healthy vols 100-500mg bid for H _~b NR NR NR NR NR NR
(15)3
>
(1984) 7 days ~
(l)
Brumfitt et al. Healthy vols 500mg bid for 7 H ~ NR NR None NR Anaerobic ~ 1 week
-<
(1984) (12) days
- strains;
sensitivity
o'
~
decreased
from 75% to
12%C
Holt et al. Healthy vols 500mg for 5 days _d None None None
H Coagulase S. aureus (1); > 1 week
(1986) (6)
- negative S.
aureus (1),
Coryne-
bacterium (30)
Coryne-
bacterium (3)8
Motohiro et al. Healthy vols 100-200mg tid for HI -~g None None None None Noneh At 10 days
(1985) (20) 5 days
-
_~i
Nord et al. Healthy vols 500mg bid for 5 H -~g NR None NR NR None < 1 week
(1985) (12) days < 3 weeksi
Rozenberg-Arska Patients 500mg bid for H ~g _~m None None NA Coagulase P. aeruginosa NR
et al. (1985) (15)k (mean) 42 days' negative S. (6);
epidermidis Acinetobacter
(7), C. (2)
albicans (4)
Scully et al. Patients 500mg bid or H ~ NR 5 pts Staph. (3) None NR
(1987a, (22)" 750mg tid for 7-42 Strept. (1)
days
Shah et al, Healthy vols 500mg bid for 10 H H NR None None None NR ~1 week
(1987a)
Watanabe et al.
(12)
Healthy vols
days
200mg tid for 7
- None 4 ptss None None None 3-4 weeks
H H
(1985)
Whitbyet al.
(7)
Patients
days
500mg bid for
- None None None Coagulase None < 4 weeks
H - -
(1985) (31) 5.5-18 days negative
staphylococci,
lactobacilli

a Subjects on a vitamin K-deficient diet.
b Decreased levels on highest dose.
c Most anaerobes originally resistant to norfloxacin.
d Some reduction in Bacteroides spp.
e Not detected at all sampling times.
f Except Klebsiella spp. which significantly increased.
g Decreased enterococci.
h 621 strains tested.
Abbreviations: ~ = reduced; H = markedly reduced or eradicated; -
staph. = staphylococci; strep. = streptococci.
i Decreased anaerobic cocci, Fusobacterium + Bacteroides spp.
j Quicker return to normal levels for aerobes than anaerobes.
k Immunocompromised - leukaemia.
I Also received amphotericin B to prevent overgrowth with Candida spp.
m Non-spore forming Gram +ve anaerobic bacilli and anaerobic cocci.
n 11 patients with cystic fibrosis. 11 other infections.
0 Very small amounts of toxin detected - no clinical effects.
= unchanged; NR= not reported; NA = .not applicable; vols = volunteers; pts = patients;
w
I \C
\C
Ciprofloxacin: A Review
with cystic fibrosis who experienced overgrowth
with C. albicans. There have, however, been sev-
eral reports of colonisation by coagulase-negative
staphylococci, and occasional reports of colonisa-
tion by Corynebacterium species and enterococci.
De Vries-Hospers et al. (1987) reported that all 10
volunteers administered ciprofloxacin 50 to 200mg
twice daily for 5 days became colonised with yeasts.
The effect of ciprofloxacin on oropharyngeal
flora has been studied by Bergan et al. (1986a) and
Nord et al. (1985). There was virtually no effect on
the number of streptococci, staphylococci, micro-
cocci or anaerobic bacteria, although the count of
Neisseria species was markedly reduced. No new
strains colonised the volunteers in either study.
2.3 Toxicity
Acute, subacute and chronic toxicity studies of
oral ciprofloxacin in rats and monkeys, and em-
bryotoxicity, teratogenicity and perinatal toxicity
studies in rats have revealed little or no evidence
of adverse effects (data on file, Bayer; Schluter
1987). Some pathological changes in the kidney
have been observed in animal studies, involving
crystal deposition of magnesium/protein com-
plexes within the renal tubular walls and lumen.
However, this is a pH-specific reaction and is more
likely to occur in species with alkaline urine, such
as rats and monkeys, than in those with neutral or
acidic urine such as humans. In any case nephro-
toxicity was only observed at doses even higher than
those required to produce crystalluria (Schluter
1987). In clinical assessments of large numbers of
patients, crystalluria clearly related to ciprofloxa-
cin was rarely observed and was not associated with
changes in renal function (Arcieri et al. 1987;
Schacht et al. 1988).
Some quinolones, such as pefloxacin and ac-
rosoxacin, have been associated with ocular changes
in animal studies. However, ciprofloxacin has not
been observed to accumulate or cause adverse ocu-
lar changes in monkeys, cats, dogs or diabetic rats
(Schluter 1987), or in 800 patients who underwent
ophthalmoscopic examination (Arcieri et al. 1987).
There has been well-documented evidence of
400
articular changes in the weight-bearing joints of
some animal species with long term administration
of some quinolones. In juvenile rats that received
oral administration of nalidixic acid, norfloxacin,
ofloxacin or ciprofloxacin, at doses of 100 to 500
rug/kg/day for 4 weeks, ciprofloxacin caused the
lowest rate of articular damage - in 10% of male
rats at the highest dose (500 mg/kg), Ofloxacin af-
fected 10% of male rats receiving 100 to 250 mg/
kg, and nalidixic acid caused the highest percentage
of cartilage alterations at all dosage levels. Also, in
juvenile dogs, articular changes were observed al-
though fewer were observed in pressure-free joints
(Schluter 1987).
3.: Pharmacokinetics
The pharmacokinetic properties of ciprofloxa-
cin have been studied in healthy volunteers and in
patients, as well as in individuals with normal or
impaired renal function. In addition, the effects of
age and cystic fibrosis on pharmacokinetics are well
reported. To date, published reports of the effect
of reduced hepatic function on the pharmacokin-
etics of ciprofloxacin are limited, but it has been
noted to cause a slight prolongation of the elim-
ination half-life (personal communication, T. Ber-
gan).
The concentrations of ciprofloxacin and/or its
metabolites in serum and biological tissues and
fluids have been determined by a number of high
performance liquid chromatography and microbio-
logical assays (Krol et al. 1986; Nilsson-Ehle 1987;
Scholl et al. 1987; Vallee et al. 1986) with generally
equal sensitivity and good agreement between the
two methods.
3.1 Absorption and Serum Concentrations
3.1.1 Oral Administration
Numerous investigations have shown ciproflox-
acin to be rapidly and well absorbed after single
oral doses of 50 to 1000mg (Bergan et al. 1986c,
1987; Brittain et al. 1985; Drusano et al. 1986b;
Hoffken et al. 1985b; Plaisance et al. 1987; Tar-
taglione et al. 1986; Ullman et al. 1984; Wingender
Ciprofloxacin: A Review 401

et al. 1984b). Peak serum concentrations occurred
between 0.5 and 2 hours after each dose and ranged
from 0.28 to 5.92 mg/L; the mean peak concen-
trations increased in proportion to the dose within
the normal therapeutic dose range. The total area
under the serum concentration-time curves (AVC)
were also proportional to dose. As the oral dose
increased a slight increase was observed in the ap-
parent time lag (tlag) before absorption, from ap-
proximately 0.3 hours after 100mg to approxi-
mately 0.5 hours after 1000mg. Table VII provides
an overview of the pharmacokinetic variables after
single oral doses of ciprofloxacin. Although food
has been shown to delay absorption by slightly in-
creasing the time to peak concentration, this does
not lead to other changes in the pharmacokinetics
of ciprofloxacin (Ledergerber et al. 1985). How-
ever, simultaneous administration of antacids con-
taining magnesium hydroxide and/or aluminium
hydroxide with ciprofloxacin leads to a reduction
in the bioavailability of the quinolone, with little
effect on the absorption rate (Beermann et al. 1986;
section 6.2).
Multiple-dose administration of ciprofloxacin
250 and 500mg twice daily for 3 to 8 days to healthy
volunteers did not result in any significant serum
accumulation of the drug, with 12-hour 'trough'
concentrations above the rmrumum inhibitory
concentrations (MIC) of most clinically important
pathogens (Aronoff et al. 1984; Bergan et al. 1986a,
1987; Ledergerber et al. 1985; Ullmann et al. 1984).
Maximum and minimum serum concentrations on
the last day (day 3 to 8) were 1.1 to 1.4 mg/L and
0.16 mg/L, respectively, after 250mg doses (Aron-
off et al. 1984; Ledergerber et al. 1985), and 2.3
and 0.18 mg/L, respectively, following 500mg doses
(Bergan et al. 1986a). In contrast, an earlier study
of Brumfitt et al. (1984) did show a significant rise
of serum concentrations (by 59%) after 7 days of
ciprofloxacin 500mg orally twice daily; there was
no apparent reason for the discrepancy, although
it may be a result of the advanced ages of the
patients assessed.
The absolute bioavailability of oral ciprofloxa-
cin has been determined with reference to the
intravenous form by use of either the AUC of
unchanged ciprofloxacin or cumulative urinary
excretion of ciprofloxacin and its metabolites.
Various studies have indicated an absolute bio-
availability which averaged between 69% and 85%
(Bergan et al. 1986c, 1987; Drusano et al. 1986b;
Plaisance et al. 1987). The relatively high bioavail-
ability of ciprofloxacin indicates that the drug is
subject to only a slight first-pass effect.

Table VII. Mean values of some pharmacokinetic variables reported for healthy volunteers after single oral or intravenous doses of
ciprofloxacin

Dose Cmax t max tv. AUC References

(mg) (mg/L) (h) (h) (mg/Lo h)

Oral administration
50 0.28 0.58 3.40 1.00 Hoffken et al. (1985b)
100 0.49 0.82 4.10 1.90
250 1.45 1.00 3.97 6.37 Brittain et al. (1985)
500 2.56 1.33 4.15 11.10
750 2.65 1.10 4.75 12.20 Hoffken et al. (1986)
1000 3.38 1.80 6.30 16.60 Tartaglione et al. (1986)

Intravenous administration
50 3.00 1.20 Hoffken et at, (1985b)
100 4.30 3.94 Drusano et al. {1986a)
200 4.40 7.22

Abbreviations: Cmax = maximum serum concentration; t max = time to maximum serum concentration; tv. = elimination half-life;
AUC = area under the plasma concentration-time curve.
Ciprofloxacin: A Review
3.1.2 Intravenous Administration
The serum concentration profile of intravenous
ciprofloxacin is best characterised by a first-order
3-compartment open model (Beermann et al. 1987;
Drusano et al. 1986a; Wingender et al. 1984b).
However, a number of studies have used a first-
order 2-compartment model to adequately de-
scribe the serum concentration-time profile (Ber-
gan et al. 1986c; Gonzalez et al. 1985a,b; Hoffken
et al. 1985b; Wise et al. 1984) [table VII]. Cipro-
floxacin concentrations in serum declined rapidly
following either a single 30-minute intravenous in-
fusion or a rapid intravenous bolus injection (50
to 200mg). A 4-fold decrease in serum concentra-
tions has occurred within 30 minutes of injection,
with little if any of the drug being detectable in
serum 24 hours after administration (Drusano et
al. 1986a; Hoffken et al. 1985b; Wise et al. 1984).
Results of multiple-dose intravenous studies in-
dicate no significant drug accumulation after as
many as 7 days' administration of ciprofloxacin in
doses of up to 200mg every 12 hours to healthy
volunteers (Gonzalez et al. 1985a,b). There is a lin-
ear dose-concentration relationship in the dose
range of 100 to 200mg, with a dose of 200mg given
every 12 hours likely to achieve concentrations in-
hibitory against most clinically important patho-
gens (Gonzalez et al. 1985a). However, the same
authors suggested that for serious infections caused
by some Pseudomonas species and Staphylococcus
aureus, a dosing schedule of 200mg every 8 hours
may be more suitable, while the manufacturer rec-
ommends increasing the dosage to 300 or 400mg
twice daily (personal communication, P. Schacht,
Bayer A.G).
3.2 Distribution
In a few studies the apparent volume of distri-
bution (Vd area ) has been estimated from the kinetic
data recorded after oral doses and found to be ap-
proximately 3.5 Lzkg, which suggests substantial
tissue penetration (Drusano et al. 1986b; Hoffken
et al. 1985b).
The distribution of ciprofloxacin was observed
to be rapid in healthy volunteers receiving various
402
single and multiple intravenous doses. Fitting the
serum profile to a 2-compartment model provides
a distribution phase with a half-life between 0.2
and 0.4 hours. The volume of distribution at steady-
state (Vd ss) and Vdarea were between 1.7 and 2.7
L'kg, The volume of the central compartment was
between 0.16 and 0.63 L'kg, which approximately
represents the total volume of extracellular water
(Drusano et al. 1986a; Gonzalez et al. 1985a,b;
Hoffken et al. 1985b; Wingender et al. 1984b).
Table VIII summarises the results of tissue and
fluid penetration of ciprofloxacin in man. Com-
pared with serum concentrations in the same
patients, the peak concentration of ciprofloxacin
was very high (> 600%) in bile, kidney, gallbladder
and liver tissue. The high ciprofloxacin concentra-
tions achieved in many tissues have been theorised
to be due to high intracellular concentrations re-
sulting from ion trapping (personal communica-
tion, G.L. Drusano). Concentrations in lung, gyn-
aecological tissue (especially after intravenous
administration) and prostatic tissue and fluid were
also much higher than serum concentrations in the
same patients. In comparison with serum concen-
trations, concentrations in otorhinolaryngological
tissue, soft tissue and muscle were slightly higher,
concentrations in skin, fat, blister fluid, cerebro-
spinal fluid (inflamed meninges) and bronchial se-
cretions were similar, concentrations in lymph and
turbinate bone were a little lower (50 to 80%), and
concentrations in cerebrospinal fluid (non-im-
flamed meninges) and subcutaneous tissue were
low.
Although relatively low concentrations of cip-
rofloxacin are observed in bronchial secretions,
Honeyboume et al. (1987) reported that in 15
patients who received ciprofloxacin 500mg twice
daily for 4 days the drug penetrated into the bron-
chial mucosa on average by 161% of serum con-
centrations.
In 18 patients who received a single oral dose
of ciprofloxacin 500, 750 or 1000mg preopera-
tively, the mean concentrations of the drug in bone
were 0.4, 0.7 and 1.6 mg/kg, respectively (Fong et
al. 1986). The authors suggested that ciprofloxacin
750mg every 12 hours should provide adequate
Ciprofloxacin: A Review 403

Table VIII. Concentrations of ciprofloxacin achieved in various body tissues and fluids after single or multiple doses

Tissue/fluid No. of Dose Time Mean peak Tissue or References

pts (mg)a (h)b tissue or fluid fluid/serum
concentration concentration
(mg/kg or (%)d
mg/L)C

Ascitic fluid 2 250 PO 3 1.18 92 Esposito et al. (1987a)

2 500 PO 3 1.38 107
Blister fluid 2e 500 PO 2.5 1.75 101' LeBel et al. (1986b)
2e 500 PO tid 2.5 1.87 110'
Mild inflammatory blister fluid 5 500 PO 2.6 1.40 1179 Wise & Donovan (1987)
5 100 IV 1.25 0.60 1219
Bile 1 750 PO 3 143 9730 Dan et at, (1987)
Bronchial secretions 4 500 PO 6 0.56 95 Berqoqne-Bsrezm et al.
(1986)
Inflamed CSF 5 200 IV bid 2 0.56 37.2 Wolff et al. (1987)
Non-inflamed CSF 1 500 PO 5 0.15 10.4 Valainis et al. (1986)
Lymph 7 500 PO 2.8 1.0 70 Bergan et al. (1986b)
Peritoneal fluid 30 100 IV 0.5 1.1 55 Wise & Donovan (1987)
Prostatic fluid 7 500 PO 2-4.4 0.02-5.7 1.5-450.4 Boerema et al. (1985a)
Fat (perirenal) 5 100 IV 0.45 0.45 99 Daschner et al. (1986)
Gynaecological tissue" 18 500 PO 2 1.26-1.58h 101-128h Goormans et al. (1986)
18 100 IV 0.5 0.95-1.56 h 160-286h
Cervix 4 500 PO 6-7 0.86 245 Segev et al. (1986)
Kidney 5 100 IV 1-2 4.66 1010 Daschner et al. (1986)
Liver 1 750 PO 3 9.8 666 Dan et al. (1987)
Lung 19 100 IV 1 2.64 310 Schlenkoff et al. (1986)
Gallbladder 1 750 PO 3 14.1 959 Dan et al. (1987)
Muscle 1 500 PO 2.5 1.3 155 Aigner & Dalhoff (1986)
5 100 IV 2-3 1.17 365 Daschner et al. (1986)
Prostatic tissue 1 500 PO 2.5 3.49 189 Boerema et al. (1985a)
Skin 1 500 PO 2.5 1.04 124 Aigner & Dalhoff (1986)
5 100 IV 2-3 0.23 72 Daschner et al. (1986)
Soft tissue 11 750 PO 1 4.03 175 Licitra et al. (1987)
Subcutaneous tissue 8 100 IV 0-1 0.29 34 Daschner et al. (1986)
Tonsil 8 250 PO 3 2.3 180 Esposito et al. (1987a)
Turbinate bone 8 250 PO 3 0.8 78

a Single dose unless otherwise indicated.

b Time may be approximate or an average or range of sampling times may be given.
c May represent the greatest reported concentration rather than actual peak.
d Calculated at time of peak tissue or fluid concentration.
e Healthy volunteers.
f Extrapolated from graphically presented results.
g Calculated from the ratio of AUCblister 'Iuid versus AUCserum.
h Vagina, portio uteri, endometrium, myometrium, parametrium, fallopian tube, and ovary; range for all tissue types.
Abbreviations: PO = oral; IV = intravenous; bid = twice daily; tid = 3 times daily.

concentrations to treat most Gram-negative and
staphylococcal infections of bone. About 40% of
ciprofloxacin that penetrates into bone reversibly
binds to inorganic bone components (Wittmann et
al. 1985).
Ciprofloxacin effectively penetrates the aqueous
humour of patients undergoing cataract extraction
who have received a single oral 1000mg dose of
the drug. A mean peak concentration of 0.56 mgj
L was achieved (Fern et al. 1986).
In non-inflamed eyes of patients undergoing
cataract surgery, a more conventional intravenous
Ciprofloxacin: A Review
dose of ciprofloxacin produced mean aqueous hu-
mour concentrations of 0.165 and 0.126 mg/L after
1 and 3 hours, respectively (Behrens-Baumann &
Martell 1987). Moreover, Luthy et al. (1986) re-
ported that in 20 patients who underwent intra-
ocular surgery, the intraocular penetration of cip-
rofloxacin after a single oral dose of 750mg was
significantly lower (p < 0.01) than after multiple
doses, which suggests accumulation in the anterior
chamber. Although the observed accumulation fol-
lowing multiple doses may lead to ciprofloxacin
concentrations which would be sufficient for the
treatment of ophthalmic infections, further studies
must be carried out to determine the optimal dose
for the effective prophylactic use of ciprofloxacin
in ophthalmological surgery.
The protein binding of ciprofloxacin has been
determined by ultrafiltration to be between 16.4
and 28.1%, independent of both concentration and
pH (Joos et al. 1985). However, slightly higher val-
ues of about 40% have been obtained using other
techniques such as ultracentrifugation (data on file,
Bayer; Hoffken et al. 1985b). The low degree of
binding indicates that conditions which alter pro-
tein binding would not unduly influence the phar-
macokinetics of ciprofloxacin.
3.3 Metabolism and Elimination
Ciprofloxacin is largelyexcreted unchanged both
renally and, to a lesser extent, extrarenally. Small
concentrations of 4 metabolites have been reported
(fig. 2): desethyleneciprofloxacin (M 1), sulpho-
ciprofloxacin (M2), oxociprofloxacin (M 3) and
formylciprofloxacin (M4) [Beermann et al. 1986;
Bomer et al. 1986; Gau et al. 1986]. All the me-
tabolites have some antibacterial activity, but less
than that of ciprofloxacin. The antibacterial activ-
ities of'M, and M 1 are comparable to those of nor-
floxacin and nalidixic acid, respectively, but M2 has
very weak activity. Whilst M4 is the most active,
it is only a very minor metabolite of ciprofloxacin
(Zeiler et al. 1987).
Following the administration of a single 259mg
oral dose of 14C-labelled ciprofloxacin to healthy
volunteers, approximately 94% of the dose was re-
404
covered in the urine and faeces over 5 days. Most
of the radioactivity was recovered in the urine
(55.4%). Unchanged ciprofloxacin was the major
radioactive moiety identified in both urine and
faeces, accounting for 45% and 25% of the dose,
respectively. Total (urine and faeces) excretion of
all metabolites was 18.8%. M 3 was the major ur-
inary metabolite, accounting for 6.2% of the dose,
with M2 and M 1 accounting for 3.7% and 1.3% of
the dose, respectively. M2 was the principal faecal
metabolite, with 5.9% of the dose being recovered
in faeces. Only very small amounts of M 1 (0.5%)
and M 3 (1.1%) were recovered in faeces. No M4
was detected in urine or faeces (Beermann et al.
1986; Drusano 1987).
After the administration of a single 107mg
intravenous dose of 14C-labelled ciprofloxacin to
healthy volunteers, 88.9% of the radioactivity was
recovered in urine and faeces over 5 days. About
75%of the radioactivity was recovered in the urine.
As with the oral dose, unchanged ciprofloxacin was
the major radioactive moiety in urine (62%) and
faeces (15%). Total excretion of all metabolites was
12.1%. The major urinary metabolite was M3
(5.6%), with M 1and M2 accounting for 1%and 2.6%
of.. the dose, respectively. Only small amounts of
metabolites were recovered in the faeces, with ap-
proximately 1.3% of M, and under 1% of both M,
and M2. Again, no M4 was recovered in urine or
faeces (Beermann et al. 1986; Drusano 1987).
The greater proportion of metabolites formed
after oral than intravenous administration is in-
dicative of a slight first-pass effect. M2 is the pref-
erentially formed first-pass metabolite since the
amount of it recovered following intravenous
administration is less than that excreted after oral
administration (Beermann et al. 1986; Drusano
1987). As 15% of ciprofloxacin is found in faeces
after intravenous administration, this suggests that
hepatic extraction and biliary excretion is a non-
renal clearance pathway for ciprofloxacin. Indeed,
direct evidence of biliary excretion of ciprofloxacin
has been obtained in patients with T-tube drainage
(Tanimura et al. 1986). A peak biliary concentra-
tion of 11 g/L was seen 4 hours after a single oral
dose of ciprofloxacin 400mg. The glucuronic acid-
Ciprofloxacin: A Review
r-'\F~co.H
HN
\..J
N"uN
If Ciprofloxacin
Formylciprofloxacin (M4 )
Desethyleneciprofloxacin (M 1)
Fig. 2. Metabolic pathways of ciprofloxacin in healthy volunteers (Beermann et al. 1986; Borner et al. 1986; Gau at al. 1986; Zeiler
et al. 1987).
conjugate of ciprofloxacin accounted for approxi-
mately 30% of the total ciprofloxacin excreted in
bile. In addition, the metabolites M2 and M3 were
also excreted in the bile, but were not quantified.
Recently Rohwedder and Bergan (1986, and un-
published data on file, Bayer AG) have postulated
that ciprofloxacin and its metabolites reach the
faeces by a transport mechanism across the intes-
tinal mucosa, 'transintestinal elimination', which
constitutes an important safety valve for the re-
moval of the drug from the body.
Numerous studies with unlabelled ciprofloxacin
have reported similar findings to the radiolabelled
studies with regard to elimination and have indi-
cated that elimination is dose independent. After
single oral doses of 50 to 1000mg, the proportion
of drug excreted in the urine varies from 29 to 44%
within 48 hours of administration (Hoffken et al.
1985b; Tartaglione et al. 1986; Wingender et al.
405
o
JJ
A
"-
Sulphociprofloxacin (M2)
1984a). After multiple doses every 12 hours, from
31 to 44% of the dose is excreted in the urine over
each dosage interval (data on file, Bayer). After
single intravenous doses of ciprofloxacin (50 to
200mg) about 45 to 60% of the dose is excreted in
the urine within 48 hours (Drusano et al. 1986a;
Dudley et al. 1987; Hoffken et al. 1985b; Wingen-
der et al. 1984a). After multiple intravenous doses,
over 70% is eliminated over each dosing interval,
with most being excreted in the first 3 to 4 hours
(data on file, Bayer).
Total serum clearance ofciprofloxacin in healthy
volunteers ranges between 23 and 43 L/h/1.73m 2,
is independent of dose, and is unaffected by mul-
tiple-dose administration. Renal clearance ac-
counts for 60% to 70% of total serum clearance,
and is approximately 3 times higher than creatin-
ine clearance. This indicates that renal excretion is
not only via glomerular filtration but involves ac-
Ciprofloxacin: A Review
tive tubular secretion (Borner et al. 1986; Drusano
1987; Drusano et al. 1986a; Gonzalez et al. 1985a,b;
Hoffken et al. 1985b; Wise et al. 1984). Active tu-
bular secretion has been confirmed by the coad-
ministration of probenecid with ciprofloxacin,
which reduced renal clearance of ciprofloxacin by
46% (Wingender et al. 1984a).
3.3.1 Elimination Half-Life
In studies involving healthy volunteers the
elimination half-life of ciprofloxacin in serum after
single and multiple oral doses (50 to 1000mg)
ranged from 3.4 to 6.9 hours. Elimination was in-
dependent of dose or duration of administration
(Aronoff et al. 1984; Brittain et al. 1985; Hoffken
et al. 1985b; Tartaglione et al. 1986; Ullmann et
al. 1984).
Following single and multiple intravenous doses
(50 to 200mg) to healthy volunteers, the elimina-
tion half-life of ciprofloxacin ranged from 3 to 4.6
hours (Drusano et al. 1986a; Dudley et al. 1987;
Gonzalez et al. 1985a; Hoffken et al. 1985b; Win-
gender et al. 1984b).
3.4 Influence of Disease on the
Pharmacokinetics of Ciprofloxacin
3.4.1 Renal Dysfunction
Since elimination of ciprofloxacin is largely via
the kidney it would seem likely that deterioration
of renal function could result in a significant al-
teration of the pharmacokinetics of the drug. Sev-
eral single oral dose studies have reported increases
in the peak serum concentrations and AUC, pro-
longed elimination half-lives and reduced renal
clearance of ciprofloxacin in patients with renal in-
sufficiency.compared with patients with normal
renal function (Boelaert et al. 1985; Gasser et al.
1987a; Singlas et al. 1987).
Gasser et al. (1987a) compared the pharmaco-
kinetics of ciprofloxacin following single oral doses
of 500 and 750mg in patients with normal renal
function (creatinine clearance ~ 50 ml/min/l.73m 2)
and patients with renal impairment (creatinine
clearance < 50 ml/rnin/L'Bm-'). At both doses,
patients with renal insufficiency had significantly
406
increased AUCs (p < p.Ol), prolonged (about 2-
fold) elimination half-lives (p < 0.01), and de-
creased renal clearances (p < 0.01). On the basis
of these findings the authors recommended a 50%
dose reduction in these patients. Similar findings
have been reported in patients with a more pro-
nounced renal insufficiency (creatinine clearance <
30 ml/min/1.73m 2 ) who received 250 or 500mg
single oral doses of ciprofloxacin (Boelaert et al.
1985; Singlas et al. 1987). In addition, Singlas et
al. (1987) found that the renal clearance of cipro-
floxacin significantly correlated (p < 0.01) with cre-
atinine clearance.
In studies involving a total of 10 patients with
severe renal failure and undergoing haemodialysis,
extraction of ciprofloxacin by dialysis was between
23 and 30%, and dialysis clearance ranged from 40
to 57.2 ml/min, following single oral doses of cip-
rofloxacin (250 to 500mg) [Boelaert et al. 1985;
Singlas et al. 1987]. Since ciprofloxacin is poorly
cleared by dialysis, no dosage adjustment appears
necessary in haemodialysis patients (Boelaert et al.
1985; Samsom 1987; Singlas et al. 1987).
The pharmacokinetic behaviour of ciprofloxa-
cin 100 to 200mg administered intravenously to
patients with various degrees of renal function im-
pairment (creatinine clearance 0 to 60 ml/min/
1.73m 2) is broadly similar to that seen following
oral administration. Prolongation of elimination
half-life occurs, along with a decrease in renal
clearance (Dirksen & Vree 1986; Drusano et al.
1987).
Because of the multiple clearance pathways of
ciprofloxacin, anephric patients still had a mean
total serum clearance of 15.4 L/h (vs 26.8 L'h in
volunteers with normal renal function) following a
200mg dose of ciprofloxacin administered intra-
venously (Drusano et al. 1987).
No detailed results have been published regard-
ing the serum concentrations of ciprofloxacin fol-
lowing multiple-dose administration in patients
with renal impairment. However, the altered phar-
macokinetic profile observed after single doses
would indicate that dosage adjustments are nec-
essary in these patients (see section 7).
Ciprofloxacin: A Review
3.4.2 Continuous Ambulatory Peritoneal
Dialysis
A few studies have reported the pharmacokin-
etics of ciprofloxacin in patients with renal dys-
function receiving continuous ambulatory perito-
neal dialysis (CAPD). Fleming et al. (1987) reported
that in 10 CAPD patients administered ciproflox-
acin 250mg orally for 2 days, plasma concentra-
tions were higher and elimination half-life was
longer (7.79 hours) than those reported for healthy
volunteers (section 3.3.1). There were no differ-
ences in plasma and dialysate kinetics in patients
with or without peritonitis. Dialysate and plasma
concentrations were significantly correlated (r 2 =
0.87; p = 0.001), with dialysate concentrations being
consistently lower than plasma concentrations. The
mean peak dialysate concentration of 2.17 mg/L
exceeded the MIC of ciprofloxacin for 32 of 34 bac-
terial strains.
The pharmacokinetics of single and multiple oral
doses of ciprofloxacin 750mg have also been re-
ported in CAPD patients. After a single oral dose
of 750mg, plasma concentrations reached a maxi-
mum of 3.6 mg/L within 1 to 2 hours (Shalit et al.
1986). The elimination half-life was 16.8 hours and
the peritoneal fluid/plasma concentration ratio was
0.64. The mean peak ciprofloxacin concentration
in peritoneal fluid was 1.3 mg/L,
Golper et al. (1987) studied the effects of ant-
acids and dialysate dwell times on the multiple-
dose pharmacokinetics of oral ciprofloxacin 750mg
in patients on CAPD. Three patients participated
in the study twice, once while taking and once while
abstaining from phosphate binding aluminium
antacids. The antacids were shown to decrease the
absorption of the drug. Peak concentrations in
plasma in the absence of antacids ranged from 2.9
to 6.4 mg/L and peak concentrations in dialysate
in the absence of antacids ranged from 1.8 to 4.5
mg/L, Peak ciprofloxacin concentrations in plasma,
achieved in patients taking antacids were 14 to 50%
of those achieved in patients without antacids. The
peak concentrations in dialysate achieved in sub-
jects on antacids were 8 to 33% of those achieved
in subjects off antacids. The clearance of cipro-
floxacin by CAPD represented 2% of the total sys-
407
temic clearance. When the simultaneous rate of
concentration in dialysate to concentration in serum
(D/S) was determined at various durations of di-
alysate dwelling within the peritonium, a progres-
sive rise in the ratio occurred. This suggests that
long-dwell exchanges may be necessary to achieve
reasonable concentrations of orally ingested cip-
rofloxacin in dialysate.
3.4.3 Cystic Fibrosis
Most studies have shown that the pharmaco-
kinetics of ciprofloxacin are not significantly al-
tered in patients with cystic fibrosis (Bender et al.
1986; Davis et al. 1987; Goldfarb et al. 1986; LeBel
et al. 1986c; Pedersen et al. 1987; Stutman et al.
1987). Therefore, dosage regimens for these patients
need only be adjusted for the reduction in body-
weight which often occurs in association with this
disease.
3.5 Influence of Age on the Pharmacokinetics
of Ciprofloxacin
A number of studies have compared the phar-
macokinetics of single oral doses of ciprofloxacin
100 to 500mg in elderly (> 65 years) and young
(20 to 30 years) healthy volunteers. In the elderly
the same dose of ciprofloxacin leads to signifi-
cantly higher maximum serum concentrations (p
< 0.005) and a 48 to 140% increase in serumAl.K'
compared with the young volunteers. The time to
peak serum concentrations, overall elimination half-
life, and urinary recovery of ciprofloxacin were
similar in both age groups (Ball et al. 1986; Bayer
et al. 1987). Any minor differences probably reflect
age-related alterations in distribution volume, pos-
sibly secondary to a reduction in both lean body
mass and total body water. This suggests that there
is no need for significant dose alteration in the el-
derly. However, LeBel et al. (1986a) reported an
almost 2-fold increase in elimination half-life, from
3.7 to 6.8 hours, in 12 ambulatory elderly subjects,
which was partly explained by' a decrease in glo-
merular filtration rate.
Guay et al. (1987) evaluated the pharmacokin-
etics of ciprofloxacin in 13 acutely ill elderly
Ciprofloxacin: A Review
patients following at least 14 days' administration
of ciprofloxacin 750mg twice daily. The phar-
macokinetic characteristics were similar to those
derived from single-dose studies, indicating that
acute illness does not alter ciprofloxacin phar-
macokinetics in the elderly.
4. Therapeutic Trials
Ciprofloxacin has demonstrated clinical efficacy
in infections of the. urinary tract, gastrointestinal
tract, respiratory tract, skin and soft tissues, bones
and several other body sites. Single-dose therapy
with ciprofloxacin has proven 100%effective in the
treatment of gonococcal urethritis. Pseudomonas
aeruginosa respiratory tract infections in patients
with cystic fibrosis have responded clinically to
treatment with oral ciprofloxacin, although the
emergence of resistant strains occurred with dis-
turbing regularity. While further study is needed,
encouraging preliminary results have been ob-
tained with the use of ciprofloxacin alone or in
combination with other antibacterial drugs in the
treatment of fever and/or documented infection in
immunocompromised patients. Ciprofloxacin has
generally appeared to be at least as effective as al-
ternative antimicrobials to which it has been com-
pared in various types of infection. This is not sur-
prising given the usual inclusion criteria requiring
susceptibility of pathogens to both study drugs in
controlled comparisons, a precaution which would
likely decrease the statistical advantage of an agent
having a broader spectrum of activity. Treatment
with ciprofloxacin eliminated nasopharyngeal car-
riage of Neisseria meningitidis and gastrointestinal
carriage of Salmonella species and nosocomial
Klebsiella species.
Prophylaxis with ciprofloxacin has proven ef-
fective in preventing Gram-negative infection in
immunocompromised patients undergoing remis-
sion induction therapy. Ciprofloxacin prophylaxis
also decreased the rate of postsurgical infections in
patients undergoing transurethral resection of the
prostate (vs untreated patients), but comparisons
with conventional antibacterial prophylaxis are
needed.
408
4.1 Worldwide Cumulated Efficacy Data
The therapeutic efficacy of ciprofloxacin has
been assessed in infections of various body systems
in clinical trials worldwide. Published cumulated
clinical results of multiple-dose therapeutic trials
conducted in the US, Europe and Japan are given
in table IX. Most of the Japanese patients were
administered a dosage of 600mg daily given as
200mg 8-hourly, whereas in Europe and the US a
daily dosage of 500 to 1500mg divided into two
12-hourly doses was most frequently administered.
Most patients received the oral dosage form of cip-
rofloxacin, but a few of the more severe infections
(i.e. lower respiratory tract infection and septicae-
mia) in Europe and the US (Schacht et al. 1985)
were treated initially with intravenous ciprofloxa-
cin. A treatment duration of 7 to 14 days was most
commonly employed.
4.1.1 Clinical Efficacy
Overall, ciprofloxacin therapy was clinically ef-
fective in approximately 95% of infections in Eur-
ope and the US; impressive clinical efficacy rates
of greater than 88% were obtained in all the infec-
tion types (table IX). In Japanese patients, clinical
efficacy rates of greater than 80% were obtained in
most infection types, and rates of approximately
75% were obtained in lower respiratory tract in-
fections and in ear, nose and throat infections (table
IX). Differences in efficacy rates between the Jap-
anese and non-Japanese studies may reflect differ-
ences in inclusion and evaluation criteria, which
were not described in detail, or differences in types
of pathogens encountered or in dosages admini-
stered.
The severity of infection was reported to affect
the ciprofloxacin clinical efficacy rates in the cu-
mulated Japanese data, with 81.3% of mild infec-
tions, 75.1% of moderate infections and 59.4% of
severe infections responding (Yamaguchi & Hara
1985). In contrast, non-Japanese studies of severe
infections have reported clinical efficacy rates (de-
fined as cure or improvement) of greater than 90%
with oral ciprofloxacin therapy or with intravenous
therapy followed by oral therapy (Parras et al. 1985;
Ciprofloxacin: A Review 409

Table IX. Clinical efficacy of ciprofloxacin based on cumulated data from 1,046 patients included in clinical studies in the US (after
Arcieri etal. 1986), 1,256 patients included in clinical studies in Europe and the US (after Schacht et al. 1985) and in 718 patients
(Baba 1985), 2,371 patients (Kobayashi 1985) and 870 patients (Yamaguchi & Hara 1985) included in clinical studies in Japan. Most
patients received the oral dosage form, but a few with more severe infections, such as lower respiratory tract infections and sep-
ticaemia [reported by Schacht et at (1985)] were treated initially with intravenous ciprofloxacin

Infection site Number of patients responding/number treated (%)a

US Europe & US Japan

Baba Kobayashi Yamaguchi & Hara

(1985)b (1985)b 1985)b

Urinary tract 502/514 (97) 574/602 (95) 803/924 (87) 98/105 (93)e
acute infection 62/62 (100)
chronic infection 28/35 (80)

Respiratory tract 201/215 (96) 189/208 (91) 585/777 (75) 529/717 (74)
acute infection 221/285 (78)
chronic infectiond 308/432 (71)

Skin or skin structure 195/218 (92) 247/257 (96) 131/148 (89) 264/305 (87)

Bone or joint 23/27 (89) 44/44 (100)

Intra-abdominal 11/13 (92) 41/44 (93)

Gastrointestinal tract 12/13 (92) 20/20 (100) 46/47 (98) 46/47 (98)

Gynaecological 24/25 (96) 97/105 (92) 49/53 (93)

Blood 39/43 (93) 52/56 (93)

Ear, nose, throat 135/164 (82) 77/101 (76)

Ophthalmological 69/83 (83) 69/83 (83)

8
Other 3/3 (100) 182/218 (84) 64/81 (79) 1/1 (100)

Total 986/1046 (94) 1191/1256 (95) 614/718 (86) 1956/2371 (83) 674/870 (78)

a Clinical efficacy was defined as: resolution or improvement (Arcieri et al. 1986), favourable response (Schacht et at 1985) and
good or excellent response (Saba 1985; Kobayashi 1985; Yamaguchi & Hara 1985).
b Identical results in some infection types (i.e. gastrointestinal tract, ophthalmological) suggest an overlap of patient populations
in the results of the 3 Japanese studies. However, details of patient populations were not provided, so this is impossible to
verify.
c Consisted of acute pyelonephritis (21 patients), acute cystitis (41 patients), chronic pyelonephritis (11 patients), chronic cystitis
(24 patients), and others (8).
d Chronic infections included exacerbations or infections associated with chronic.conditions such as chronic bronchitis, bronchiec-
tasis, bronchial asthma and pulmonary emphysema.
e Surgical infections.

Scully & Neu 1987; Wiley et al. 1985). Indeed, in
a prospective study involving 66 patients with sev-
ere infections of various body sites (mostly respi-
ratory tract) who were randomised to treatment
with either ciprofloxacin (250 to 500mg orally, or
100mg intravenously, every 8 or 12 hours) or im-
ipenem/cilastatin (500/500 to l000/1000mg intra-
venously every 6 or 8 hours) only 2 of 30 evaluable
ciprofloxacin-treated patients (6.7%) failed to re-
spond clinically versus 6 of 30 evaluable imipe-
nem/cilastatin patients (p = 0.25) [Lode et al. 1987].
Of the identified pathogens, consisting mostly of
Enterobacteriaceae, P. aeruginosa, Staphylococcus
aureus, Haemophilus influenzaeand streptococci,
67% and 79% were eradicated by ciprofloxacin and
imi penem/cilastatin, respectively.
Ci pro floxaci n: A Re view
P aerugmosa
I sistant to I or more alternative antibacterial drugs
n = 81
Other Pseudomonas spp.
I nosocomial infect ion s du e to multiresistant patho-
n = 5
Acinetobacter spp.
I
n = 5
S. aureus
I Cumulated bacterial eradication rates have been
n = 35
C'""" , " _ v.... from 75% to
1~. In Infections due to most other
~ section 4. I and table IX. Bacteriological erad ica-
Gram-posmve and Gram-negative species
n = 382
o 10 20 30 40 50 60 70 80
Clinical efficacy (%)
Fig. 3. Clinical effica cy of ciprofloxacin in infections due to sel-
ected pathogens in Japanese patients (after Yamaguchi & Hara
1985).
In analysing cumulated Japanese data. Yama-
guchi and Hara ( 1985) also classified clinical effi-
cacy according to pathogen. Clinical efficacy rates
of75% or greater were obtained for single pathogen
infections or mixed infections due. in most in-
stances. to Gram-positive and Gram-negative
orga nisms. However. an exception was P. aerugin-
osa infections, of which onl y 43.2% of 8 I re-
sponded clin icall y to ciprofloxacin therapy (fig. 3).
In contrast. several non -comparati ve studies con -
ducted in Europe and the US, which assessed pseu -
domonal infe ctions of va rious bod y sites (in many
cases due to multiresistant but ciprofloxacin-sus-
ccptible strains), reported sat isfactory clinical re-
sponses in approximately 75% of patients (Eron et
al. 1985; Follath et al. 1986; Giamarellou et al. 1986;
Pankey et al. 1985; Scully et al. 1986). In addition.
3 non-comparative studies reported clini cal effi-
cacy in approximatel y 90% of pat ients (total treated
410
105) infected with various species of Gram-posi -
tive and Gram-negative pathogens which were re-
(Eron et al. 1985; Meht ar et al. 1986; Scull y & Neu
1986). 91% of 54 pat ients with 'd ifficult to treat'
gens were also cured or improved (Gi amarello u &
Galanaki s 1987).
4./.2 Bacteriological Efficacy
derived from . clinical studi es involving the several
thousand patients in vario us countries described in
tion rat es for ciprofloxacin against mo st infecting
species of G ram-positi ve and Gram-negative aero-
bic pathogen s were 75% or greater: being 85% or
greater usu ally. Ho wever. eradication rates for P.
90 100 aerugin osa ranged from only 22.7% of 75 infec-
tions (Yamaguchi & Hara 1985) to 82% of 238 in-
fections (Arcieri et al. 1986); this difference is likely
a consequ ence of the lower dosages used in Japan
than in the rest of the world . Schacht et al. (1985)
reported that P. aeruginosa strains were eradi cated
from 9 1% of 257 skin stru cture infectio ns. 89% of
44 bon e a nd joint infect ions. 80% of 602 urinary
tract infections but only 65% of208 respiratory tract
infections. Th e latter figure reflects the persistence
of P. aerugin osa in cystic fibrosis patients despite
a satisfactory clinical response in many cases . Aci-
netobacter species were eradicated by ciprofloxacin
from 2 of 5 patients (Yamaguchi & Hara 1985). 6
of II pati ent s (Kobayashi 1985) and 9 of I 3 patien ts
(Arcieri et al. (986). Also. enterococci were eradi-
cat ed in onl y 8 of 13 pat ients (62%) in th e US (Ar-
cier i et al. 1986). but in 80 to 100% of Japanese
pati ents (Baba 1985; Koba yash i 1985; Yamaguchi
& Hara 1985). Schacht et al. (1985 ) reported that
Streptococcus fa ecalis was eliminated from all 25
gynaecological infection s, 80% of 602 urinary tract
infections, but only 64% of 257 skin structure in-
fection s. Interestingly. although only a small num-
ber of cases ha ve been treated. erad ication rates for
anaerobic pathogens from various sites were greater
Ciprofloxacin: A Review
than 90% (Kobayashi 1985; Schacht et al. 1985;
Yamaguchi & Hara 1985).
The bacteriological efficacy of ciprofloxacin in
104 episodes ofbacteraemia was cumulated by the
manufacturer from clinical trial data involving al-
most 4,000 evaluable patients worldwide (unpub-
lished data on file, Bayer AG). Ciprofloxacin ad-
ministered intravenously was able to eradicate the
bacterial pathogen in all cases of bacteraemia due
to Escherichia coli (25), Enterobacter cloacae (5),
Serratia marcescens (3), Providencia stuartii (3), S.
faecalis (3), Staphylococcus aureus (4), and Strep-
tococcus pneumoniae and Corynebacterium JK (1
each). Ciprofloxacin therapy also eradicated Sal-
monella typhi from 37 of 38 bacteraemic patients,
Pseudomonas species from 5 of 7 patients and Sta-
phylococcus epidermidis from 2 of 3 patients.
Bacteriological data from 107 intra-abdominal
infections (e.g. peritonitis, cholecystitis/cholangitis
and intra-abdominal abscess) treated with cipro-
floxacin was also analysed by the manufacturer
from cumulated worldwide data (unpublished data
o~ file, Bayer AG). The pathogen most frequently
treated was E. coli (53 patients) with an eradication
rate of 87%. All Enterobacter species were eradi-
cated (n = 12) as well as all S. aureus (n = 11),
Bacteroides species (n = 2) and Peptococcus species
(n = I), the anaerobic bacteria being encountered
in mixed infections.
4.1.3 Superinfection and the Development of
Resistance
Superinfection
Superinfection with a new infecting species,
among US patients included in the cumulated data
described above, occurred in only 5% of 514 with
urinary tract infection and 5.3% of 532 infection
sites outside the urinary tract (Arcieri et al. 1986).
However, much higher rates than this have been
reported in individual clinical trials; superinfec-
tion, usually due to Pseudomonas maltophilia, oc-
curred in 6 of 19 outpatients treated with cipro-
floxacin for soft tissue infections included in a non-
comparative study (Pien & Yamane 1987). In
patients administered ciprofloxacin, superinfec-
411
tions have occurred with P. aeruginosa (Cox 1986;
Saavedra et al. 1986; Scully & Neu 1987; Van Pop-
pel et al. 1986a), enterococci (Cox 1986; Eron et
al. 1985; Ryan et al. 1987;Van Poppel et al. 1986a),
Enterobacteriaceae (Cox 1986; Ryan et al. 1987;
Saavedra et al. 1986; Van Poppel et al. 1986a), P.
maltophilia (Pien & Yamane 1987),S. faecalis (Pien
& Yamane 1987), Acinetobacter calcoaceticus (Gia-
marellou & Galanakis 1987), methicillin-resistant
S. aureus (Greenberg et al. 1987a) as well as with
Candida species (Eron et al. 1985; Ryan et al, 1987).
The manufacturer has cumulated data on 3,822
patients treated with ciprofloxacin worldwide and
found that superinfections were caused mainly by
Gram-positive species of bacteria: S. faecalis in 17
urinary tract infections; S. pneumoniae and S. au-
reus in 6 and 4 respiratory tract infections, respec-
tively; streptococci, S. aureus and S. epidermidis
in 6, 5 and 4 skin structure infections, respectively;
and S. aureus in 4 bone and joint infections (un-
published data on file, Bayer AG). In addition, P.
aeruginosa caused superinfection in 16 urinary tract
infections.
Development of Resistance
The development of resistance or reduced sus-
ceptibility to ciprofloxacin among initially infect-
ing strains generally appears to be an uncommon
occurrence. The assessment of resistance inci-
dences is complicated by the infrequency with
which phage typing was reported, thus making it
impossible in most instances to differentiate be-
tween the true development of resistance and the
selection of a resistant strain of the same species.
Nonetheless, increased MICs during or after treat-
ment have been reported for infections due to
Klebsiella species (Chapman et al. 1985; Mehtar et
al. 1986), E. cloacae (Chapman et al. 1985),S. mar-
cescens (Scully & Neu 1986), A. calcoaceticus (Eron
et al. 1985; Giamarellou & Galanakis 1987), Ach-
romobacter species (Parry 1985), methicillin-sus-
ceptible S. aureus (Humphreys & Mulvihill 1985),
methicillin-resistant S. aureus (Greenberg et al.
1987a), S. epidermidis (Smith 'et al. 1985), Coryn-
ebacterium jeikeium (Murphy & Ferguson 1987),
and most frequently, P. aeruginosa (Azadian et al.
Ciprofloxacin: A Review
1986; Bryant & Harstein 1987; Chapman et al.
1985; Crook et al. 1985; Eron et al. 1985; Follath
et al. 1986; Giamarellou et al. 1985; Giamarellou
& Galanakis 1987; Greenberg et al. 1987a,b; Hod-
son et al. 1987; Leigh et al. 1986; Lode et al. 1987;
Pankey et at. 1985; Parry 1985; Preheim et al. 1987;
Sauerwein et at. 1985; Scully & Neu 1986, 1987).
In several of these cases ciprofloxacin failed to re-
solve the infection. These resistant strains were
usually encountered among patients whose ability
to fight infection was compromised by defects of
their immune system or health (e.g. underlying dis-
eases such as diabetes mellitus) or in patients suf-
fering from chronic and/or complicated infections.
In the case of P. aeruginosa, resistance to cipro-
floxacin, as with other antipseudomonal antibac-
terial drugs, is seen most frequently in the setting
of lower respiratory tract infections.
The incidence of emergence of resistance to cip-
rofloxacin (defined as MIC > 2 mg/L) has been
quantified among 1,836 patients included in 59
clinical studies conducted mostly in Europe
(Schacht & Hullmann 1986, 1987; unpublished data
on file, Bayer AG); 1,933 isolates from 1540 eva-
luable patients were assessed. Resistance to cip-
rofloxacin emerged in 14 infections due to P. aeru-
ginosa (5.2% of all isolates of this species), 3 S.
marcescens (21.4%), 2 E. coli (0.6%), 2 Klebsiella
pneumoniae (3.2%), 2 S. pneumoniae (3.4%) and 1
each of Proteus mirabilis (1%), S. aureus (0.5%) and
Branhamella catarrhalis (1.5%). However, a clear
correlation between the development of resistance
and clinical failure was found in only 5 of the 1,540
evaluable patients (0.3%).
Among patients with cystic fibrosis, resistant P.
aeruginosa isolates emerge frequently during or
following ciprofloxacin treatment, but their clinical
significance remains to be determined (Raeburn et
al. 1987) because in many instances the patient im-
proved clinically and the resistance was unstable,
being lost on cessation of therapy. However, in a
minority of cystic fibrosis patients, resistance to P.
aeruginosa has persisted (Roberts et al. 1985; Salh
& Webb 1987).
Cross-resistance has been reported between cip-
rofloxacin-resistant strains of Pseudomonas species
412
and ticarcillin (Greenberg et al. 1987a), gentamicin
and carbenicillin (Parry 1985), and enoxacin and
several ureidopenicillins and cephalosporins (Pid-
dock et at. 1987). Cross-resistance has also been
reported between ciprofloxacin and aminoglycos-
ides in strains ofS. aureus (Greenberg et al. 1987a).
4.2 Urinary Tract Infections
Published reports of cumulated data in several
thousand North American, European and Japanese
patients have shown clinical efficacy rates of 87%
or greater with ciprofloxacin in urinary tract infec-
tions (UTI) [table IX, section 4.1.1]. Similarly, Ku-
mazawa (1985) analysed cumulated UTI data in
Japanese patients and reported good to excellent
clinical responses in 98.3% of287 patients with un-
complicated cystitis, 74.2% of 325 patients with
cystitis complicated by underlying urological ab-
normalities, all 12 patients with uncomplicated
pyelonephritis and 78.7% of 89 patients with com-
plicated pyelonephritis.
4.2.1 Non-Comparative and Dose
Response Studies
In the report of cumulated Japanese data by
Kumazawa (1985) the bacteriological eradication
rate was 98.9% for 187 patients with acute uncom-
plicated cystitis due to E. coli. Various other Gram-
negative and Gram-positive aerobic pathogens were
also eradicated from all of the 42 other patients
with acute uncomplicated cystitis. Not surpris-
ingly, bacteriological eradication rates were lower
among the patients with complicated UTI. None-
theless, eradication rates were 85% or greater for
all Gram-positive pathogens encountered in com-
plicated infections and 80% or greater for most En-
terobacteriaceae; exceptions were S. marcescens
(72.7% eradicated), Serratia species (77.8% eradi-
cated) and P. aeruginosa (72.6% eradicated). Un-
fortunately the time of assessment post-treatment,
which would have influenced the recurrence and
reinfection rates in these patients with complicated
infections, was not reported. Several non-compar-
ative studies reported bacteriological eradication
rates of 90% or greater during treatment with cip-
Ciprofloxacin: A"Review
rofloxacin for complicated UTI (Boerema et a1.
1985b; Fass 1987a; Kamidono & Arakawa 1981;
Leigh et a1. 1986; Preheim et a1. 1987). Cure rates,
based on long term bacteriological follow-up were
82% 5 to 9 days after treatment (Fass 1987a) and
17 to 71% 4 to 6 weeks after treatment (Boerema
et a1. 1985b; Leigh et a1. 1986; Preheim et a1. 1987;
Van Poppel et a1. 1986a). The presence of an in-
dwelling catheter reduced the cure rates in these
patients (Kamidono & Arakawa 1987; Leigh et a1.
1986; Van Poppel et a1. 1986a).
Non-comparative studies which assessed UTIs
due to P. aeruginosa or organisms resistant to other
antibacterial drugs reported very high rates of bac-
teriological eradication during treatment with cip-
rofloxacin. Long term (4 to 8 weeks) follow-up
eradication rates were 27% in 11 multiple sclerosis
patients with P. aeruginosa infections (Van Poppel
et a1. 1986b), 68 to 89% in complicated or un-
complicated infections due to P. aeruginosa or other
co-trimoxazole (trimethoprim/sulphamethoxa-
zole)-resistant organisms (Cox 1987; Ryan et a1.
1987; Saavedra et a1. 1986), 43% in 8 patients with
chronic P. aeruginosa infections (Brown et a1. 1986),
56% among 25 non-catheterised elderly men with
complicated infections due to co-trimoxazole-re-
sistant Gram-negative organisms (Preheim et a1.
1987), and 71% among 28 patients with compli-
cated UTI due in most cases to co-trimoxazole-
and/or nalidixic acid-resistant organisms (Boerema
et a1. 1985b).
Several randomised studies examined the com-
parative efficacy of different dosage regimens of
ciprofloxacin in urinary tract infections. There were
no statistically significant differences in clinical or
bacteriological efficacy between single doses of
100mg and 250mg in 38 women with uncompli-
cated UTI (Garlando et al. 1987), between single
doses of 250mg and 3 days' therapy with 100mg
twice daily in gynaecological patients with symp-
tomatic or asymptomatic postoperative UTI (Graeff
et al. 1985), or between 250mg, 500mg and 750mg
doses administered 12-hourly to either 110 patients
with complicated UTI (Gasser et a1. 1987b) or 176
non-catheterised men with complicated or uncom-
plicated UTI (Cox 1986).
413
In addition to the above studies, ciprofloxacin
has also been assessed in an open, l-year follow-
up study in a few patients with chronic bacterial
prostatitis (Weidner et al. 1987)~ 12 men infected
with E. coli, 3 with S. faecalis and 1 each with P.
aeruginosa and Enterobacter aerogenes were ad-
ministered ciprofloxacin 500mg orally twice daily
for 2 weeks. Two of the 12 patients with E. coli
infections were not evaluable (1 had not completed
the 12-month follow-up and 1 stopped therapy be-
cause of severe headaches), but none of the re-
maining patients had signs of bacterial infection
during therapy, and recurrent bacterial prostatitis
occurred in only 3 patients during the next 12
months. The patient with E. aerogenes prostatitis
was also cured. However, treatment of P. aerugin-
osa prostatitis failed despite 2 therapeutic courses.
Infection persisted in 2 of the 3 men with S. fae-
calis prostatitis and recurred at 12 and 15 months
in the third.
4.2.2 Comparative Studies
Several small studies assessed the efficacy of
ciprofloxacin versus that of comparative antibac-
terial drugs in uncomplicated UTI and/or in in-
fections complicated by underlying urological ab-
normalities (table X). All of the studies except that
of Newsom et al. (1986) were stated to be random-
ised. However, the placement by Williams and
Gruneberg (1986) of all patients infected with co-
trimoxazole-resistant pathogens in the ciprofloxa-
cin treatment group casts doubt on the legitimacy
of the randomisation in this study. All of the other
studies required that the infecting organism be sus-
ceptible to both study drugs - a precaution which
would decrease the advantage of an agent having
a broader spectrum of activity, but which would
safeguard the randomisation process. Only 2 of the
studies were reported to be double-blind (Henry et
al. 1986; Goldstein et a1. 1987) and 2 were single-
blind (Newsom et al. 1986; Williams & Gruneberg
1986). Unfortunately, one of these was only a pre-
liminary report, not including results for all patients
enrolled (Henry et al. 1986). Among the studies
which provided details of group comparability,
there did not appear to be any clinically significant
differences between groups. An exception is the re-
Table X. Clinical and bacteriological efficacy of ciprofloxacin and comparative antibacterial drugs in urinary tract infections (UTI) 0
'e
..,
References Diagnosis Group Drug, dosage. route No. of pts .Efficacy 0
~
and duration evaluated 0
comparability >ol
clinical (%) bacteriological (per patient) l»
O.
F!
cured· improved eradicated persisted relapsed >
or reinfected ~
0
<
(ij'
Comparisons with co-trimoxazole ~
Age, symptoms 29 (93.5) 31 2
I
Henry et al. Uncomp. CIP 250mg PO bid x 10d 31
(1986)b acute cystitis TMP/SMX 160/800mg PO 34 26 (76.4) 32 2 6
in women bid x 10d
Kosmidis et al. Compo UTI Diagnosis. CIP 250mg PO bid x 7-10d 12 12 (100) 12
(1986) pathogens, TMP/SMX 13 8 (62) 3 (23) 7 6
complicating 160/800mg PO bid x 7-1Od
factors
Uncomp. UTI age, sex CIP 250mg PO bid x 7-10d 18 18 (100) 18 1
TMP/SMX 160/800mg PO 17 16 ( 94) 15 2 2
bid x 7-10d
Schmicker & Compo UTI Sex, diagnosis CIP 250mg PO bid x 10d 30 22 (73) 8 (27) 29 10
Naumann (acute vs chronic), TMP/SMX 160/800mg PO 30 19 (63) 10 (33) 25 16
(1986) severity, bid x 10d
general healthC
Williams & Uncomp. or ( ... )d CIP 250mg PO bid x 5d 26 23 (88) 21 3 2
Gruneberg comp. UTI; CIP 100mg PO bid x 5d 33 31 (94) 25 2 6
(1986) hospitalised TMP/SMX 160/800mg PO 16 14 (87) 12 2 2
patients bid x 5d

Comparisons with other antibacterials

Goldstein et al. Acute Gram- Age. sex, CIP 250mg PO bid x 10d 24 20 (83) 20 1
(1987) neg. UTle baseline infection CIN 500mg PO bid x 10d 21 15 (72) 15 3
Kumazawa et al. Compo UTI Not provided CIP 200mg PO tid x 7d 131' 104 (79) ~. 170/190 (89) ~ •
(1987) NOR 200mg PO qid x 7d 121' 81 (67) 138/173 (80)
Naber & Bartosik- Compo UTI Not provided CIP 500mg PO qd x 7-15d 30 29 1 10
Wich (19Q6) NOR 800mg PO qd x 7-15d 30 29 1 9
N.ewsom at al. Uncomp. Not provided CIP 100mg PO bid x 5d 16 16 4
(1986) acute UTI; TMP 200mg PO bid x 5d 16 15 1 3
elderly
patients

I ~
~
Ciprofloxacin: A Review 415

port of Williams and Gruneberg (1986), in which

the sex ratio varied greatly between groups. Given
the difficulty of successfullyresolving UTI in men,
in whom tissue invasion or anatomical abnormal-
"0 ity is usually involved (Tolkoff-Rubin & Rubin
:0
1987), this variable could have influenced the re-
.E
~
sults.
o
.s::.
Nil)
'G) Bacteriological eradication rates, usually as-
E sessed 5 to 9 days after the completion of therapy,
E
appeared similar for ciprofloxacin and the anti-
bacterial drugs with which it was compared. Also,
there did not appear to be any gross differences
between treatment groups in the rates of relapse

--,...- and/or reinfection within the 4- to 6-week follow-

up period; serotyping of re-isolated species was sel-
dom reported and so it is generally impossible to
differentiate between reinfections and true re-
lapses. Superinfections were seldom noted to oc-
cur, although Goldstein et a1. (1987) reported an
equal number in both the ciprofloxacin-treated (3/
24) and cinoxacin-treated (3/21) patients.
Cure rates, based on short term symptom res-
--
elDCD
olution or long term bacterial eradication, also ap-
peared to be generally similar for ciprofloxacin and
the antibacterial drugs with which it was com-
pared.
The incidence of side effects reported in patients
administered ciprofloxacinwas generallylower than
that in those administered co-trimoxazole (Kos-
midis et a1. 1986; Schmicker & Naumann 1986;
Williams & Gruneberg 1986). Indeed, in the pre-
liminary results reported by Henry et a1. (1986) the
difference was statistically significant (p < 0.05),
with 3 of 31 and 10 of 34 patients in the cipro-
floxacin and co-trimoxazole groups, respectively,
experiencing adverse effects consisting mostly of
nausea, anorexia, headache and diarrhoea.
~ The similarities in clinical and bacteriological
::::l
ci. efficacy rates between treatment groups in these
E
studies is not surprising given the usual inclusion
8
criteria requiring susceptibility of pathogens to both
study drugs. None of the studies reported statistical
analyses of results, and it is unlikely that statisti-
cally significant differences would be demonstrable
0-
~CO
Cl)elD under such study conditions unless much larger
'G)CD
Il.=' .0 0 "0 numbers of patients were examined. A largedouble-
Ciprofloxacin: A Review
blind study comparing the efficacy of oral cipro-
floxacin 200mg 3 times daily with that of oral
norfloxacin 200mg 4 times daily in patients with
complicated UTI has been conducted in Japan
(Kumazawa et aI. 1987; table X). Ciprofloxacin was
significantly more effective overall [104/131 (79.4%)
ciprofloxacin patients cured vs 81/121 (66.9%) nor-
floxacin patients; p < O.OS] as well as in the
subgroups of patients with indwelling catheters [13/
24 (S4.2%) vs 6/22 (27.3%); p < O.OS] and patients
who had failed to respond to previous antibacterial
therapy [12/19 (61.2%) vs 4/16 (2S.0%); p < O.OS].
Bacteriological eradication rates were also signifi-
cantly higher in the ciprofloxacin group overall
[170/190 (89.S%) vs 138/173 (79.8%); p < O.OS] and
for S. marcescens [6/8 (7S%) vs 1/11 (9.1%); p <
0.01].
Thus, in the treatment of UTI due to suscep-
tible organisms, orally administered ciprofloxacin
appears to be similar in clinical and bacteriological
efficacy to orally administered co-trimoxazole
(complicated and uncomplicated infections), tri-
methoprim (uncomplicated infections), norfloxa-
cin (complicated infections) and cinoxacin (un-
complicated infections), and intravenous
ciprofloxacin appears to be similar in clinical and
bacteriological efficacy to intravenous mezlocillin
(complicated infections).
4.3 Sexually Transmitted Diseases
4.3.1 Gonorrhoea
Many comparative and non-comparative stud-
ies involving hundreds of men with gonococcal ur-
ethritis have shown that single oral doses of cip-
rofloxacin 100 to 2000mg (usually 100 to SOOmg)
produce 100% bacteriological cure (Aznar et a1.
1986; De Lalla et a1. 1987; Loo et a1. 1985; Roddy
et a1. 1986; Scott G.R. et a1. 1987; Shahmanesh et
a1. 1986; Stolz et a1. 1987; Szarmach et a1. 1986;
Tegelberg-Stassen et a1. 1986). Single oral doses of
ampicillin 2 to 3.Sg plus probenecid lg tended to
produce a lower bacteriological cure rate (90 to 92%)
than single oral doses of ciprofloxacin 2S0mg
(100%) in comparative studies in men with uncom-
plicated gonococcal urethritis due to {j-lactamase-
416
negative N. gonorrhoeae (Roddy et a1. 1986; Scott
G.R. et a1. 1987). Ciprofloxacin was bacteriologi-
cally effective against both {j-lactamase-producing
strains and chromosomally mediated penicillin-re-
sistant strains of Neisseria gonorrhoeae, and was
often effective in curing patients with oropharyn-
geal or rectal infections, although there were too
few patients to determine efficacy rates reliably in
these latter infections. Thus, while ciprofloxacin
may be an effective alternative treatment for men
with gonococcal urethritis, more studies are re-
quired to determine bacteriological efficacy in
women, and in. patients with rectal or oropharyn-
geal infections.
4.3.2 Non-Gonococcal Urethritis
An important consideration in the treatment of
gonococcal urethritis is the development of post-
gonococcal urethritis, which may necessitate ad-
ditional antimicrobial therapy when it is caused by
Chlamydia trachomatis or Ureaplasma urealyti-
cum. The rate of postgonococcal urethritis after
ciprofloxacin treatment varied widely between
studies from 0% (Szarmach et a1. 1986) to 79%
(Shahmanesh et a1. 1986). Single-dose ciprofloxa-
cin was generally ineffective bacteriologically
against primary C. trachomatis or U. urealyticum
infection of the urethra or against urethral infec-
tions associated with N. gonorrhoeae (Aznar et a1.
1986; Loo et a1. 1985; Roddy et a1. 1986; Shah-
manesh et a1. 1986). Prolonged administration with
ciprofloxacin 300 to SOO rug/day for up to 7 days
did not increase effectiveness against these patho-
gens (Arya et a1. 1986; Saito et a1. 1985). Treatment
of 32 men with ciprofloxacin Ig daily for 7 days
eliminated C. trachomatis and U. urealyticum from
29 (91%) and 28 (88%), respectively, but 2 weeks
after the end of treatment these pathogens had
reappeared in 6 (19%) and 8 (2S%) of patients, re-
spectively (Stolz et a1. 1987).
Fong et a1. (1987) compared ciprofloxacin 7S0mg
twice daily and doxycycline 100mg twice daily for
7 days in 22S men with non-gonococcal urethritis
or postgonococcal urethritis primarily caused by C.
trachomatis and U. urealyticum. Ciprofloxacin
tended to be more effective than doxycycline in
Ciprofloxacin: A Review
curing U. urealyticum infections (69% vs 45%) but
as it was significantly less effective than the tetra-
cycline in curing chlamydial infections (45.5% vs
75%; p < 0.05) and in preventing relapses of such
infections, the authors concluded that ciprofloxa-
cin could not be recommended for use in non-
gonococcal urethritis.
4.3.3 Other Sexually Transmitted Diseases
In a non-comparative study in 22 patients with
nonspecific vaginitis caused by Corynebacterium
species, Bacteroides species and Gardnerella vagin-
alis, ciprofloxacin 500mg twice daily for 7 days gave
clinical cure and bacteriological eradication in 17
and 18 patients, respectively (Carmona et al. 1987).
Comparative assessments of ciprofloxacin versus
standard antibacterial therapies' for vaginitis will
be awaited with interest.
In a randomised double-blind parallel study in-
volving 139 men with chancroid genital ulcers
caused by H aemophilus ducreyi, 3 oral regimens
were compared: single-dose ciprofloxacin 500mg,
ciprofloxacin 500mg twice daily for 3 days, and co-
trimoxazole (trimethoprim/sulphamethoxazole)
160/800mg twice daily (Naamara et al. 1987). The
3-day ciprofloxacin regimen successfully eradi-
cated H. ducreyi from 100%of 40 patients, result-
ing in rapid clinical improvement with no clinical
failures. Bacteriological and clinical failure oc-
curred in 2/41 and 3/42 patients receiving single-
dose ciprofloxacin and 3-day co-trimoxazole regi-
mens, respectively. The authors concluded that
ciprofloxacin may become a first-line therapy for
chancroid if resistance to co-trimoxazole increases.
4.4 Gastrointestinal Infections
4.4.1 Non-Comparative Studies
Encouraging results have been obtained from
preliminary non-controlled studies in patients with
bacteriologically confirmed (Salmonella typhi cul-
tured) typhoid fever. Within 5 days of starting
treatment with ciprofloxacin 500mg orally twice or
3 times daily, clinical symptoms, such as fever,
chills, headache and diarrhoea, had" markedly im-
proved or disappeared. Blood cultures became ne-
417
gative within 48 hours (Eykyn & Williams 1987;
Limson 1986; Ramirez et al. 1986). Properly con-
trolled comparisons with chloramphenicol and
other standard therapies are required to establish
the usefulness of ciprofloxacin in this disease. The
use of ciprofloxacin in the treatment of Salmonella
carriers is discussed in section 4.12.
4.4.2 Comparative Studies
In 2 double-blind placebo-controlled studies, 5
days' administration of ciprofloxacin 500mg twice
daily was evaluated for efficacy in acute diarrhoea.
Pichler et al. (1987) reported that ciprofloxacin
(route of administration not reported) was signifi-
cantly better than placebo in 76 patients presenting
with diarrhoea of 4 days mean duration; Salmo-
nella species and Campylobacter jejuni comprised
the majority of isolated pathogens. Both fever and
diarrhoea lasted for approximately 1.5 days in
patients treated with ciprofloxacin compared with
about 3 days in those given placebo. Within 3 days
of starting therapy, rates of clinical-cure were 97%
and 66% in the ciprofloxacin and placebo groups,
respectively (p < 0.001). Corresponding values for
positive stool cultures recorded 3 weeks after
therapy were 8% and 36%. In the second double-
blind study twice daily administration of oral cip-
rofloxacin 500mg and oral co-trimoxazole 160/
800mg were similarly effective and superior to pla-
cebo (p < 0.0001) in a study of 191 patients with
travellers' diarrhoea caused mainly by enterotoxi-
genic E. coli. Both active treatments resolved the
diarrhoea within 30 hours of starting treatment and,
compared with placebo, abdominal cramps were
significantly (p < 0.001) relieved by the second day
(Ericsson et al. 1987).
4.5 Respiratory Tract Infections
As discussed in section 4.1, clinical efficacyrates
of greater than 90% were reported for cumulated
data on the use of ciprofloxacin in the treatment
of respiratory tract infections in Europe and North
America (Arcieri et al. 1986; Schacht et al. 1985).
Japanese clinical efficacy rates were somewhat
lower - approximately 75% (Kobayashi 1985; Ya-
Ciprofloxacin: A Review
maguchi & Hara 1985) - but this difference may
reflect differences in methodology, such as inclu-
sion and evaluation criteria (details of which were
not available), or differences in types of pathogens
encountered or dosages administered. Yamaguchi
and Hara (1985) reported an 'excellent' or 'good'
clinical response in 221 of 285 patients with acute
respiratory tract infections (78%) but only 308 of
432 patients with chronic infections (71%).
4.5.1 Non-Comparative Studies
In a large Japanese multicentre open study,
clinical efficacy of oral ciprofloxacin 200 to 1200mg
daily in 2 to 3 divided doses (68.5% of patients
received 600mg daily) was evaluated in 542 patients
with lower respiratory tract infections (Kobayashi
1987). Excellent to good results were obtained in
81 of 100 patients with, bacterial pneumonia, 94 of
121 patients (77.7%) with infected bronchiectasis
and 149 of 214 patients (69.6%) with acute exac-
erbations of chronic bronchitis. Clinical efficacy
rates were generally greater than 75% for infections
caused by most Gram-positive and Gram-negative
organisms. Notable exceptions were infections due
to P. aeruginosa (31/74 patients; 41.9%), Klebsiella
species (8/11 patients; 72.7%), K. pneumoniae (4/
6 patients; 66.7%), and polymicrobial infections in
which P. aeruginosa (11/17 patients; 64.7%) or K.
pneumoniae (8/11 patients; 72.7%) were a com-
ponent. Similarly, bacterial eradication rates were
greater than 75% for most species, notable excep-
tions being P. aeruginosa (21/94 isolates eradi-
cated; 23.9%) and Klebsiella species (8/12 eradi-
cated; 72.7%). Interestingly, only 26/42 isolates
(68.4%) of S. aureus and 29/42 isolates (60.0%) of
S. pneumoniae were eradicated, but clinical effi-
cacy rates for infections due to these species were
76.0 and 92.0%, respectively.
In another large open study, the clinical results
of the treatment of almost 300 patients with vari-
ous quinolones administered orally were cumu-
lated (Davies & Maesen 1987). These patients were
all suffering from acute infectious exacerbations of
chronic lung diseases such as chronic bronchitis,
bronchiectasis or silicosis. Ciprofloxacin dosages
varied from 250 to 500mg twice daily, and dosages
418
of the other quinolones varied from 400 to 800mg
daily as 1 or 2 doses. Among 75 evaluable patients
administered the 3 dosage levels of ciprofloxacin,
excellent clinical results were obtained in 58 to 81%
at the end of the 5 to 10 days' treatment, falling to
39 to 50% after 7 days' follow-up. These results
were generally lower than those obtained for the
other quinolones, but it must be remembered that
this was not a controlled comparison. Nearly all
infections associated with H. influenzae and/or
Branhamella catarrhalis were successfully eradi-
cated by the oral quinolones. However, many in-
fections due to S. pneumoniae failed to respond to
treatment, the least efficacious dosages being cip-
rofloxacin 375mg twice daily, enoxacin 300mg twice
daily and pefloxacin 200mg twice daily (29 to 37%
failures). The clinical failure rate associated with
ciprofloxacin 500mg twice daily, which is the rec-
ommended dosage for mild to moderate respira-
tory tract infections, was only 11% (2/18 patients).
Bacteriological assessment revealed that S. pneu-
moniae persisted or recurred in many patients, and
that reinfection with the species was similarly com-
mon; combining these 3 bacteriological categories
reveals S. pneumoniae isolation rates post-treat-
ment of 14% for ofloxacin (20 of 141 evaluable
patients), 24% for enoxacin (4/17), 27% for cipro-
floxacin (20/75) and 30% for pefloxacin (14/47).
Although the numbers of P. aeruginosa infections
treated with each quinolone were small (~ 10
patients per drug group), in general only about half
of the infections were clinically cured and bacte-
riologically eradicated. While clinical improve-
ment was frequently seen in P. aeruginosa infec-
tions, 40 to 57% of infections treated with
pefloxacin (4/7 patients), ciprofloxacin (5/9
patients) and ofloxacin (4/10) persisted or re-
curred; a reinfection in 1 patient in each of these
treatment groups increased the total P. aeruginosa
isolation rate post-treatment to 71%,67% and 50%,
respectively. Only 2 patients infected with P. aeru-
ginosa were treated with enoxacin, 1 of whom suf-
fered a reinfection with this species. Other open
studies have also reported less than satisfactory
bacteriological and/or clinical efficacy rates with
oral ciprofloxacin in P. aeruginosa infections of the
Ciprofloxacin: A Review
lower respiratory tract (Fass 1987b; Haverkorn
1987; Nix et al. 1987).
4.5.2 Comparative Studies
Several randomised studies have assessed the
efficacy of orally administered ciprofloxacin versus
that of comparative orally administered antibac-
terial drugs in lower respiratory tract infections,
mostly acute bronchitis or pneumonia, or acute in-
fectious exacerbations of chronic bronchitis (table
XI). Three of the studies were double-blind (Hara
et al. 1986; Kobayashi et al. 1986; Wollschlager et
al. 1987), but controls to avoid bias were not re-
ported in the others. In general, treatment groups
appeared to be similar as to age, sex and diagnosis.
However, Feist et al. (1986) gave no details of diag-
nosis and Bantz et al. (1987) had 64% more women
in the ciprofloxacin group than the doxycycline
group. In addition, several of the studies reported
that treatment groups were similar regarding se-
verity of infection and the species of isolated pa-
thogens, while Kobayashi et al. (1986) found no
statistically. significant difference between treat-
ment groups in the incidence of infections due to
H. influenzae.
In general, clinical efficacy rates appeared sim-
ilar or were not statistically different between cip-
rofloxacin and the antibacterial drugs with which
it was compared. However, a significantly (p < 0.05)
greater percentage of outpatients with acute bron-
chitis were cured with ciprofloxacin 250mg twice
daily than with ampicillin 500mg 3 times daily
(Gellermann 1987), and a significantly (p < 0.001)
greater percentage of patients with infectious ex-
acerbations of chronic bronchitis or other chronic
lung diseases were cured with ciprofloxacin 200mg
3 times daily than with cefaclor 250mg 3 times daily
(Kobayashi et al. 1986).
Several of the studies reported higher bacterio-
logical eradication rates for ciprofloxacin than for
the comparative drugs. In patients with bacterial
pneumonia, ciprofloxacin eradicated 83.3% of pa-
thogens versus 56.3% eradicated by bacampicillin,
a difference which was not statistically significant
(Hara et al. 1986). In contrast, statistical signifi-
cance was shown for the difference between cip-
419
rofloxacin (75%) and cefaclor (52.6%) in patients
with infectious exacerbations of chronic diseases
(Kobayashi et al. 1986; p < 0.05), between cipro-
floxacin (95%)and ampicillin (75%) in patients with
mild to moderate bacterial bronchitis (Wollschla-
ger et al. 1987; p < 0.05) and between ciprofloxacin
(82%) and cephalexin (61%) in lower respiratory
tract infections (Feist et al. 1986; p < 0.01).
Thus, in the treatment of infectious exacerba-
tions of chronic bronchitis and other chronic lung
diseases, orally administered ciprofloxacin was sta-
tistically superior to cefaclor in clinical and bac-
teriological efficacy. In outpatients with acute
bronchitis ciprofloxacin was statistically superior
to ampicillin in clinical efficacy. Ciprofloxacin was
superior in bacteriological eradication rates but not
clinical efficacy to ampicillin in mild to moderate
bronchitis and to cephalexin in lower respiratory
tract infections. Ciprofloxacin was not statistically
different in clinical efficacy from doxycycline in the
treatment of acute bronchitis or pneumonia in out-
patients, or from bacampicillin in bacterial pneu-
monia. In addition, ciprofloxacin appeared to be
similar in clinical efficacy to amoxycillin and co-
trimoxazole in patients with various lower respi-
ratory tract infections. Further well-designed stud-
ies, in particular large double-blind comparisons in
patients with Gram-negative nosocomial pneu-
monia, are needed to fully clarify the comparative
efficacy of intravenous and oral ciprofloxacin and
standard antibacterial therapies.
4.6 ,Respiratory Tract Infections in Patients
with Cystic Fibrosis
Pulmonary colonisation with mucoid-produc-
ing strains of P. aeruginosa causes debilitating
infectious exacerbations and progressive lung de-
terioration in fibrocystic patients. Previously, anti-
pseudomonal therapy has required hospital admis-
sion of these patients for administration of
parenteral antibacterial drugs, in some instances for
periods of several weeks. Thus, the possibility of
safe and effective orally administered antibacterial
therapy has stimulated much interest.
Table XI. Clinical efficacy of orally administered ciprofloxacin and comparative antibacterial drugs in lower respiratory tract infections I '00
References Diagnosis Group comparability Drug, dosage, duration No. of pts Clinical efficacy (%) a
0
=
evaluated
cured b improved failed
~
O.
?
Bantz et al. Outpatients with acute Age, diagnosis, severity CIP 250mg q12h x 4-12d 54 53 ( 98) ( 1 ( 2) >
(1987) bronchitis (93) or acute of infection DO 100mg q12h x td, then 53 53 (100) ,NS ~
0
pneumonia (15) qd x 4-11d <
n·
~
Feist et al. Lower respiratory tract Age, sex, pathogens CIP 500mg bid x 7-13d 28 27 ( 96) 1 ( 4)
(1986) infection CN 19 bid x 7-13d 23 22 ( 96) 1 ( 4)

Gellermann Outpatients, most with Age, sex, diagnosis, CIP 250mg bid x 10d 40 38 ( 95) ( <0.05 2 ( 5)
(1987) acute bronchitis severity of infection and AM 500mg tid x 10d 40 34 ( 85)P 6 (15)
underlying disease

Gleadhill et al. Hospitalised patients, Age, sex, severity of CIP 500mg bid x 9.8d8 25 12 ( 48) 9 (36) 4 (16)
(1986) most with pneumonia or infection, pathogens AMX 250mg ~id x 9.4d8 22 7 ( 32) 11 (50) 2 ( 9)
exacerbations of chronic
bronchitis

Hara et al. Bacterial pneumonia Age, sex, severity of CIP 200mg tid x 7-14d 54 45 ( 83)( 6 (11) 3 ( 6)
NS
(1986) infection, pathogens, BAM 250mg qid x 7-14d 45 40 ( 89) 3 ( 7) 2 ( 4)
signs and symptoms

Kobayashi et al. Infectious exacerbations Age, sex, diagnosis, CIP 200mg tid X 7-14d 103 87 (84) ( 12 (12) 4 (4)
(1986) of chronic bronchitis, signs and symptoms, CEC 250mg tid x 7-14d 97 60 (62) Ip<0.001 16 (16) 21 (22)
bronchiectasis and other severity of infection and
chronic lung diseases underlying disease

Magnani et al. Exacerbations of chronic Age, sex, height, CIP 500mg q12h x 9.3d8 15 11 ( 73) 4 (27)
(1986) bronchitis (9), pneumonia diagnosis TMP/SMX 160/800mg q12h x 14 8 ( 57) 4 (29) 2 (14)
(15), acute bronchitis (3), 8.8d8
bronchiectasis (3)

Wollschlager et at, Mild to moderate bacterial Age, sex, diagnosis CIP 750mg q12h x 9.1d8 42 41 (98) ( 1 ( 2)
NS
(1987) bronchitis AM 500mg q6h x 8.7d 42 40 (95) 2 ( 5)

a Mean duration.
b Results for studies by Bantz et al. (1987) and Feist et al. (1986) include patients 'cured' or 'improved' in this category.
Abbreviations: CIP = ciprofloxacin; DO = doxycycline; AM = ampicillin; AMX = amoxycillin; BAM = bacampicillin; CEC = cefaclor; TMP/SMX = co-trimoxazole;
CN = cephalexin; bid = twice daily; tid = 3 times daily; qid = 4 times daily; d = days; NS = not statistically different. ~
N
o
Ciprofloxacin: A Review
4.6.1 Non-Comparative and Dose
Response Studies
Very high rates of clinical response have been
reported in several small (n ~ 30) non-comparative
studies in young adult cystic fibrosis patients with
infectious pulmonary exacerbations due to P. aeru-
ginosa; ciprofloxacin dosages of 1500 to 2250mg
daily were administered orally in 2 or 3 divided
doses for varying durations (Bosso & Black 1987;
Goldfarb et al. 1987; Michalsen et al. 1985; Scully
et al. 1987b; Smith et al. 1986b). As is usually the
case with these patients, P. aeruginosa was not
eradicated from the sputum (Michalsen et al. 1985;
Scully et al. 1987b; Smith et al. 1986b), but there
was frequently a marked reduction in purulence and
bacterial counts. Several studies have reported the
development of resistance or decreased suscepti-
bility to ciprofloxacin in isolates of P. aeruginosa
colonising cystic fibrosis patients who were admin-
istered the drug; in most instances this resistance
was transitory, but it has persisted in a few patients
(section 4.1.2). Scully et al. (1987b) found that
patients from whom resistant strains were isolated,
but who did not require re-treatment for 3 months,
would again be harbouring susceptible strains.
However, during subsequent courses of ciproflox-
acin therapy, the rate of clinical improvement was
slower and the percentage of patients responding
decreased. Thus, the manufacturer recommends
only short (14-day) courses of treatment with cip-
rofloxacin, the next episode of infectious exacer-
bation to be treated with conventional antibacter-
ial therapy (personal communication, P. Schacht,
Bayer AG).
The efficacy of 2 different dosage regimens of
ciprofloxacin in the treatment of chronic broncho-
pulmonary infection in clinically stable adult
patients with cystic fibrosis was assessed in a well
designed and reported randomised single-blind
study (Shalit et al. 1987). Ciprofloxacin 750mg twice
daily (14 patients) or Ig twice daily (15 patients)
was administered orally for 14 days. The combined
results of both groups for all clinical parameters
[clinical score and peak expiratory flow rate
(PEFR)] were significantly improved (p < 0.05). 15
of the 28 patients who completed the study were
421
considered to have a major clinical improvement,
and there was no significant difference between the
2 dosage regimens. Even though there were sig-
nificant reductions in the quantity of P. aeruginosa
and S. aureus after 7 days of treatment, levels had
increased again by day 21. All bacteria except 2 P.
aeruginosa strains were susceptible to ciprofloxa-
cin prior to treatment. The number of patients with
ciprofloxacin-resistant P. aeruginosa was 11/23 on
day 7, 14/23 on day 14 and 16/23 on day 21.
4.6.2 Comparative Studies
Four small randomised studies have assessed the
comparative efficacy of oral ciprofloxacin and other
antibacterial regimens in young adult patients
with infectious pulmonary exacerbations of cystic
fibrosis.
In a non-blind study, Hodson et al. (1987) ad-
ministered either ciprofloxacin 500mg orally or
azlocillin 5g plus gentamicin 80mg intravenously
3 times daily for 10 days to patients (20 in each
group) with infections due to P. aeruginosa. The
treatment groups were comparable as to sex but no
further details of comparability were provided. Be-
tween days 1 and 10 both treatment groups im-
proved significantly (p < 0.001) in mean lung func-
tion [PEFR, forced expiratory volume in 1 second
(FEV.) and forced vital capacity (FVC)], but PEFR
and FEV. improved significantly (p < 0.05) more
in the ciprofloxacin-treated group. At the 6-week
assessment 5 patients from each group had been
lost to follow-up; lung function had decreased in
the remaining patients in each group but the results
in the ciprofloxacin group remained significantly
superior to pretreatment values. There was no sta-
tistically significant difference between the groups
for any other clinical parameter: duration of pyr-
exia, relapse rate prior to follow-up, survival rate
at 3 months, degree of reduction in sputum weight,
and subjective assessments.
The combination of intravenous azlocillin (75
rug/kg 6-hourly) plus an aminoglycoside (tobra-
mycin at a dosage sufficient to achieve a serum
concentration of 2 to 10 mg/L) was also compared
with oral ciprofloxacin 750mg twice daily in a sec-
ond non-blind study (Bosso et al. 1987). The 2
Ciprofloxacin: A Review
groups, each of which contained 10 patients, were
not statistically different before treatment regard-
ing age, weight or Shwachman (Shwachman &
Kulcyzcki 1958) scores, clinical scores, white blood
cell counts or pulmonary function tests. However,
only 12 patients completed the 14-day course of
therapy. Analysis of the 18 patients who completed
at least 7 days' therapy revealed no statistically sig-
nificant differences between the treatment groups
in the degree of clinical improvement of the para-
meters listed above.
Two randomised crossover studies have com-
pared oral ciprofloxacin with orally administered
ofloxacin 400mg administered twice daily in
patients with infections due to P. aeruginosa. Jen-
sen et al. (1987) used a ciprofloxacin dosage of
750mg twice daily, a treatment duration of 14 days
and a 3-month period prior to crossover in a
double-blind comparison. Among patients com-
pleting the first treatment period (n = 26) all clinical
parameters improved significantly (p < 0.005) in
each drug group between pretreatment and day 15
and there was no statistically significant difference
between the groups. However, clinical improve-
ment was no longer evident 3 months after treat-
ment. A period effect was observed in that the in-
crease in FEY 1 seen in treatment period I was
higher than the increase during crossover treat-
ment regardless of the order of administration. In
the second crossover study (n = 20) there was also
no difference in clinical efficacy between ofloxacin
400mg and ciprofloxacin 500mg, both of which
were administered twice daily for 10 days (Kurz et
al. 1986).
Three of the above comparative studies re-
ported bacteriological results (Bosso et al. 1987;
Hodson et al. 1987; Jensen et al. 1987). In general,
a small percentage of patients administered cip-
rofloxacin, ofloxacin or azlocillin plus an amino-
glycoside had temporary eradication of P. aerugin-
osa from their lungs, and a small percentage of
colonising P. aeruginosa strains developed transi-
tory resistance or diminished susceptibility to the
administered antibacterial drug(s). Among 10
strains of P. aeruginosa which developed resistance
or diminished susceptibility to ciprofloxacin or of-
422
loxacin, serogrouping and phage typing revealed
that the increase in minimum inhibitory concen-
tration (MIC) was mainly due to mutation of the
original susceptible strain (ciprofloxacin 5/7; oflox-
acin 2/3), whereas selection of a less susceptible
subpopulation was involved for the remaining 3
strains (Jensen et al. 1987).
Thus, in young adult cystic fibrosis patients suf-
fering infectious exacerbations due to P. aerugin-
osa, ciprofloxacin is an effective alternative to
intravenous azlocillin plus gentamicin or tobra-
mycin. However, because of the potential for the
development of resistance, ciprofloxacin is not rec-
ommended for long term prophylaxis or multiple
sequential courses of treatment in recurrent infec-
tions. In addition, it should probably be admini-
stered in combination with another anti pseudo-
monal antibacterial drug ifthe MIC ofthe infecting
strain is ~ 1 mg/L (section 8).
Ciprofloxacin is not recommended for use in
children because of the findings of arthropathy in
immature animals. Thus, information as to its
safety and efficacy in children is limited (Rubio
1987). However, given that P. aeruginosa may co-
lonise the lungs of cystic fibrosis patients during
infancy or early life, and the mean age of onset of
colonisation has been reported as 9 to 10 years
(Szaff et al. 1983), further investigation into the
efficacy and safety of ciprofloxacin in paediatric
patients may be warranted.
4.7 Skin and Soft Tissue Infections
While ciprofloxacin is unlikely to supplant the
'agents of choice' for most skin and soft tissue in-
fections (e.g. penicillins and erythromycin), the
broad spectrum and oral route of administration
ofthe quinolones would appear to recommend their
use in skin and soft tissue infections due to Gram-
negative species. Cumulated data from studies per-
formed in the US, Europe and Japan have shown
that ciprofloxacin cured or improved the clinical
condition of approximately 90% of nearly 1000
patients with skin or soft tissue infections (table
IX). In individual non-comparative and compar-
ative studies the clinical efficacy of ciprofloxacin
Ciprofloxacin: A Review
was at least as good as and frequently better than
this value. Patients with various infections of the
skin and soft tissues were studied - cellulitis, ab-
scesses and infected ulcers and wounds comprised
the majority of disorders. Many patients were also
suffering from underlying disorders such as dia-
betes and peripheral vascular disease.
4.7.1 Non-Comparative Studies
In 4 non-comparative trials, groups of 20 to 32
patients with skin or soft tissue infections were
treated with orally administered ciprofloxacin
250mg 3 times daily or 500 or 750mg twice daily
for between I and 10 weeks. A fifth trial assessed
16 patients with severe soft tissue or skin infections
and a single patient with pneumonia, due in all
cases to S. aureus; intravenous ciprofloxacin 200mg
was administered 12-hourly until defervescence,
followed by 750mg 12-hourly,orally (Righter 1987).
Clinical cure rates of 84, 76, 71, 70 and 58%
were reported by Fass (1986), Licitra et al. (1987),
Righter (1987), Wood and Logan (1986) and Va-
lainis et al. (1987), respectively. In addition to a
high rate of cure, Fass (1986) reported improve-
ment in a further 8% of patients. In most of the
other studies, improvement occurred in approxi-
mately an additional 25% of patients. There were
few treatment failures, except in the study of Righ-
ter (1987) in which 5 of 17 patients (29%) with sev-
ere infections due to S. aureus were clinical and
bacteriological failures. Valainis et al. (1987) re-
corded the second highest incidence (15%), noting
that all failures were elderly patients (mean age 70
years) with peripheral vascular disease.
In 3 of the above studies, over 90% of organ-
isms considered to be of pathological significance
were eradicated, S. aureus, S. epidermidis and P.
aeruginosa having been isolated most frequently
before treatment (Fass 1986; Licitra et al. 1987;
Valainis et al. 1987). However, only 42% eradica-
tion of Gram-positive species was reported by
Wood and Logan (1986), and only 29% eradication
ofS. aureus was reported by Righter (1987), results
which prompted the latter investigators to rec-
ommend caution before using ciprofloxacin to treat
staphylococcal infections causing systemic inva-
423
sion or affecting neutropenic patients. In contrast,
ciprofloxacin bacterial eradication rates of at least
85%were reported for S. aureus in the comparative
studies below.
4.7.2 Comparative Studies
Orally administered ciprofloxacin has been
compared with intravenous cefotaxime in double-
blind trials of patients with skin or soft tissue in-
fections. Unfortunately, comparisons with the
antibacterial drugs of choice in many skin and soft
tissue infections (e.g. penicillins and erythromycin)
are lacking.
The results of comparisons with cefotaxime are
summarised in table XII. Treated patients were
hospitalised and described as having mild to mod-
erate (Parish & Asper 1987; Ramirez-Ronda et al.
1987), moderate to severe (Perez-Ruvalcaba et al.
1987) or severe (Self et al. 1987) skin or soft tissue
infections. All 4 studies employed the same dosage
regimens, administered according to individual re-
quirements. Patients received oral ciprofloxacin
750mg twice daily or intravenous cefotaxime 2g 3
times daily. Both drugs attained clinical cure rates
which were generally in excess of 70% and nearly
all of the remaining patients showed signs of im-
provement. Ramirez-Ronda et al. (1987) reported
more clinical failures among the cefotaxime-treated
patients (21% vs 3%; p < 0.05). Otherwise, both
drugs displayed efficacies which were similar (Self
et al. 1987) or not statistically different (Parish &
Asper 1987; Perez-Ravalcaba et al. 1987), with cip-
rofloxacin possessing the advantage of oral admin-
istration. Ramirez-Ronda et al. (1987) conducted
follow-up examinations 1 week after treatment but
the other studies did not report whether this im-
portant procedure was carried out.
4.8 Osteomyelitis
In addition to the cumulated results presented
in table IX on the efficacy of ciprofloxacin in bone
or joint infections, several small (n ~ 40) non-com-
parative studies have been published. Generally,
patients were suffering from chronic osteomyelitis
of several weeks to many years duration which had
Ciprofloxacin: A Review 424

Teble XII. Summary of the results of double-blind, randomised comparative studies of orally administered ciprofloxacin (CIP) 750mg
twice daily and intravenously administered cefotaxime (CTX) 2g 3 times daily in patients with skin and soft tissue infections

References Infections Duration of No. of pts Efficacy: number of patients or sites (%)
(no. of pts) treatment evaluated
(days) (no. clinical bacteriological
of infection
cured improved failed eradicated persisted relapsed b
sites)S

Parish & Asper Ulcer (53), 5-21 CIP: 24 (25) 22 (88) 2 (8) 1 (4) 22 (88) 3 (12) 0(0)
(1987) skin (6), skin (range) CTX: 32 (36) 25 (69) 9 (25) 2 (6) 25 (69) 8 (22) 2 (6)
structure (1)

Perez-Ruvalcaba Cellulitis (18), Not CIP: 31 24 (77) 7(23) 0(0) 28 (90) 1 (3) 2 (6)
et al. (1987) ulcer (17), reported CTX: 28 (29) 22 (76) 6 (21) 1 (3) 26 (90) 3 (10) 0(0)
abscess (9),
skin structure
(8), surgical
wound (7),
wound (1)

Ramirez-Ronda Cellulitis (19), 9 (mean) CIP: 28c 22 (79) 5 (18) 1 (3) ~ 19 (90) 1 (5) 1 (5)
et al. (1987) cellulitis + CTX: 28d 18 (64) 4 (14) 6 (21) e 18 (82) 2 (9) 2 (9)
ulcers (10),
cellulitis +
abscess (12),
surgical wound
(8), abscess (5),
trauma wound
(1)

Self et al. Cellulitis (28), ~5.f CIP: 38 34 (89) 3 (8) 1 (3)

(1987) abscess (19), CTZ: 35 33 (94) 2 (6) 0(0)
wound (18),
miscellaneous
(8)

a Parish & Asper (1987) and Perez-Ruvalcaba et al. (1987) evaluated efficacy at individual infection sites, of which some patients
had more than 1.
b Includes cases of reinfection and superinfection.
c Bacteriological evaluation performed in 21 patients.
d Bacteriological evaluation performed in 22 patients.
e p < 0.05.
f Until patients remained afebrile for 3 days.

failed to respond to previous antibacterial therapy.
Infecting organisms were usually Gram-negative,
with P. aeruginosa isolated most frequently. Cip-
rofloxacin (usual dosage 500 to 750mg) was ad-
ministered orally twice daily for at least 4 weeks,
sometimes in conjunction with other antibacterial
drugs or surgical debridement. Patients were fol-
lowed for between 1 and 21 months, which sug-
gests an inadequate duration of follow-up for
patients at the shorter end of the range. Clinical
and bacteriological cure rates at final assessment
were 50%(Greenberg et al. 1987b), about 70%(Gil-
bert et al. 1987; Hoogkamp-Korstanje 1987; Slama
et al. 1987;Stuyck et al. 1987),about 80%(Norrby,
unpublished data on file, BayerAG), and over 90%
(Lesse et al. 1987; Trexler Hessen et al. 1987). Thus,
the preliminary data supporting the therapeutic ef-
fectiveness of ciprofloxacin in the management of
Ciprofloxacin: A Review
these difficult infections are most encouraging; re-
sults of controlled studies assessing the suitability
of ciprofloxacin as an alternative to intravenous
administration of conventional antibacterial drugs
are eagerly awaited.
4.9 Prophylaxis in Immunocompetent Patients
4.9.1 Surgical Prophylaxis
Three randomised trials have demonstrated the
efficacy of oral ciprofloxacin as prophylaxis against
infection in patients undergoing transurethral re-
section of the prostate or urethrotomy. A 3-day
course of ciprofloxacin 250mg twice daily, begin-
ning with premedication or with the last preoper-
ative meal, significantly reduced the postoperative
infection rate (1 of 50 ciprofloxacin patients vs 8
of 51 untreated patients; p = 0.03), median dura-
tion of hospitalisation (4 vs 5 days; p = 0.023) and
rate of postoperative bacteriuria (6% vs 38%; p =
0.002) following transurethral resection, but had no
effect on the median duration of catheterisation;
12%(ciprofloxacin group) and 16%(control group)
of patients had had bacteriuria preoperatively
(Murdoch et al. 1987). Similarly, either short (3 to
4 days) or long (8 to 9 days) term prophylaxis with
ciprofloxacin 500mg twice daily, beginning 1 day
prior to surgery, significantly reduced the incidence
of postoperative bacteriuria following transurethral
resection at 14 days after discharge (15 of 75 short
term treated patients and 3 of 70 long term treated
patients vs 31 of 69 untreated patients; p = 0.002
and p < 0.001, respectively, vs untreated) [Grabe
et al. 1987]. Bacteriuria had been present in ap-
proximately half of the patients in each group pre-
operatively; 4 months postsurgery bacteriuria per-
sisted in 17.2% of the short term group, 22.1% of
the untreated group but only 1.5%of the long term
group. In the latter study the incidence of septi-
caemia and upper urinary tract infections was sig-
nificantly greater among the untreated patients than
among the ciprofloxacin recipients (8 vs 2; p =
0.004). 23 male patients undergoing urethrotomy
were randomised to receive either no prophylaxis
or a short (2.5-day) perioperative course of cipro-
floxacin 250mg orally twice daily. Four of 11
425
patients administered no prophylaxis developed
postoperative bacteriuria, whereas all 12 patients
administered ciprofloxacin had sterile urine (Mur-
doch & Badenoch 1987). The results of compara-
tive assessments of ciprofloxacin versus standard
antibacterial prophylaxis in urinary tract surgery
will be awaited with interest.
Ciprofloxacin 500mg twice daily was admini-
stered for 7 days postoperatively to 20 patients
undergoing emergency surgery for acute cholecys-
titis or acute appendicitis. However, the presence
of risk factors necessitating prophylaxis in these
patients (e.g. perforated appendix; advanced age or
the presence of stones in cholecystitis) was not re-
ported. Of 34 isolates obtained during surgery 29
were susceptible to ciprofloxacin in vitro. Post-
surgical monitoring showed that none of the
patients experienced intraperitoneal abscess or sep-
tic shock (Ronconi et al. 1986).
4.9.2 Prophylaxis for Recurrent Cholangitis
Preliminary findings have shown that ciproflox-
acin may prevent recurrence of cholangitis. Three
infants (~ 4 months) developed this condition fol-
lowing hepatic portoenterostomy; Klebsiella spe-
cies and E. coli were identified in 2. Ciprofloxacin
25 or 50mg orally twice daily alleviated symptoms
in all 3 patients, and long term (up to 2 years) treat-
ment prevented recurrence in 2; the other patient
quickly relapsed when ciprofloxacin was discon-
tinued after 6 months' administration (Houwen et
al. 1987). In a 74-year-old patient with polycystic
kidney disease, recurrence of suspected cholangitis
was prevented by administration of ciprofloxacin
250mg twice daily (Lonka & Pedersen 1987).These
findings require confirmation and further study to
determine the necessary duration of treatment.
4.10 Immunologically Compromised Patients
While the numbers of patients treated have been
small, encouraging early results have been reported
with.the use of ciprofloxacin in the prophylaxis and
treatment of fever and/or documented infection in
immunologically compromised patients. A broad
spectrum of antibacterial coverage has been dem-
Ciprofloxacin: A Review
onstrated in these patients with the occasional ex-
ception of streptococci and staphylococci.
4.10.1 Fever and Documented Infections
Case reports have revealed the successful treat-
ment with ciprofloxacin of systemic infection due
to S. typhimurium in a neutropenic patient with
lymphoblastic leukemia (ciprofloxacin 400mg
loading dose followed by 200mg 12-hourly intra-
venously) [Patton et a1. 1985], in a patient with the
acquired immune deficiency syndrome (AIDS)
[ciprofloxacin 750mg 12-hourly, orally, for 3 weeks]
(Connolly et a1. 1986) and in a renal transplant re-
cipient on immunosuppressive therapy (ciproflox-
acin 500mg twice daily, orally for 30 days )[Bruns
& Wallace 1987]. In the first patient the isolated
strain of S. typhimurium was resistant in vitro to
ampicillin, trimethoprim, co-trimoxazole and
chloramphenicol, and had proven resistant to
treatment with a succession of fj-Iactam antibac-
terial drugs - ceftazidime, imipenem, and mecil-
linam - despite in vitro susceptibility. In the latter
2 patients the infection had previously relapsed 2
and 3 times, respectively, following treatment with
ampicillin or amoxycillin despite in vitro suscep-
tibility.
In addition to the above patients, 2 additional
AIDS patients with Salmonella septicaemia (Klein
et a1. 1986) and a 4-year-old child with neuroblas-
toma and septicaemia due to chloramphenicol-re-
sistant S. tennessee (Kiess et a1. 1984) responded
clinically to ciprofloxacin therapy. The use of cip-
rofloxacin in gastrointestinal Salmonella infections
is discussed in section 4.4.1 and in Salmonella car-
riers in section 4.12.
Two case reports have discussed the use of
intravenous ciprofloxacin 200mg 12-hourly plus
amikacin and granulocyte transfusions in the treat-
ment of P. aeruginosa septicaemia in neutropenic
patients (Bendig et a1. 1987). Both patients re-
covered initially but the second patient's focus of
infection (right axilla) never completely healed and,
following his second course of cytotoxic chemo-
therapy for acute lymphoblastic leukemia, all anti-
bacterials failed despite the pathogen's continued
susceptibility to both amikacin and ciprofloxacin.
426
Intravenous ciprofloxacin 200mg twice daily was
ineffective against Nocardia asteroides pneumonia
in a patient with AIDS. The ciprofloxacin MIC
against this pathogen was greater than 16 mg/L
(Shah et a1. 1987b).
In a non-comparative study, 17 neutropenic
patients (neutrophil count < 1 X 109/L) with fever
were administered intravenous ciprofloxacin,
400mg 12-hourly for 24 hours, then 200mg 12-
hourly, as their sole antibacterial therapy (Smith et
a1. 1986a). Two of these patients were not evalu-
able because fever resulted from a fungal infection,
and in a third patient fever was attributed to pseu-
domembranous colitis. Seven of the 14 evaluable
patients improved and 2 others, 1 of whom had P.
aeruginosa septicaemia, improved temporarily.
Four of 8 patients with septicaemia improved and
2 died; 2 septicaemias which failed to respond were
due to S. epidermidis, and a third was due to S.
faecalis. Ciprofloxacin was well tolerated and was
particularly active against Gram-negative bacteria.
However, as evidenced by a failure to respond, re-
sistance to ciprofloxacin was apparent for some
strains of staphylococci and streptococci, necessi-
tating the use of other antimicrobial drugs. Indeed,
resistant streptococci were implicated in 3 of 4
patients who developed superinfection.
Preliminary results were reported from a ran-
domised non-blind comparison of intravenously
administered ciprofloxacin 200mg 12-hourly plus
benzylpenicillin 2 million units 6-hourly versus ne-
tilmicin 2 mg/kg 8-hourly plus piperacillin 4g 6-
hourly in immunocompromised cancer patients
(Wood & Newland 1986). Five of6 non-fungal in-
fections in the ciprofloxacin plus benzylpenicillin
group and 2 of 4 non-fungal infections in the ne-
tilmicin plus piperacillin group have responded to
treatment. Isolated pathogens included E. coli, S.
epidermidis and E. aerogenes - no pathogens were
isolated from the 3 treatment failures. The com-
prehensive results of this study will be awaited with
interest. <;
4.10.2 Prophylaxis
In non-comparative studies, oral ciprofloxacin
500mg twice daily has been administered to 15
patients (Rozenberg-Arska et a1. 1985) and 34
Ciprofloxacin: A Review
patients (Dennig et al. 1987) as prophylaxis for re-
mission induction treatment of cancer, and to 23
recipients of lymphocyte-depleted allogeneic bone
marrow grafts (De Witte et al. 1987). In addition,
the same dosage of ciprofloxacin was assessed in a
comparison with the combination of colistin plus
co-trimoxazole as prophylaxis for remission induc-
tion treatment (Dekker et al. 1987). Antifungal
therapy was administered concomitantly and pro-
phylaxis was generally continued until granulocyte
counts exceeded 1000/~l.
Rozenberg-Arska et al. (1985) reported that 5
bacteriologically confirmed infections occurred
during prophylaxis (5/15, 33%); pathogens were S.
epidermidis (2 patients), a-haemolytic streptococci
(2 patients) and Bacteroides species (1 patient).
Dennig et al. (1987) noted fever during 18 of 46
induction courses, but bacteriologically confirmed
infection was implicated in only 2 of these: 'septi-
caemia due to E. cloacae and urinary tract infec-
tion due to K. pneumoniae (2/46, 4%).
Nine of 23 bone marrow graft recipients re-
ported by De Witte et al. (1987) who received cip-
rofloxacin had no infections during the 90 days of
prophylaxis. In the remaining 14 patients, 19 fe-
brile episodes occurred, but none could be attrib-
uted to Gram-negative or fungal organisms. One
infection, a pneumonia due to Bacteroides melan-
inogenicus, proved fatal.
60 patients were included in the comparative
study ofciprofloxacin 500mg orally twice daily ver-
sus co-trimoxazole 160/800mg plus colistin 200mg
orally 3 times daily as prophylaxis for remission
induction treatment. Four patients died during or
after the first cytotoxic treatment and so were ex-
cluded from analysis. Among the 28 patients re-
maining in each treatment group, bacteriologically
proven infections occurred in 5 receiving cipro-
floxacin (3 due to ,a-haemolytic streptococci, 1 to
Corynebacterium species and 1 to anaerobic bac-
teria) and 14 in the comparative group (2 due to
,a-haemolytic streptococci, 4 to S. epidermidis, 1 to
,a-haemolytic streptococci plus S. epidermidis, 2 to
Enterobacteriaceae and 5 to P. aeruginosa). The
difference in infection rate was significant (p < 0.05)
in favour of ciprofloxacin.
427
4.11 Decontamination of Pathogen 'Carriers'
4.11.1 Neisseria meningitidis
Two double-blind randomised studies demon-
strated the ability of oral ciprofloxacin admini-
stered twice daily to eliminate nasopharyngeal car-
riage of N. meningitidis. A dosage of 250mg twice
daily for 2 days resulted in negative cultures 4 days
later in all but 2 of 56 subjects (vs only 7 negative
cultures among 53 placebo recipients) [Renkonen
et al. 1987]. Similarly, all 20 subjects administered
ciprofloxacin 500mg 12-hourly for 5 days yielded
negative cultures on each day of treatment and then
on day 6 and 13 post-treatment versus a positive
culture rate of 66 to 95% on the various days among
21 placebo recipients (Pugsley et al. 1987).
4.11.2 Methicillin-Resistant Staphylococcus
aureus (MRSA)
20 hospitalised patients colonised with MRSA
- all of whom had chronic medical problems and
the majority of whom had previously received un-
successful treatment with vancomycin, co-trimox-
azole and/or rifampicin - were treated with cip-
rofloxacin 750mg orally 12-hourly for 7 to 28 days
(mean 17 days) [Mulligan et al. 1987]. Ciproflox-
acin was discontinued before eradication of the pa-
thogens in 6 patients because of adverse effects, in
1 because of progression of the underlying disease
and in 1 because therapy of an accompanied rel-
ative was discontinued. Therapy was successful in
11/14 completed courses (79%). However, 5 of the
patients were recolonised within 1 month (n = 4)
or 10 months (n = 1). Post-treatment MICs for pa-
thogens isolated following the 3 unsuccessful
courses of therapy had increased from 0.5 mg/L or
less to 2 to 32 mg/L.
In another group of nasal MRSA carriers, cip-
rofloxacin was used at a dose of 750mg twice daily.
Successful eradication was observed in only 6 of
23 subjects after 5 to 7 days of therapy, and 3 of
7 after 10 days of therapy. More disturbingly, al-
most all patients became recolonised after therapy
was stopped. Extending the period of treatment to
3 weeks and combining ciprofloxacin with 300mg
oral rifampicin in an additional 6 patients resulted
Ciprofloxacin: A Review
in eradication of MRSA from 5 of 6 carriers. The
patient failing treatment was colonised with a rif-
ampicin-resistant strain. The MIC of only 1 isolate
increased during ciprofloxacin treatment (from 1
to 4 mg/L). Inadequate sample for culture was the
most common cause of a falsely successful treat-
ment result (personal communication, Smith S.M.
& Eng R.H.K.).
4.11.3 Nosocomial Klebsiella species
Administration of oral ciprofloxacin 100mg
twice daily for 5 days resulted in elimination of
gentamicin-resistant Klebsiella species from 14 of
17 gastrointestinal carriers in an orthopaedic ward
(Warren & Newsom 1984).
4.11.4 Salmonella species
In addition to the efficacy demonstrated by cip-
rofloxacin in the treatment of systemic (section
4.10.1) and gastrointestinal infection due to Sal-
monella species, chronic Salmonella carriers have
also benefited from ciprofloxacin therapy (Diridl
et al. 1986; Heise-Reinecker et al. 1986), including
a patient allergic to penicillin and co-trimoxazole
(Hudson et al. 1985).
4.12 Other Infections
Individual case studies have reported favoura-
ble clinical responses following administration of
intravenous ciprofloxacin to an infant with ven-
triculitis caused by a multiresistant strain of P.
aeruginosa (Isaacs et al. 1986) and (in combination
with tobramycin) to an adult with meningitis due
to a multiresistant strain of P. aeruginosa (Millar
et al. 1986). In both patients, previously admini-
stered antipseudomonal therapy had been unsuc-
cessful.
Oral administration of ciprofloxacin 100 or
200mg 2 to 3 times daily resulted in 'excellent' to
'good' clinical responses in 79% of 62 patients with
ocular infections such as blepharitis, conjunctivitis
and corneal and orbital infections, due, in most
cases, to staphylococci (Ooishi et al. 1985).
A small number of patients on continuous am-
bulatory peritoneal dialysis who developed peri-
428
tonitis due to Gram-positive species were treated
successfully with ciprofloxacin administered orally
(Scott A.C. et al. 1987).
Five patients with Mediterranean spotted fever,
a rickettsiosis caused by Rickettsia conorii, were
cured after 2 days of intravenous ciprofloxacin
200mg twice daily followed by 8 days of oral cip-
rofloxacin 750mg twice daily (Raoult et al. 1986).
In suppurative otitis, encouraging results were
reported in a non-comparative pilot study includ-
ing 29 infections in 28 patients treated with oral
ciprofloxacin 750mg twice daily (Van de Heyning
et al. 1986) and in several other small open studies
reviewed by Van de Heyning et al. (1987). In ad-
dition, oral ciprofloxacin 600mg daily was not sta-
tistically different in clinical efficacy from pipem-
idic acid 2g orally daily in the treatment of
suppurative otitis media [79/131 (60.3%) cipro-
floxacin patients clinically responded vs 62/122
(50.8%) pipemidic acid patients] (Kawamura et al.
1987).
The combination of oral ciprofloxacin 750mg
twice daily plus rifampicin 600mg twice daily for
6 to 8 weeks was administered to 8 diabetic patients
with malignant otitis extema due to P. aeruginosa.
All 8 patients responded to oral therapy, although
1 patient relapsed 4 months later (Yu et al. 1987).
The combination of oral ciprofloxacin with rif-
ampicin may be a major advance in the therapy of
this difficult-to-treat infection, which has previ-
ously required parenteral therapy.
In a large (n = 260) double-blind study, 7 days'
therapy with ciprofloxacin 200mg 3 times daily
orally was not statistically different in clinical or
bacteriological efficacy to an equal dosage of nor-
floxacin in the treatment of acute tonsillitis (Baba
et al. 1987).
5. Side Effects
5.1 Clinical Symptoms
The incidence of side effects considered to be
at least possibly related to treatment with cipro-
floxacin is low. Serious adverse experiences with
Ciprofloxacin: A Review
ciprofloxacin are rare, most reactions are mild and
therapy has had to be discontinued in less than 2%
of patients (Arcieri et a1. 1986).
Ball (1986) reviewed adverse reactions probably
or possibly attributable to oral ciprofloxacin therapy
in worldwide clinical experience involving over 500
patients. The data are based partly on company
reports and partly on published reports (Arcieri et
al, 1986; Kobayashi 1985; Schacht et al. 1985) and
are summarised in table XIII. The increased in-
cidence of side effects in the US (13.4%) versus Ja-
pan and Europe may relate to different dosages
employed or different methods of recording. The
lower incidence of reactions amongst Japanese
patients (3.0%) is unexplained, but is in keeping
with similar reduced figures for other quinolones,
such as norfloxacin, in that country (Holmes et al.
1985). The overall worldwide incidence of adverse
reactions among patients treated with ciprofloxa-
cin was found to be 5.4% by Ball (1986) and 10.2%
among 8861 patients worldwide assessed by Schacht
et a1. (1988) [table XIV].
Adverse gastrointestinal symptoms occur most
commonly (up to 10% of patients treated), and
usually are comprised of nausea, vomiting, diar-
rhoea and abdominal pain, but are generally mild
and transient. Stimulatory effects on the central
nervous system such as anxiety, nervousness, in-
somnia, euphoria and tremor are seen in 1 to 4%
of patients, but are usually also mild. Convulsive
seizures occurred in 1 patient administered cipro-
floxacin plus theophylline (Arcieri et al, 1986) and
in 2 patients with neurological diseases associated
with previous seizures and focal neurological def-
Table XIII. Worldwide reported incidences of adverse reactions probably or possibly related to ciprofloxacin [adapted from
Ball (1986)]
References Location No. of pts
assessed
Arcieri et al, (1986) USA 1241
Kobayashi (1985) Japan 2575
Schacht et al. (1985) Europe/US 1693
a % of total patients assessed.
429
icits (Mulligan et al, 1987). However, no changes
were observed in the EEGs of 12 healthy subjects
administered intravenous infusions of ciprofloxa-
cin 300mg 12-hourly for 4 days (Thorsteinsson et
al. 1987). Hallucinations have been reported rarely
in patients administered ciprofloxacin, but con-
comitant theophylline administration could have
contributed to this reaction (Schacht et al. 1988).
Nonspecific effects such as headache, dizziness and
confusion have also occurred but their relationship
to the administration of the drug is unclear. Hyper-
sensitivity reactions, most commonly skin rash or
pruritus, have been reported in about 1% of patients
but are usually mild to moderate in severity (Ar-
cieri et aI. 1986; Ball 1986; Kobayashi 1985; Schacht
et al. 1985; Smith 1987). Local erythema at the site
of the infusion may be minimised by using the
cubital or larger veins, and avoiding smaller peri-
pheral veins.
In relation to gastrointestinal side effects, Ko-
bayashi (1985) reported a higher incidence in
patients treated with ciprofloxacin in oral doses of
800 mg/day or greater, as compared with those re-
ceiving 600 rug/day or less (8% vs 3%). This dose-
response correlation for gastrointestinal side effects
was confirmed in clinical trials in the US, with in-
cidences of 3 to 4% at dosages of 500 to 1000mg
orally daily, but an incidence of 10% at daily dos-
ages of 1500mg (unpublished data on file, Bayer
AG).
Ciprofloxacin is not recommended for use in
children because it inhibits the growth of juvenile
cartilage as well as causing cartilage alteration and
arthropathy in animals (Schluter 1986). However,
Adverse reactions (%)8
gastrointestinal nervous system skin (allergy)
8.1 4.4 0.9
2.1 0.4 0.4
4.5- 1.0 1.0
Ciprofloxacin: A Review 430

Table XIV. Comprehensive listing of adverse events probably or possibly related to ciprofloxacin in 8,861 patients assessed world-
wide (after Schacht et al. 1988)

Adverse event No. of Adverse event No. of Adverse event No. of

pts pts pts

Gastrointestinal Tremors 16 Cardiovascular

Nausea 141 Lethargy/drowsiness/somnolence 11 Phlebitis/thrombophlebitis 12
Diarrhoea 108 Confusion 5 Palpitations 9
Vomiting 51 Hallucinations 5 Vasodilatations 3
Dyspepsia 44 Insomnia 4 Hot flushes 3
Abdominal pain 33 Convulsive seizures 2 Hypertension 2
Anorexia 25 Nightmares 1 Chest pain 1
Difficulty swallowing drug 8 Depression 1 Cardiac failure 1
Flatulence 7 Manic reaction 1 Syncope 1
Increased salivation/bad taste 6 Neurosis 1 Migraine 1
Mouth dryness 5 Total 138 Total 33
Stomatitis' 5
2 Skin
Oesophagitis
Eructation 2 Rash 60 Urinogenital
Constipation 2 Pruritus 29 Vaginitis 12
White plaque on denture 1 Injection site reacnons 14 Albuminuria 6
Pseudomembranous colitis 1 Local oedema 6 Crystalluria 3
1 Urticaria 4 Haematuria 3
Tenesmus
442 Increased perspiration 4 Dysuria 1
Total
Photosensitivity reaction 3 Total 25
Angioedema 1
Metabolic and nutritional
Acne 1 Special senses
Elevated AST 121
115
Total 122 Paraesthesia 5
Elevated ALT
Elevated alkaline-phosphatase 39 Hypaesthesia 3
Elevated r-glutamyl transpeptidase 30 Haemlc/lymphatic Blurred vision 4
Elevated LDH 23 Eosinophilia 57 Tinnitus 3
Elevated serum creatinine 23 Leucopenia 14 Eye disorder 2
Elevated BUN 23 Elevated leucocytes 5 Retro-ocular pain 2
Elevated bilirubin 9 Reduced platelets 4 Ear pain 1
Elevated uric acid 7 Elevated platelets 3 Deafness 1
Elevated cholesterol 5 Elevated monocytes 2 Corneal opacity 1
Acute renal failure 2 Erythrocyte sedimentation 1 Total 22
Creatinine clearance decreased 2 rate increased
Acidosis 2 Haemolysis 1 Respiratory
Hepatomegaly 2 Anaemia 1 Dyspnoea 1
Nephritis 2 Total 88 Laryngeal oedema 1
Hypernatraemia 1 Pneumonia 1
Hypercalcaemia 1 General Coughing 1
Jaundice 1 Weakness 14 Hiccough 1
Total 408 Fever 11 Stridor 1
Malaise 6 Voice alteration 1
Neuralgia/pain 3 Total 7
Central nervous system b Neuritis 1
Dizziness/light-headedness 37 Candidiasis 9 Musculoskeletal
Headache 29 Total 44 Arthralgia 9
Nervousness/anxiety/ 25
agitation/restlessness

a Caused by Candida spp.

b Patients may have been receiving concomitant theophylline.
c Pain and redness.
Ciprofloxacin: A Review
the relationship of these experimental results to
rheumatological symptoms observed in patients
receiving ciprofloxacin is unclear. To date there is
very little evidence that ciprofloxacin causes joint
damage, although a recent case report (Alfaham et
al. 1987) described a 16-year-old girl with cystic
fibrosis who developed severe joint pain and in-
flammation (arthropathy) after 3 weeks' treatment
with ciprofloxacin 750mg twice daily. The arthro-
pathy completely resolved within 2 weeks of ceas-
ing ciprofloxacin treatment. In an additional report
involving paediatric patients, 5 of 6 fibrocystic
patients aged 8 to 22 years, who were administered
ciprofloxacin for severe pulmonary disease, devel-
oped signs consistent with interstitial nephritis
(sterile pyuria, white blood cell casts, increased
serum creatinine) [Stutman 1987]. However Rubio
(1987)administered ciprofloxacin 375 to 750mg 12-
hourly to 9 fibrocystic children aged 8 to 16 years
and noted no neurological, gastrointestinal or
hypersensitivity (skin) reactions, as well as no joint
pain, swelling or limitation of range of motion; la-
boratory evaluations, including urinalysis, re-
vealed no abnormalities.
Ophthalmological studies, including fundus-
copy, visual acuity, and colour testing, were per-
formed in more than 800 patients pre- and post-
therapy with ciprofloxacin; no significant drug-re-
lated ocular changes were revealed (Arcieri et al.
1987).
5.2 Effects on Laboratory Indices
The reviews ofJapanese, European and US data
revealed only small incidences of abnormal la-
boratory data « 4%) in patients treated with cip-
rofloxacin (Kobayashi 1985; Schacht et al. 1985).
Biochemicaltoxicity is very rare. Some studies have
noted mild and reversible elevations in serum cre-
atinine, AST (SGOT), ALT (SGPT) and blood urea
nitrogen related to ciprofloxacin therapy. How-
ever, the clinical significance of these rises is un-
known (Arcieri et al. 1986;Kobayashi 1985;Schacht
et al. 1985).
There is little evidence for haematological tox-
icity due to ciprofloxacin. Kobayashi (1985) re-
431
ported that less than 1% of patients treated with
ciprofloxacin developed eosinophilia. Haematuria
is also rare; after 1 month's administration of cip-
rofloxacin lg daily, a patient developed micro-
scopic haematuria with granular red blood cellcasts.
Ciprofloxacin was discontinued and the haematu-
ria resolved after 5 days. However, on a further 2
occasions when the patient was rechallenged with
ciprofloxacin, haematuria developed after 4 days,
resolution occurring within 3 days of discontinua-
tion of treatment (Garlando et al. 1985).
Animal studies suggest that the relative insol-
ubility of ciprofloxacin at alkaline pH might lead
to crystalluria and resultant tubular damage
(Schluter 1986). Thorsteinsson et al. (1986) re-
ported that a single dose of ciprofloxacin (1OOOmg)
led to the development of crystalluria in a healthy
volunteer, whose regular diet was supplemented by
sodium bicarbonate to obtain alkaline urine.
Healthy volunteers receiving single doses of cip-
rofloxacin (500 or l000mg), who received a regular
diet or one supplemented by ammonium chloride
to obtain acidic urine did not develop crystalluria.
Given that urinary pH is normally below 6.8 the
chance of crystalluria formation appears remote.
In addition, in a healthy volunteer experiencing
crystalluria, crystals of ciprofloxacin did not ap-
pear to cause any tubular cell damage as assessed
by clinical and biochemical parameters, urinalysis,
or immune techniques (monoclonal antibodies)
[personal communication, T: Bergan]. However, it
may be prudent to ascertain urinary acidity in
patients receiving high doses of ciprofloxacin dur-
ing long term therapy. In addition to the paediatric
patients noted above (section 5.1), one case of in-
terstitial nephritis has been recorded following cip-
rofloxacin administration to an adult (Arcieri et al.
1986), but the relationship of this adverse effect to
the development of crystalluria is uncertain.
6. Drug Interactions
6.1 Xanthine Derivatives
There have been several studies reporting in-
teractions between ciprofloxacin and xanthine de-
rivatives, with theophylline receiving considerable
Ciprofloxacin: A Review
attention. The site of this interaction is presumed
to be the cytochrome P450 enzyme system. Raoof
et al. (1987) reported that 20 of 33 patients (61%)
treated with both oral ciprofloxacin (750mg twice
daily) and theophylline had serum theophylline
concentrations increased by a mean value of 10.5
mg/L, For 30% of the patients who experienced in-
creases, and most frequently in elderly patients,
theophylline concentrations were in the toxic range.
In a comparative study, Wijnands et al. (1986,
1987) found increased plasma theophylline con-
centrations during coadministration of enoxacin
(110.9% increase), and to a lesser degree during
coadministration of pefloxacin (19.6%) and cipro-
floxacin (22.8%). Total body clearance of theo-
phylline was decreased by enoxacin (63.6%), cip-
rofloxacin (30.4%) and pefloxacin (29.4%).
However, ofloxacin did not significantly affect
either of these theophylline parameters when com-
pared with the control (Wijnands et al. 1987). It is
thought that the 4-oxo-metabolites of these com-
pounds and not the parent compounds are respon-
sible for the interaction with theophylline
(Wijnands et al. 1986).
Multiple-dose administration of oral ciproflox-
acin 750mg twice daily for 7 days to 8 healthy male
volunteers significantly raised the volume of dis-
tribution of theophylline (p < 0.05) in addition to
increasing its elimination half-life. However, theo-
phylline clearance was not significantly decreased
(Nix et al. 1986).
A multiple-dose regimen ofciprofloxacin (250mg
twice daily for 5 days) also had a significant in-
hibitory effect on the single-dose pharmacokinetics
of caffeine. In 12 healthy volunteers, treatment with
ciprofloxacin led to a prolongation of the caffeine
half-life by 15% and a decrease in the volume of
distribution and. total body clearance of caffeine by
25% and 33%, respectively (Staib et al. 1987).
6.2. Studies with Antacids and Other Drugs
Affecting Absorption
Simultaneous administration of antacids con-
taining magnesium and/or aluminium hydroxide
with ciprofloxacin leads to a reduction in the bio-
432
availability of the latter, with little effect on the
absorption rate (Beermann et al. 1986; Golper et
al. 1987). This interaction is of potential concern
not just in patients using antacids for gastrointes-
tinal symptoms, but also in patients with compro-
mised renal function and on haemodialysis or con-
tinuous ambulatory peritoneal dialysis, who utilise
antacids as phosphate binders. A 6- to 10-fold re-
duction in peak serum concentrations to levels that
would be subtherapeutic against staphylococci,
Pseudomonas aeruginosa and some other bacteria
with intermediate susceptibility to ciprofloxacin,
has been observed following the concomitant
administration of ciprofloxacin 500mg with mag-
nesium- and/or aluminium-containing antacids
(Hoffken et al. 1985a; Preheim et al. 1986). Thus,
antibacterial drug therapy with ciprofloxacin may
prove less effective in patients receiving antacids.
Pirenzepine and N-butyl-scopolaminium bro-
mide (agents which delay gastric emptying) admin-
istered concomitantly with ciprofloxacin delay the
absorption of the quinolone, thus prolonging the
time to peak serum concentrations (Hoffken et al.
1986; Wingender et al. 1985). In contrast, meto-
clopramide 40mg administered intravenously im-
mediately prior to oral ciprofloxacin 500mg short-
ened the time to maximum serum concentrations
of ciprofloxacin (Wingender et al. 1985). However,
the clinical importance of these findings remains
to be established.
7. Dosage and Administration
Ciprofloxacin is usually administered orally in
a twice daily regimen. Recommended total daily
doses in approved indications are presented in table
xv. These vary according to the nature and se-
verity of the infection. A notable exception is that
in Japan the standard dosage is 200mg 3 times
daily. In general, treatment is usually continued for
at least 2 days after the signs and symptoms of in-
fection have disappeared, with 7 to 14 days being
the most common duration of therapy. However,
5 to 7 days' therapy is usually sufficient for infec-
tious diarrhoea, while severe and complicated in-
fections may require prolonged .administration.
Ciprofloxacin: A Review
Table XV. Recommended total daily doses of ciprofloxacin ad-
ministered orally as a twice daily regimen (Miles Inc., package
insert).
Type of infection Total daily dosea
(mg)
Urinary tract
Mild/moderate 500
Severe/complicated 1000
Respiratory tract, bone and joint, skin and skin structure
Mild/moderate 1000
severe/complicated 1500
Infectious diarrhoea
Mild/r1l9derate/severe 1000
a In Japan the standard oral dosage is 200mg 3 times daily.
Bone and joint infections are usually treated for 4
to 6 weeks or longer.
The recommended dosage for the intravenous
formulation of ciprofloxacin is 100 to 200mg twice
daily, each dose being infused over 30 to 60 min-
utes. In patients with pseudomonal or staphylo-:
coccal infections, or in immunocompromised
patients, a dosage of 300mg twice daily may be used
(personal communication, P. Schacht, Bayer AG).
A dosage of 100mg twice daily is usually sufficient
in patients with upper or lower urinary tract in-
fections, while the higher dosage of 200mg twice
daily is recommended in those with respiratory tract
infections or most other infections.
Dosage adjustment for altered renal function is
usually not required unless creatinine clearance is
20 mljmin or less. If adjustment is necessary, the
total daily dosage may be reduced by one-half.
Ciprofloxacin should not be administered to
pregnant women, and it is not recommended in
children in view of the findings of arthropathy in
immature animals and the lack of clinical experi-
ence. However, where the benefit of ciprofloxacin
therapy is considered to outweigh the potential risk,
the intravenous dosage should be 5 to 10 mg/kg/
day and the oral dosage should be 7.5 to 15 mg/
kg/day (depending on the severity of the infection)
administered in 2 divided doses.
433
8. Place 0/ Ciprofloxacin in Therapy
Ciprofloxacin is an orally administered broad
spectrum antibacterial drug to which most Gram-
negative species of bacteria are highly susceptible
in vitro and most Gram-positive species of bacteria
are susceptible or moderately susceptible. It attains
concentrations in most tissues and body fluids
which are at least equivalent to the minimum in-
hibitory concentration designated as the break-
point for bacterial susceptibility in vitro (~ 1 mg/
L). The antibacterial and pharmacokinetic profiles
of ciprofloxacin, and clinical trials in several types
of infection, suggest a broad clinical application.
Many studies in patients with urinary tract or
respiratory tract infections demonstrated that cip-
rofloxacin was effective both in acute and chronic
infections, as well as in patients with or without
underlying complications. Oral ciprofloxacin ap-
peared to be similar in clinical and bacteriological
efficacy to orally administered co-trimoxazole, tri-
methoprim, norfloxacin, and cinoxacin in uncom-
plicated and/or complicated urinary tract infec-
tions (UTI). Of note, the incidence ofadverse effects
was lower with ciprofloxacin than with co-trimox-
azole. Intravenous ciprofloxacin appeared to be
similar in clinical and bacteriological efficacy to
intravenous mezlocillin in complicated UTI. In
hospitalised patients or patients with major struc-
tural abnormalities of the urinary tract the most
common pathogens are multiresistant Enterobac-
teriaceae and P. aeruginosa, both of which are sus-
ceptible to treatment with ciprofloxacin. As urin-
ary tract infections are the most common
nosocomial infection and are often a source of bac-
teraemia, the therapeutic and cost containment ad-
vantages of an orally administered antibacterial
drug effective against these pathogens is readily ap-
parent. Importantly, decreased susceptibility of
strains of P. aeruginosa to ciprofloxacin has oc-
curred in patients with chronic or complicated UTI.
However, the high concentrations of ciprofloxacin
achieved in the urine have virtually negated the
impact of these strains on therapeutic outcome.
In comparative studies, oral ciprofloxacin was
superior in clinical efficacy to cefaclor in infectious
Ciprofloxacin: A Review
exacerbations of chronic bronchitis and other
chronic lung diseases, and to ampicillin in acute
bronchitis. In addition, ciprofloxacin was similar
to or, in those studies which statistically analysed
the results, not significantly different in clinical
efficacy to doxycycline, cephalexin, amoxycillin,
bacampicillin or co-trimoxazole in various lower
respiratory tract infections. Quinolones should
probably not be considered the agents of first choice
for community-acquired pneumonia because they
may not reliably eradicate S. pneumoniae from the
lungs, and should never be used initially alone in
aspiration pneumonia, in which an anaerobic
organism is the most likely pathogen. However, oral
ciprofloxacin is an effective alternative to current
antibacterial drug treatment in infectious exacer-
bations of chronic lung diseases, although the pos-
sibility of a drug interaction between ciprofloxacin
and theophylline, a drug widely used in patients
with chronic respiratory diseases, should be con-
sidered. Although clinical trials assessing compar-
ative efficacy are lacking, and bacteriological effi-
cacy against P. aeruginosa may be somewhat
unreliable, the results of open studies suggest that
oral monotherapy with ciprofloxacin may provide
a potential beneficial alternative to existing intra-
venously administered antibacterial combinations
(e.g. a p-Iactam plus an aminoglycoside) during the
3 to 4 week therapy often necessary for Gram-ne-
gative pneumonia; results of comparative assess-
ments, and further trials involving the intravenous
dosage form of ciprofloxacin, which could be used
as initial therapy in these infections, will be awaited
with interest.
In young adult patients with cystic fibrosis, suf-
fering from infectious respiratory exacerbations due
to chronically colonising P. aeruginosa, oral cip-
rofloxacin was at least equivalent in clinical effi-
cacy to the combination of intravenous azlocillin
plus an aminoglycoside. However, the frequency
with which transitory, or occasionally persistent,
resistance of P. aeruginosa to ciprofloxacin has
emerged in these patients demands care to prevent
the potential loss of efficacy of the quinolone. Thus,
in cystic fibrosis patients ciprofloxacin is not rec-
ommended for long term prophylaxis or for mul-
434
Table XVI. Strategies for use of ciprofloxacin in cystic fibrosis
(after Neu 1987)
• Do not use as long term outpatient therapy
• Use only against susceptible pathogens (MIC < 2 mg/L)
• Combine with another antipseudomonal antibacterial (e.g.
azlocillin) if MIC ~ 1 mg/L
• Alternate ciprofloxacin therapy with use of other
antibacterial therapies
tiple sequential courses of treatment in recurrent
infections. Proposed guidelines for the use of cip-
rofloxacin in cystic fibrosis are shown in table XVI.
Studies assessing the safety and efficacy of cipro-
floxacin in paediatric cystic fibrosis patients could
expand the utility of this important new antibac-
terial drug.
In skin and soft tissue infections ciprofloxacin
administered orally was at least as effective as an-
other broad spectrum antibacterial drug, cefotax-
ime, which is administered intravenously. How-
ever, ciprofloxacin bacterial eradication rates for
some Gram-positive species were unsatisfactory in
some open studies. Nonetheless, ciprofloxacin of-
fers an orally administered alternative to existing
therapies for decubitus ulcers, infected wounds and
abscesses, and other skin and soft tissue infections
due to Gram-negative species.
Ciprofloxacin also offers a potentially major ad-
vantage in the treatment of osteomyelitis due to
Gram-negative species. Intravenous therapy for os-
teomyelitis requires extended hospitalisation. If
controlled comparisons reveal equivalent efficacy
of ciprofloxacin with existing antibacterial regi-
mens, outpatient oral therapy with ciprofloxacin
will offer both convenience and cost-reduction
benefits (such as reduced pharmacy preparation and
nursing administration time, in addition to the cost
savings of shortened hospitalisations).
Single oral doses of ciprofloxacin achieved 100%
efficacy in the treatment of gonococcal urethritis,
including that due to {j-Iactamase-producing strains
of Neisseria gonorrhoeae. Ciprofloxacin prophy-
laxis decreased the rate of Gram-negative infection
in cancer patients undergoing remission induction
therapy, and the rate of postsurgical infection in
Ciprofloxacin: A Review
patients undergoing transurethral resection of the
prostate or urethrotomy; controlled comparisons
with standard antibacterial prophylaxis in these in-
dications will be awaited with interest.
Ciprofloxacin has been shown to be well toler-
ated. The incidence of superinfection and the de-
velopment of resistance appears to be quite low,
except where underlying pathology contributes,
such as in P. aeruginosa respiratory tract infections
in patients with underlying disease of the respira-
tory tract Nonetheless, due to the risk of emerg-
ence of resistant strains the use of ciprofloxacin is
not advised in uncomplicated UTI and other triv-
ial infections for which a number of established
effective antibacterials are already available (Hoiby
1986).
In conclusion, ciprofloxacin should prove to be
a valuable broad spectrum, orally administered
antibacterial drug for use in a wide range of clinical
infections, having particular usefulness in difficult
infections due to multiresistant pathogens or in in-
fections which can only be treated at present with
intravenously administered antibacterial drugs.
References
Aigner KR, Dalhoff A. Penetration activities ofciprofloxacin into
muscle, skin and fat following oral administration. Journal of
Antimicrobial Chemotherapy 18: 644-645, 1986
Aldridge KE, Janney A, Sanders CV. Comparison of the activities
of coumermycin, ciprofloxacin, teicoplanin, and other non p-
lactam-antibiotics against clinical isolates of methicillin-resist-
ant Staphylococcus aureus from various geographical loca-
tions. Antimicrobial Agents and Chemotherapy 28: 634-638,
1985a
Aldridge KE, Schiro DD, Tsai L, Janney A, Sanders CV, et at.
Ciprofloxacin (Bay 0 9867): an in vitro comparison with other
broad spectrum antibiotics. Current Therapeutic Research 37:
754-762, 1985b
Alfaham M, Holt ME, Goodchild Me. Arthropathy in a patient
with cystic fibrosis taking ciprofloxacin. British Medical Jour-
nal 295: 699, 1987
Aoki FY, Conly JM, Hoban D, McLeod J, Chubb H, et al. Phar-
macokinetics of ciprofloxacin and effect of ciprofloxacin on
the fecal flora in volunteers on a vitamin Kr-deficient diet.
Proceedings of the 24th Interscience Conference on Antimi-
crobial Agents and Chemotherapy, abstract no. 765, Washing-
ton n.c., USA, 1984
Appelbaum PC, Spangler SK, Sollenberger L. Susceptibility of non-
fermentative Gram-negative bacteria to ciprofloxacin, norflox-
acin, amifloxacin, pefloxacin and cefpirome. Journal of Anti-
microbial Chemotherapy 18: 675-679, 1986
Arcieri G, August R, Becker N, Doyle C, Griffith E, et at. Clinical
experience with ciprofloxacin in the USA. European Journal
of Clinical Microbiology 5: 220-225, 1986 .
435
Arcieri G, et at. Ciprofloxacin: an update on clinical experience.
American Journal of Medicine 82 (Suppl. 4A): 381-386, 1987
Aronoff GE, Kenner CH, Sloan RS, Pottratz ST. Multiple-dose
ciprofloxacin kinetics in normal subjects. Clinical Pharmacol-
ogy and Therapeutics 36: 384-388 1984
Arya OP, Hobson D, Hart CA, Bartzokas C, Pratt Be. Evaluation
of ciprofloxacin 500mg twice daily for one week in treating
uncomplicated gonococcal, chlamydial, and non-specific ur-
ethritis in men. Genitourinary Medicine 62: 170-174, 1986
Auckenthaler R, Michea-Hamzehpour M, Pechere Je. In-vitro ac-
tivity of newer quinolones against aerobic bacteria. Journal of
Antimicrobial Chemotherapy 17 (Suppl. B): 29-39, 1986
Azadian BS, Bendig JWA, Samson DM. Emergence of ciproflox-
acin-resistant Pseudomonas aeruginosa after combined therapy
with ciprofloxacin and amikacin. Journal of Antimicrobial
Chemotherapy 18: 771, 1986
Aznar J, Prados R, Rodriguez Pichardo A, Hernandez I, De Mig-
uel C, et al. Comparative clinical efficacy of two different single-
dose ciprofloxacin treatments for uncomplicated gonorrhea.
Sexually Transmitted Diseases 13: 169-171, 1986
Aznar J, Caballero MC, Lozano MC, de Miguel C, Palomares JC,
et al. Activities of new quinolone derivatives against genital
pathogens. Antimicrobial Agents and Chemotherapy 27: 76-
78, 1985
Baba S. Clinical evaluation of ciprofloxacin in the fields of sur-
gery, obstetrics and gynecology, dermatology, otorhinolaryn-
gologyand ophthalmology. Proceedings of the 14th Interna-
tional Congress of Chemotherapy, Kyoto, Japan, Jun, 1985
Baba S, Kinoshita H, Mori Y, Suzuki K, Shimada J, et al. Com-
parative study of ciprofloxacin (Bay 0 9867) and norfloxacin
in the treatment of acute lacunar tonsillitis. JIBI (Ear and Nose)
33: 312-336, 1987
Ball AP, Fox C, Ball ME, Brown IRF, Willis JV. Pharmacokin-
etics of oral ciprofloxacin, lOOmg single dose, in volunteers
and elderly patients. Journal of Antimicrobial Chemotherapy
17: 629-635, 1986
Ball AP. Ciprofloxacin: an overview of adverse experiences. Jour-
nal of Antimicrobial Chemotherapy 18 (Suppl, D): 187-193,
1986
Bamberger OM, Peterson LR, Gerding ON, Moody JA, Fasching
CEo Ciprofloxacin, azlocillin, ceftizoxime and amikacin alone
and in combination against Gram-negative bacilli in an in-
fected chamber model. Journal of Antimicrobial Chemother-
apy 18: 51-63, 1986
Banerjee OK. Ciprofloxacin (4-quinolone) and Mycobacterium le-
prae. Leprosy Reviews 57: 159-162, 1986
Bantz P-M, Grote J, Peters-Haertel W, Stahmann J, Timm J, et
at. Low-dose ciprofloxacin in respiratory tract infections. A
randomized comparison with doxycycline in general practice.
American Journal of Medicine 82 (Suppl. 4A): 208-210, 1987
Barry AL, Jones RN. Cross-resistance among cinoxacin, cipro-
floxacin, DJ-6783, enoxacin, nalidixic acid, norfloxacin, and
oxolinic acid after in vitro selection of resistant populations.
Antimicrobial Agents and Chemotherapy 25: 775-777, 1984
Barry AL, Jones RN, ThornsberryC, Ayers LW, Gerlach EH, et
al. Antibacterial activities of ciprofloxacin, Iiorfloxacin, oxo-
linic acid, cinoxacin, and nalidixic acid. Antimicrobial Agents
and Chemotherapy 25: 633-637, 1984
Bayer AS, Blomquist IK, Kim KS. Ciprofloxacin in experimental
aortic valve endocarditis due to Pseudomonas aeruginosa.
Journal of Antimicrobial Chemotherapy 17: 641-649, 1986a
Bayer AS, Kim KS. In vivo efficacy of azlocillin and amikacin
versus ciprofloxacin with and without amikacin in experimen-
tal right-sided endocarditis due to Pseudomonas aeruginosa.
Chemotherapy 32: 364-373, 1986
Bayer AS, Lindsay P, YihJ, Hirano L, Lee 0, Blomquist IK.
Efficacy of ciprofloxacin in experimental aortic valve endo-
carditis caused by a multiply-d-lactam-resistant variant of
Pseudomonas aeruginosa stably derepressed for p-Iactamase
Ciprofloxacin: A Review
production. Antimicrobial Agents and Chemotherapy 30: 528-
531, 1986b
Bayer AS, Norman DC, Blomquist IK. Comparative efficacy of
ciprofloxacin and ceftriaxone in experimental arthritis caused
by Escherichia coli. Antimicrobial Agents and Chemotherapy
30: 184-186, 1986c
Bayer AS, Norman D, Anderson D. Efficacy of ciprofloxacin in
experimental arthritis caused by Escherichia coli - in vitro and
in vivo correlations. Journal of Infectious Diseases 152: 811-
816, 1985
Bayer A, Gajewska A, Stephens M, Marshal-Stark J, Pathy J.
Pharmacokinetics of ciprofloxacin in the elderly. Respiration
51: 292-295, 1987
Beermann D, Wingender W, Horstmann R. Intravenous infusion
regimen for rapidly achieving steady-state levels of ciproflox-
acin. American Journal of Medicine 82 (Suppl, 4A): 360-362,
1987
Beermann D, Scholl H, Wingender W, Forster D, Beubler E, et
al. Metabolism of ciprofloxacin in man. In Neu HC & Weuta
H (Eds) 1st International Ciprofloxacin Workshop, Leverku-
sen 1985, pp. 141-146, Excerpta Medica, Amsterdam, 1986
Behrens-Baumann W, Martell J. Ciprofloxacin concentrations in
human aqueous humor following intravenous administration.
Chemotherapy (Basel) 33: 328-330, 1987
Bender SW, Dalhoff A, Shah PM, Strehl R, Posselt HG. Cipro-
floxacin pharmacokinetics in patients with cystic fibrosis. In-
fection 14: 17-21, 1986
Bendig JW A, Kyle PW, Giangrande PLF, Samson DM, Azadian
BS. Two neutropenic patients with multiple resistant Pseu-
domonas aeruginosa septicaemia treated with ciprofloxacin.
Journal of the Royal Society of Medicine 80: 316-317, 1987
Bergan T, Delin C, Johansen S, Kolstad 1M, Nord CE, et al. Phar-
macokinetics of ciprofloxacin and effect of repeated dosage on
salivary and fecal microflora. Antimicrobial Agents and
Chemotherapy 29: 298-302, 1986a
Bergan T, Engeset A, Olszewski W, Ostby N, Solberg R. Phar-
macokinetics of ciprofloxacin in peripheral lymph and skin
blisters. European Journal of Clinical Microbiology 5: 458-461,
1986b
Bergan T, Thorsteinsson SB, Kolstaad 1M, Johansen S. Phar-
macokinetics of ciprofloxacin and increasing oral doses. Euro-
pean Journal of Clinical Microbiology 5: 187-192, 1986c
Bergan T, Thorsteinsson SB, Solberg R, Bjornskou L, Kolstad 1M,
et al. Pharmacokinetics of ciprofloxacin: intravenous and in-
creasing oral doses. American Journal of Medicine 82 (Suppl.
4A): 97-102, 1987
Bergogne-Berezin E, Berthelot G, Even P, Stem M, Reynaud P.
Penetration of ciprofloxacin into bronchial secretions. Euro-
pean Journal of Clinical Microbiology 5: 197-200, 1986
Blaser J, Dudley MN, Gilbert D, Zinner SH. Influence of medium
and method on the in vitro susceptibility of Pseudomonas
aeruginosa and other bacteria to ciprofloxacin and enoxacin.
Antimicrobial Agents and Chemotherapy 29: 927-929, 1986
Boelaert J, Valcke Y, Schurgers M, Daneels R, Rosseneu M, et
al. The pharmacokinetics of ciprofloxacin in patients with im-
paired renal function. Journal of Antimicrobial Chemotherapy
16: 87-93, 1985
Boerema JBJ, Dalhoff A, Debruyne FMY. Ciprofloxacin distri-
bution in prostatic tissue and fluid following oral administra-
tion. Chemotherapy 31: 13-18, 1985a
Boerema J, Boll B, Muytjens H, Branolte J. Efficacy and safety
of ciprofloxacin (Bay 0 9867) in the treatment of patients with
complicated urinary tract infections. Journal of Antimicrobial
Chemotherapy 16: 211-217, 1985b
Bomer K, Lode H, Hoffken G. Renal elimination of sulpho-cip-
rofloxacin, a new metabolite of ciprofloxacin. European Jour-
nal of Clinical Microbiology 5: 476, 1986
Borobio MV, Perea EJ. Effect of inoculum, pH, and medium on
436
the activity of ciprofloxacin against anaerobic bacteria. Anti-
microbial Agents and Chemotherapy 25: 342-343, 1984
Bosch J, Linares J, Lopez de Goicoechea MJ, Ariza J, Cisnal MC,
et al. In-vitro activity of ciprofloxacin, ceftriaxone and five other
antimicrobial agents against 95 strains of Brucella melitensis.
Journal of Antimicrobial Chemotherapy 17: 459-461, 1986
Bosso JA, Black PG. Efficacy of ciprofloxacin in adults with cystic
fibrosis (Abstract No. 30). Drug Intelligence and Clinical Phar-
macy 21: 8A, 1987
Bosso JA, Black PG, Matsen JM. Ciprofloxacin versus tobra-
mycin plus azlocillin in pulmonary exacerbations in adult
patients with cystic fibrosis. American Journal of Medicine 82
(Suppl. 4A): 180-184, 1987
Brittain DC, Scully BE, McElrath MJ, Steinman R, Labthavikul
P, et al. The pharmacokinetics and serum and urine bacteri-
cidal activity of ciprofloxacin. Journal of Clinical Pharmacol-
ogy 25: 82-88, 1985
Brown EM, Morris R, Stephenson TP. Efficacy and safety of cip-
rofloxacin in the treatment of chronic Pseudomonas aerugin-
osa urinary tract infection. Journal of Antimicrobial Chemo-
therapy 18 (Suppl. D): 123-127, 1986
Brumfitt W, Franklin I, Grady D, Hamilton-Miller JMT, Iliffe
A. Changes in the pharmacokinetics of ciprofloxacin and fecal
flora during administration of a 7-day course to human volun-
teers. Antimicrobial Agents and Chemotherapy 26: 757-761,
1984
Brunner H, Zeiler H-J, Luckhaus G. Efficacy of ciprofloxacin in
experimental Mycoplasma pneumoniae infection of hamsters.
Abstract no. 272 of the 24th Interscience Conference on Anti-
microbial Agents and Chemotherapy, Washington D.e., USA,
1984
Bruns BJ, Wallace MR. Treatment of Salmonella typhimurium
infection in a renal transplant patient with ciprofloxacin. New
Zealand Medical Journal 100: 190, 1987
Bryant RE, Harstein AI. Oral ciprofloxacin in refractory gram-
negative bacillary infections. International Journal of Clinical
Pharmacology Research 7: 187-194, 1987
Carmona 0, Hernandez-Gonzalez S, Kobelt R. Ciprofloxacin in
the treatment of nonspecific vaginitis. American Journal of
Medicine 82 (Suppl. 4A): 321-323, 1987
Carpenter TC, Hackbarth CJ, Chambers HF, Sande MA. Efficacy
of ciprofloxacin for experimental endocarditis caused by meth-
icillin-susceptible or -resistant strains of Staphylococcus au-
reus. Antimicrobial Agents and Chemotherapy 30: 382-384,
1986
Casal M, Rodriguez F, Villalba R, Benavente MC, Gonzalez AI.
In vitro susceptibility of Mycobacterium fortuitum, Mycobac-
terium chelonae and Mycobacterium avium against some quin-
olones. Chemioterapia 6: 431-433, 1987
Chapman ST, Speller DCE, Reeves DS. Resistance to ciproflox-
acin. Lancet 2: 39, 1985
Chau PY, Leung YK, Ng WS. Comparative in vitro antibacterial
activity of ofloxacin and ciprofloxacin against some selected
Gram-positive and Gram-negative isolates. Infection 14 (Suppl,
4): 237-239, 1986
Chin NX, Jules K, Neu He. Synergy of ciprofloxacin and azlo-
cillin in vitro and in a neutropenic mouse model of infection.
European Journal of Clinical Microbiology 5: 23-28, 1986
Chin N-X, Neu He. Ciprofloxacin, a qui no lone carboxylic acid
compound active against aerobic and anaerobic bacteria. Anti-
microbial Agents and Chemotherapy 25: 319-326, 1984
Chin N-X, Neu He. Post-antibiotic suppressive effect of cipro-
floxacin against Gram-positive and Gram-negative bacteria.
American Journal of Medicine 82: 58-62, 1987a
Chin N-X, Neu He. Synergy ofimipenem - a novel carbapenem,
and rifampin and ciprofloxacin against Pseudomonas aerugin-
osa, Serratia marcescens and Enterobacter species. Chemo-
therapy 33: 183-188, 1987b •
Chow AW, Cheng N, Bartlett KH. In vitro susceptibility of Clos-
Ciprofloxacin: A Review
tridium difficile to new p-Iactam and quinolone antibiotics.
Antimicrobial Agents and Chemotherapy 28: 842-844, 1985
Cohen J, McConnell JS. Antibiotic-induced endotoxin release.
Lancet 2: 1069-1070, 1985
Cohen J, McConnell JS. Release of endotoxin from bacteria ex-
posed to ciprofloxacin and its prevention with polymyxin B.
European Journal of Clinical Microbiology 5: 13-17, 1986
Collins CH, Uttley He. In-vitro susceptibility of mycobacteria to
ciprofloxacin. Journal of Antimicrobial Chemotherapy 16: 575-
580, 1985
Collins MS, Hector RF, Roby RE, Edwards AA, Ladehoff DK,
Dorsey JH. Prophylaxis of gram-negative and gram-positive
infections in rodents with 3 intravenous immunoglobulins and
therapy of experimental polymicrobial burn wound sepsis with
pseudomonas immunoglobulin and ciprofloxacin. Infection 15
(Suppl. 2): 51-59, 1987
Connolly MJ, Snow MH, Ingham HR. Ciprofloxacin treatment
of recurrent Salmonella typhimurium septicaemia in a patient
with acquired immune deficiency syndrome. Journal of Anti-
microbial Chemotherapy 18: 647-648, 1986
Cornaglia G, Pompei R, Dainelli B, Satta G. In vitro activity of
ciprofloxacin against aerobic bacterial isolated in a Southern
European hospital. Antimicrobial Agents and Chemotherapy
31: 1651-1655, 1987
Courvalin P, Derlot E, Chabbert YA. Cross resistance to quino-
lone derivatives of Enterobacteriaceae and Pseudomonas mu-
tants selected on pefloxacin and ciprofloxacin, Abstract 40 I
presented at the 24th Interscience Conference on Antimicrob-
ial Agents and Chemotherapy, Washington, USA, 1984
Cox CEo Comparative study of three dosage regimens of cipro-
floxacin in the treatment of urinary tract infections. In Neu
HC & Weuta H (Eds) 1st International Ciprofloxacin Work-
shop, Leverkusen, 1985, pp. 291-296, Excerpta Medica, Am-
sterdam, 1986
Cox e. Brief report: ciprofloxacin in the treatment of urinary tract
infections caused by Pseudomonas species and organisms re-
sistant to trimethoprim/sulfamethoxazole. American Journal
of Medicine 82 (Suppl. 4A): 228-229, 1987
Crook SM, Selkon JB, McLardy Smith PD. Clinical resistance to
long-term oral ciprofloxacin. Lancet I: 1275, 1985
Cullmann W, Stieglitz M, Baars B, Opferkuch W. Comparative
evaluation of recently developed quinolone compounds - with
a note on the frequency of resistant mutants. Chemotherapy
31: 19-28, 1985
Dan M, Verbin N, Gorea A, Nagar H, Berger SA. Concentrations
of ciprofloxacin in human liver, gallbladder and bile after oral
administration. European Journal of Clinical Pharmacology 32:
217-218, 1987
Daschner FD, Westenfelder M, Dalhoff A. Penetration of cip-
rofloxacin into kidney, fat, muscle and skin tissue. European
Journal of Clinical Microbiology 5: 212-213, 1986
Davies BI, Maesen FPV. Respiratory infections: clinical experi-
ences with the new quinolones. Pharmaceutisch Weekblad Sci-
entific Edition 9 (SuppI.): 53-57, 1987
Davies GSR, Cohen J. In-vitro study of the activity of ciproflox-
acin alone and in combination against strains of Pseudomonas
aeruginosa with multiple antibiotic resistance. Journal of Anti-
microbial Chemotherapy 16: 713-717, 1985
Davies S, Sparham PD, Spencer Re. Comparative in-vitro activ-
ity of five fluoroquinolones against mycobacteria. Journal of
Antimicrobial Chemotherapy 19: 605-609, 1987
Davis RL, Koup JR, Williams-Warren J, Weber A, Heggen L, et
al. Pharmacokinetics of ciprofloxacin in cystic fibrosis. Anti-
microbial Agents and Chemotherapy 31: 915-919, 1987
De Lalla F, Rizzardini G, Angelucci B. Oral ciprofloxacin in the
treatment of uncomplicated gonococcal urethritis in men.
Chemioterapia 6: 50-51, 1987
Dekker AW, Rozenberg-Arska M, Verhoeff J. Infection prophy-
laxis in acute leukemia: a comparison of ciprofloxacin with
437
trimethoprim-sulfamethoxazole and colistin. Annals of Inter-
nal Medicine 106: 7-12, 1987
Delfino D, Bonina L, Berlinghieri MC, Mastroeni P. Effects of a
new quinolone derivative, ciprofloxacin, on some professional
phagocytic cell functions. Chemioterapia 4: 463-466, 1985
Delmee M, Avesani V. Comparative in vitro activity of seven
quinolones against 100 clinical isolates of Clostridium difficile.
Antimicrobial Agents and Chemotherapy 29: 374-375, 1986
Dennig D, Hille H, Hellriegel KP. Chemoprophylaxis of bacterial
infections in granulocytopenic patients with ciprofloxacin. On-
kologie 10: 57-58, 1987
De Vries-Hospers HG, Welling GW, Van der Waaij D. Influence
ofquinolones on throat- and faecal flora of healthy volunteers.
Pharmaceutisch Weekblad Scientific Edition 9 (Suppl.): 41-44,
1987
De Witte T, Novakova I, Branolte J, Muytjens H, De Pauw B.
Long-term oral ciprofloxacin for infection prophylaxis in al-
logenic bone marrow transplantation. Pharmaceutisch Week-
blad Scientific Edition 9 (Suppl.): 48-50, 1987
Digranes A, Dibb WL, Benonisen E. In vitro activities of cipro-
floxacin, ofloxacin, norfloxacin and rosoxacin compared with
cinoxacin and trimethoprim. Chemotherapy 31: 466-471, 1985
Digranes A. In vitro activity of amifloxacin (WIN 49 375) com-
pared with those of ciprofloxacin and ofloxacin. Acta Path-
ologica, Microbiologica et Immunologica Scandinavica section
B 95: 29-32, 1987
Diridl G, Pichler H, Wolf D. Treatment of chronic salmonella
carriers with ciprofloxacin. European Journal of Clinical
Microbiology 5: 260-261, 1986
Dirksen MSC, Vree TB. Pharmacokinetics of intravenously ad-
ministered ciprofloxacin in intensive care patients with acute
renal failure. Pharmaceutisch Weekblad - Scientific Edition 8:
35-39, 1986
Domagala JM, Hanna LD, Heifetz CL, Hutt MP, Mich TF, et aI.
New structure-activity relationships of the quinolone antibac-
terials using the target enzyme: the development and appli-
cation of a DNA gyrase assay. Journal of Medicinal Chemistry
29: 394-404, 1986
Drusano GL. An overview ofthe pharmacology of intravenously
administered ciprofloxacin, American Journal of Medicine 82
(SuppI. 4A): 339-345, 1987
Drusano GL, Plaisance KI, Forrest A, Standiford He. Dose rang-
ing study and constant infusion evaluation of ciprofloxacin.
Antimicrobial Agents and Chemotherapy 30: 440-443, 1986a
Drusano GL, Standiford HC, Plaisance K, Forrest A, Leslie J, et
aI. Absolute oral bioavailability of ciprofloxacin. Antimicrob-
ial Agents and Chemotherapy 30: 444-446, 1986b
Drusano GL, Weir M, Forrest A, Plaisance K, Emm T, et at
Pharmacokinetics of intravenously administered ciprofloxacin
in patients with various degrees of renal function. Antimi-
crobial Agents and Chemotherapy 31: 860-864, 1987
Dudley MN, Ericson J, Zinner SH. Effect of dose on serum phar-
macokinetics of intravenous ciprofloxcin with identification
and characterization of extravascular compartments using
noncompartmental and compartmental pharrnacokinetic
models. Antimicrobial Agents and Chemotherapy 31: 1782-
1786, 1987
Duncker D, Ullmann U. Influence of various antimicrobial agents
on the chemiluminescence of phagocytosing human granulo-
cytes. Chemotherapy 32: 18-24, 1986
Easmon CSF, Blowers A. Ciprofloxacin treatment of systemic in-
fection in sensitive and resistant mice. Journal of Antimicrob-
ial Chemotherapy 16: 615-519, 1985
Easmon CSF, Crane JP, Blowers A. Effect of ciprofloxacin on
intracellular organisms: in-vitro and in-vivo studies. Journal of
Antimicrobial Chemotherapy 18 (Suppl. D): 43-48, 1986
Easmon CSF, Crane JP. Uptake of ciprofloxacin by human neu-
trophils. Journal of Antimicrobial Chemotherapy 16: 67-73,
1985
Ciprofloxacin: A Review
Easmon CSF. Protective effectsof ciprofloxacin in a murine model
of salmonella infection. American Journal of Medicine 82
(Suppt. 4A): 71-72, 1987
Edlund C, Nord Ee. Comparative in vitro activities of ciproflox-
acin, enoxacin, norfloxacin, ofloxacin and pefloxacin against
Bacteroides fragilis and Clostridium dijJicile. Scandinavian
Journal of Infectious Diseases 18: 149-151, 1986
Efstratiou E, Sahin A, Giamarellou H. In vitro studies with BAY
09867 a nalidixic acid analogue. Proceedings of the 13th Inter-
national Congress of Chemotherapy, Vienna, part 112, pp. 9-
12,1983
Eliopoulos GM, Gardella A, Moellering RC. In vitro activity of
ciprofloxacin, a new carboxyquinolone antimicrobial agent.
Antimicrobial Agents and Chemotherapy 25: 331-335, 1984
Ericsson CD, Johnson PC, Dupont HL, Morgan DR, Bittsra JAM,
et at. Ciprofloxacin or trimethoprim-sulphamethoxazole, as in-
itial therapy for travelers' diarrhea. Annals of Internal Medi-
cine 106: 216-220, 1987
Eron U, Harvey L, Hixon DL, Poretz DM. Ciprofloxacin therapy
of infections caused by Pseudomonas aeruginosa and other re-
sistant bacteria. Antimicrobial Agents and Chemotherapy 27:
308-310, 1985
Escalante A, Aznar J, De Miguel C, Perea EJ. Activity of nine
antimicrobial agents against Mycoplasma hominis and Urea-
plasma urealyticum. European Journal of Sexually Transmit-
ted Diseases 2: 85-87, 1985
Esposito S, Galante D, Barba D, D'errico G, Mazzone A, et at.
Ciprofloxacin concentrations in human fluids and tissues fol-
lowing a single oral dose. International Journal of Pharma-
ceutical Research VII: 181-186, 1987a
Esposito S, Gupta A, Thadepalli H. In vitro synergy of ciproflox-
acin and three other antibiotics against Bacteroides fragilis.
Drugs Under Experimental and Clinical Research 8: 489-492,
1987b
Eykyn SJ, Williams H. Treatment of multiresistant Salmonella
typhi with oral ciprofloxacin. Lancet 2: 1407-1408, 1987
Fass RJ. Efficacy and safety of oral ciprofloxacin for treatment
of serious urinary tract infections. Antimicrobial Agents and
Chemotherapy 31: 148-150, 1987a
Fass RJ. Efficacy and safety of oral ciprofloxacin in the treatment
of serious respiratory infections. American Journal of Medi-
cine 82 (Suppl. 4A): 202-207, 1987b
Fass RJ. Treatment of skin and soft tissue infections with oral
ciprofloxacin. Journal of Antimicrobial Chemotherapy 18
(Suppl. D): 153-157, 1986
Fass RJ. In vitro activity of ciprofloxacin (Bay 0 9867). Anti-
microbial Agents and Chemotherapy 24: 568-574, 1983
Feist H, Vetter N, Dr1icek M, Otupa I, Weuta H. Comparative
study of ciprofloxacin and cefalexin in the treatment of patients
with lower respiratory tract infections. In Neu HC & Weuta
H (Eds) Proceedings of the 1st International Ciprofloxacin
Workshop, Leverkusen, 1985, pp, 265-267, Excerpta Medica,
Amsterdam 1986
Felmingham D, O'Hare MD, Robbins MJ, Wall RA, Williams
AH, et at. Comparative in vitro studies with 4-quinolone anti-
microbials. Drugs in Experimental Clinical Research 11: 317-
329, 1985
Fenlon CH, Cynamon MH. Comparative in vitro activities ofcip-
rofloxacin and other 4-quinolones against Mycobacterium tu-
berculosis and Mycobacterium intracellulare. Antimicrobial
Agents and Chemotherapy 29: 386-388, 1986
Fern AI, Sweeney G, Doig M, Lindsay G. Penetration of cipro-
floxacin into aqueous humor. Transactions of the Ophthal-
mological societies ofthe United Kingdom 105: 650-652, 1986
Fernandez-Guerrero ML, Rouse MS, Henry NK, Wilson WR.
Ciprofloxacin treatment of methicillin-sensitive or methicillin-
resistant Staphylococcus aureus experimental endocarditis. 14th
International Congress of Chemotherapy, abstract no. 32-39,
Kyoto, Japan, 1985
438
Fernandez-Roblas R, Prieto S, Santamaria M, Ponte C, Soriano
F. Activity of nine antimicrobial agents against Corynebacte-
rium Group D2 strains isolated from clinical specimens and
skin. Antimicrobial Agents and Chemotherapy 31: 821-822,
1987
Fietta A, Sacchi F, Bersani C, Grassi F, Mangiarotti P, et at. Effect
of ,B-Iactam antibiotics on migration and bactericidal activity
of human phagocytes. Antimicrobial Agents and Chemother-
apy 23: 930-931, 1983
Fitzgeorge RB, Gibson DH, Jepras R, Baskerville A. Studies on
ciprofloxacin therapy of experimental Legionnaires' disease.
JournalofInfection 10: 194-203, 1985
Fleming LW, Moreland TA, Scott AC, Stewart WK, White LO.
Ciprofloxacin in plasma and peritoneal dialysate after oral
therapy in patients on continuous ambulatory peritoneal di-
alysis. Journal of Antimicrobial Chemotherapy 19: 493-503,
1987
Fliegelman RM, Petrak RM, Goodman U, Segreti J, Trenholme
GM, et at. Comparative in vitro activities of twelve antimi-
crobial agents against Campylobacter species. Antimicrobial
Agents and Chemotherapy 27: 429-430, 1985
Floyd-Reising SA, Kelley SG, Hind1er JA, Young LS. In vitro
activity ofCI-934 compared with ciprofloxacin, enoxacin, nor-
floxacin, and vancomycin. Diagnostic Microbiology and In-
fectious Disease 6: 301-306, 1987
Follath F, Bindschedler M, Wenk M, Frei R, Stalder H, et at. Use
of ciprofloxacin in the treatment of Pseudomonas aeruginosa
infections. European Journal of Clinical Microbiology 5: 236-
240, 1986
Fong IG, Ledbetter WH, Van den broucke C, Simbul M, Rahm
V. Ciprofloxacin concentrations in bone and muscle after oral
dosing. Antimicrobial Agents and Chemotherapy 29: 405-408,
1986
Fong IW, Linton W, Simbul M, Thorup R, McLaughlin B, et at.
Treatment of nongonococcal urethritis with ciprofloxacin.
American Journal of Medicine 82 (Suppl. 4A): 311-316, 1987
Forsgren A, Bergkvist PI. Effect of ciprofloxacin on phagocytosis.
European Journal of Clinical Microbiology 4: 575-578, 1985
Forsgren A, Bredberg A, Pardee AB, Schlossman SF, Tedder TF.
Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide
biosynthesis and cell growth. Antimicrobial Agents and
Chemotherapy 31: 774-779, 1987a
Forsgren A. Comparative in vitro activity of three new quinolone
antibiotics against recent clinical isolates. Scandinavian Jour-
nal of Infectious Diseases 17: 91-94, 1985
Forsgren A, Schlossman SF, Tedder TF. 4-quinolone drugs affect
cell cycle progression and function of human lymphocytes in
vitro. Antimicrobial Agents and Chemotherapy 31: 768-773,
1987b
Forsgren A, Schmeling D, Quie PG. Effect of tetracycline on the
phagocytic function of human leucocytes. Journal of Infectious
Diseases 130: 412-415, 1974
Fu KP, Vince T, Bloom R, Gregory FJ, Hung PP. Therapeutic
efficacy and pharmacokinetic properties of ciprofloxacin in
intra-abdominal abscesses caused by Bacteroides jragilis and
Escherichia coli. Drugs Under Experimental and Clinical Re-
search 8: 493-496, 1987
Fuursted K. Post-antibiotic effect and killing activity of cipro-
floxacin against Staphylococcus aureus. Acta Pathologica Mi-
crobiologica et Immunologica Scandinavica Section B -
Microbiology 95: 199-202, 1987
Garlando F, Rietiker S, Tauber MG, Flepp M, Meier B, et at.
Single-dose ciprofloxacin at 100 versus 250mg for treatment
of uncomplicated urinary tract infections in women. Antimi-
crobial Agents and Chemotherapy 31: 354-356, 1987
Garlando F, Tauber MG, Joos B, Oelz 0, Luthy R. Ciprofloxacin-
induced hematuria. Infection l3: 177-178, 1985 •
Gasser TC, Ebert SC, Graversen PH, Madsen PO. Ciprofloxacin
Ciprofloxacin: A Review
pharmacokinetics with normal and impaired renal function.
Antimicrobial Agents and Chemotherapy 31: 709·712, 1987a
Gasser TC, Graversen PH, Madsen PO. Treatment of compli-
cated urinary tract infections with ciprofloxacin. American
Journal of Medicine 82 (Suppl. 4A): 278-279, 1987b
Gau W, Kurz J, Petersen U, Ploschke HJ, Wuensche C. Isolation
and structural elucidation of urinary metabolites of ciproflox-
acin. Arzneimittel-Forschung 36: 1545-1549, 1986
Gay JD, DeYoung DR, Roberts GD. In vitro activities of nor-
floxacin and ciprofloxacin against Mycobacterium tuberculosis.
M. avium complex, M. chelonei, M. fortuitum, and M. ran-
sasii. Antimicrobial Agents and Chemotherapy 26: 94-96, 1984
Gellermann H-J. Therapy of lower respiratory tract infections with
ciprofloxacin [Therapie von unteren atemwegsinfektionen mit
ciprofloxacin]. Medizinische Welt 38: 69-72, 1987
Giamarellou H, Daphnis E, Galanakis N, Dendrinos Ch, Petrik-
kos G, et aJ. Ciprofloxacin in the treatment of Gram-negative
infections including Pseudomonas aeruginosa. Proceedings of
the 14th International Congress of Chemotherapy Kyoto, Ja-
pan, Jun, 1985
Giamarellou H, Galanakis N. Use of intravenous ciprofloxacin
in difficult-to-treat infections. American Journal of Medicine
82 (Suppl, 4A): 346-351, 1987
Giamarellou H, Galanakis N, Dendrinos C, Stefanou J, Daphnis
E, et al. Evaluation of ciprofloxacin in the treatment of Pseu-
domonas aeruginosa infections. European Journal of Clinical
Microbiology 5: 232-235, 1986
Giamarellou H, Petrikkos G. Ciprofloxacin interactions with im-
ipenem and amikacin against multiresistant Pseudomonas
aeruginosa. Antimicrobial Agents and Chemotherapy 31: 959-
961, 1987
Gilbert ON, Tice AD, Marsh PK, Craven PC, Preheim LC. Oral
ciprofloxacin therapy for chronic contiguous osteomyelitis
caused by aerobic Gram-negative bacilli. American Journal of
Medicine 82 (SuppJ. 4A): 254-258, 1987
Gleadhill IC, Ferguson WP, Lowry RC. Efficacy and safety of
ciprofloxacin in patients with respiratory tract infections in
comparison with amoxycillin. Journal of Antimicrobial
Chemotherapy 18 (Suppl. D): 133-138, 1986
Gobernado M, Canton E, Santos M. In vitro activity of cipro-
floxacin against Brucella melitensis. European Journal of
Clinical Microbiology 3: 371, 1984
Goldfarb J, Stern RC, Reed MD, Yamashita TS, Myers CM, et
aJ. Ciprofloxacin monotherapy for acute pulmonary exacer-
bations of cystic fibrosis. American Journal of Medicine 82
(Suppl. 4A): 174-179, 1987
Goldfarb J, Wormser GP, Inchiosa MA, Guideri G, Diaz M, et
aJ.Singledose pharmacokinetics of oral ciprofloxacin in patients
with cystic fibrosis. Journal of Clinical Pharmacology 26: 222-
226, 1986
Goldstein EJC, Kahn RM, Alpert ML, Ginsberg BP, Greenway
FI, et aJ. Ciprofloxacin versus cinoxacin in therapy of urinary
tract infections. American Journal of Medicine 82 (SuppJ. 4A):
284-287, 1987
Gollapudi SVS, Prabhala RH, Thadepalli H. Effect of ciproflox-
acin on mitogen-stimulated lymphocyte proliferation. Anti-
microbial Agents and Chemotherapy 29: 337-338, 1986
Golper TA, Hortsfein AI, Morthland VH, Christensen JM. Effects
of antacids and dialysate dwell times on multiple dose phar-
macokinetics of oral ciprofloxacin in patients on continuous
ambulatory peritoneal dialysis. Antimicrobial Agents and
Chemotherapy 31: 1787-1790,1987
Gombert ME, Aulicino TM. Comparison of agar dilution, mi-
crotitre broth dilution and tube macrodilution susceptibility
testing of ciprofloxacin against several pathogens at two dif-
ferent inocula. Journal of Antimicrobial Chemotherapy 16:709-
712, 1985
Gombert ME, Aulicino TM. Susceptibility of multiply antibiotic-
resistant pneumococci to the new quinolone antibiotics, nali-
439
dixie acid, coumermycin, and novobiocin. Antimicrobial Agents
and Chemotherapy 26: 933-934, 1984
Gonzalez MA, Moranchel AH, Duran S, Pichardo A, Magana JL,
et aJ. Multiple dose ciprofloxacin dose ranging and kinetics.
Clinical Pharmacology and Therapeutics 37: 633-637, 1985a
Gonzalez MA, Moranchel AH, Duran S, Pichardo A, Magana JL.
Multiple dose pharmacokinetics of ciprofloxacin administered
intravenously to normal volunteers. Antimicrobial Agents and
Chemotherapy 28: 235-239, 1985b
Goormans E, Dalhoff A, Kazzaz B, Branolte J. Penetration of
ciprofloxacin into gynecological tissues following oral and
intravenous administration. Chemotherapy 32: 7-77, 1986
Goosens H, De Mol P, Coignau H, Levy J, Grados 0, et al. Com-
parative in vitro activities of aztreonam, ciprofloxacin, nor-
floxacin, ofloxacin, HR 810 (a new cephalosporin), RU 28965
(a new macrolide), and other agents against enteropathogens.
Antimicrobial Agents and Chemotherapy 27: 388-392, 1985
Gordin PM, Hackbarth CJ, Scott KG, Sande MA. Activities of
pefloxacin and ciprofloxacin in experimentally induced Pseu-
domonas pneumonia in neutropenic guinea-pigs. Antimicrob-
ial Agents and Chemotherapy 27: 452-454, 1985
Grabe M, Forsgren A, Bjork T, Hellsen S. Controlled trial of a
short and a prolonged course with ciprofloxacin in patients
undergoing transurethral prostatic surgery. European Journal
of Clinical Microbiology 6: 11-17, 1987
Graeff H, Loos W, Hugo RV, Machka K, Fischbach F. Cipro-
floxacin in the treatment of patients with symptomatic and
asymptomatic urinary tract infections: a comparative study of
single dose application versus three days' treatment concerning
efficacy and safety (Abstract S-50-9) Proceedings of the 14th
International Congress of Chemotherapy, Kyoto, Japan, Jun,
1985
Greenberg RN, Kennedy DJ, Reilly PM, Luppen KL, Weinandt
WJ, et aJ. Treatment of bone, joint, and soft-tissue infections
with oral ciprofloxacin. Antimicrobial Agents and Chemo-
therapy 31: 151-155, 1987a
Greenberg RN, Tice AD, Marsh PK, Craven PC, Reilly PM, et
aJ. Randomized trial of ciprofloxacin compared with other
antimicrobial therapy in the treatment of osteomyelitis. Amer-
ican Journal of Medicine 82 (SuppJ. 4A): 266-269, 1987b
Guay DRP, Awni WM, Peterson PK, Obaid S, Breitenbucher R,
et aJ. Pharmacokinetics of ciprofloxacin in acutely ill and con-
valescent elderly patients. American Journal of Medicine 82
(Suppl, 14A): 124-129, 1987
Guay D, Klicker R, Pence T, Peterson P. In vitro antistaphylo-
coccal activity of teicoplanin and ciprofloxacin in peritoneal
dialysis effluent. European Journal of Clinical Microbiology 5:
661-663, 1986
Guelpa-Lauras C-C, Perani EG, Giroir A-M, Grosset JH. Activ-
ities of pefloxacin and ciprofloxacin against Mycobacterium le-
prae in the mouse. International Journal of Leprosy 55: 70-77,
1987
Hackbarth CJ, Chambers HF, Stella F, Shibl AM, Sande MA.
Ciprofloxacin in experimental Pseudomonas aeruginosa men-
ingitis in rabbits. Journal of Antimicrobial Chemotherapy 18
(Suppl, D): 65-69, 1986
Haller I. Comprehensive evaluation of ciprofloxacin - aminogly-
coside combinations against Enterobacteriaceae and Pseudo-
monas aeruginosa strains. Antimicrobial Agents and Chemo-
therapy 28: 663-666, 1985
Hara H, Saito A, Yamaguchi K, Suzuyama Y, Shigeno Y, Kohno
S, et aJ. Comparative study of Bay 09867 (ciprofloxacin) and
bacampicillin on bacterial pneumonia by double blind method.
Chemotherapy (Tokyo) 34: 629-653, 1986
Hart CA, How SJ, Hobson D. Activity of ciprofloxacin against
genital tract pathogens. British Journal of Venereal Diseases
60: 316-318, 1984
Haverkorn MJ. Ciprofloxacin for respiratory tract infection with
Ciprofloxacin: A Review
Pseudomonas aeruginosa. Pharmaceutisch Weekblad Scien-
tific Edition 9 (Suppl.): 64-67, 1987
Heise-Reinecker E, Ruschmeyer J, Rosenfeld M. Clinical efficacy
of ciprofloxacin in Salmonella carriers. In Neu HC & Weuta
H (Eds) Ist International Ciprofloxacin Workshop, Leverku-
sen, 1985, pp. 373-377, Excerpta Medica, Amsterdam, 1986
Henry NK, Rouse MS, Whitesell AL, McConnell ME, Wilson
WR. Treatment of methicillin-resistant staphylococcus aureus
experimental osteomyelitis with ciprofloxacin or vancomycin
alone or in combination with rifampin. American Journal of
Medicine 82: 73-75, 1987
Henry NK, Schultz HJ, Grubbs NC, Muller SM, I1stup DM, et
al. Comparison of ciprofloxacin and co-trimoxazole in the
treatment of uncomplicated urinary tract infection in women.
Journal of Antimicrobial Chemotherapy 18 (Suppl. D): 103-
106, 1986
Hodson ME, Roberts CM, Butland RJA, Smith MJ, Batten JC
Oral ciprofloxacin compared with conventional intravenous
treatment for Pseudomonasaeruginosa infection in adults with
cystic fibrosis. Lancet 1: 235-237, 1987
HofH, Pfannemuller B, Christen A. Therapeutic activities of cip-
rofloxacin on infection of mice with Listeria monocytogenes,
Salmonella typhimurium, Escherichia coli and Pseudomonas
aeruginosa. 2nd European Congress of Clinical Microbiology,
abstract no. 22/17, Brighton, England, 1985
Hoffken G, Borner K, Glatzel PD, Koeppe P, Lode H. Reduced
enteral absorption of ciprofloxacin in the presence of antacids.
European Journal of Clinical Microbiology 4: 345, 1985a
Hoffken G, Lode H, Prinzing C, Bomer K, Koeppe P. Phar-
macokinetics of ciprofloxacin after oral and parenteral admin-
istration. Antimicrobial Agents and Chemotherapy 27: 375-379,
1985b
Hoffken G, Lode H, Willey PD. Pharmacokinetics and interac-
tion in the bioavailability of new quinolones. Abstract from
Proceedings of the International Symposium on the New
Quinolones, Geneva, 1986
Hoffler U. In-vitro sensitivity of Bacteroidaceae, clostridia and
propionibacteria to newer antimicrobial agents. Journal of
Antimicrobial Chemotherapy 18 (Suppl. E): 41-46, 1986
Hoiby N. Clinical use of nalidixic acid analogues: the fluoro-
quinolones. European Journal of Clinical Microbiology 5: 138-
140, 1986
Holmes B, Brogden RN, Richards DM. Norfloxacin: a review of
its antibacterial activity, pharmacokinetic properties and ther-
apeutic use. Drugs 30: 482-513, 1985
Holt HA, Lewis DA, White LO, Bastable SY, Reeves DS. Effect
of oral ciprofloxacin on the faecal flora of healthy volunteers.
European Journal of Clinical Microbiology 5: 201-205, 1986
Honeybourne D, Wise R, Andrews JM. Ciprofloxacin penetration
into lungs. Lancet 2031: 1040, 1987
Hoogkamp-Korstanje JAA. Comparative in vitro activity of five
quinolone derivatives and five other antimicrobial agents used
in oral therapy. European Journal of Clinical Microbiology 3:
333-338, 1984
Hoogkamp-Korstanje JAA. Treatment of chronic postsurgical os-
teomyelitis with ciprofloxacin. Pharmaceutisch Weekblad Sci-
entific Edition 9 (Suppl.): 90-92, 1987
Hooper DC, Wolfson J5, Ng EY, Swartz MN. Mechanisms of
action of and resistance to ciprofloxacin. American Journal of
Medicine 82 (Suppl, 4A): 12-20, 1987
Houwen RHJ, Bijleveld CMA, DeVries-Hospers HG. Ciproflox-
acin for cholangitis after hepatic portoenterostomy. Lancet I:
1367, 1987
Hudson SJ, Ingham HR, Snow MH. Treatment of Salmonella
typhi carrier state with ciprofloxacin. Lancet I: 1047, 1985
Humphreys H, Mulvihill E. Ciprofloxacin-resistant Staphylococ-
cus aureus: Lancet I: 383, 1985
Iannello D, Delfino D, Carbone M, Fera M, Curo TF. In vitro
effects of cephalosporin and ampicillin on some human leu-
440
kocyte functions. Drugs in Experimental and Clinical Research
9: 67-71, 1983
Isaacs D, Slack MPE, Wilkinson AR, Westwood AW. Successful
treatment of pseudo mona I ventriculitis with ciprofloxacin.
Journal of Antimicrobial Chemotherapy 17: 535-538, 1986
Janknegt R. Fluorinated quinolones: a review of their mode of
action, antimicrobial activity, pharmacokinetics and clinical
efficacy. Pharmaceutisch Weekblad - Scientific Edition 8: 1-
21,1986
Jensen T, Pedersen SS, Neilsen CH, Heiby N, Koch C. Efficacy
and safety of ciprofloxacin and ofloxacin in chronic Pseudo-
monas aeruginosa infection in cystic fibrosis. Journal of Anti-
microbial Chemotherapy 20: 585-594, 1987
Joly-Guillou ML, Bergogne-Berezin E. In vitro activity of anti-
microbial agents against Acinetobacter calcoaceticus. Drugs in
Experimental Clinical Research 12: 949-952, 1986
Joos B, Ledergerber B, F1epp M, Betex JD, Luthy R, et al. Com-
parison of high liquid chromatography and bioassay for de-
termination of ciprofloxacin in serum and urine. Antimicrob-
ial Agents and Chemotherapy 27: 353-356, 1985
Jules K, Neu HC The efficacy of fluorinated carboxyquinolones
in protecting neutropenic mice from Pseudomonasaeruginosa.
24th Interscience Conference on Antimicrobial Agents and
Chemotherapy, p. 94, Washington D.C., USA, 1984
Kaatz GW, Barriere SL, Schaberg DR, Fekety R. Emergence of
resistance to ciprofloxacin during experimental Staphylococcus
aureus endocarditis, Journal of Antimicrobial Chemotherapy
20: 753-758, 1987b
Kaatz GW, Barriere SL, Schaberg DR, Fekety R. Ciprofloxacin
versus vancomycin in the therapy of experimental methicillin-
resistant Staphylococcus aureus endocarditis. Antimicrobial
Agents and Chemotherapy 31: 527-530, 1987a
Kamidono S, Arakawa S. Brief report: ciprofloxacin treatment of
complicated urinary tract infections. American Journal of
Medicine 82 (Suppl. 4A): 301-302, 1987
Kawamura S, Itabashi T, Watanabe H, Fujimaki Y, Horikawa H,
et aI. Comparative study of ciprofloxacin (Bay 0 9867) and
pipemidic acid in the treatment of suppurative otitis media.
JIBI. (Ear and Nose) 33: 100-125, 1987
Kayser FM. The quinolones: mode of action and mechanism of
resistance. Research and Clinical Forums 7: 17-27, 1985
Kelley SG, Bertram MA, Young LS. Activity of ciprofloxacin
against resistant clinical isolates. Journal of Antimicrobial
Chemotherapy 17: 281-286, 1986
Kemmerich B, Borner K, Pennington JE. Comparative efficacies
of ciprofloxacin, ampicillin and chloramphenicol in treatment
of experimental Haemophilus influenzae pneumonia. Journal
of Antimicrobial Chemotherapy 20: 77-83, 1987
Kemmerich B, Small GJ, Pennington JE. Comparative evaluation
of ciprofloxacin, enoxacin and ofloxacin in experimental Pseu-
domonas aeruginosa pneumonia. Antimicrobial Agents and
Chemotherapy 29: 395·399, 1986
Kiess W, Haas R, Marget W. Chloramphenicol-resistant Salmo-
nella tennesse osteomyelitis. Correspondence. Infection 12: 359,
1984
King A, Phillips I. The comparative in vitroactivity of eight newer
quinolones and nalidixic acid. Journal of Antimicrobial
Chemotherapy 18 (Suppl. D): 1-20, 1986
Klein E, Trautmann M, Hoffmann H-G. Ciprofloxacin in Sal-
monella infection and abdominal typhoid. Deutsche Medizin-
ische Wochenschrift Ill: 1599-1602, 1986
Klietmann W, Focht J, Nosner K. Comparative in vitro activity
of ciprofloxacin against aerobic and anaerobic bacteria from
clinical isolates. Arzneimittel-Forschung 37: 661-666, 1987
Knoche H, Glogau U, Enzensberger R; Schafer V, Kipp JP, et al.
Effect of oral ofloxacin on bowel flora in human volunteers.
(Abstract S 2/2) 2nd European Congress of Clinical Microbio-
logy, Brighton, 1985
Kobayashi H. Clinical efficacy of ciprofloxacin in the treatment
 Ciprofloxacin: A Review
of patients with respiratory tract infections in Japan. American
Journal of Medicine 82: 169-173, 1987
Kobayashi H. Summary of clinical studies on ciprofloxacin: ef-
ficacy and adverse reactions. Proceedings of the 14th Inter-
national Congress of Chemotherapy, Kyoto, Japan, Jun, 1985
Kobayashi H, Takamura H, Takeda H, Kono K, Saito A, et al.
Comparative clinical study of ciprofloxacin and cefaclor in the
treatment of respiratory tract infections. Chemotherapy (To-
kyo) 34: 1011-1037, 1986
Kosmidis J, Macrygiannis E, Aboudabash B. Ciprofloxacin in ur-
inary tract infections: its efficacy as compared with that of co-
trimoxazole. In Neu HC & Weuta H (Eds) lst International
Ciprofloxacin Workshop, Leverkusen, 1985, pp. 310-313, Ex-
cerpta Medica, Amsterdam, 1986
Krol GJ, Noe AJ, Beerman D. Liquid chromatographic analysis
of ciprofloxacin and ciprofloxacin metabolites in body fluids.
Journal of Liquid Chromatography 9: 2897-2919, 1986
Kumazawa J. Clinical evaluation of the use of ciprofloxacin in
urological infections. Presented at the 14th International Con-
gress of Chemotherapy, Kyoto, 1985
Kumazawa J, Matsumoto T, Tsuchida S, Niijima T, Machida T,
et al. Comparative clinical study of ciprofloxacin (Bay 0 9867)
and norfloxacin in the treatment of complicated urinary tract
infections. Nishinihon Journal of Urology 49: 1620-1622,1987
Kurz CC, Marget W, Harms K, Bertele RM. Crossover study on
the efficacy of oral ofloxacin and ciprofloxacin. Infection 14
(Suppl. 1): S82-S86, 1986
Lagast H, Husson M, Klastersky J. Bactericidal activity of cip-
rofloxacin in serum and urine against Escherichia coli. Pseu-
domonas aeruginosa, Klebsiella pneumoniae, Staphylococcus
aureus and Streptococcus faecalis. Journal of Antimicrobial
Chemotherapy 16: 341-347, 1985
leBel M, Barbeau G, Bergeron MG, Roy D, Vallee F. Phar-
macokinetics of ciprofloxacin in elderly subjects. Pharmaco-
therapy 6: 87-91, 1986a
leBel M, Bergeron MG, Vallee F, Fiset C, Chasse G, et al. Phar-
macokinetics and pharmacodynamics of ciprofloxacin in cystic
fibrosis patients. Antimicrobial Agents and Chemotherapy 30:
260-266, 1986c
leBel M, Vallee F, Bergeron MG. Tissue penetration of cipro-
floxacin after single and multiple doses. Antimicrobial Agents
and Chemotherapy 29: 501-505, 1986b
Ledergerber B, Bettex JD, Joos B, Flepp M, Luthy R. Effect of
standard breakfast on drug absorption and multiple-dose phar-
macokinetics of ciprofloxacin. Antimicrobial Agents and
Chemotherapy 27: 350-352, 1985
Lefrock JL, Smith BR, Bihl-Donato J. Ciprofloxacin: a compar-
ative study of in vitro antimicrobial activity. Current Thera-
peutic Research 39: 789-797, 1986
Leigh DA, Emmanuel FXS, Petch VJ. Ciprofloxacin therapy in
complicated urinary tract infections caused by Pseudomonas
aeruginosa and other resistant bacteria. Journal of Antimi-
crobial Chemotherapy 18 (Suppl. D): 117-121, 1986
Lesse AJ, Freer C, Salata RA, Francis 18, Scheid WM. Oral cip-
rofloxacin therapy for Gram-negative bacillary osteomyelitis.
American Journal of Medicine 82 (Suppl. 4A): 247-253, 1987
Levison ME, Pitsakis PG, Rosenberg AF. Comparison of the ef-
ficacy of ciprofloxacin, BMY-28142 and ceftazidime in therapy
of experimental Pseudomonas aeruginosa endocarditis in the
rat. 14th International Congress on Chemotherapy, abstract no.
S-32-8, Kyoto, Japan, 1985
Lewin CS, Smith JT. Detection of a third bacterial mechanism
of ciprofloxacin and ofloxacin. Journal of Pharmacy and
Pharmacology 38 (Suppl.): 44P, 1986
Licitra CM, Brooks RG, Siegler BE. Clinical efficacy and levels
of ciprofloxacin in tissue in patients with soft tissue infection.
Antimicrobial Agents and Chemotherapy 31: 805-807, 1987
Liebowitz LD, Saunders J, Fehler G, Ballard RC, Koornhof HJ.
In vitro activity of A-56619 (difloxacin), A-56620, and other
441
new quinolone antimicrobial agents against genital pathogens.
Antimicrobial Agents and Chemotherapy 30: 948-950, 1986
Limson BM. Efficacy and safety of ciprofloxacin in uncompli-
cated typhoid fever. In Neu HC & Weuta H (Eds) 1st Inter-
national Ciprofloxacin Workshop, Leverkusen 1985, pp. 362-
364, Excerpta Medica, Amsterdam, 1986
Lode H, Wiley R, Hoffken G, Wagner J, Borner K. Prospective
randomized controlled study of ciprofloxacin versus imipe-
nem-cilastatin in severe clinical infections. Antimicrobial Agents
and Chemotherapy 31: 1491-1496, 1987
Lonka L, Pedersen RS. Ciprofloxacin for cholangitis. Lancet 2:
212, 1987
Loo PS, Ridgway GL, Oriel JD. Single dose ciprofloxacin for
treating gonococcal infections in men. Genitourinary Medicine
61: 302-305, 1985
Luthy R, Joos B, Gassmann F. Penetration of ciprofloxacin into
the human eye. In Neu HC & Weuta H (Eds) 1st International
Ciprofloxacin Workshop, Leverkusen 1985, pp. 192-195, Ex-
cerpta Medica, Amsterdam 1986
Machka K, Milatovic D. Serum bactericidal activity of cipro-
floxacin and ofloxacin in volunteers. European Journal of
Clinical Microbiology 6: 59-62, 1987
Magnani C, Fregni S, Valli G, Cosentina R, Bisetti A. Compar-
ative clinical study of ciprofloxacin and co-trirnoxazole in res-
piratory tract infections. In Neu HC & Weuta H (Eds) lst
International Ciprofloxacin Workshop, Leverkusen, 1985, pp.
260-264, Excerpta Medica, Amsterdam, 1986
Manning M, Edison A, Gadebusch M. Inhibition of DNA gyrase
by norfloxacin and ten other quinolone carboxylic acids. Ab-
stract no. 979 presented at the 24th Interscience Conference
on Antimicrobial Agentsand Chemotherapy, Washington, USA,
8-10 Oct, 1984
Marinis E, Legakis NJ. In vitro activity of ciprofloxacin against
clinical isolates of mycobacteria resistant to antimycobacterial
drugs. Journal of Antimicrobial Chemotherapy 16: 527-530,
1985
McConnell JS, Cohen J. Release of endotoxin from Escherichia
coli by quinolones. Journal of Antimicrobial Chemotherapy
18: 765-773, 1986
McCormick EM, Echols RM. Effect of peritoneal dialysis fluid
and pH on bactericidal activity of ciprofloxacin. Antimicrobial
Agents and Chemotherapy 31: 657-659, 1987
McNulty CAM, Dent J, Wise R. Susceptibility of clinical isolates
of Campylobacter pyloridis to II antimicrobial agents. Anti-
microbial Agents and Chemotherapy 28: 837-838, 1985
Mehtar S, Blakemore PH, Ellis K. Brief report: In vivo curing of
plasmids from multi-drug-resistant Serratia marcescens by cip-
rofloxacin. American Journal of Medicine 82 (Suppl. 4A): 55-
57, 1987
Mehtar S, Drabu Y, Blakemore P. Ciprofloxacin in the treatment
of infections caused by gentamicin-resistant Gram-negative
bacteria. European Journal of Clinical Microbiology 5: 248-
251, 1986
Michalsen H, Stiris T, Bergan T. Peroral ciprofloxacin in the
treatment of infections with Pseudomonas aeruginosa in patients
with CF. Abstract. Proceedings of the 13th Annual Meeting of
the European Working Group for Cystic Fibrosis, Jerusalem,
3-8 Nov, 1985
Michea-Hamzepour M, Auckenthaler R, Regamey P, Pechere J-
e. Resistance occurring after fluoroquinolone therapy of ex-
perimental Pseudomonas aeruginosa peritonitis. Antimicrob-
ial Agents and Chemotherapy 31: 1803-1808, 1987
Michel-Briand Y, Uccelli V, Laporte J-M, Plesiat P. Elimination
of plasmids from Enterobacteriaceae by 4-quinolone deriva-
tives. Journal of Antimicrobial Chemotherapy 18:667-674, 1986
Millar MR, Bransby-Zachary MA, Tompkins DS, Hawkey PM,
Gibson RM. Ciprofloxacin for Pseudomonas aeruginosa men-
ingitis. Lancet 1: 1325, 1986
Monk JP, Campoli-Richards DM. Ofloxacin: a review of its anti-
Ciprofloxacin: A Review
bacterial activity, pharmacokinetic properties and therapeutic
use. Drugs 33: 346-391, 1987
Moody JA, Gerding DN, Peterson LR. Evaluation of ciproflox-
acin's synergism with other agents by multiple in vitro meth-
ods. American Journal of Medicine 82 (Suppl. 4A): 44-54, 1987
Moorhouse EC, Mulvihill TE, Jones L, Mooney D, Falkiner FR,
et al. The in-vitro activity of some antimicrobial agents against
methicillin-resistant Staphylococcus aureus. Journal of Anti-
microbial Chemotherapy 15: 291-295, 1985
Motohiro T, Aramaki M, Kawakami A, Tanaka K, Koga T, et
al. Effect of BAY 0 9867 (Ciprofloxacin), a new quinolone anti-
bacterial agent, on human fecal flora. Chemotherapy 33 (S7):
100-139, 1985
Mulligan ME, Ruane PJ, Johnston L, Wong P, Wheelock JP, et
al. Ciprofloxacin for eradication of methicillin-resistant Sta-
phylococcus aureus colonization. American Journal of Medi-
cine 82 (Suppl. 4A): 215-219, 1987
Murdoch DA, Badenoch DF. Oral ciprofloxacin as prophylaxis
for optical urethrectomy. British Journal of Urology 60: 352-
354, 1987
Murdoch DA, Badenoch DF, Gatchalian ER. Oral ciprofloxacin
prophylaxis in transurethral resection of the prostate. British
Journal of Urology 60: 153-156,1987
Murphy PG, Ferguson WP. Corynebacterium jeikeium (Group
JK) resistance to ciprofloxacin emerging during therapy. Jour-
nal of Antimicrobial Chemotherapy 20: 922-923, 1987
Muszynski MJ, Scribner RK, Lewis TD, Marks MI. Activity of
ciprofloxacin in combination with azlocillin against Pseudo-
monas aeruginosa. Abstract no. 1091 from the 25th Intersci-
ence Conference on Antimicrobial Agents and Chemotherapy,
Minneapolis, USA, Sep 29-0ct 2, 1985a
Muszynski MJ, Scribner RK, Marks MI. In vitro activity of cip-
rofloxacin, in combination with other antimicrobials, against
Pseudomonas aeruginosa isolates from patients with cystic fi-
brosis. Abstract no. A19 from American Society for Microbio-
logy 85th Annual Meeting, Las Vegas, USA, March 3-7, 1985b
Muytjens HL, van der Ros-van de Repe J, van Veldhuizen G.
Comparative activities of ciprofloxacin (Bay 0 9867), norflox-
acin, pipemidic acid, and nalidixic acid. Antimicrobial Agents
and Chemotherapy 24: 302-304, 1983
Naamara W, Plummer FA, Greenblatt RM, D'Costa U, Ndinya-
Achola U, et al. Treatment of chancroid with ciprofloxacin.
American Journal of Medicine 82 (Suppl. 4A): 317-320, 1987
Naber KG, Bartosik-Wich B. Ciprofloxacin versus norfloxacin in
the treatment of complicated urinary tract infections: in vitro
activity, serum and urine concentrations, safety and therapeu-
tic efficacy. In Neu HC & Weuta H (Eds) Ist International
Ciprofloxacin Workshop, Leverkusen 1985, pp. 314-317, Ex-
cerpta Medica, Amsterdam, 1986
NCCLS. Thornsberry C, et al. (Eds) Methods for dilution anti-
microbial susceptibility tests for bacteria that grow aerobically:
approved standard. National Committee for Clinical Labora-
tory Standards publication M7-A, Villanova Pa., NCCLS, 1985
Neu HC Ciprofloxacin: an overview and prospective appraisal.
American Journal of Medicine 82 (Suppl. 4A): 395-404, 1987
Neu HC, Kumada T, Chin N-X, Mandell W. The post-antibiotic
suppressive effect of quinolone agents. Drugs in Experimental
Clinical Research 13: 63-67, 1987
Newsom SWB, Murphy P, Matthews J. A comparative study of
ciprofloxacin and trimethoprim in the treatment of urinary tract
infections in geriatric patients. Journal of Antimicrobial
Chemotherapy 18 (Suppl, D): 111-115, 1986
Nilsson-Ehle I. Assay for ciprofloxacin and norfloxacin in serum
and urine by high performance liquid chromatography. Jour-
nal of Chromatography 416: 207-211, 1987
Nix DE, DeVito JM, Whitbread MA, Schentag JJ. Effect of mul-
tiple dose oral ciprofloxacin on the pharmacokinetics of theo-
phylline and in docyanine green. Journal of Clinical Pharma-
cology 26: 545, 1986
442
Nix DE, Sands MF, Peloquin CA, Vari AJ, Cumbo TJ, et al. Dual
individualization of intravenous ciprofloxacin in patients with
nosocomial lower respiratory tract infections. American Jour-
nal of Medicine 82 (Suppl>(A): 352-356, 1987
Nord CE, Delin C, Bergan T, Johansen S, Kolstad 1M, et al. The
effect of ciprofloxacin on oropharyngeal and colon microflora.
Research and Clinical Forum 7: 89-95, 1985
Norden CW, Shinners E. Ciprofloxacin as therapy for experi-
mental osteomyelitis caused by Pseudomonas aeruginosa.
Journal of Infectious Diseases 151: 291-294, 1985
Norden CW, Shinners E. Ciprofloxacin is effective therapy in
Pseudomonas aeruginosa experimental osteomyelitis. 24th In-
terscience Conference on Antimicrobial Agents and Chemo-
therapy, abstract no. 273, Washington D.C., USA, 1984
Ogawa K, Tabuchi E, Hirota J, Haraguchi K, Ohyama M. Effi-
cacy of ofloxacin and ciprofloxacin, new antimicrobial agents
of pyridone carboxylic acid derivative, on experimental sinus-
itis. 14th International Congress on Chemotherapy, abstract
no. S-48-11, Kyoto, Japan, 1985
Ooishi M, Sakaue F, Oomomo A, Yoneyama K. Fundamental
and clinical studies on Bay 09867 in ophthalmology. Chemo-
therapy (Tokyo) 33: 1014-1021, 1985
Overbeek BP, Rozenberg-Arska M, Verhoef J. Interaction be-
tween ciprofloxacin and tobramycin or azlocillin against multi-
resistant strains of Acinetobacter anitratum in vitro. European
Journal of Clinical Microbiology 4: 140-141, 1985
Pankey GA, Valainis GT, Katner HP, Cortez LM, Dalovisio JR.
Pseudomonas aeruginosa infections treated with ciprofloxacin.
Abstract P-38-92 of the 14th International Congress ofChemo-
therapy, Kyoto, Japan, Jun, 1985
Parish LC, Asper R. Systemic treatment of cutaneous infections:
a comparative study of ciprofloxacin and cefotaxime. Ameri-
can Journal of Medicine 82 (Suppl, 4A): 227-229, 1987
Parras F, Ezpeleta C, Erice AI, Loza E, Martinez-Beltran J, et al.
Evaluation of ciprofloxacin in the treatment of severe infec-
tions in non-neutropenic patients. Abstract P-38-93 of the 14th
International Congress of Chemotherapy, Kyoto, Japan, Jun,
1985
Parry MF, Folta D, Nossek H, Anderson M, Azzarello L, et al.
Comparative activity of ciprofloxacin and other new agents
against 1454 clinical isolates at a community hospital. Current
Therapeutic Research 38: 755-761, 1985
Parry MF. The in vitro activity and clinical role of ciprofloxacin:
observations during treatment of patients with systemic and
urinary tract infections due to Gram-negative bacilli. Abstract
no. S-50-11 presented at the International Congress ofChemo-
therapy, Kyoto, Japan, Jun, 1985
Patton WN, Smith GM, Leyland MJ, Geddes AM. Multiply re-
sistant Salmonella typhimurium septicaemia in an immuno-
compromised patient successfully treated with ciprofloxacin.
Journal of Antimicrobial Chemotherapy 16: 667-669, 1985
Pedersen SS, Jensen T, Hvidberg EF. Comparative pharmaco-
kinetics of ciprofloxacinand ofloxacin in cystic fibrosis patients.
Journal of Antimicrobial Chemotherapy 20: 575-583, 1987
Peerbooms PGM, Maclaren DM. Comparative activities of five
antimicrobial agents in experimental Proteus pyelonephritis in
mice. Pharmaceutisch Weekblad Scientific Edition 9 (Suppl.):
30-32, 1987
Peeters M, Van Dyck E, Piot P. In vitro activities of the spec-
tinomycin analog U-63366 and four quinolone derivatives
against Neisseria gonorrhoeae. Antimicrobial Agents and
Chemotherapy 26: 608-609, 1984
Perrone CM, Malinverni R, Glauser MP. Treatment of Staphylo-
coccus aureus endocarditis in rats with coumermycin Al and
ciprofloxacin, alone or in combination. Antimicrobial Agents
and Chemotherapy 31: 539-543, 1987
Peters HJ. Comparison of intravenous ciprofloxacin and mezlo-
cillin in treatment of complicated urinary tract infection. Euro-
pean Journal of Clinical Microbiology 5: 253-255, 1986
Ciprofloxacin: A Review
Piccolomini R, Ravagnan G. Comparative in vitro activity of cip-
rofloxacin (Bay 0 9867) and other antimicrobial agents against
urinary bacterial isolates. Chemioterapia 5: 249-256, 1986
Pichler HET, Diridl G, Stickler K, Wolf D. Clinical efficacy of
ciprofloxacin compared with placebo in bacterial diarrhoea.
American Journal of Medicine 82 (Supp!. 4A): 329-332, 1987
Piddock UV, Diver JM, Wise R. Cross-resistance of nalidixic
acid resistant Enterobacteriaeceae to new quinolones and other
antimicrobials. European Journal of Microbiology 5: 411-415,
1986
Piddock UV, Wijnands WJA, Wise R. Quinolone/ureidopeni-
cillin cross-resistance. Lancet 2: 907, 1987
Pien FD, Yamane KK. Ciprofloxacin treatment of soft tissue and
respiratory infections in a community outpatient practice.
American Journal of Medicine 82 (Suppl. 4A): 236-238, 1987
Plaisance KI, Drusano GL, Forrest A, Bustamante CI, Standiford
He. Effect of dose size on bioavailability of ciprofloxacin.
Antimicrobial Agents and Chemotherapy 31: 956-958, 1987
Prabhala RH, Rao B, Marshall R, Bansal MB, Thadepalli H. In
vitro susceptibility of anaerobic bacteria to ciprofloxacin (Bay
09867). Antimicrobial Agents and Chemotherapy 26: 785-786,
1984
Preheim LC, Cuevas TA, Roccaforte JS, Mellencamp MA, Bitt-
ner MJ. Ciprofloxacin and antacids. Lancet 2: 48, 1986
Preheim LC, Cuevas TA, Roccaforte JS, Mellencamp MA, Bitt-
ner MJ. Oral ciprofloxacin in the treatment of elderly patients
with complicated urinary tract infections due to trimethoprirn/
sulfamethoxazole-resistant bacteria. American Journal of
Medicine 82 (Suppl. 4A): 295-300, 1987
Pugsley MP, Dworzack DL, Horowitz EA, Cuevas TA, Sanders
Jr WE, et al. Efficacy of ciprofloxacin in the treatment of na-
sopharyngeal carriers of Neisseria meningitidis. Journal of In-
fectious Diseases 156: 211-213, 1987
Perez-Ruvalcaba JA, Quintero-Perez NP, Morales-Reyes JJ, Hui-
tron-Ramirez JA, Rodriguez-Chagollan J, et al. Double-blind
comparison of ciprofloxacin and cefotaxime in the treatment
of skin and skin structure infections. American Journal of
Medicine 82 (Suppl. 4A): 242-246, 1987
Raeburn JA, Govan JRW, McCrae WM, Greening AP, Collier
PS, et al. Ciprofloxacin therapy in cystic fibrosis. Journal of
Antimicrobial Chemotherapy 20: 295-296, 1987
Ramirez CA, Bran JL, Mejia CR, Garcia JF. Clinical efficacy of
ciprofloxacin in typhoid fever. In Neu HC & Weuta H (Eds)
lst International Ciprofloxacin Workshop, Leverkusen, 1985,
pp. 365-369, Excerpta Medica, Amsterdam, 1986
Ramirez-Ronda CH, Saavedra S, Rivera-Vazques CR. Compar-
ative, double-blind study of oral ciprofloxacin and intravenous
cefotaxime in skin and skin structure infections. American
Journal of Medicine 82 (Suppl, 4A): 220-223, 1987
RaoofS, Wollschager C, Khan FA. Ciprofloxacin increases serum
levels of theophylline. American Journal of Medicine 84 (Supp!.
4A): 115-118, 1987
Raoult D, Gallais H, De Micco P, Casanova P. Ciprofloxacin
therapy for mediterranean spotted fever. Antimicrobial Agents
and Chemotherapy 30: 606-607, 1986
Ratcliffe NT, Smith JT. Ciprofloxacin and ofloxacin exhibit a
rifampicin-resistant bactericidal mechanism not detectable in
other 4-quinolone antibacterial agents. Journal of Pharmacy
and Pharmacology 36 (Supp!.): 59P, 1984a
Ratcliffe NT, Smith JT. Effects of magnesium on the activity of
4-quinolone antibacterial agents. Journal of Pharmacy and
Pharmacology 35 (Suppl.): 61P, 1983
Ratcliffe NT, Smith JT. The mechanism of reduced activity of
4-quinolone agents in urine. Fortschritte der Antimikrobiellen
und Antineoplastischen Chemotherapie (Band 3-5): 563-569,
1984b
Reeves DS, Bywater MJ, Holt HA, White La. In-vitro studies
with ciprofloxacin, a new 4-quinolone compound. Journal of
Antimicrobial Chemotherapy 13: 333-346, 1984
443
Reinhardt JF, George WL. Comparative in vitro activities of sel-
ected antimicrobial agents against Aeromonas species and Ple-
siomonas shigelloides. Antimicrobial Agents and Chemother-
apy 27: 643-645, 1985
Renkonen a-v, Sivonen A, Visakorpi R. Effect of ciprofloxacin
on carrier rate of Neisseria meningitidis in army recruits in
Finland. Antimicrobial Agentsand Chemotherapy 31: 962-963,
1987
Ridgway GL, Mumtaz G, Gabriel FG, Oriel JD. The activity of
ciprofloxacin and other 4-quinolones against Chlamydia
trachomatis and Mycoplasmas in vitro. European Journal of
Clinical Microbiology 3: 344-346, 1984
Righter J. Ciprofloxacin treatment of Staphylococcus aureus in-
fections. Journal of Antimicrobial Chemotherapy 20: 595-597,
1987
Righter J. In vitro activity of ciprofloxacin, azthreonam and cef-
tazidime against Serratia marcescens and Pseudomonas aeru-
ginosa. European Journal of Clinical Microbiology 3: 368-369,
1984
Roberts CM, Batten J, Hodson ME. Ciprofloxacin-resistant Pseu-
domonas. Lancet I: 1442, 1985
Robson HG. Ciprofloxacin comparative efficacy against Pseu-
domonas aeruginosa bacteremia in a neutropenic rat mode!.
Proceedings of the 14th International Congress of Chemo-
therapy, abstract no. S-32-11, Kyoto, Japan, 1985
Roddy RE, Handsfield HH, Hook EW. Comparative trial of single-
dose ciprofloxacin and ampicillin plus probenecid for treat-
ment of gonococcal urethritis in men. Antimicrobial Agents
and Chemotherapy 30: 267-269, 1986
Rohwedder RW, Bergan T. Non-renal elimination of ciproflox-
acin. Proceedings of the Congress on Bacterial and Parasitic
Drug Resistance, Bangkok, 10-13 Dec, 1986
Rolin 0, Huet Y, Bouanchand DH. Comparative efficacy of pe-
floxacin and six other antimicrobial agents on Staphylococcus
aureus experimental abscesses. Journal of Antimicrobial
Chemotherapy 17 (Supp!. B): 49-52, 1986
Ronconi P, Carosi M, Cosentina R, Pittiruti M, Castiglioni Ge.
Clinical efficacy of ciprofloxacin in surgical infections. 1st
International Ciprofloxacin Workshop, Leverkusen, Nov. 6-8,
1985, Current Clinical Practice Series 34, pp. 390-392, Ex-
cerpta Medica, Amsterdam, 1986
Ronnlund RD, Chartrand SA, Gaubatz JW. Inhibition of ATP
dependent DNA gyrase supercoiling activity by quinolone
antibiotics. Abstract A26 presented at the 85th Annual Meet-
ing of the American Society for Microbiology, Las Vegas,USA,
1985
Roosendaal R, Bakker-Woudenberg IAJM, Van den Berghe-Van
Raffe M, Vink-Van den Berg, JC, Michel MF. Comparative
activities of ciprofloxacin and ceftazidime against Klebsiella
pneumoniae in vitro and in experimental pneumonia in leu-
kopenic rats. Antimicrobial Agentsand Chemotherapy 31: 1809-
1815, 1987
Roszkowski W, Ciborowski P, Ko HL, Schumacher-Pertreau F,
Roszkowski K, et al. The effect of subinhibitory concentrations
of selected antibiotics on bacteria-phagocyte interaction. In
Adam et al. (Eds) The influence of antibiotics on the host par-
asite relationship, pp. 179-187, Springer Verlag, Berlin, 1985
Roy C, Foz A, Segura C, Tirado M, Teixell M, et al. Activity of
ciprofloxacin (BAY 0 9867) against Pseudomonas aeruginosa
and ampicillin-resistant Enterobacteriaceae. Infection II: 326-
328, 1983
Rozenberg-Arska M, Dekker AW, Verhoef J. Ciprofloxacin for
selective decontamination of the alimentary tract in patients
with acute leukemia during remission induction treatment: the
effect on fecal flora. Journal of Infectious Diseases 152: 104-
107, 1985
Rubinstein E, Mark Z, Samra Y, Alkan M, Berger S. In vitro
activity of ciprofloxacin compared with other agents against
recent hospital isolates. Chemioterapia 5: 75-82, 1986
Ciprofloxacin: A Review
Rubio T. Oral ciprofloxacin in the treatment of P. aeruginosa
infection in children with cystic fibrosis. Pediatric Pulmonol-
ogy I (Suppl.): 128-129, 1987
Ruckdeschel G, Ehret W, Ahl A. Susceptibility of Legionella spp.
to quinolone derivatives and related organic acids. European
Journal of Clinical Microbiology 3: 373, 1984
Rudin JE, Norden CW, Shinners EM. In vitro activity of cipro-
floxacin against aerobic Gram-negative bacteria. Antimicrob-
ial Agents and Chemotherapy 26: 597-598, 1984 '
Rudrik JT, Cavalieri SJ, Britt EM. Proposed quality control and
interpretive criteria for disk diffusion susceptibility testing with
enoxacin. Journal of Clinical Microbiology 21: 332-334, 1985
Ryan JL, Berenson CS, Greco TP, Mangi RJ, Sims M, et al. Oral
ciprofloxacin in resistant urinary tract infections. American
Journal of Medicine 82 (Suppl, 4A): 303-306, 1987
Saavedra S, Ramirez-Ronda CH, Nevarez M. Ciprofloxacin in
the treatment of urinary tract infections caused by Pseudo-
monas aeruginosa and multiresistant bacteria. European Jour-
nal of Clinical Microbiology 5: 255-257, 1986
Saito A, Koga H, Shigeno H, Watanabe K, Mori K, et aI. The
antimicrobial activity of ciprofloxacin against Legionella spe-
cies and the treatment of experimental Legionella pneumonia
in guinea pigs. Journal of Antimicrobial Chemotherapy 18: 251-
260, 1986
Saito I, Terada Y, Yokozawa M, Ono K, Yamaguchi K, et aI.
Clinical study on Bay 0 9867 in gonococcal urethritis. Chemo-
therapy (Tokyo) 33 (SuppI. 7): 621-631, 1985
Salh B, Webb AK. Ciprofloxacin resistance. Lancet I: 749-750,
1987
Samonis G, Ho DH, Gooch GF, Rolston KVI, Bodey GP. In vitro
susceptibility of Citrobacter species to various antimicrobial
agents. Antimicrobial Agents and Chemotherapy 31: 829-830,
1987
Samsom JP. Influence of haemodialysis on the pharmacokinetics
of ciprofloxacin. Pharmaceutisch Weekblad Scientific Edition
9 (Suppl.): 23-25, 1987
Sanders CC, Sanders WE, Goering RV. Overview of preclinical
studies with ciprofloxacin. American Journal of Medicine 82
(Suppl. 4A): 2-11, 1987
Sanders CC, Sanders WE, Goering RV, Werner V. Selection of
multiple antibiotic resistance by quinolones, ~-Iactams, and
aminoglycosides with special reference to cross-resistance be-
tween unrelated drug classes. Antimicrobial Agents and
Chemotherapy 26: 797-801, 1984
Sanson-Le Pors M-J, Casin 1M, Thebault M-C, Arlet G, Perol Y.
In vitro activities of U-63366, a spectinomycin analog; roxi-
thromycin (RU 28965), a new macrolide antibiotic; and five
quinolone derivatives against Haemophilus ducreyi. Antimi-
crobial Agents and Chemotherapy 30: 512-513, 1986
Sato K, Inoue Y, Yamashita S, Inoue M, Mitsuhashi S. Inhibitory
effect of ofloxacin and other new pyridonecarboxylic acids on
the activities of DNA gyrase isolated from Escherichia coli.
Pseudomonas aeruginosa and Bacteroides fragilis. In Mitsu-
hashi & Daikos (Eds) Ofloxacin: a new quinolone antibacterial
agent. Proceedings of a Workshop held at the 14th Interna-
tional Congress of Chemotherapy, Kyoto, Japan, 1985, pp. 21-
25, University of Tokyo Press, Tokyo, 1985
Sauerwein D, Bauernfeind A, Petermuller e. Clinical and bac-
teriological evaluation of ciprofloxacin in treatment of UTIs
of para- and tetraplegic patients. 14th International Congress
of Chemotherapy, Kyoto, Japan, Jun, 1985
Schacht P, Arcieri G, Branolte J, Bruck H, Chysky V, et al.
Worldwide clinical data on efficacyand safety of ciprofloxacin.
In Neu HC (Ed.) Ciprofloxacin: clinical monograph, pp. 69-
79, ADIS Press International Ltd, Manchester, 1988
Schacht P, Bruck H, Chysky V, Hullmann R, Weuta H, et al.
Overall clinical results with ciprofloxacin. Proceedings of the
14th International Congress of Chemotherapy, Kyoto, Japan,
Jun, 1985
444
Schacht P, Arcieri G, Branolte J, Bruck H, Chysky V, et al.
Worldwide clinical data on efficacy and safety of ciprofloxacin.
In Neu HC (Ed.) Ciprofloxacin: clinical monograph, pp. 69-
79, ADIS Press International Ltd, Manchester, 1988
Schacht P, Hullmann R. Development of resistance during phase
II and III clinical trials with ciprofloxacin. Proceedings of the
Congress on Bacterial and Parasitic Drug Resistance, Bangkok,
1O-l3 Dec, 1986
Schacht P, Hullmann R. Changes of susceptibility of infecting
organisms to ciprofloxacin during treatment. Abstract No. 15.
Proceedings of the Biennial Conference on Chemotherapy of
Infectious Diseases and Malignancies, Munich, 26-29 April,
1987
Schentag JJ, Domagala JM. Structure-activity relationship with
the quinolone antibiotics. Research and Clinical Forums 7: 9-
15, 1985
Schiff JB, Small GJ, Pennington JE. Comparative activities of
ciprofloxacin, ticarcillin, and tobramycin against experimental
Pseudomonas aeruginosa pneumonia. Antimicrobial Agentsand
Chemotherapy 26: 1-4, 1984
Schlenkoff D, Dalhoff A, Knopf J, Opferkuch W. Penetration of
ciprofloxacin into human lung tissue following intravenous in-
jection. Infection 14: 299-300, 1986
Schluter G. Ciprofloxacin: review of potential toxicologic effects.
American Journal of Medicine 82 (Suppl. 4A): 91-93, 1987
Schluter G. Toxicology of ciprofloxacin. In Neu HC, Weuta H
(Eds) l st International Ciprofloxacin Workshop, Leverkusen
1985, pp, 291-296, Excerpta Medica, Amsterdam, 1986
Schmicker R, Naumann G. Efficacy of ciprofloxacin in urinary
tract infections in geriatric patients. In Neu HC & Weuta H
(Eds) lst International Ciprofloxacin Workshop, Leverkusen,
1985, pp, 305-309, Excerpta Medica, Amsterdam, 1986
Scholl H, Schmidt K, Weber B. Sensitive and selective determ-
ination of picogram' amounts of ciprofloxacin and its metab-
olites in biological samples using high-performance liquid
chromatography and photothermal post-column derivatiza-
tion. Journal of Chromatography 416: 321-330, 1987
Scott AC, Fleming LW, Stewart WK. Efficacy of ciprofloxacin in
treatment of CAPD. European Journal of Clinical Microbio-
logy 6: 599, 1987
Scott GR, McMillan A, Young H. Ciprofloxacin versus ampicillin
and probenecid in the treatment of uncomplicated gonorrhoea
in men. Journal of Antimicrobial Chemotherapy 20: 117-121,
1987
Scribner RK, Muszynski MJ, Marks MI. In vitro activity of anti-
microbials, alone and in combination, against Pseudomonas
cepacia. Abstract 394, 24th Interscience Conference on Anti-
microbial Agents and Chemotherapy, Washington DC, 1984
Scully BE, Jules K, Chin N-X, Neu He. Effect of ciprofloxacin
on fecal flora of patients with cystic fibrosis and other patients
treated with oral ciprofloxacin. American Journal of Medicine
82 (Suppl, 4A): 336-338, 1987a
Scully BE, Nakatomi M, Ores C, Davidson S, Neu He. Cipro-
floxacin therapy in cystic fibrosis. American Journal of Med-
icine 82 (SuppI. 4A): 196-201, 1987b
Scully BE, Neu He. Oral ciprofloxacin therapy of infection caused
by multiply resistant bacteria other than Pseudomonas aeru-
ginosa. Journal of Antimicrobial Chemotherapy 18 (SuppI. D):
179-185,1986
Scully BE, Neu He. Treatment of serious infections with intra-
venous ciprofloxacin. American Journal of Medicine 82 (SuppI.
4A): 369-375, 1987
Scully BE, Parry MF, Neu HC, Mandell W. Oral ciprofloxacin
therapy of infections due to Pseudomonas aeruginosa. Lancet
I: 819-822, 1986
Segev S, Rubinstein E, Shick J, Rabinovitch 0, Dolitsky M. Pen-
etration of ciprofloxacin into female pelvic tissues. European
Journal of Clinical Microbiology 5: 207-209, 1986
Self PL, Zeluff BA, Sollo D, Gentry LO. Use of ciprofloxacin in
 Ciprofloxacin: A Review
the treatment of serious skin and skin structure infections.
American Journal of Medicine 82 (Suppl. 4A): 239-241, 1987
Selwyn S, Bakhtiar M. Comparative in-vitro studies on a new
azaquinolone, enoxacin. Drugs in Experimental Clinical Re-
search 10: 653-668, 1984
Shah PM, Enzenberger R, Glogau 0, Knothe H. Influence oforal
ciprofloxacin or ofloxacin on the fecal flora of healthy volun-
teers. American Journal of Medicine 82 (SuppI. 4A): 333-335,
1987a
Shah PM, Just G, Staszewski S, Helm EB, Brodt R, et aI. Cip-
rofloxacin und Imipenem bei Nocardiose. Deutsche Medizin-
ische Wochenschrift 112: 1101, 1987b
Shahmanesh M, Shukla SR, Phillips I, Westwood A, Thin RN.
Ciprofloxacin for treating urethral gonorrhoea in men. Geni-
tourinary Medicine 62: 86-87, 1986
Shalit I, Greenwood RB, Marks MI, Pederson JA, Frederick DL.
Pharmacokinetics of single-dose oral ciprofloxacin in patients
undergoing chronic ambulatory peritoneal dialysis. Antimi-
crobial Agents and Chemotherapy 30: 152-156, 1986
Shalit I, Stutman HR, Marks MI, Chartrand SA, Hilman Be.
Randomized study of two dosage regimens of ciprofloxacin for
treating chronic bronchopulmonary infection in patients with
cystic fibrosis. American Journal of Medicine 82 (SuppI. 4A):
189-195, 1987
Shalit I, Welch OF, San Joaquin VH, Marker MI. In vitro anti-
bacterial activities of antibiotics against Pseudomonas aeru-
ginosa in peritoneal dialysis fluid. Antimicrobial Agents and
Chemotherapy 27: 908-911, 1985
Shwachman H, Kulcyzcki LL. Long-term study of one hundred
five patients with cystic fibrosis. American Journal of Diseases
of Children 96: 6-15, 1958
Simberkoff MS, Rahal 11. Bactericidal activity of ciprofloxacin
against amikacin- and cefotaxime-resistant Gram-negative ba-
cilli and methicillin-resistant staphylococci. Antimicrobial
Agents and Chemotherapy 29: 1098-1100, 1986
Singlas E, Taburet AM, Landru I, Albin H, Ryckelinck JP. Phar-
macokinetics of ciprofloxacin tablets in renal failure: influence
of haemodialysis 31: 589-593, 1987
Slama TG, Misinski J, Sklar S. Oral ciprofloxacin therapy for
osteomyelitis caused by aerobic Gram-negative bacilli. Amer-
ican Journal of Medicine 82 (Suppl. 4A): 259-261, 1987
Smith CR. The adverse effects of fluoroquinolones. Journal of
Antimicrobial Chemotherapy 19: 709-712, 1987
Smith GM, Cashmore C, Leyland MJ. Ciprofloxacin-resistant sta-
phylococci. Lancet 2: 949, 1985
Smith GM, Leyland MJ, Farrell 10, Geddes AM. Preliminary
evaluation of ciprofloxacin, a new 4-quinolone antibiotic in
the treatment of febrile neutropenic patients. Journal of Anti-
microbial Chemotherapy 18 (SuppI. D): 165-174, 1986a
Smith JT. Awakening the slumbering potential ofthe 4-quinolone
antibacterials. Pharmaceutical Journal 233: 299-305, 1984a
Smith JT. Chemistry and mode of action of 4-quinolone agents.
Fortschritte der Antimikrobiellen und Antineoplastischen
Chemotherapie 3: 493-508, 1984b
Smith JT. Mutational resistance to 4-quinolone antibacterial
agents. European Journal of Clinical Microbiology 3: 347-350,
1984c
Smith JT. The mode of action of 4-quinolones and possible
mechanisms of resistance. Journal of Antimicrobial Chemo-
therapy 18 (Suppl. D): 21-29, 1986a
Smith MJ, Hodson ME, Barten J'C, Ciprofloxacin in cystic fibro-
sis. Correspondence. Lancet I: 1103, 1986b
Smith SM, Eng RHK. Activity of ciprofloxacin against methicil-
lin-resistant Staphylococcus aureus. Antimicrobial Agents and
Chemotherapy 27: 688-691, 1985
Smith SM, Eng RHK, Berman E. The effect of ciprofloxacin on
methicillin-resistant Staphylococcus aureus. Journal of Anti-
microbial Chemotherapy 17: 287-295, 1986c
Smith SM. In vitro comparison of A-56619, A-56620, amifloxa-
445
cin, ciprofloxacin, enoxacin, norfloxacin, and ofloxacin against
methici1Iin resistant Staphylococcus aureus. Antimicrobial
Agents and Chemotherapy 29: 325-326, 1986b
Sobieski MW, ScheId WM. Comparative activity ofciprofloxacin
and ofloxacin in experimental H. influenzae meningitis. Pro-
ceedings of the 25th Interscience Conference on Antimicrobial
Agents and Chemotherapy, abstract no. 216, Minneapolis, USA,
1985
Staib AH, Harder S, Mieke S, Beer C, Stille W, et aI. Gyrase-
inhibitors impair caffeine elimination in man. Methods and
Findings in Experimental and Clinical Pharmacology 9: 193-
198, 1987 '
Standiford HC, Drusano GL, Forrest A, Tatem B, Plaisance K.
Bactericidal activity of ciprofloxacin compared with that of
cefotaxime in normal volunteers. Antimicrobial Agents and
Chemotherapy 31: 1172-1182, 1987
Stille W, Schafer-Lotz G, Puppel H. Activity of ~-Iactam-antibi­
otics against Yersinia enterocolitica. Presented at the 13th
International Congress of Chemotherapy, Vienna, 1983
Stolz E, Wagenvoort JHT, Van der Willigen AH. Quinolones in
the treatment of gonorrhoea and Chlamydia trachomatis in-
fection. Pharmaceutisch Weekblad Scientific Edition 9 (Suppl.)
82-85, 1987
Stratton CW, Lin C, Weeks LS. Activity ofLY 146032 compared
with that of methicillin, cefazolin, cefamandole, cefuroxime,
ciprofloxacin, and vancomycin against Staphylococci as deter-
mined by kill-kinetic studies. Antimicrobial Agents and
Chemotherapy 31: 1210-1215, 1987
Strunk RW, Gratz JC, Maserati R, ScheId WM. Comparison of
ciprofloxacin with azlocillin plus tobramycin in the therapy of
experimental Pseudomonas aeruginosa endocarditis. Antimi-
crobial Agents and Chemotherapy 28: 428-432, 1985
Stutman HR, Shalit I, Marks MI, Greenwood R, Chartrand SA,
et aI. Pharmacokinetics of two dosage regimens of ciproflox-
acin during a two-week therapeutic trial in patients with cystic
fibrosis. American Journal of Medicine 82 (Suppl. 4A): 142-
145, 1987
Stutman HR. Summary of a workshop on ciprofloxacin use in
patients with cystic fibrosis. Pediatric Infectious Diseases Jour-
nal 6: 932-935, 1987
Stuyck J, Verbist L, Mulier Je. Treatment of chronic osteomye-
litis with ciprofloxacin. Pharmaceutisch Weekblad Scientific
Edition 9 (Suppl): 93-95, 1987
Suerbaum S, Leying H, Kroll H-P, Gmeiner J, Opferkuch W. In-
fluence of ~-Iactam antibiotics and ciprofloxacin on cell en-
velope of Escherichia coli. Antimicrobial Agents and Chemo-
therapy 31: 1106-1110, 1987
Sutter VL, Kwok V-V, Bulkacz J. Comparative activity of cip-
rofloxacin against anaerobic bacteria. Antimicrobial Agents and
Chemotherapy 27: 427-428, 1985
Swenson JM, Wallace RJ, Silcox VA, Thornsberry e. Antimi-
crobial susceptibility of five subgroups of Mycobacterium lor-
tuitum and Mycobacterium chelonae. Antimicrobial Agents and
Chemotherapy 28: 807-811, 1985
Szaff M, Heiby N, F1ensborg EW. Frequent antibiotic therapy
improves survival in cystic fibrosis patients with chronic Pseu-
domonas aeruginosa infection. Acta Paediatrica Scandinavica
72: 651-657, 1983
Szarmach H, Weuta H, Skazynski J, Wronski A. Ciprofloxacin
in acute male gonorrhea. Arzneimittel-Forschung 36: 1840-1842,
1986
Tanimura H, Tominaga S, Rai F, Matsumoto H. Transfer of cip-
rofloxacin to bile and determination of biliary metabolites in
humans. Arzneirnittel-Forschung 36: 1417-1420, 1986
Tartaglione TA, Raffalovich AC, Poynor WJ, Espinel-Ingroff A,
Kerkering TM. Pharmacokinetics and tolerance of ciproflox-
acin after sequential increasing oral doses. Antimicrobial Agents
and Chemotherapy 29: 62-66, 1986
Taylor DN, Echeverria P, Hanchalay S, Pitarangsi C, Slootmans
Ciprofloxacin: A Review
L, et al. Antimicrobial susceptibility and characterization of
outer membrane proteins of Haemophilus ducreyi isolated in
Thailand. Journal of Clinical Microbiology 21: 442-444, 1985
Tegelberg-Stassen MJAM, van der Hoek JCS, Mooi L, Wagen-
voort JHT, van Joost T, et al. Treatment of uncomplicated
gonococcal urethritis in men with two dosages ofciprofloxacin.
European Journal of Clinical Microbiology 5: 244-246, 1986
Thadepalli H, Prabhala R, Bansal M. Evaluation of ciprofloxacin
and cefotaxime in treatment of experimental subcutaneous ab-
scess in mice. 14th International Congress of Chemotherapy,
abstract no. 32-14, Kyoto, Japan, 1985
Thorsteinsson SB, Bergan T, Johannesson G, Thorsteinsson HS,
Rohwedder R. Tolerance of ciprofloxacin at injection site, sys-
temic safety and effect on electroencephalogram. Chemother-
apy 33: 448-451, 1987
Thorsteinsson SB, Bergan T, Oddsdottir S, Rohwedder R, Holm
R. Crystalluria and ciprofloxacin, influence of urinary pH and
hydration. Chemotherapy 32: 408-417, 1986
Tietgen K, Schulz E, Boness J, Marre R. Ciprofloxacin und Ce-
fotaxim: pharmakokinetik und therapeutische Effektivitat bei
der E. coli-Pyelonephritis der Ratte. Immunologie und Infek-
tion 14: 152-155, 1986
Tolkoff-Rubin N, Rubin RH. New approaches to the treatment
of urinary tract infection. American Journal of Medicine 82
(SuppJ. 4A): 270-277, 1987
Trautmann M, Krause B, Birnbaum D, Wagner J, Lenk K. Serum
bactericidal activity of two newer quinolones against Sa/mo-
nel/a typhi compared with standard therapeutic regimens.
European Journal of Microbiology 5: 297-302, 1986
Trexler Hessen M, Ingerman MJ, Kaufman DH, Weiner P, San-
toro J, et al. Clinical efficacyof ciprofloxacin therapy for Gram-
negative bacillary osteomyelitis. American Journal of Medi-
cine 82 (Suppl. 4A): 262-265, 1987
Turgeon PL, Gaudreau CL, Mantha R. Comparative in vitro ac-
tivity of four quinolones and four other agents against enter-
opathogens. Current Therapeutic Research 41: 584-588, 1987
VIImann V, Giebel W, Dalhoff A, Koeppe P. Single and multiple
dose pharmacokinetics of ciprofloxacin. European Journal of
Clinical Microbiology 5: 193-196, 1984
Vlrich E, Tautmann M, Weinke T, Hahn H. Treatment of ex-
perimental Pseudomonas septicemia with ciprofloxacin and
other antipseudomonal drugs. Proceedings of the International
Symposium on New Quinolones, abstract no. 112, Geneva,
1986
Valainis GT, Pankey GA, Katner HP, Cortez LM, Dalovisio JR.
Ciprofloxacin in the treatment of bacterial skin infections.
American Journal of Medicine 82 (Suppl. 4A): 230-232, 1987
Valainis G, Thomas D, Pankey G. Penetration of ciprofloxacin
into cerebrospinal fluid. European Journal of Clinical Micro-
biology 5: 207-209, 1986
Vallee F, Lebel M, Bergeron MG. Determination of ciprofloxacin
in biological samples by reversed-phase high performance li-
quid chromatography. Therapeutic Drug Monitoring 8: 340-
345, 1986
Van Caekenberghe DL, Pattyn SR. In vitro activity of ciproflox-
acin compared with those ofother new fluorinated piperazinyl-
substituted quinolone derivatives. Antimicrobial Agents and
Chemotherapy 25: 518-521, 1984
Van de Heyning PH, Pattyn SR, Valcke HD. Ciprofloxacin in
oral treatment of ear infections. Pharmaceutisch Weekblad -
Scientific Edition 8: 63-66, 1986
Van de Heyning PH, Pattyn SR, Valcke HD, Van Caekenberghe
DL, C1aesJ. The use offluoroquinolones in chronic otitis sup-
purativa. Pharmaceutisch Weekblad Scientific Edition 9
(Suppl.): 87-89, 1987
Van der Auwera P, Klastersky J. Bactericidal activity and killing
rate of serum in volunteers receiving ciprofloxacin alone or in
combination with vancomycin. Antimicrobial Agents and
Chemotherapy 30: 892-895, 1986
446
Van der Auwera P, Scorneaux B. In vitro susceptibility of Cam-
py/obacter jejuni to 27 antimicrobial agents and various com-
binations of (j-Iactams with c1avulanic acid and sulbactam.
Antimicrobial Agents and Chemotherapy 28: 37-40, 1985
Van Poppel H, Wegge M, Dammekens H, Chysky V. Oral treat-
ment of Pseudomonas-induced urinary tract infections with
ciprofloxacin. Chemotherapy 32: 83-87, 1986b
Van Poppel H, Wegge M, Dammekens H, Chysky V. Ciproflox-
acin in the treatment of urinary tract infection in patients with
multiple sclerosis. European Journal of Clinical Microbiology
5: 251-253, 1986a
Vanhoof R, Hubrechts JM, Roebben E, Nyssen HJ, Nulens E, et
al. The comparative activity of pefloxacin, enoxacin, cipro-
floxacin and 13 other antimicrobial agents against enteropath-
ogenic microorganisms. Infection 14: 294-298, 1986
Van der Waaij D. Colonisation resistance of the digestive tract:
clinical consequences and implications. Journal of Antimi-
crobial Chemotherapy 10: 263-270, 1982
Van Saene JJM, van Saene HKF, Geitz JN, Jarko-Smit WJP,
Lerk CF. Quinolones and colonisation resistance in human
volunteers. Pharmaceutisch Weekblad - Scientific Edition 8:
67-71, 1986
Venezio FR, Tatarowicz W, DiVincenzo CA, O'Keefe JP. Activ-
ity of ciprofloxacin against multiply resistant strains of Pseu-
domonas aeruginosa, Staphylococcus epidermidis, and Group
JK corynebacteria. Antimicrobial Agents and Chemotherapy
30: 940-941, 1986
Verbist L. Comparative in vitro activity of the new quinolone
CI-934. European Journal of Clinical Microbiology 5: 343-345,
1986
WaIl RA, Mabey DCW, Bello CSS, Felmingham D. The com-
parative in-vitro activity of twelve 4-quinolone antimicrobials
against Haemophi/us ducreyi. Journal of Antimicrobial
Chemotherapy 16: 165-168, 1985
Warren RE, Newsom SWB. Ciprofloxacin vs nalidixic acid gut
decontamination to stop spread of gentamicin-resistant Kleb-
sie//as. Abstract No. 932 of 24th Interscience Conference on
Antimicrobial Agents and Chemotherapy, 8-10 Oct, 1984
Watanabe K, Aoki M, Kobayashi T, Sawa K, Veno K. Effect of
BAYo 9867 on human fecal flora. Chemotherapy 33 (Suppl.
7): 88-99, 1985
Watt B, Brown FV. Is ciprofloxacin active against c1inicaIly im-
portant anaerobes? Journal of Antimicrobial Chemotherapy 17:
605-613, 1986
Weber AH, Scribner RK, Marks MI. In vitro activity of cipro-
floxacin against pediatric pathogens. Chemotherapy (Basel) 31:
456-465, 1985
Weidner W, Schiefer HG, Dalhoff A. Treatment of chronic bac-
terial prostatitis with ciprofloxacin: results of a one-year fol-
low-up study. American Journal of Medicine 82 (Suppl. 4A):
280-283, 1987
Weinstein RA, Nathan G, Delzell D, Kabins SA. In vitro suscep-
tibility of nosocomial Pseudomonas aeruginosa, Enterobacter-
iaceae, and staphylococci to ciprofloxacin and ten other broad-
spectrum antibiotics. Chemioterapia 6: 315-318, 1987
Weiss D, Trautmann M, Wagner J, Bomer K, Hahn H. Cipro-
floxacin: a comparative evaluation of its bactericidal activity
in human serum against four enterobacterial species. Drugs in
Experimental Clinical Research 12: 889-894, 1986
Weissauer-Condon C, Engels I, Daschner FD. In vitro activity of
four new quinolones in MueIler-Hinton broth and peritoneal
dialysis fluid. European Journal of Clinical Microbiology 6:
324-326, 1987
Weisser J, Wiedemann B. Brief report: effect of ciprofloxacin on
plasmids. American Journal of Medicine 82: 21-22, 1987
Whitby M, Edwards P, Holliday A, Finch RG. Ciprofloxacin: A
clinical evaluation and assessment of its effect on faecal flora.
14th International Congress on Chemotherapy, p, 400, Kyoto,
Japan, 1985
Ciprofloxacin: A Review
Whiting JL, Cheng N, Chow AW. Interactions of ciprofloxacin
with clindamycin, metronidazole, cefoxitin, cefotaxime, and
mezlocillin against Gram-positive and Gram-negative anaer-
obic bacteria. Antimicrobial Agents and Chemotherapy 31:
1379-1382, 1987
Wijnands WJA, Vree TB, Baars AM, Van Herwaarden CLA.
Steady-state kinetics of the quinolone derivatives ofloxacin,
enoxacin, ciprofloxacin and pefloxacin during maintenance
treatment with theophylline. Drugs 34 (Suppl, I): 159-169, 1987
Wijnands WJA, Vree TB, Van Herwaarden CLA. The influence
of quinolone derivatives on theophylline clearance. British
Journal of Clinical Pharmacology 22: 677-683, 1986
Wiley R, Lode H, Hoffken G, Wagner J, Bomer K. Ciprofloxacin
versus imipenem/cilastatin: a prospective randomized study in
60 patients with severe infections. Abstract S-51-5 of the 14th
International Congress of Chemotherapy, Kyoto, Japan, Jun,
1985
Williams AH, Gruneberg RN. Ciprofloxacin and co-trimoxazole
in urinary tract infections. Journal of Antimicrobial Chemo-
therapy 18 (Suppl. D): 107-110, 1986
Williams P. Sub-MIC's of cefuroxime and ciprofloxacin influence
interaction of complement and immunoglobulins with Kleb-
siella pneumoniae. Antimicrobial Agents and Chemotherapy
31: 758-762, 1987
Wingender W, Beerman D, Foerster D, Graefe K-H, Schacht P,
et al. Mechanism of renal excretion of ciprofloxacin (Bay 0
9867), a new quinolone carboxylic acid derivative, in humans.
Abstract 621 of the 4th Mediterranean Congress of Chemo-
therapy, Rhodes, 1984a
Wingender W, Foerster D, Beerman D, Rohwedder R, Graefe
KH, et al. Effect of gastric emptying time on rate and extent
of systemic availability of ciprofloxacin. Abstract no. P-37-91
of the 14th International Congress of Chemotherapy, Kyoto,
Japan, 1985
Wingender W, Graefe K-H, Gau W, Forster D, Beerman D, et
al. Pharmacokinetics of ciprofloxacin after oral and intraven-
ous administration in healthy volunteers. European Journal of
Clinical Microbiology 3: 355-359, 1984b
Wise R, Andrews JM, Edwards U. In vitro activity of Bay 0
9867, a new quinolone derivative, compared with those of other
antimicrobial agents. Antimicrobial Agents and Chemotherapy
23: 559-564, 1983
Wise R, Donovan IA. Tissue penetration and metabolism of cip-
rofloxacin. American Journal of Medicine 82 (Suppl. 4A): 103-
107, 1987
Wise R, Lockley RM, Webberly M, Dent J. Pharmacokinetics of
447
intravenously administered ciprofloxacin. Antimicrobial Agents
and Chemotherapy 26: 208-210, 1984
Wittmann DH, Teichmann W, Huebner A, Fock R, Bauernfeind
A. Penetration of ciprofloxacin into inorganic and organic bone
compartments. Abstract S-40-7, International Congress of
Chemotherapy, Kyoto, Japan, 1985
Wolff M, Boutron L, Singlas E, Clair B, Decazes JM, et al. Pen-
etration of ciprofloxacin into cerebrospinal fluid of patients
with bacterial meningitis. Antimicrobial Agents and Chemo-
therapy 3 I: 899-902, 1987
Wollschlager CM, Raoof S, Khan FA, Guarneri J, LaBombardi
V, et al. Controlled, comparative study of ciprofloxacin versus
ampicillin in treatment of bacterial respiratory tract infections.
American Journal of Medicine 82: 164-168,1987
Wood ME, Newland AC. Intravenous ciprofloxacin in the treat-
ment of infection in immunocompromised patients. Journal
of Antimicrobial Chemotherapy 18 (Suppl. D): 175-178, 1986
Wood MJ, Logan MN. Ciprofloxacin for soft tissue infections.
Journal of Antimicrobial Chemotherapy 18 (Suppl. D): 159-
164, 1986
Yamaguchi K, Hara K. Clinical evaluation ofciprofloxacin in the
field of internal medicine in Japan. Proceedings of the 14th
International Congress of Chemotherapy, Kyoto, Japan, Jun,
1985
Yu VL, Stoehr G, Rubin J, Matador A, Kamarer D. Efficacy of
oral ciprofloxacin plus rifampin for therapy of malignant otitis
externa. Abstract no. 188. Proceedings of the 27th Interscience
Conference of Antimicrobial Agents and Chemotherapy, New
York, Oct 4-7, 1987
Zeiler H-J. Influence of pH and human urine on the antibacterial
activity of ciprofloxacin, norfloxacin and ofloxacin. Drugs in
Experimental Clinical Research II: 335-338, 1985
Zeiler H-J, Voigt WHo Efficacy of ciprofloxacin on stationary-
phase bacteria in vivo. American Journal of Medicine 82 (Suppl.
4A): 87-91, 1987
Zeiler H-J, Petersen D, Gau W, Ploschke HJ. Antibacterial ac-
tivity of the metabolites of ciprofloxacin and its significance
in the bioassay. Arzneimittel-Forschung 37: 131-134, 1987
Zweerink MM, Edison A. Inhibition of Micrococcus luteus DNA
gyrase by norfloxacin and 10 other quinolone carboxylic acids.
Antimicrobial Agents and Chemotherapy 29: 598-601, 1986
Authors' address: Deborah M. Campoli-Richards, ADIS Drug In-
formation Services, 41 Centorian Drive, Private Bag, Mairangi
Bay, Auckland 10 (New Zealand).