Journal of Antimicrobial Chemotherapy (2003) 51, Suppl.

S1, 1–11
DOI: 10.1093/jac/dkg212

Development of the quinolones
Monique I. Andersson and Alasdair P. MacGowan*
Bristol Centre for Antimicrobial Research and Evaluation, North Bristol NHS Trust and University of Bristol,
Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK

Keywords: quinolones, pharmacokinetics, pharmacodynamics, drug development

Introduction

been patented. This review will trace the development of
quinolones from their sole use as treatment for urinary tract
infections, via systemic use, to those agents whose primary
use is for the treatment of respiratory tract infections. This
development may be described in terms of structures,
potency, pharmacokinetics and pharmacodynamics, and
finally indications and clinical use.

Quinolones have been the centre of considerable scientific
and clinical interest since their discovery in the early 1960s.
This is because they potentially offer many of the attributes of
an ideal antibiotic, combining high potency, a broad spectrum
of activity, good bioavailability, oral and intravenous formulations, high serum levels, a large volume of distribution indicating concentration in tissues and a potentially low incidence
of side-effects. Much research has attempted to make these
potential attributes real. Nalidixic acid was the first quinolone
to be developed (Table 1), but it took more than a decade
before additional compounds, such as flumequin, norfloxacin
and enoxacin became available for clinical use. The main use
for all these agents was the treatment of urinary tract infection. In the late 1980s more systemically active drugs, such as
ciprofloxacin and ofloxacin, were marketed. Recently, there
has been a considerable increase in the number of agents that
are in development, and to date over 10 000 molecules have

Structural developments
Quinolones were derived from quinine. Figure 1 shows the
basic fluoroquinolone molecule or ‘pharmacore’.1 The addition of a fluorine molecule at position 6 was one of the earliest
changes to the structure. This single alteration provides a
more than 10-fold increase in gyrase inhibition and up to
100-fold improvement in MIC. Two major groups have been
developed from the basic structure: quinolones and naphthyridones.1–5 The presence of a nitrogen at position 8 identi-

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*Corresponding author. Tel: +44-117-959-5652; Fax: +44-117-959-3154; E-mail: alasdair.macgowan@north-bristol.swest.nhs.uk
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1
© 2003 The British Society for Antimicrobial Chemotherapy

Downloaded from http://jac.oxfordjournals.org/ by guest on October 6, 2016

Since their discovery in the early 1960s, the quinolone group of antibacterials has generated
considerable clinical and scientific interest. Nalidixic acid, the first quinolone to be developed,
was obtained as an impurity during the manufacture of quinine. Since this time, many derivatives have been synthesized and evaluated for their antibacterial potency. Two major groups of
compounds have been developed from the basic molecule: quinolones and naphthyridones.
Manipulations of the basic molecule, including replacing hydrogen with fluorine at position 6,
substituting a diamine residue at position 7 and adding new residues at position 1 of the quinolone ring, have led to enhanced antibacterial efficacy. In general these compounds are well tolerated. However, some of these structural changes have been found to correlate with specific
adverse events: the addition of fluorine or chlorine at position 8 being associated with photoreactivity, e.g. Bay y 3118 and sparfloxacin; and the substitution of an amine or a methyl group at
position 5 having a potential role in QTc prolongation, e.g. sparfloxacin and grepafloxacin. Progressive modifications in molecular configuration have resulted in improved breadth and
potency of in vitro activity and pharmacokinetics. One of the most significant developments has
been the improved anti-Gram-positive activity of the newer compounds, such as moxifloxacin
and garenoxacin. In the current millennium, these new agents may play an important role in the
treatment of respiratory infections.

P.g.M. Figure 4). moxifloxacin. fies the naphthyridones. moxifloxacin. A difluoromethyl ether (OHF2) group is found at position 8 in garenoxacin. . A cyclopropyl group at position 1 is found in sparfloxacin. The addition of a 2. The structure of norfloxacin illustrates these developments and subsequent to this all quinolones (except garenoxacin) have a fluorine at position 6 and many have six-membered rings at position C-7 (Figure 2). grepafloxacin. grepafloxacin. clinafloxacin. ofloxacin.org/ by guest on October 6. especially in improving activity against anaerobes. tosufloxacin. clinafloxacin. fluorine was retained at position 6. enoxacin. C-5 and C-7 positions of their respective basic molecules. ofloxacin and levofloxacin. norfloxacin. Where X is a nitrogen atom the molecule is a naphthyridone (nalidixic acid. There are data to suggest that a piperazine ring may play a role in inhibiting efflux mechanisms. temafloxacin. clinafloxacin) improves activity against Gram-positive organisms. ciprofloxacin. possibly gemifloxacin and garenoxacin in 2003 or later Figure 2. Structure of the quinolone and napthyridone molecule. moxifloxacin and garenoxacin. gemifloxacin). Modifications of quinolone structures: norfloxacin.g. A fivemembered ring or azabiocyclo rings at position 7 are found in clinafloxacin and trovafloxacin (five-membered ring) or moxifloxacin and garenoxacin (azabicyclo rings). the molecule is a quinolone (cinoxacin. A methoxy group at position 8 is found in moxifloxacin and gatifloxacin. temafloxacin. trovafloxacin) also improves potency. levofloxacin. a cyclopropyl group was introduced to the N1 position and is best exemplified by ciprofloxacin. norfloxacin) improves activity against Gram-negative organisms. ofloxacin temafloxacin. In addition to piperazine at the C-7 position. Figure 1.4-difluorophenyl group at position 1 (e. Andersson and A. trovafloxacin moxifloxacin. gatifloxacin and garenoxacin. A number of other structural manipulations have been tried to improve the anti-Gram-positive activity of fluoroquinolones. sparfloxacin. Modification of quinolone structures: moxifloxacin. One of the first additions was an NH2 group at position 2 Downloaded from http://jac. sparfloxacin. I. which was first synthesized in 1983 (Figure 3). gatifloxacin). trovafloxacin. except garenoxacin. This increases the potency of the drug and many subsequent quinolones have a cyclopropyl group (e. levofloxacin. grepafloxacin.2 Figure 4. The addition of piperazine to the C-7 position (e. sparfloxacin grepafloxacin. In all subsequent molecules. a carbon and associated group at position 8 identifies the quinolones. 2016 Figure 3. thereby improving the potency of these drugs. A six-membered ring at position 7 is found in ciprofloxacin. Modification of quinolone structures: ciprofloxacin. The presence of a pyrrolodinyl group at position C-7 (e.g.oxfordjournals. In molecules where X is a carbon atom. Adapted from Domagala (1994).g. Chronology of quinolones that reached the UK market Date 1960–1969 1970–1975 1975–1985 1985–1990 1990–1995 1995–2000 2000–2005 Quinolone nalidixic acid cinoxacin norfloxacin ciprofloxacin. MacGowan Table 1. gatifloxacin.1–5 The quinolones and napththyridones were further enhanced by the addition of groups to the N1.

the early drugs (nalidixic acid and cinoxacin) did not have very good anti-pseudomonal potency. Gram-negative or atypical bacteria. The most common substituents are cyclic amino groups. many of the newer agents. as this is shared by trovafloxacin. 2016 by temafloxacin. may be responsible for some of the immunologically mediated adverse events seen with these drugs. temafloxacin and tosufloxacin1 but not by gemifloxacin.6 The addition of azabicyclo groups onto position 7 has resulted in agents (moxifloxacin and trovafloxacin) with significant anti-Grampositive activity. and some have improved activity against Gram-negative anaerobes. lomefloxacin. such as gatifloxacin. levofloxacin and sparfloxacin.16 Much speculation has also surrounded the likely structural correlates of the haemolytic uraemic-like syndrome caused . it also improves tissue penetration and extends the half-life by increasing lipophilicity. whereas gemifloxacin has an MIC90 of 0.32–35 This is one of the key advances in terms of the development of these agents. have either a NH2 or a CH3 group in this position. Introduction of methyl groups on the pyrrolidine ring helps to overcome some of these physical properties.22–31 In terms of their MIC90s. aureus. is a good example of the advantages and disadvantages associated with a pyrrolidine ring at position 7. as with grepafloxacin. moxifloxacin or gatifloxacin). which improves anti-Gram-positive activity. such as antibacterial spectrum.6. broadening the spectrum of activity and reducing the selection of mutants.8 C-5.17 hepatic eosinophilia caused by trovafloxacin.9–13 Whilst alkylation has been shown to increase further anti-Gram-positive activity. The addition of methyl groups can improve both oral absorption and in vivo activity.8 Manipulation of the group at position 8 has also been shown to play a role in altering oral pharmacokinetics. the newer agents have improved activity against pathogens such as Mycoplasma pneumoniae and other atypical bacteria.03 mg/L for S. such as Bacteroides fragilis (Tables 2 and 3). enoxacin or ciprofloxacin) and confer potency against Gram-negative bacteria. Gemifloxacin. a naphthyridone. such as sparfloxacin and grepafloxacin. garenoxacin and moxifloxacin. Table 422–31. other groups have been less successful. Nalidixic acid. clinafloxacin.org/ by guest on October 6.12.4-difluorophenyl group at position 1. The structural changes to the quinolone molecule and correlation with adverse events are now well documented. the improved activity against Gram-positive bacteria can sometimes be at the expense of activity against Pseudomonas aeruginosa. The naphthyridones can be modified by the addition of cyclopropyl groups in the same way as the quinolones. this group is associated with low water solubility and low oral bioavailability so in vivo activity may be compromised. as indicated by MIC90s. A more powerful association is that of the 2. and the hypoglycaemia seen with temafloxacin and clinafloxacin. are not as potent as ciprofloxacin against P. The substituents at position C-7 are associated with a number of key attributes.3.14 Photo-reactivity is probably most influenced by position 8. cinoxacin and enoxacin have no activity at all.6 A further hypothesis is that metabolites of these agents (as yet not fully identified).g. pneumoniae. Piperazine rings are particularly common (e. Pyrrolidine rings (five-membered) are also common substituents at position 7. This is seen with sparfloxacin which otherwise has a very similar structure to ciprofloxacin. In terms of anti-Gram-negative potency. a piperazine at position C-7 and is alkylated. marked lipophilicity and half-lives of >10 h.g. with fluorine or chlorine producing most phototoxic potential (e.18. and is 3 Downloaded from http://jac. Although it is unlikely any fluoroquinolone will have activity against ciprofloxacin-resistant Staphylococcus aureus. It has been suggested that substitution at position 5 may have a role in QTc prolongation as those agents that have been associated with significant problems.18 pulmonary interstitial eosinophilia and other immunological side-effects caused by tosufloxacin19 and gemifloxacin. increases the half-life and results in resistance to efflux pumps. tosufloxacin and gemifloxacin) others are fluoroquinolones (temafloxacin).Development of the quinolones Developments in potency The development of these agents can be described in terms of their potency against Gram-positive.oxfordjournals. bioavailability and side-effects.36–39 lists the fluoroquinolones on the basis of their MIC90s for five Gram-positive species.7. Sparfloxacin also has a fluorine at position C-6. Grepafloxacin is also substituted at position C-5 but by a CH3 group and has improved anti-Gram-positive potency compared with ciprofloxacin. hence it is unclear whether this difference is relevant.15. However. In general. gemifloxacin. for example piperazine or pyrrolidine rings. and are associated with enhanced potency against Gram-positive bacteria.g.10. has not changed significantly since the development of norfloxacin (Table 2). Streptococcus pneumoniae and Group A streptococci. One of the more interesting developments in terms of potency is the area of anti-Gram-positive activity. Garenoxacin has fluorine incorporated through a C-8 difluoromethyl ether linkage as there is no fluorine at C-6. However. aeruginosa. which resulted in a general increase in anti-Gram-positive activity. a major development has been in the activity of these drugs against ciprofloxacin-sensitive S. Trovafloxacin has an azabicyclo ring. However.21 Although a number of these agents are naphthyridones (trovafloxacin. norfloxacin.20. the activity of quinolones against Enterobacteriaceae such as Escherichia coli and Klebsiella spp. A fivemembered ring has been added to the molecule of gemifloxacin at position 7. Bay y 3118 and sparfloxacin) and methoxy groups the least (e. which share common structures.

aeruginosa B.12 0.25 0.5 0. The activity against enterococci is less clearly defined because different species are often classified together.06 0.06 0.12 0.0 >64 >64 4 2 0.12 0.06 0.03 Ureaplasma urealyticum >64 16 16 4 1 1 0. Development of quinolone potency against Gram-negative bacteria MIC90 (mg/L) Quinolone Klebsiella spp.5 1 0. Development of quinolone potency against atypical bacteria MIC90 (mg/L) Quinolone Nalidixic acid Enoxacin Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Trovafloxacin Clinafloxacin Sparfloxacin Grepafloxacin Moxifloxacin Gatifloxacin Gemifloxacin Garenoxacin Legionella pneumophila 0.03 0. whilst pharmacodynamics (PD) refers to how the drug action changes with concentration or dose.25 0. pneumoniae Chlamydia spp.25 4 2 2 1 2 2 2 2 0.01 0.03 >64 >64 2 2 1 4 2 1 1 0.25 0.5 0.03 0.12 0.008 M.25 0.5 0.06 0. faecalis. Pharmacokinetics (PK) refers to changes in drug concentration as the drug moves through the body.06 0.01 0.5 >64 >64 1 0.5 0. faecium is more resistant than E.12 0.016 >64 8 8 1 0.06 Developments in pharmacodynamics and pharmacokinetics equivalent to the earlier compounds in terms of activity against the majority of Gram-negatives (Table 2).06 0.12 0.5 0.12 0.03 0.06 16 8 2 0.01 0.oxfordjournals.008 0.06 0.5 0.25 0.5 0.12 0.01 0.M.06 0.03 0.12 0.06 0.25 0.12 0. fragilis 8 8 0. and the proportions of Enterococcus faecium and Enterococcus faecalis are not provided.25 0.5 0.5 0.01 0.01 0.5 0. coli .03 0.5 0.03 0.12 0.12 0.01 0.5 0.06 0. P. Andersson and A.25 0.12 0. Enterobacter/ Citrobacter spp.03 0.org/ by guest on October 6.06 0.5 4 8 8 4 4 16 >64 >64 >64 >64 16 16 8 4 0.008 0.03 0.03 0.12 0.12 0.01 0. Haemophilus influenzae P.5 0.06 >64 8 16 2 2 1 0. Mycoplasma hominis >64 4 16 2 2 1 0.25 0.12 0.5 0.25 0.03 0. This is important as E.25 0.5 0.5 1.25 0.5 1 0. I.25 4 8 1 1 ND 1 Nalidixic acid Cinoxacin Enoxacin Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Temafloxacin Trovafloxacin Clinafloxacin Sparfloxacin Grepafloxacin Moxifloxacin Gatifloxacin Gemifloxacin Garenoxacin Table 3.06 0.25 0.25 0.01 0.5 1 0.12 0. Serratia spp.03 0.12 0.5 0.12 0.03 0.06 0.06 0.01 0.01 0. MacGowan Table 2.5 0.5 0.25 0. 4 Downloaded from http://jac. 2016 E.5 0.

25 0.03 0.6 (×2) 0.6 1.4 (×2) 0.6.5 1 0.4 3.44 No trend in protein binding has become apparent over time with some agents having a binding of <30% (norfloxacin. Essentially it is not a systemic drug.12 0.4 (×1) 0. but a urinary agent.03 0.06 0. However.12 >64 >64 64 1 2 1 0.5 0. Development of quinolone pharmacokinetics Quinolone Nalidixic acid Enoxacin Enoxacin Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Temafloxacin Trovafloxacin Clinafloxacin Sparfloxacin Grepafloxacin Moxifloxacin Gatifloxacin Gemifloxacin Garenoxacin Dose (g) (frequency per day) 1 (×4) 0.5 3.1 4.8 variable 19 29 10 30 64 48 134 40 18 20 14 30 37 9 59 1.25 1 0.2 7.25 0.5 2 6 3 4 6 7 8 12 6 18 14 13 9 7 15 90 60 70 15 40 40 40 25 85 40 40 50 50 20 60 87 renal renal renal renal and hepatic renal and enteral renal renal renal hepatic renal renal and hepatic hepatic hepatic renal renal and other renal and other to the molecule.31.0 5.4 (×1) Cmax (mg/L) AUC (mg⋅h/L) Half-life (h) Protein binding (%) Elimination route variable 1.06 0.5 1. >64 >64 2 1 0.43.5 4.06 0. and oral absorption has markedly improved compared with that of nalidixic acid (Table 5).org/ by guest on October 6.42 a long halflife is not an absolute prerequisite for once-daily dosing.12 ND 0.25 >64 >64 8 4 2 2 2 2 4 1 1 2 0.5 0.06 0.25 0. pneumoniae Group A streptococci Enterococcus spp.25 0.30.25 0.75 (×2) 0.0 2.2 (×2) 0. and they have a prolonged post-antibiotic effect (PAE).4 (×1) 0. Development of quinolone potency against Gram-positive bacteria MIC90 (mg/L) Quinolone S.12 0. larger serum area under the curve (AUC) or peak serum (Cmax) values are consistently seen as the quinolones have developed.25 Table 5.oxfordjournals.0 1.5 0.25 0.25 0.0 1.5 1 0.5 (×1) 0.0 0.12 0.7 1.03 >64 >64 64 2 2 1 0.0 1.12 0.5 1. since the activity of quinolones is concentration dependent.32 (×1) 0.12 0. temafloxacin and gatifloxacin) and others >70% (nalidixic Nalidixic acid is a drug that is excreted in urine and has very variable systemic absorption. meaning that the extent of bacterial killing increases as drug concentrations increase.41 The half-life of these agents has also tended to increase as structural modifications have been made 5 Downloaded from http://jac.4 (×1) 0.6 (×1) 0.25 0. 2016 S.25 0.25 0.25 4 0.3 (×1) 0.4 (×1) 0.4 (×2) 0.5 3.5 0. aureus (methicillin sensitive) .14.8 5.5 Nalidixic acid Cinoxacin Enoxacin Ciprofloxacin Ofloxacin Levofloxacin Temafloxacin Sparfloxacin Grepafloxacin Gatifloxacin Trovafloxacin Moxifloxacin Clinafloxacin Gemifloxacin Garenoxacin Clostridium perfringens >64 >64 >64 0.06 0.5 (×2) 0.Development of the quinolones Table 4.40. Over time.

gatifloxacin. pneumoniae. temafloxacin. although many fluoroquinolones and naphthyridones are eliminated primarily by metabolism and renal clearance (glomerular filtration and active tubular secretion). pharmacodynamic variables (for example.48 In contrast. moxifloxacin. trovafloxacin and garenoxacin). Non-renal clearance seems to have become a feature of a number of the newer agents (e. norfloxacin enoxacin ciprofloxacin sparfloxacin. combined with lower MIC. gemifloxacin. garenoxacin and the emergence of resistance. as ciprofloxacin has an AUC/MIC between 25 and 50 for the therapy of P. cinoxacin. aureus <12. are a significant advance because they will have the effect of increasing the value of Cmax/MIC or AUC/MIC ratios. clinafloxacin.47. Andersson and A. enoxacin. sparfloxacin. There is always a certain amount of debate as to whether the Cmax/MIC or the AUC/MIC is more important in terms of fluoroquinolone bacteriological and clinical outcomes in man. Pharmacodynamics would predict that all but the very early quinolones will have good clinical activity acid. norfloxacin S.46 For predicting efficacy against most infections. clinafloxacin. MacGowan Table 6. levofloxacin. For example. influenzae P. 2016 12. enoxacin. moxifloxacin and garenoxacin). while a target of free AUC/MIC of 30–40 is required for S. cinoxacin. trovafloxacin. Development of quinolone pharmacodynamics against Gram-positive pathogens AUC/MIC (total) S. trovafloxacin. whereas the pharmacokinetic changes are probably at most five-fold between any of these agents. levofloxacin sparfloxacin temafloxacin.5 nalidixic acid nalidixic acid 12. The other area of considerable pharmacodynamic debate has been what breakpoint or critical PK/PD ratio is required to optimize microbiological or clinical outcomes. This is probably not important because the co-variable nature of these two pharmacokinetic parameters makes it difficult to identify which one is dominant in determining microbiological and clinical outcome. cinoxacin. aeruginosa. grepafloxacin. clinafloxacin norfloxacin all others all others temafloxacin Table 7. trovafloxacin. if there is a range of values. levofloxacin. norfloxacin. trovafloxacin. pneumoniae . I. aeruginosa (Table 6). gatifloxacin.45 At present it is reasonable to assume that almost all the drugs that have AUC/MIC ratios >100 are likely to have useful activity against Enterobacteriaceae and P. gemifloxacin or garenoxacin. some of the newer drugs. norfloxacin nalidixic acid.M. Clearly. moxifloxacin. gatifloxacin.5–25 25–50 50–100 >100 nalidixic acid. In general.org/ by guest on October 6. ofloxacin. the bigger numbers are more likely to be predictive of good clinical outcome in terms of the microbiology 6 Downloaded from http://jac. enoxacin. grepafloxacin ciprofloxacin ofloxacin. such as grepafloxacin.oxfordjournals. enoxacin.5 50–100 >100 Group A streptococci nalidixic acid. AUC/MIC or Cmax/MIC) are driven by changes in potency. gemifloxacin. aeruginosa. aeruginosa at present doses.g. ofloxacin ciprofloxacin. Development of quinolone pharmacodynamics against Gram-negative pathogens AUC/MIC (total) E. For example. it can be anticipated that levofloxacin. P. grepafloxacin ciprofloxacin. trovafloxacin.5–25 25–50 nalidixic acid. moxifloxacin. gemifloxacin. levofloxacin. clinafloxacin. gatifloxacin. agents with large AUC also have high Cmax concentrations. gemifloxacin. moxifloxacin. trovafloxacin and clinafloxacin will have similar activity to ciprofloxacin against P. ofloxacin. much more than they are driven by changes in pharmacokinetics. a high free-drug Cmax and AUCs. garenoxacin garenoxacin gatifloxacin. temafloxacin. coli H. moxifloxacin. The MIC changes are sometimes 100-fold between agents. sparfloxacin. grepafloxacin. are unlikely to have significant clinical activity against P. grepafloxacin. together with some of the older urinary drugs like norfloxacin. garenoxacin enoxacin. aeruginosa <12.

54 unexpected hypoglycaemia with clinafloxacin and temafloxacin.org/ by guest on October 6. active against Gram-positives. moxifloxacin and garenoxacin. renal elimination main use in UTI wide activity against Gram-negatives. longer serum half-lives widely used against tissue-based and urinary infections wide activity against Gram-negatives. This has shifted from agents used predominantly for the treatment of urinary tract infections in the 1960s/70s. gemifloxacin.52 Many of the more recently developed quinolones do not have the toxicological disadvantages of the earlier compounds. variable activity against anaerobes.51 The small amount of existing clinical data also implies that these agents are clinically active against ciprofloxacin-susceptible S.56 a number of immunologically mediated adverse events with tosufloxacin.32–35. aeruginosa. long serum half-life main use in respiratory tract infection Toxicology against E. including P. levofloxacin. gatifloxacin. Other effects include a haemolytic uraemic-like syndrome with temafloxacin. it is clear that the urinary drugs are not going to have useful clinical activity against S. aureus or Streptococcus pyogenes (Table 7). ratios should probably be higher.17 a metallic taste with grepafloxacin. aureus and Group A streptococci. pneumoniae. for some agents long serum half-lives. aeruginosa for some agents. are likely to have useful clinical activity against S.6 To date there are little toxicological data on garenoxacin. to the treatment of respiratory tract infections. active against atypical bacteria. 2016 Respiratory agents (1995 onwards) levofloxacin sparfloxacin grepafloxacin moxifloxacin gatifloxacin gemifloxacin garenoxacin Activity . pneumoniae. The more recently developed fluoroquinolones. coli and H.18 and an immune-mediated rash in young women with gemifloxacin.oxfordjournals. some activity against anaerobes widely used against a broad range of tissuebased infections wide activity against Enterobacteriaceae.53 hepatitis with trovafloxacin. especially S. to more systemic use in the 1980s/90s. Proposed classification of fluoroquinolones Agents Urinary agents (1960–1985) nalidixic acid cinoxacin enoxacin norfloxacin Gram-negative systemic agents (1985–1995) ciprofloxacin ofloxacin levofloxacin Broad spectrum systemic agents (1990–2000) temafloxacin clinafloxacin trovafloxacin Clinical applications activity against common Enterobacteriaceae. Indications and use The pharmacokinetic and in vitro potency profiles of fluoroquinolones determine the areas of clinical use.Development of the quinolones Table 8. influenzae causing systemic infection (Table 6). Sparfloxacin and grepa7 Downloaded from http://jac. including P. Whereas with ofloxacin. With respect to the Gram-positive organisms.21. and Gram-positives. pneumoniae.50.55. a prediction now supported by clinical trials data in community-acquired pneumonia49 and acute exacerbation of chronic bronchitis (AECB). for example the QTc prolongation that has limited the use of sparfloxacin and grepafloxacin. grepafloxacin and sparfloxacin. such as trovafloxacin. and in the current millennium. S. marginal activity against Gram-positives. short serum half-lives. In the context of immunocompromised patients (those with co-morbidity or ITU patients) or in order to prevent the emergence of resistance. AUC/MIC ratios of >25 are beginning to predict clinically useful outcomes for non-immunocompromised patients with mild to moderate communityacquired disease.

Andersson and A. but in terms of marketing the main focus appears to be respiratory.org/ by guest on October 6. indicate that they can be used for Gram-negative infection and as anti-pseudomonal agents.M. exploiting their activity against S. The third group. debate about their use in various areas of Gram-positive infection. gemifloxacin and garenoxacin) with more convincing potential in the respiratory tract have been developed. have sufficiently broad activity in terms of anti-Gram-negative. however. quinolones can be classified into four groups according to clinical use. I. according to their pharmacokinetics and activity. P. On this basis. The first group consists of urinary agents that are.oxfordjournals. of which trovafloxacin and temafloxacin are the best examples. levofloxacin and ofloxacin which. The second group includes the anti-Gram-negative systemic agents such as ciprofloxacin. Development of quinolones. floxacin were the first agents to focus on the respiratory tract. pneumoniae and atypical organisms. gatifloxacin. 8 . MacGowan Downloaded from http://jac. in general. 2016 Figure 5. Thus development has moved from the urinary to the respiratory tract via a miscellaneous group of systemic indications. pharmacokinetics and pharmacodynamics. More recently a further group of agents (moxifloxacin. There is. the older drugs which are active against the common Enterobacteriaceae and tend to have short halflives and renal elimination (Table 8). potency. Levofloxacin is one example of a drug where there is a wide range of potential uses.

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