CHAPTER 43

ANTIBACTERIAL DRUGS

● Principles of antibacterial chemotherapy 323 ● Prophylactic use of antibacterial drugs 325

● Bacterial resistance 324 ● Commonly prescribed antibacterial drugs 325
● Drug combinations 325

factors (in particular age, weight, renal function). In addition,

PRINCIPLES OF ANTIBACTERIAL the dose may be guided by plasma concentration measurements
CHEMOTHERAPY of drugs with a narrow therapeutic index (e.g. aminoglyco-
sides). The duration of therapy depends on the nature of the
Bacteria are a common cause of disease, but have beneficial as infection and response to treatment.
well as harmful effects. For example, the gastrointestinal bac- The British National Formulary provides a good guide to ini-
terial flora of the healthy human assists in preventing colo- tial treatments for common bacterial infections. In view of
nization by pathogens. The widespread use of antibacterial regional variations in patterns of bacterial resistance, these
drugs has led to the appearance of multiresistant bacteria may be modified according to local guidelines.
which are now a significant cause of morbidity and mortality Close liaison with the local microbiology laboratory provides
in the UK. Consequently, antibacterial therapy should not be information on local prevalence of organisms and sensitivities.
used indiscriminately. The minimum inhibitory concentration (MIC) is often
A distinction is conventionally drawn between bactericidal quoted by laboratories and in promotional literature. It is the
drugs that kill bacteria and bacteriostatic drugs that prevent minimal concentration of a particular agent below which bac-
their reproduction, elimination depending on host defence terial growth is not prevented. Although the MIC provides
(Table 43.1A). This difference is relative, as bacteriostatic drugs useful information for comparing the susceptibility of organ-
are often bactericidal at high concentrations and in the pres- isms to antibacterial drugs, it is an in vitro test in a homoge-
ence of host defence mechanisms. In clinical practice, the dis- nous culture system, whilst in vivo the concentration at the
tinction is seldom important unless the body’s defence
mechanisms are depressed. Antibacterial drugs can be further Table 43.1B: Classification of antibacterial agents according to mechanism
classified into five main groups according to their mechanism of action
of action (Table 43.1B).
Mechanism of action Antibacterial agent
The choice of antibacterial drug, together with its dose and
route of administration, depend on the infection (in particular Inhibition of cell wall synthesis Penicillins
the responsible pathogen(s), but also anatomical site and
Cephalosporins
severity), absorption characteristics of the drug, and patient
Monobactams
Vancomycin
Table 43.1A: Classification of antibacterial agents into bactericidal
and bacteriostatic Inhibition of DNA gyrase Quinolones
Inhibition of RNA polymerase Rifampicin
Bactericidal Bacteriostatic
Inhibition of protein synthesis Aminoglycosides
Penicillins Erythromycin Tetracyclines
Cephalosporins Tetracyclines Erythromycin
Aminoglycosides Chloramphenicol Chloramphenicol
Co-trimoxazole Sulphonamides Inhibition of folic acid metabolism Trimethoprim
Trimethoprim Sulphonamides
324 ANTIBACTERIAL DRUGS

Diagnosis of bacterial infection confirmed

– clinical symptoms/signs plus
– positive microbiology
Yes No

Is bacterial sensitivity profile available? Is bacterial infection likely?

Yes No Yes No

Treat with appropriate antibiotic Treat with most appropriate antibiotic No antibiotic
according to predominant causative treatment
organism(s) and sensitivities (including
local sensitivity patterns)

Consider other measures (e.g. drainage of abscess)

Consider length of antibiotic treatment according to appropriate guidelines

Are signs, symptoms and markers of infection

(e.g. CRP, ESR, temperature, white cell count) improving?

Yes No

Complete course Consider

of treatment – alternative (or additional) diagnosis
– poor penetrance of antibiotic to site of infection
– possible change in antibiotic therapy

Figure 43.1: General algorithm for the treatment of bacterial infections.

site of infection may be considerably lower than the plasma
concentration which one might predict to be bactericidal (e.g.
drug penetration and concentration in an abscess cavity are
very low).
Figure 43.1 gives a general algorithm for the treatment of
bacterial infections.
BACTERIAL RESISTANCE
The resistance of bacterial populations to antimicrobial agents
is constantly changing and can become a serious clinical prob-
lem, rendering previously useful drugs inactive. Overuse of
antibiotics will lead to a future where infectious disease has
the same impact as in in the pre-antibiotic era. The dates on
tombstones in Victorian cemeteries should be required read-
ing for over-enthusiastic prescribers and medical students!
(Whole families of infants died in infancy, followed by their
mother from puerperal sepsis.) Although most multiresistant
bacteria have developed in hospitalized patients, the majority
of antimicrobial prescribing in the UK takes place in primary
care. Current guidelines therefore emphasize the following
points:
1. no prescribing of antibiotics for coughs and colds or viral
sore throats;
2. limit prescribing for uncomplicated cystitis to three days
for otherwise fit women; and
3. limit prescribing of antibiotics over the telephone to
exceptional cases.
Antimicrobial resistance is particularly common in intensive care
units and transplant units, where the use of antimicrobial agents
is frequent and the patients may be immunocompromised.
The evolution of drug resistance involves:
1. selection of naturally resistant strains (which have arisen
by spontaneous mutation) that exist within the bacterial
population by elimination of the sensitive strain by
therapy. Thus the incidence of drug resistance is related to
the prescription of that drug. The hospital environment
with intensive and widespread use of broad-spectrum
antibacterials is particularly likely to promote the
selection of resistant organisms;

2. transfer of resistance between organisms can occur by
transfer of naked DNA (transformation), by conjugation
with direct cell-to-cell transfer of extrachromosomal DNA
(plasmids), or by passage of the information by
bacteriophage (transduction). In this way, transfer of
genetic information concerning drug resistance
(frequently to a group of several antibiotics
simultaneously) may occur between species.
Mechanisms of drug resistance can be broadly divided into
three groups:
1. inactivation of the antimicrobial agent either by
disruption of its chemical structure (e.g. penicillinase) or
by addition of a modifying group that inactivates the drug
(e.g. chloramphenicol, inactivated by acetylation);
2. restriction of entry of the drug into the bacterium by
altered permeability or efflux pump (e.g. sulphonamides,
tetracycline);
3. modification of the bacterial target – this may take the
form of an enzyme with reduced affinity for an inhibitor,
or an altered organelle with reduced drug-binding
properties (e.g. erythromycin and bacterial ribosomes).
DRUG COMBINATIONS
Most infections can be treated with a single agent. However,
there are situations in which more than one antibacterial drug
is prescribed concurrently:
• to achieve broad antimicrobial activity in critically ill
patients with an undefined infection (e.g. aminoglycoside
plus a penicillin to treat septicaemia);
• to treat mixed bacterial infections (e.g. following
perforation of the bowel) in cases where no single agent
would affect all of the bacteria present;
• to prevent the emergence of resistance (e.g. in treating
tuberculosis; see Chapter 44);
• to achieve an additive or synergistic effect (e.g. use of
co-trimoxazole in the treatment of Pneumocystis carinii
pneumonia).
PROPHYLACTIC USE OF ANTIBACTERIAL
DRUGS
On a few occasions it is appropriate to use antibacterial drugs
prophylactically. Wherever possible a suitably specific narrow-
spectrum drug should be used.
ANTIBIOTIC PROPHYLAXIS OF INFECTIVE
ENDOCARDITIS
An important recent change is that fewer patients are deemed
to require antibiotic prophylaxis against infective endocarditis;
it should be restricted to patients who have previously had
COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 325
endocarditis, cardiac valve replacement surgery (mechanical or
biological prosthetic valves), or surgically constructed systemic
or pulmonary shunts or conduits. In such patients, all dental
procedures involving dento-gingival manipulation will require
antibiotic prophylaxis, as will certain genito-urinary, gastro-
intestinal, respiratory or obstetric/gynaecological procedures.
Intravenous antibiotics are no longer recommended unless the
patient cannot take oral antibiotics. The latest guidelines (2006)
by the Working Party of the British Society for Antimicrobial
Chemotherapy can be found at http://jac.oxfordjournals.org/
cgi/reprint/dkl121v1. These are updated periodically.
For dental procedures, in addition to prophylactic anti-
biotics, the use of chlorhexidine 0.2% mouthwash five minutes
before the procedure may be a useful supplementary measure.
PROPHYLACTIC PREOPERATIVE ANTIBIOTICS
GENERAL PRINCIPLES
1. Prophylaxis should be restricted to cases where the
procedure commonly leads to infection, or where
infection, although rare, would have devastating results.
2. The antimicrobial agent should preferably be bactericidal
and directed against the likely pathogen.
3. The aim is to provide high plasma and tissue concentrations
of an appropriate drug at the time of bacterial
contamination. Intramuscular injections can usually be
given with the premedication or intravenous injections at
the time of induction. Drug administration should seldom
exceed 48 hours. Many problems in this area arise because
of failure to discontinue ‘prophylactic’ antibiotics, a
mistake that is easily made by a busy junior house-surgeon
who does not want to take responsibility for changing a
prescription for a patient who is apparently doing well
post-operatively. Local hospital drug and therapeutics
committees can help considerably by instituting sensible
guidelines on the duration of prophylactic antibiotics.
4. If continued administration is necessary, change to oral
therapy post-operatively wherever possible.
The British National Formulary provides a good summary
of the use of antibacterial drugs preoperatively, which may be
varied according to local guidelines based on regional pat-
terns of bacterial susceptibility/resistance.
COMMONLY PRESCRIBED ANTIBACTERIAL
DRUGS
β-LACTAM ANTIBIOTICS
These drugs each contain a β-lactam ring. This can be broken
down by β-lactamase enzymes produced by bacteria, notably
by many strains of Staphylococcus and Haemophilus influenzae,
which are thereby resistant. β-Lactam antibiotics kill bacteria by
inhibiting bacterial cell wall synthesis. Penicillins are excreted
in the urine. Probenecid blocks the renal tubular secretion
326 ANTIBACTERIAL DRUGS
of penicillin. This interaction may be used therapeutically to
produce higher and more prolonged blood concentrations of
penicillin. Antibiotics in this group include the penicillins,
monobactams, carbapenems and cephalosporins.
PENICILLINS
Use
Benzylpenicillin (penicillin G) is the drug of choice for strep-
tococcal, pneumococcal, gonococcal and meningococcal infec-
tions, and is also useful for treatment of anthrax, diphtheria,
gas gangrene, leptospirosis, syphilis, tetanus, yaws and Lyme
disease in children.
Adverse effects
The adverse effects include:
1. anaphylaxis (in approximately 1 in 100 000 injections);
2. rashes (3–5% of patients) can, rarely, be severe (e.g.
Stevens–Johnson syndrome – see Chapter 12);
3. serum sickness – type III hypersensitivity;
4. other idiosyncratic reactions including haemolytic
anaemia and thrombocytopenia;
5. in renal failure, high-dose penicillin causes
encephalopathy and seizures.
Limitations of benzylpenicillin include:
1. It is acid labile and so must be given parenterally
(inactivated in gastric acid).
2. It has a short half-life, so frequent injections are required.
3. Development of resistant β-lactamase-producing strains
can occur.
4. It has a narrow antibacterial spectrum.
Two preparations with similar antibacterial spectra are
used to overcome the problems of acid lability/frequent
injection:
1. Procaine benzylpenicillin – this complex releases
penicillin slowly from an intramuscular site, so a twice
daily dosage only is required.
2. Phenoxymethylpenicillin (‘penicillin V’) – this is acid
stable and so is effective when given orally (40–60%
absorption). Although it is useful for mild infections,
blood concentrations are variable, so it is not used in
serious infections or with poorly sensitive bacteria.
Tablets are given on an empty stomach to improve
absorption.
β-LACTAMASE-RESISTANT PENICILLIN
Flucloxacillin was developed to overcome β-lactamase-produc-
ing strains. Otherwise, it has a similar antibacterial spectrum to
benzylpenicillin. It is effective against β-lactamase-producing
organisms. It is used for the treatment of staphylococcal infec-
tions (90% of hospital staphylococci are resistant to benzylpeni-
cillin and 5–10% are resistant to flucloxacillin).
EXTENDED-RANGE PENICILLINS
AMPICILLIN/AMOXICILLIN
Uses
In addition to streptococcal (including pneumococcal) strains,
ampicillin and amoxicillin are also effective against many
strains of Haemophilus influenzae, E. coli, Streptococcus faecalis and
Salmonella. They are used for a variety of chest infections (e.g.
bronchitis, pneumonia), otitis media, urinary tract infections,
biliary infections and the prevention of bacterial endocarditis
(amoxicillin). Amoxicillin is somewhat more potent than
ampicillin, penetrates tissues better and is given three rather
than four times daily. Both are susceptible to β-lactamases.
Adverse effects
Rashes are common and may appear after dosing has stopped.
There is an especially high incidence in patients with infec-
tious mononucleosis or lymphatic leukaemia.
Pharmacokinetics
The half-life of each drug is about 1.5 hours and they are pre-
dominantly renally excreted.
CO-AMOXICLAV
Co-amoxiclav is a combination of amoxicillin and clavulanic
acid, a β-lactamase inhibitor. In addition to those bacteria that
are susceptible to amoxicillin, most Staphylococcus aureus, 50% of
E. coli, some Haemophilus influenzae strains and many Bacteroides
and Klebsiella species are susceptible to co-amoxiclav. Adverse
effects are similar to those of amoxicillin, but abdominal dis-
comfort is more common.
ANTIPSEUDOMONAL PENICILLINS
Standard penicillins are not effective against Pseudomonas. This
is not usually a problem, as these organisms seldom cause dis-
ease in otherwise healthy people. However, Pseudomonas infec-
tion is important in neutropenic patients (e.g. those undergoing
cancer chemotherapy) and in patients with cystic fibrosis.
Penicillins with activity against Pseudomonas have been devel-
oped and are particularly useful in these circumstances. These
include piperacillin, azlocillin and ticarcillin.
Uses
These expensive intravenous penicillins are not used routinely.
Their efficacy against Gram-positive organisms is variable and
poor. They are useful against Gram-negative infections, partic-
ularly with Pseudomonas and they are also effective against
many anaerobes. These drugs have a synergistic effect when
combined with aminoglycosides in Pseudomonas septicaemias.
Combinations of ticarcillin or of piperacillin with β-lactamase
inhibitors designed to overcome the problem of β-lactamase
formation by Pseudomonas are commercially available.
Adverse effects
These drugs predispose to superinfection. Rashes, sodium over-
load, thrombocytopenia and platelet dysfunction can occur.

Pharmacokinetics
Absorption of these drugs from the gut is inadequate in the
life-threatening infections for which they are mainly indicated.
They are given intravenously every 4–6 hours. Their half-lives
range from 1 to 1.5 hours and they are renally excreted.
CEPHALOSPORINS
FIRST-GENERATION CEPHALOSPORINS
So-called first-generation cephalosporins (e.g. cephalexin,
cefaclor, cefadroxil) are effective against Streptococcus pyo-
genes and Streptococcus pneumoniae, E. coli and some staphylo-
cocci. They have few absolute (i.e. uniquely advantageous)
indications. Their pharmacology is similar to that of the peni-
cillins and they are principally renally eliminated.
SECOND- AND THIRD-GENERATION
CEPHALOSPORINS
Second- and third-generation cephalosporins are active
against H. influenzae and in some instances Pseudomonas and
anaerobes, at the expense of reduced efficacy against Gram-
positive organisms. β-Lactamase stability has been increased.
Arguably the most generally useful member of the group is
cefuroxime, which combines lactamase stability with activity
against streptococci, staphylococci, H. influenzae and E. coli. It
is given by injection eight-hourly (an oral preparation is also
available, as cefuroxime axetil). It is expensive, although
when used against Gram-negative organisms that would other-
wise necessitate use of an aminoglycoside, this cost is partly
offset by savings from the lack of need for plasma concentra-
tion determinations.
Of the third-generation cephalosporins, ceftazidime, cef-
triaxone and cefotaxime are useful in severe sepsis, especially
because (unlike earlier cephalosporins) they penetrate the
blood–brain barrier well and are effective in meningitis.
Adverse effects
About 10% of patients who are allergic to penicillins are also
allergic to cephalosporins. Some first-generation cephalosporins
are nephrotoxic, particularly if used with furosemide, amino-
glycosides or other nephrotoxic agents. Some of the third-
generation drugs are associated with bleeding due to increased
prothrombin times, which is reversible with vitamin K.
MONOBACTAMS
Monobactams (e.g. aztreonam) contain a 5-monobactam ring
and are resistant to β-lactamase degradation.
AZTREONAM
Uses
Aztreonam is primarily active against aerobic Gram-negative
organisms and is an alternative to an aminoglycoside. It is used
COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 327
in severe sepsis, often hospital acquired, especially infections of
the respiratory, urinary, biliary, gastro-intestinal and female
genital tracts. It has a narrow spectrum of activity and cannot be
used alone unless the organism’s sensitivity to aztreonam is
known.
Mechanism of action
The 5-monobactam ring binds to bacterial wall transpepti-
dases and inhibits bacterial cell wall synthesis in a similar way
to the penicillins.
Adverse effects
Rashes occur, but there appears to be no cross-allergenicity
with penicillins.
Pharmacokinetics
Aztreonam is poorly absorbed after oral administration, so it
is given parenterally. It is widely distributed to all body com-
partments, including the cerebrospinal fluid. Excretion is
renal and the usual half-life (one to two hours) is increased in
renal failure.
IMIPENEM–CILASTATIN AND MEROPENEM
Uses
Imipenem, a carbapenem, is combined with cilastatin, which
is an inhibitor of the enzyme dehydropeptidase I found in the
brush border of the proximal renal tubule. This enzyme breaks
down imipenem in the kidney. Imipenem has a very broad
spectrum of activity against Gram-positive, Gram-negative and
anaerobic organisms. It is β-lactamase stable and is used for treat-
ing severe infections of the lung and abdomen, and in patients
with septicaemia, where the source of the organism is unknown.
Meropenem is similar to imipenem, but is stable to renal dehy-
dropeptidase I and therefore can be given without cilastatin.
Adverse effects
Imipenem is generally well tolerated, but seizures, myoclonus,
confusion, nausea and vomiting, hypersensitivity, positive
Coombs’ test, taste disturbances and thrombophlebitis have all
been reported. Meropenem has less seizure-inducing potential
and can be used to treat central nervous system infection.
Pharmacokinetics
Imipenem is filtered and metabolized in the kidney by dehy-
dropeptidase I. This is inhibited by cilastatin in the combina-
tion. Imipenem is given intravenously as an infusion in three
or four divided daily doses.
AMINOGLYCOSIDES
Uses
Aminoglycosides are highly polar, sugar-containing deriva-
tives. They are powerful bactericidal agents that are active
against many Gram-negative organisms and some Gram-
positive organisms, with activity against staphylococci and
328 ANTIBACTERIAL DRUGS
Enterococcus faecalis, but not (when used alone) against other
streptococci. They synergize with penicillins in killing
Streptococcus faecalis in endocarditis. Aminoglycosides are used
in serious infections including septicaemia, sometimes alone
but usually in combination with other antibiotics (penicillins
or cephalosporins). Gentamicin is widely used and has a
broad spectrum, but is ineffective against anaerobes, many
streptococci and pneumococci.
Tobramycin is probably somewhat less nephrotoxic than
gentamicin. Amikacin is more effective than gentamicin for
pseudomonal infections and is occasionally effective against
organisms resistant to gentamicin. It is principally indicated
in serious infections caused by Gram-negative bacilli that are
resistant to gentamicin. Topical gentamicin or tobramycin
eye drops are used to treat eye infections.
Mechanism of action
These drugs are transported into cells and block bacterial pro-
tein synthesis by binding to the 30S ribosome.
Adverse effects
These are important and are related to duration of therapy and
trough plasma concentrations. They are more frequent in the
elderly and in renal impairment. Therapeutic monitoring is
performed by measuring plasma concentrations before dosing
(trough) and at ‘peak’ levels (usually at an arbitrary one hour
after dosing). Eighth nerve damage is potentially catastrophic
and is often irreversible. Acute tubular necrosis and renal fail-
ure are usually reversible if diagnosed promptly and the drug
stopped or the dose reduced. Hypersensitivity rashes are
uncommon. Bone marrow suppression is rare. Exacerbation of
myasthenia gravis is predictable in patients with this disease.
Pharmacokinetics
Aminoglycosides are poorly absorbed from the gut and are
given by intramuscular or intravenous injection. They are
poorly protein bound (30%) and are excreted renally. The half-
life is short, usually two hours, but once daily administration
is usually adequate. This presumably reflects a post-antibiotic
effect whereby bacterial growth is inhibited following clear-
ance of the drug. In patients with renal dysfunction, dose
reduction and/or an increased dose interval is required.
Cerebrospinal fluid (CSF) penetration is poor.
Drug interactions
Aminoglycosides enhance neuromuscular blockade of non-
depolarizing neuromuscular antagonists. Loop diuretics
potentiate their nephrotoxicity and ototoxicity.
CHLORAMPHENICOL
Uses
Chloramphenicol has a broad spectrum of activity and pene-
trates tissues exceptionally well. It is bacteriostatic, but is
extremely effective against streptococci, staphylococci,
H. influenzae, salmonellae and others. Uncommonly it causes
aplastic anaemia, so its use is largely confined to life-threatening
disease (e.g. H. influenzae epiglottitis, meningitis, typhoid fever)
and to topical use as eyedrops.
Mechanism of action
Chloramphenicol inhibits bacterial ribosome function by
inhibiting the 50S ribosomal peptidyl transferase, thereby pre-
venting peptide elongation.
Adverse effects
These include:
1. haematological effects – dose-related erythroid suppression
is common and predictable, but in addition aplastic
anaemia occurs unpredictably with an incidence of
approximately 1:40 000. This is irreversible in 50% of cases.
It is rarely, if ever, related to the use of eyedrops.
2. grey baby syndrome – the grey colour is due to shock
(hypotension and tissue hypoperfusion).
Chloramphenicol accumulates in neonates (especially if
premature) due to reduced glucuronidation in the
immature liver (see Chapter 10).
3. other – sore mouth, diarrhoea, encephalopathy and optic
neuritis.
Pharmacokinetics
Chloramphenicol is well absorbed following oral administra-
tion and can also be given by the intramuscular and intra-
venous routes. It is widely distributed and CSF penetration is
excellent. It mainly undergoes hepatic glucuronidation, but in
neonates this is impaired.
Drug interactions
Chloramphenicol inhibits the metabolism of warfarin,
phenytoin and theophylline.
MACROLIDES
Macrolide antibiotics (e.g. erythromycin, clarithromycin,
azithromycin) have an antibacterial spectrum similar, but not
identical to that of penicillin. Distinctively, they are effective
against several unusual organisms, including Chlamydia,
Legionella and Mycoplasma.
ERYTHROMYCIN
Uses
Uses include respiratory infections (including Mycoplasma
pneumoniae, psittacosis and Legionnaires’ disease), whooping
cough, Campylobacter enteritis and non-specific urethritis.
Erythromycin is a useful alternative to penicillin in penicillin-
allergic patients (except meningitis: it does not penetrate the
CSF adequately). It is useful for skin infections, such as low-
grade cellulitis and infected acne, and is acceptable for patients
with an infective exacerbation of chronic bronchitis. It is most
commonly administered by mouth four times daily, although
when necessary it may be given by intravenous infusion.
 COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 329

Mechanism of action Adverse effects

Macrolides bind to bacterial 50S ribosomes and inhibit protein These include:
synthesis.
1. nausea, vomiting and diarrhoea (pseudomembranous
Pharmacokinetics colitis due to Clostridium difficile reported occasionally);
2. hypersensitivity reactions (including rash, exfoliative
Well absorbed orally and distributed adequately to most sites
dermatitis, Stevens–Johnson syndrome, urticaria,
except the brain, macrolides are inactivated by hepatic
angioedema, anaphylaxis, pericarditis);
N-demethylation,
15% being eliminated unchanged in the
3. worsening of renal failure;
urine. Food delays absorption but may reduce gastro-intestinal
4. hepatotoxicity (rare);
side effects.
5. discoloration and damage of the teeth and bones of the
Adverse effects fetus if the mother takes tetracyclines after the fifth month
of pregnancy, and of children; they should therefore be
Erythromycin is remarkably safe and may be used in pregnancy
avoided in pregnancy and children under 12 years.
and in children. Nausea, vomiting, diarrhoea and abdominal
cramps are the most common adverse effects reported, related to Pharmacokinetics
direct pharmacological actions rather than allergy. Cholestatic
Tetracyclines are well absorbed orally when fasting, but their
jaundice has been reported following prolonged use.
absorption is reduced by food and antacids. They undergo
Intravenous administration frequently causes local pain and
elimination by both the liver and the kidney. The half-life
phlebitis.
varies between different members of the group, ranging from
Drug interactions six to 12 hours. The shorter-acting drugs are given four times
daily and the longer-acting ones once daily. Doxycycline is
Erythromycin inhibits cytochrome P450 and causes accumu-
given once daily, can be taken with food and is not contraindi-
lation of theophylline, warfarin and terfenadine. This can
cated in renal impairment.
result in clinically important adverse effects.
Drug interactions
AZITHROMYCIN AND CLARITHROMYCIN
Tetracyclines chelate calcium and iron in the stomach, and
Each of these has greater activity than erythromycin against
their absorption is reduced by the presence of antacids or
H. influenzae. Azithromycin is less effective against Gram-
food.
positive bacteria than erythromycin, but has a wider spectrum
of activity against Gram-negative organisms. Clarithromycin
is an erythromycin derivative with slightly greater activity
SODIUM FUSIDATE
than the parent compound; tissue concentrations are higher
than with erythromycin. It is given twice daily.
Uses
Azithromycin and clarithromycin are more expensive than
erythromycin, but cause fewer gastro-intestinal side effects. Fusidic acid is combined with other drugs to treat staphylo-
coccal infections, including penicillin-resistant strains. It pen-
etrates tissues (including bone) well. It is normally used in
conjunction with flucloxacillin for serious staphylococcal
TETRACYCLINES
infections. It is also available as eyedrops for the treatment of
bacterial conjunctivitis.
Uses
Tetracyclines (e.g. tetracycline, oxytetracycline, doxycycline) Mechanism of action
have a broad range of antibacterial activity covering both It inhibits bacterial protein synthesis.
Gram-positive and Gram-negative organisms and, in addition
organisms such as Rickettsia, Chlamydia and Mycoplasma. They Adverse effects
are used in atypical pneumonias and chlamydial and rick- Adverse effects are rare, but include cholestatic jaundice.
ettsial infections, and remain useful in treating exacerbations
of chronic bronchitis or community-acquired pneumonia. Pharmacokinetics
They are not used routinely for staphylococcal or streptococ- When administered either orally or intravenously, its half-life
cal infections because of the development of resistance. is four to six hours and it is excreted primarily via the liver.
Tetracyclines are used in the long-term treatment of acne
(Chapter 51).
VANCOMYCIN
Mechanism of action
Tetracyclines bind to the 30S subunit of bacterial ribosomes Uses and antibacterial spectrum
and prevent binding of the aminoacyl-tRNA to the ribosome Vancomycin is valuable in the treatment of resistant infections
acceptor site, thereby inhibiting protein synthesis. due to Staphylococcus pyogenes. It is also rarely used to treat
330 ANTIBACTERIAL DRUGS

other infections, for example Staphylococcus epidermidis endo- Pharmacokinetics

carditis, and is given orally for pseudomembranous colitis
caused by Clostridium difficile.
Mechanism of action
Vancomycin inhibits bacterial cell wall synthesis.
Metronidazole is well absorbed after oral or rectal administra-
tion, but is often administered by the relatively expensive
intravenous route. The half-life is approximately six hours. It is
eliminated by a combination of hepatic metabolism and renal
excretion. Dose reduction is required in renal impairment.

Drug interactions
Adverse effects
Metronidazole interacts with alcohol because it inhibits alde-
These include: hyde dehydrogenase and consequently causes a disulfiram-
• hearing loss; like reaction. It is a weak inhibitor of cytochrome P450.
• venous thrombosis at infusion site;
• ‘red man’ syndrome due to cytokine/histamine release
following excessively rapid intravenous administration; SULPHONAMIDES AND TRIMETHOPRIM
• hypersensitivity (rashes, etc.);
• nephrotoxicity. Sulphonamides and trimethoprim inhibit the production of folic
acid at different sites of its synthetic pathway and are synergistic
in vitro. There is now widespread resistance to sulphonamides,
Pharmacokinetics
and they have been largely replaced by more active and less toxic
Vancomycin is not absorbed from the gut and is usually given antibacterial agents. The sulfamethoxazole–trimethoprim combi-
as an intravenous infusion (except for the treatment of nation (co-trimoxazole) is effective in urinary tract infections,
pseudomembranous colitis). It is eliminated by the kidneys. prostatitis, exacerbations of chronic bronchitis and invasive
Because of its concentration-related toxicity, the dose is Salmonella infections, but with the exception of Pneumocystis
adjusted according to the results of plasma concentration carinii infections (when high doses are used), trimethoprim alone
monitoring. is generally preferred as it avoids sulphonamide side effects,
whilst having similar efficacy in vivo.
Sulphonamides are generally well absorbed after oral
TEICOPLANIN administration and are widely distributed. Acetylation and
glucuronidation are the most important metabolic pathways.
Teicoplanin has a longer duration of action, but is otherwise They may precipitate in acid urine. They frequently cause
similar to vancomycin. unwanted side effects, including hypersensitivity reactions
such as rashes, fever and serum sickness-like syndrome and
Stevens–Johnson syndrome (see Chapter 12). Rarely, agranu-
METRONIDAZOLE locytosis, megaloblastic, aplastic or haemolytic anaemia and
thrombocytopenia occur. Sulphonamides are oxidants and
Uses can precipitate haemolytic anaemia in glucose-6-phosphate
Metronidazole is a synthetic drug with high activity against dehydrogenase (G6PD)-deficient individuals.
anaerobic bacteria. It is also active against several medically Sulphonamides potentiate the action of sulphonylureas,
important protozoa and parasites (see Chapter 47). It is used oral anticoagulants, phenytoin and methotrexate due to inhi-
to treat trichomonal infections, amoebic dysentery, giardiasis, bition of their metabolism.
gas gangrene, pseudomembranous colitis and various abdom- Trimethoprim is well absorbed, highly lipid soluble and
inal infections, lung abscesses and dental sepsis. It is used pro- widely distributed. At least 65% is eliminated unchanged in
phylactically before abdominal surgery. the urine. Trimethoprim competes for the same renal clear-
ance pathway as creatinine. It is generally well tolerated, but
occasionally causes gastro-intestinal disturbances, skin reac-
Mechanism of action
tions and (rarely) bone marrow depression. Additionally, the
Metronidazole binds to DNA and causes strand breakage. In high doses used in the management of Pneumocystis pneumonia
addition, it acts as an electron acceptor for flavoproteins and in immunosuppressed patients cause vomiting (which can be
ferredoxins. improved by prophylactic anti-emetics), a higher incidence of
serious skin reactions, hepatitis and thrombocytopenia.
Adverse effects
These include:
QUINOLONES
1. nausea and vomiting;
2. peripheral neuropathy; Nalidixic acid was available for many years, but poor tissue
3. convulsions, headaches; distribution and adverse effects limited its use to a second- or
4. hepatitis. third-line treatment for urinary tract infections. Changes to the

basic quinolone structure dramatically increased the antibacter-
ial potency of the more modern quinolones, particularly against
Pseudomonas. Oral bioavailability is good and thus the 4-fluoro-
quinolones offer an oral alternative to parenteral aminoglyco-
sides and antipseudomonal penicillins for treatment of
Pseudomonas urinary and chest infections. Although the 4-fluo-
roquinolones have a very broad spectrum of activity, all of those
currently available have very limited activity against strepto-
cocci. Most experience has been obtained with ciprofloxacin,
which has the additional advantage of being available for intra-
venous use. The quinolones inhibit bacterial DNA gyrase.
Uses
Ciprofloxacin is used for respiratory (but not pneumococcal),
urinary, gastro-intestinal and genital infections, septicaemia
and meningococcal meningitis contacts. In addition to
Pseudomonas, it is particularly active against infection with
Salmonella, Shigella, Campylobacter, Neisseria and Chlamydia. It
is ineffective in most anaerobic infections. The licensed indica-
tions for the other quinolones are more limited. Ciprofloxacin
is generally well tolerated, but should be avoided by epilep-
tics (it rarely causes convulsions), children (it causes arthritis in
growing animals) and individuals with glucose-6-phosphate
dehydrogenase deficiency. Anaphylaxis, nephritis, vasculitis,
dizziness, hepatic and renal damage have all been reported.
An excessively alkaline urine and dehydration can cause uri-
nary crystallization.
Pharmacokinetics
Approximately 80% of an oral dose of ciprofloxacin is system-
ically available. It is widely distributed entering all body com-
partments including the eye and the CSF. Ciprofloxacin is
removed primarily by glomerular filtration and tubular secre-
tion. The half-life is four hours.
Drug interactions
Co-administration of ciprofloxacin and theophylline causes
elevated blood theophylline concentrations due to inhibition
of cytochrome P450. As both drugs are epileptogenic, this
interaction is particularly significant.
RECENTLY INTRODUCED ANTIBACTERIAL
AGENTS
Increasing antibiotic resistance (especially meticillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant ente-
rococci) is a matter of deep concern. Although the spread of
multi-resistant organisms can be minimized by judicious use
of antibiotics and the instigation of tight infection-control
measures, there is a continuing need for the development of
well-tolerated, easily administered, broad-spectrum anti-
biotics. Table 43.2 lists some recently introduced antibiotics
which fulfil these criteria, together with their main features.
At present, their use is restricted and should be administered
under close microbiological supervision.
COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 331
Key points
• If practicable, take specimens for microbiological
analyses before starting antibacterial therapy.
• Consider the severity of the illness.
• Consider the likely pathogen(s).
• Consider patient factors, particularly allergies and
potential drug interactions (see text).
• Select the most appropriate route of administration.
• Monitor the response and alter the therapy and route
of administration as appropriate.
• Some drugs require routine plasma concentration
monitoring (e.g. aminoglycosides, vancomycin).
• For most bacterial infections other than those involving
bone, joint or heart valve tissue, five to seven days of
treatment are sufficient.
Case history
While on holiday in Spain, a 66-year-old man develops a
cough, fever and breathlessness at rest. He is told that his
chest x-ray confirms that he has pneumonia. He is started on
a seven-day course of oral antibiotics by a local physician and
stays in his hotel for the remainder of his ten-day holiday.
When he returns home, he is reviewed by his own GP who
notices that he looks pale and sallow and is still breathless on
exertion, but his chest examination no longer reveals any
signs of pneumonia. A full blood count reveals a haemoglo-
bin level of 6.7 g/dL (previously normal), normal white blood
count and platelets, and a reticulocyte count of 4.1%.
Question
What other tests should you do and what antibiotics would
be most likely to cause this clinical scenario?
Answer
The patient received a course of antibiotics for pneumonia
and then developed what appears to be a haemolytic
anaemia. This could be further confirmed by raised uncon-
jugated bilirubin levels and low haptoglobin levels, and
observation of target cells and poikilocytosis on the blood
film. Mycoplasma pneumonia should be excluded by per-
forming Mycoplasma titres, as this can itself be complicated
by a haemolytic anaemia.
However, considering the drugs as the potential cause, it is
important to define the patient’s glucose-6-phosphate dehy-
drogenase status, and if he was deficient then to consider such
agents as co-trimoxazole (containing sulfamethoxazole, a
sulphonamide), the fluoroquinolones (e.g. ciprofloxacin
or nitrofurantoin) or chloramphenicol, which can cause
haemolytic anaemia in susceptible individuals. Note that chlo-
ramphenicol is more commonly prescribed in certain countries
on the European mainland. Aplastic anaemia (not the picture
in this patient) is a major concern with the use of systemic
chloramphenicol. If the patient’s glucose-6-phosphate dehy-
drogenase status is normal, then rarely the β-lactams (peni-
cillins or early (first- and second-) generation cephalosporins)
or (less likely) rifampicin may cause an autoimmune
haemolytic anaemia due to the production of antibodies to
the antibiotic which binds to the red blood cells. This could be
further confirmed by performing a direct Coombs’ test in
which the patient’s serum in the presence of red cells and the
drug would cause red cell lysis. Management involves stop-
ping the drug, giving folic acid and monitoring recovery of the
haemoglobin. It should be noted in the patient’s record that
certain antibiotics led him to have a haemolytic anaemia.
Table 43.2: New antibacterial agents
Linezolid
Antibiotic class Oxazolidinone
Mechanism Inhibits formation of
of action the 70S ribosomal initiation
complex, preventing
bacterial protein
synthesis; primarily
bacteriostatic action
Spectrum of Gram-positive bacteria
activity and a few Gram-negative
anaerobic bacteria; active
against staphylococci,
pneumocococci and
enterococci, including
those resistant to
penicillin and vancomycin
From Lever A. Recently introduced antibiotics: a guide for the general physician. Clinical Medicine 2004; 4: 494–8.
Moxifloxacin
Fluoroquinolone with an
8-methoxyquinolone structure
Inhibits topoisomerase II and
IV with bactericidal activity
Gram-positives, including staphylococci,
enterococci, Streptococcus pneumoniae,
including penicillin-resistant strains;
atypicals, including Legionella and
Mycoplasma pneumoniae; Gram-negatives,
including Haemophilus influenzae,
Moraxella catarrhalis, coliforms,
Neisseria gonorrhoeae; low activity against
Pseudomonas and some enterobacteriaceae;
active against Mycobacterium tuberculosis,
including multiresistant strains; inhibits
90% of anaerobic bacteria including
clostridia, Bacteroides, Fusobacterium,
Porphyromonas
Telithromycin
Ketolide; a semisynthetic member
of the macrolide-lincosamide-
streptogramin B family of antibiotics
Inhibits bacterial protein synthesis by
direct binding to the 50S subunit of
bacterial ribosomes, preventing
translation and ribosome assembly
Gram-positives, including Streptococcus
pneumoniae (including erythromycin
resistant strains), Streptococcus pyogenes,
MRSA; some Gram-negative bacteria,
including Haemophilus influenzae,
Moraxella catarrhalis; atypicals, including
Mycoplasma pneumoniae, Chlamydia
pneumoniae and Legionella; not active
against erythromycin resistant strains
of MRSA
Ertapenem
Carbapenem
Attaches to penicillin-binding
proteins, inhibiting bacterial
cell wall synthesis; bactericidal
activity
Most enteric bacteria, including
those producing beta-lactamase;
Gram-negative respiratory
pathogens, including Moraxella
catarrhalis and Haemophilus
influenzae; Gram-positive
bacteria, including Streptococcus
pneumoniae (including those
resistant to penicillin) and MRSA;
also effective against many
anaerobes, including Bacteroides,
Prevotella and Porphyromonas;
limited activity against
Pseudomonas aeruginosa
Acinetobacter; Enterococcus,
Lactobacillus, MRSA

Case history
A 70-year-old man with a history of chronic obstructive pul-
monary disease visits his GP in December during a local flu
epidemic. He complains of worsening shortness of breath,
productive cough, fever and malaise. On examination, his
sputum is viscous and green, his respiratory rate is 20 breaths
per minute at rest but, in addition to wheezes, bronchial
breathing is audible over the right lower lobe. The GP pre-
scribes amoxicillin which has been effective in previous exac-
erbations of chronic obstructive pulmonary disease in this
patient. Twenty-four hours later, the patient is brought to
the local Accident and Emergency Department confused,
cyanosed and with a respiratory rate of 30 breaths per
minute. His chest x-ray is consistent with lobar pneumonia.
Question
In addition to controlled oxygen and bronchodilators, which
three antibacterial drugs would you prescribe and why?
Answer
This patient is seriously ill with community-acquired lobar
pneumonia. The previously abnormal chest, the concurrent flu
epidemic and the rapid deterioration suggest Staphylococcus,
but Streptococcus pneumoniae and Legionella are also possi-
ble pathogens. The following antibacterial drugs should be
prescribed:
• Flucloxacillin – active against Staphylococcus and
Gram-positive organisms;
• Cefuroxime – broad spectrum and active against
Staphylococcus;
• Erythromycin – active against Legionella and
Mycoplasma, and also some Staphylococcus and other
Gram-positive bacteria.
COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 333
Case history
A 20-year-old man presented to his GP during a flu epi-
demic complaining of a throbbing headache which was
present when he woke up that morning. He had been
studying hard and was anxious about his exams. Physical
examination was normal and he was sent home with parac-
etamol and vitamins. He presented to casualty 12 hours
later with a worsening headache. Examination revealed a
temperature of 39°C, blood pressure of 110/60 mmHg, neck
stiffness and a purpuric rash on his arms and legs which did
not blanch when pressure was applied.
Question
Which antibacterial drugs would you use and why?
Answer
This young man has meningococcal meningitis and requires
benzylpenicillin i.v. immediately.
REMEMBER: Treatment of bacterial meningitis must never
be delayed.
FURTHER READING
British National Formulary, www.bnf.org.