Clinical Pharmacology and Therapeutics

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 protein
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 failure
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 halflife
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 clearance
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 nondepolarizing
neuromuscular antagonists. Loop diuretics
potentiate their nephrotoxicity and ototoxicity.
CHLORAMPHENICOL
Uses
Chloramphenicol has a broad spectrum of activity and penetrates
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 preventing
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 administration
and can also be given by the intramuscular and intravenous
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 penicillinallergic
patients (except meningitis: it does not penetrate the
CSF adequately). It is useful for skin infections, such as lowgrade
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.