A Textbook of Clinical Pharmacology and Therapeutics

Enterococcus faecalis, but not (when used alone) against other
streptococci. They synergize with penicillins in killing
Streptococcus faecalisin endocarditis. Aminoglycosides are used
in serious infections including septicaemia, sometimes alone
but usually in combination with other antibiotics (penicillins
or cephalosporins). Gentamicinis widely used and has a
broad spectrum, but is ineffective against anaerobes, many
streptococci and pneumococci.
Tobramycinis probably somewhat less nephrotoxic than
gentamicin.Amikacinis more effective than gentamicinfor
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 gentamicinortobramycin
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

Chloramphenicolhas 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. influenzaeepiglottitis, 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).
   Chloramphenicolaccumulates 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

Chloramphenicolis 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,

phenytoinandtheophylline.

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,

LegionellaandMycoplasma.

ERYTHROMYCIN

Uses

Uses include respiratory infections (including Mycoplasma

pneumoniae, psittacosis and Legionnaires’ disease), whooping

cough, Campylobacter enteritis and non-specific urethritis.

Erythromycinis a useful alternative to penicillinin 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.

328 ANTIBACTERIALDRUGS