A Textbook of Clinical Pharmacology and Therapeutics

other infections, for example Staphylococcus epidermidisendo-
carditis, and is given orally for pseudomembranous colitis
caused by Clostridium difficile.

Mechanism of action

Vancomycininhibits bacterial cell wall synthesis.

Adverse effects

These include:

• hearing loss;


• venous thrombosis at infusion site;


• ‘red man’ syndrome due to cytokine/histamine release
  following excessively rapid intravenous administration;


• hypersensitivity (rashes, etc.);


• nephrotoxicity.

Pharmacokinetics

Vancomycinis not absorbed from the gut and is usually given
as an intravenous infusion (except for the treatment of
pseudomembranous colitis). It is eliminated by the kidneys.
Because of its concentration-related toxicity, the dose is
adjusted according to the results of plasma concentration
monitoring.

TEICOPLANIN

Teicoplaninhas a longer duration of action, but is otherwise
similar to vancomycin.

METRONIDAZOLE

Uses

Metronidazoleis a synthetic drug with high activity against
anaerobic bacteria. It is also active against several medically
important protozoa and parasites (see Chapter 47). It is used
to treat trichomonal infections, amoebic dysentery, giardiasis,
gas gangrene, pseudomembranous colitis and various abdom-
inal infections, lung abscesses and dental sepsis. It is used pro-
phylactically before abdominal surgery.

Mechanism of action

Metronidazolebinds to DNA and causes strand breakage. In
addition, it acts as an electron acceptor for flavoproteins and
ferredoxins.

Adverse effects

These include:

1. nausea and vomiting;
   2.peripheral neuropathy;
   3.convulsions, headaches;
   4.hepatitis.

Pharmacokinetics

Metronidazoleis 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

Metronidazoleinteracts with alcohol because it inhibits alde-

hyde dehydrogenase and consequently causes a disulfiram-

like reaction. It is a weak inhibitor of cytochrome P450.

SULPHONAMIDES AND TRIMETHOPRIM

Sulphonamides and trimethopriminhibit the production of folic

acid at different sites of its synthetic pathway and are synergistic

in vitro. There is now widespread resistance to sulphonamides,

and they have been largely replaced by more active and less toxic

antibacterial agents. The sulfamethoxazole–trimethoprim combi-

nation (co-trimoxazole) is effective in urinary tract infections,

prostatitis, exacerbations of chronic bronchitis and invasive

Salmonellainfections, but with the exception of Pneumocystis

cariniiinfections (when high doses are used), trimethoprimalone

is generally preferred as it avoids sulphonamide side effects,

whilst having similar efficacy in vivo.

Sulphonamides are generally well absorbed after oral

administration and are widely distributed. Acetylation and

glucuronidation are the most important metabolic pathways.

They may precipitate in acid urine. They frequently cause

unwanted side effects, including hypersensitivity reactions

such as rashes, fever and serum sickness-like syndrome and

Stevens–Johnson syndrome (see Chapter 12). Rarely, agranu-

locytosis, megaloblastic, aplastic or haemolytic anaemia and

thrombocytopenia occur. Sulphonamides are oxidants and

can precipitate haemolytic anaemia in glucose-6-phosphate

dehydrogenase (G6PD)-deficient individuals.

Sulphonamides potentiate the action of sulphonylureas,

oral anticoagulants, phenytoinandmethotrexatedue to inhi-

bition of their metabolism.

Trimethoprimis well absorbed, highly lipid soluble and

widely distributed. At least 65% is eliminated unchanged in

the urine. Trimethoprimcompetes for the same renal clear-

ance pathway as creatinine. It is generally well tolerated, but

occasionally causes gastro-intestinal disturbances, skin reac-

tions and (rarely) bone marrow depression. Additionally, the

highdoses used in the management of Pneumocystispneumonia

in immunosuppressed patients cause vomiting (which can be

improved by prophylactic anti-emetics), a higher incidence of

serious skin reactions, hepatitis and thrombocytopenia.

QUINOLONES

Nalidixic acidwas available for many years, but poor tissue

distribution and adverse effects limited its use to a second- or

third-line treatment for urinary tract infections. Changes to the

330 ANTIBACTERIALDRUGS