27.12.2012 Views

A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

SHOW MORE
SHOW LESS

You also want an ePaper? Increase the reach of your titles

YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.

330 ANTIBACTERIAL DRUGS<br />

other infections, for example Staphylococcus epidermidis endocarditis,<br />

<strong>and</strong> is given orally for pseudomembranous colitis<br />

caused by Clostridium difficile.<br />

Mechanism <strong>of</strong> action<br />

Vancomycin inhibits bacterial cell wall synthesis.<br />

Adverse effects<br />

These include:<br />

• hearing loss;<br />

• venous thrombosis at infusion site;<br />

• ‘red man’ syndrome due to cytokine/histamine release<br />

following excessively rapid intravenous administration;<br />

• hypersensitivity (rashes, etc.);<br />

• nephrotoxicity.<br />

Pharmacokinetics<br />

Vancomycin is not absorbed from the gut <strong>and</strong> is usually given<br />

as an intravenous infusion (except for the treatment <strong>of</strong><br />

pseudomembranous colitis). It is eliminated by the kidneys.<br />

Because <strong>of</strong> its concentration-related toxicity, the dose is<br />

adjusted according to the results <strong>of</strong> plasma concentration<br />

monitoring.<br />

TEICOPLANIN<br />

Teicoplanin has a longer duration <strong>of</strong> action, but is otherwise<br />

similar to vancomycin.<br />

METRONIDAZOLE<br />

Uses<br />

Metronidazole is a synthetic drug with high activity against<br />

anaerobic bacteria. It is also active against several medically<br />

important protozoa <strong>and</strong> parasites (see Chapter 47). It is used<br />

to treat trichomonal infections, amoebic dysentery, giardiasis,<br />

gas gangrene, pseudomembranous colitis <strong>and</strong> various abdominal<br />

infections, lung abscesses <strong>and</strong> dental sepsis. It is used prophylactically<br />

before abdominal surgery.<br />

Mechanism <strong>of</strong> action<br />

Metronidazole binds to DNA <strong>and</strong> causes str<strong>and</strong> breakage. In<br />

addition, it acts as an electron acceptor for flavoproteins <strong>and</strong><br />

ferredoxins.<br />

Adverse effects<br />

These include:<br />

1. nausea <strong>and</strong> vomiting;<br />

2. peripheral neuropathy;<br />

3. convulsions, headaches;<br />

4. hepatitis.<br />

Pharmacokinetics<br />

Metronidazole is well absorbed after oral or rectal administration,<br />

but is <strong>of</strong>ten administered by the relatively expensive<br />

intravenous route. The half-life is approximately six hours. It is<br />

eliminated by a combination <strong>of</strong> hepatic metabolism <strong>and</strong> renal<br />

excretion. Dose reduction is required in renal impairment.<br />

Drug interactions<br />

Metronidazole interacts with alcohol because it inhibits aldehyde<br />

dehydrogenase <strong>and</strong> consequently causes a disulfiramlike<br />

reaction. It is a weak inhibitor <strong>of</strong> cytochrome P450.<br />

SULPHONAMIDES AND TRIMETHOPRIM<br />

Sulphonamides <strong>and</strong> trimethoprim inhibit the production <strong>of</strong> folic<br />

acid at different sites <strong>of</strong> its synthetic pathway <strong>and</strong> are synergistic<br />

in vitro. There is now widespread resistance to sulphonamides,<br />

<strong>and</strong> they have been largely replaced by more active <strong>and</strong> less toxic<br />

antibacterial agents. The sulfamethoxazole–trimethoprim combination<br />

(co-trimoxazole) is effective in urinary tract infections,<br />

prostatitis, exacerbations <strong>of</strong> chronic bronchitis <strong>and</strong> invasive<br />

Salmonella infections, but with the exception <strong>of</strong> Pneumocystis<br />

carinii infections (when high doses are used), trimethoprim alone<br />

is generally preferred as it avoids sulphonamide side effects,<br />

whilst having similar efficacy in vivo.<br />

Sulphonamides are generally well absorbed after oral<br />

administration <strong>and</strong> are widely distributed. Acetylation <strong>and</strong><br />

glucuronidation are the most important metabolic pathways.<br />

They may precipitate in acid urine. They frequently cause<br />

unwanted side effects, including hypersensitivity reactions<br />

such as rashes, fever <strong>and</strong> serum sickness-like syndrome <strong>and</strong><br />

Stevens–Johnson syndrome (see Chapter 12). Rarely, agranulocytosis,<br />

megaloblastic, aplastic or haemolytic anaemia <strong>and</strong><br />

thrombocytopenia occur. Sulphonamides are oxidants <strong>and</strong><br />

can precipitate haemolytic anaemia in glucose-6-phosphate<br />

dehydrogenase (G6PD)-deficient individuals.<br />

Sulphonamides potentiate the action <strong>of</strong> sulphonylureas,<br />

oral anticoagulants, phenytoin <strong>and</strong> methotrexate due to inhibition<br />

<strong>of</strong> their metabolism.<br />

Trimethoprim is well absorbed, highly lipid soluble <strong>and</strong><br />

widely distributed. At least 65% is eliminated unchanged in<br />

the urine. Trimethoprim competes for the same renal clearance<br />

pathway as creatinine. It is generally well tolerated, but<br />

occasionally causes gastro-intestinal disturbances, skin reactions<br />

<strong>and</strong> (rarely) bone marrow depression. Additionally, the<br />

high doses used in the management <strong>of</strong> Pneumocystis pneumonia<br />

in immunosuppressed patients cause vomiting (which can be<br />

improved by prophylactic anti-emetics), a higher incidence <strong>of</strong><br />

serious skin reactions, hepatitis <strong>and</strong> thrombocytopenia.<br />

QUINOLONES<br />

Nalidixic acid was available for many years, but poor tissue<br />

distribution <strong>and</strong> adverse effects limited its use to a second- or<br />

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

Hooray! Your file is uploaded and ready to be published.

Saved successfully!

Ooh no, something went wrong!