A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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