Cephalosporins were first obtained from a filamentous fungus Cephalosporium cultured from the sea near a Sardinian sewage outfall in 1945; their molecular structure is closely related to that of penicillin, and many semisynthetic forms have been introduced. They now comprise a group of antibiotics having a wide range of activity and low toxicity. The term cephalosporins will be used here in a general sense although some are strictly cephamycins, e.g. cefoxitin and cefotetan.
Mode of action is that of the p-lactams, i.e. cephalosporins impair bacterial cell wall synthesis and hence are bactericidal. They exhibit time-dependent bacterial killing (see p. 203).
Addition of various side-chains on the cephalosporin molecule confers variety in pharmacokinetic and antibacterial activities. The [i-lactam ring can be protected by such structural manoeuvring, which results in compounds with improved activity against Gram-negative organisms; a common corollary is that such agents lose some anti-Gram-positive activity. The cephalosporins resist attack by (3-lactamases but bacteria develop resistance to them by other means. Methicillin-resistant Staphylococcus aureus (MRSA) should be considered resistant to all cephalosporins.
Pharmacokinetics. Usually, cephalosporins are excreted unchanged in the urine, but some, including cefotaxime, form a desacetyl metabolite which possesses some antibacterial activity. Many are actively secreted by the renal tubule, a process which can be blocked with probenecid. As a rule, the dose of cephalosporins should be reduced in patients with poor renal function. Cephalosporins in general have a t'/2 of 1-4 h although there are exceptions (e.g. ceftriaxone, t'/2 8 h). Wide distribution in the body allows treatment of infection at most sites, including bone, soft tissue, muscle and (in some cases) CSF. Data on individual cephalosporins appear in Table 12.1.
Classification and uses. The cephalosporins are conventionally categorised by generations having broadly similar antibacterial and pharmacokinetic properties; newer agents have rendered this classification less precise but it retains sufficient usefulness to be presented in Table 12.1.
Adverse effects. Cephalosporins are well tolerated. The most usual unwanted effects are allergic reactions of the penicillin type. There is cross-allergy between penicillins and cephalosporins involving about 7% of patients; if a patient has had a severe or immediate allergic reaction or if serum or skin testing for penicillin allergy is positive (see p. 217), then a cephalosporin should not be used. Pain may be experienced at the sites of i.v. or i.m. injection. If cephalosporins are continued for more than 2 weeks, thrombocytopenia, haemolytic anaemia, neutropenia, interstitial nephritis or abnormal liver function tests may occur especially at high dosage; these reverse on stopping the drug. The broad spectrum of activity of the third generation cephalosporins may predispose to opportunist infection with resistant bacteria or Candida albicans and to Clostridium difficile diarrhoea. Ceftriaxone achieves high concentrations in bile and, as the calcium salt, may precipitate to cause symptoms resembling cholelithiasis (biliary pseudolithiasis). Cefamandole may cause prothrombin deficiency and a disulfiram-like reaction after ingestion of alcohol.
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