Miscellaneous Antibacterial Antibiotics

MISCELLANEOUS  ANTIBACTERIAL  ANTIBIOTICS    

CLINDAMYCIN

Clindamycin (Figure 11.11A) is another antibiotic possessing significant bacteristatic activity towards Gram-positive cocci (including MRSA, but not Ent. faecalis), although rather less activity is shown towards Gram-negative cocci and none at all against enterobacteria. Clindamycin is not related structurally to the macrolides (section 4) but has a similar mechanism of action, so cross-resistance may occur between them. The streptogramins also have a similar mechanism of action, but it is claimed that the quinupristin-dalfopristin combination does not demonstrate cross-resistance to clindamycin or the macrolide antibiotics.

Clindamycin is currently recommended for the oral treatment of staphylococcal bone and joint infections, acne, peritonitis, infections by anaerobic bacteria and falciparum malaria. Together with oral cephalosporins, it is one of the antibiotics most firmly associated with pseudomembranous colitis caused by Cl. difficile, and this reputation limits its use.

FUSIDIC ACID

Fusidic acid (Figure 11.11B) is a steroid-like, bactericidal antibiotic used primarily for its activity against staphylococci. It does possess activity against other Gram-positive species, although streptococci are relatively resistant and Gram-negative bacilli completely so. It is active against penicillin-resistant strains of Staph. aureus, including MRSA, and may be administered in combination with erythromycin or clindamycin for severe staphylococcal infections. Fusidic acid is available as a paediatric oral suspension, cream and ointment, and, in the form of its water-soluble sodium salt, as tablets or an intravenous injection. Resistance arises with relative ease in vitro, but despite this, resistance is relatively uncommon in clinical isolates.

MUPIROCIN

Mupirocin (Figure 11.11C) is an antibiotic active against staphylococci, streptococci and a limited range of Gramnegative species. Its use is largely confined to topical treatment of Staph. aureus infections, particularly the eradication of MRSA from the nose; for this purpose it is claimed normally to be more effective than chlorhexidine or fusidic acid.

COLISTIN

Colistin (Figure 11.11D) is the only member of the polymyxin group of peptide antibiotics that is still in use. It is active against many types of Gram-negative bacteria, but not against cocci, Serratia marcescens and Proteus spp.; it is inactive against Gram-positive organisms. Its use is largely restricted to the treatment of Ps. aeruginosa lung infections in cystic fibrosis sufferers, in which case it is nebulized or given by intravenous injection, and in the treatment of infections, particularly in burns, caused by Acinetobacter species.

CHLORAMPHENICOL

Chloramphenicol (Figure 11.11E) is a true antibiotic but is manufactured totally by chemical synthesis. It has a broad spectrum of activity including some rickettsias and larger viruses, but aplastic anaemia, which is dose-related may result from treatment in a proportion of patients and this has largely restricted its use as a systemic antibiotic to life-threatening infections with H. influenzae. It is, however, still used significantly in the treatment of ophthalmic infections and in veterinary medicine.

METRONIDAZOLE AND OTHER NITROIMIDAZOLES

The nitroimidazoles are a group of synthetic antimicrobials that are unusual in possessing activity against a wide range of organisms including bacteria, protozoa, and some helminths. They are similar in terms of their structure, mode of action, uses and toxicity and the principal factor distinguishing them is their pharmacokinetics. Metronidazole (Figure 11.11F) is by far the most commonly used, and is the only one considered in this section, although nimorazole (no longer available in the UK) and tinidazole are alternative drugs that may afford the advantage of less frequent dosing. They may all be regarded as prodrugs in the sense that they become active only after reduction of the nitro group in low redox environments, so they are able to kill cells growing anaerobically by damaging their DNA. This damage could, in theory, occur in any type of cell regardless of its taxonomic status, and the fact that sufficiently reducing conditions do not arise in mammalian cells is the reason for the drugs’ lack of toxicity for humans.

Metronidazole was introduced in 1960 for the treatment of vaginitis caused by the protozoan Trichmonas vaginalis, and its wider application for the treatment of bacterial anaerobic infections was recognized later. Currently metronidazole is used alone, or quite commonly in combination with other antibiotics, for the treatment of a wide variety of bacterial infections shown in Table 11.7. For the treatment of amoebiasis, giardiasis or trichomonal vaginitis, metronidazole is often used alone. Metronidazole is available in more dosage forms (oral, topical, injectable or suppositories) than most other antibiotics, and by the oral route is often given two or three times daily. Toxicity and side effects are relatively uncommon, although it does exhibit a disulphiram-like reaction with alcohol in some patients.

NITROFURANTOIN

Nitrofurantoin (Figure 11.11G) is the one remaining member of the nitrofuran group of drugs that is still in common use. Like metronidazole, nitrofurantoin requires its nitro group to be reduced in order to exhibit anti-microbial activity, and it too exhibits bactericidal activity by damaging DNA. It has a wide spectrum of activity which includes Gram-positive cocci and many Gram-negative enteric bacteria, but after oral administration the blood levels achieved are very low and a significant fraction of the dose is rapidly excreted in the urine, so its use is restricted to the treatment of cystitis. The size of the drug crystals used in tablet manufacture has an effect on the dissolution of the drug, and it is claimed that the macrocrystalline form affords steadier release. Its antimicrobial activity is substantially greater in acid urine, which unfortunately conflicts with the common symptomatic treatment of cystitis by alkalizing the urine with potassium citrate or similar compounds. Nitrofurantoin is unusual in being one of the few antimicrobial drugs to which resistance has not significantly increased since its introduction, and for this reason there is a degree of renewed interest in it.