N-Formimidoyl thienamycin (imipenem) is the only drug of this class available.
STRUCTURE. Imipenem has a novel structure with a carbon replacing the sulphur in the five-membered ring
MECHANISM OF ACTION. Inhibition of bacterial cellwall synthesis. Imipenem is partially inactivated in the kidney by enzymatic inactivation and is therefore administered in combination with cilastatin.
INDICATIONS FOR USE. Imipenem has the broadest spectrum of activity of all known antibiotics. It is active against Gram-positive cocci (similar potency to penicillins), Gram-negative organisms and anaerobes (similar potency to metronidazole and clindamycin). It should only rarely be used for community-acquired infection, its main indications being nosocomial infections when multiple-resistant Gram-negative bacilli or mixed aerobe and anaerobe infections are suspected.
TOXICITY is similar to that of other ,B-lactam antibiotics. Nausea, vomiting and diarrhoea occur in less than 5%. There is no evidence of nephrotoxicity or coagulation abnormalities.
STRUCTURE. These antibiotics are derived from Streptomyces spp. and are polycationic compounds of amino sugars (Fig. 1.9).
MECHANISMS OF ACTION. Aminoglycosides interrupt bacterial protein synthesis by inhibiting ribosomal function (messenger and transfer RNA).
INDICATIONS FOR USE. Streptomycin is bactericidal for susceptible organisms but is not often used. Neomycin is only used for the topical treatment of eye and skin infections and orally for preoperative ‘bowel sterilization’ and in the management of portosystemic encephalopathy. Even though it is poorly absorbed, prolonged oral administration can produce toxic effects such as ototoxicity. Gentamicin and tobramycin are given parenterally.
They are highly effective against many Gram-negative organisms including Pseudomonas. They are synergistic with a penicillin against Streptococcus Jaecalis. The newer aminoglycosides, netilmicin and amikacin, have a similar spectrum of antibacterial activity and are generally resistant to the aminoglycoside-inactivating enzymes produced by some bacteria. Their use should be restricted to gentamicin- resistant organisms.
RESISTANCE. Some bacteria produce phosphorylating, adenylating or acetylating enzymes that inactivate aminoglycoside antibiotics. These enzymes are coded for and transferred by R factors (extrachromosomal DNA, see p. 10).
INTERACTIONS. Enhanced nephrotoxicity occurs with other nephrotoxic drugs, ototoxicity with some diuretics, and neuromuscular blockade with curariform drugs. TOXICITY. Aminoglycosides are nephrotoxic and ototoxic (vestibular and auditory), particularly in the elderly. Blood levels must be checked (see p. 747).
STRUCTURE. These are bacteriostatic drugs possessing a four-ring hydronaphthacene nucleus (Fig. 1.10). Variation of the native compound is obtained by different
substitutions to give, for example, oxytetracycline and chlortetracycline, or doxycycline.
MECHANISM OF ACTION. Tetracyclines inhibit bacterial protein synthesis by interrupting ribosomal function (transfer RNA). INDICATIONS FOR USE. Tetracyclines are active against Gram-positive and Gram-negative bacteria but their use is now limited. Tetracycline is used for the treatment of acne and rosacea. Tetracyclines are also active against v. cholerae, Rickettsia, Mycoplasma, Coxiella burnetii, Chlamydia and Brucella.
RESISTANCE. Some bacteria possess reduced cell permeability to tetracycline, which is coded for by an R factor. Resistance is particularly important in infections with pneumococci and H. influenzae.
INTERACTIONS. The efficacy of tetracyclines is reduced by antacids, barbiturates and oral iron-replacement therapy.
TOXICITY. Tetracyclines are generally safe drugs, but they may enhance established or incipient renal failure, although doxycycline is safer than others in this group. They cause brown discoloration of growing teeth, and thus these drugs are not given to children or pregnant women. Photosensitivity can occur.