STRUCTURE. Penicillins, like cephalosporins, have a beta-Iactam ring fused to a thiazolidine ring (Fig. 1.5). Relatively minor changes to the side-chain of benzylpenicillin render the phenoxymethyl derivative acid resistant and allow it to be absorbed well when given orally. The presence of an amino group in the phenyl radical of benzylpenicillin increases the antimicrobial spectrum of the native penicillin and makes it active against both Gram-negative and Gram-positive organisms. More extensive modification of the side-chain (e.g. as in cloxacillin) renders the drug insensitive to bacterial
penicillinase, a major advance in treating infections caused by penicillinase (f3-lactamase)-producing staphylococci.
MECHANISMS OF ACTION. Penicillins block the terminal cross-linking reaction (between alanine and glycine) of bacterial cell-wall mucopeptide formation. Penicillins and other f3-lactam antibiotics bind to and inactivate specific penicillin-binding proteins (PBPs) which are peptidases involved in the final stages of cell wall assembly and remodelling during growth and divISIOn.
INDICATIONS FOR USE. Benzylpenicillin can only be given parenterally and is often the drug of choice for serious infections, notably infective endocarditis, pneumococcal, eningococcal, streptococcal and gonococcal infections, clostridial infections (tetanus, gas gangrene), actinomycosis, anthrax, and spirochaetal infections (syphilis, yaws).
Phenoxymethylpenicillin (penicillin V) is an oral preparation that is chiefly used as maintenance therapy for rheumatic fever prophylaxis. Flucloxacillin is used in infections caused by penicillinase- producing staphylococci. Methicillin is also effective but must be given by injection. Ampicillin is susceptible to penicillinase, but its antimicrobial activity includes Gram-negative organisms such as Salmonella, Shigella, E. coli, H. influenzae and Proteus. It is useful in the treatment of urinary tract and upper respiratory tract infections. Amoxycillin has a similar sphere of activity to ampicillin, but is better absorbed when given by mouth.
Clavulanic acid is a powerful inhibitor of many bacterial f3-lactamases and when given in combination with an otherwise susceptible agent such as amoxycillin or ticarcillin can broaden the spectrum of activity of the drug. The extended-spectrum penicillins carbenicillin and ticarcillin are active against Pseudomonas infection and the acylureidopenicillin derivatives (azlocillin and piperacillin) have increased activity against Gram-negative organisms, including Pseudomonas, compared with other penicillins. However, they are susceptible to staphylococcal f3-lactamases and are therefore not reliable for treating staphylococcal disease. Oral pivrnecillinam (a mecillinam) is active against many Gram-negative bacteria including salmonellae but excluding Pseudomonas.
RESISTANCE. Bacteria producing penicillinase are resistant to some penicillins.
INTERACTIONS. Penicillins inactivate aminoglycosides when mixed in the same solution.
TOXICITY. Hypersensitivity (skin rash, urticaria, anaphylaxis), encephalopathy and tubule-interstitial nephritis can occur. Ampicillin also produces a hypersensitivity rash in approximately 90% of patients with infectious mononucleosis who receive this drug. Generally, the penicillins are very safe.
The cephalosporins have major advantages over the penicillins in that they are innately resistant to staphylococcal penicillinases and have a broader range of activity that includes both Gram-negative and Gram-positive organisms. Like the penicillins they have a f3-lactam ring, but this is associated with a dihydrothiazine ring in place of the thiazolidine ring found in penicillins. Sidechain modifications increase their potency and range of activity. Structural modifications have produced orally active drugs such as cephalexin and cephradine and a variety of highly potent parenteral preparations such as cefuroxime, cefotaxirne and ceftazidime.
MECHANISM OF ACTION. Like penicillins, cephalosporins inhibit bacterial cell-wall synthesis.
INDICATIONS FOR USE. These potent broad-spectrum antibiotics are useful for the treatment of serious systemic infections, particularly when the precise nature of the infection is unknown. They are commonly used for serious postoperative sepsis and in immunocompromised patients, particularly during treatment of leukaemia and other malignancies.
RESISTANCE. Cephalosporins generally resist the action of f3-lactamase-producing bacteria. They are inactive against enterococci and Pseudomonas aeruginosa (except ceftazidime).
INTERACTIONS. Increased nephrotoxicity is seen when cephalosporins are used in conjunction with other nephrotoxic antibiotics such as aminoglycosides and some diuretics.
TOXICITY. This is as for penicillin; some patients (about 10%) are allergic to both groups of drugs. The early cephalosporins caused proximal tubule damage, although the newer derivatives have less nephrotoxic effects.
MONOBACTAMS Aztreonam is the only member of this class currently available.
STRUCTURE. Aztreonam is a synthetic analogue of an antibiotic found in soil bacteria (Fig. 1.7), with a novel structure containing f3-lactam ring in core configuration.
MECHANISM OF ACTION is inhibition of bacterial cellwall synthesis. It is resistant to most ,B-lactamases and does not induce ,B-lactamase production.
NDICATIONS FOR USE. Aztreonarn’s spectrum of activity is limited to aerobic Gram-negative bacilli, thus to some extent resembling aminoglycosides. With the exception of urinary tract infections, aztreonam should be used in combination with metronidazole (for anaerobes) and an agent active against Gram-positive cocci (a penicillin or erythromycin). It is a useful alternative to aminoglycosides in combination therapy.