Write an essay on the pharmacology of the cephalosporins.

Outline:

·        Mechanism of action.

·        Pharmacokinetics.

·        Spectrum of antibacterial activity and resistance.

·        Adverse effects.

Suggested Answer:

Cephalosporins are semisynthetic antibiotic derivatives of cephalosporin C, a substance produced by the fungus Cephalosporium acremonium. The drugs are beta-lactam antibiotics structurally and pharmacologically related to penicillins, carbacephems (e.g.,loracarbef), and cephamycins (e.g., cefotetan, cefoxitin). All commercially available cephalosporins contain the 7-aminocephalosporanic acid (7-ACA) nucleus. Modifications at 3 and 7 positions of the 7-aminocephalosporanic acid nucleus produce cephalosporins that vary widely in spectrum of anti-bacterial activity and pharmacokinetic properties. 2 antibiotics which are included in the family of cephalosporins but are technically not cephalosporins are cefoxitin and moxalactam.

Cephalosporins are usually bactericidal in action. The antibacterial activity of the cephalosporins, like penicillins, carbacephems, and cephamycins, results from inhibition of mucopeptide synthesis in the bacterial cell wall. The target enzymes of beta-lactam antibiotics have been classified as penicillin-binding proteins (PBPs) and appear to vary substantially among bacterial species.

In general, cephalosporins are active in vitro against many gram-positive aerobic bacteria, some gram-negative aerobic bacteria, and some anaerobic bacteria; however, there are substantial differences among the cephalosporins in spectra of activity as well as levels of activity against susceptible bacteria. Cephalosporins are inactive against fungi and viruses. Currently available cephalosporins are generally divided into 4 groups based on their spectra of activity: first, second, third, and fourth generation cephalosporins. Closely related beta-lactam antibiotics (e.g., cephamycins) also may be classified in these groups because of their similar spectra of activity.

First generation cephalosporins are cephalorindin, cephalothin, cefazolin and cephradine. First generation cephalosporins usually are active in vitro against gram-positive cocci including penicillinase-producing and nonpenicillinase-producing Staphylococcus aureus and S. epidermidis; Streptococcus pyogenes (group A beta-hemolytic streptococci); S. agalactiae (group B streptococci); and S. pneumoniae. First generation cephalosporins have limited activity against gram-negative bacteria, although some strains of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Shigella may be inhibited in vitro by the drugs. First generation cephalosporins are inactive against enterococci methicillin-resistant staphylococci, Bacteroides fragilis, Citrobacter, Enterobacter, Listeria monocytogenes, Proteus other than P. mirabilis, Providencia, Pseudomonas, and Serratia.

Second generation drugs are cefoxitin, cefamandole, cefuroxime and cefaclor. The second generation drugs may be active in vitro against some strains of Acinetobacter, Citrobacter, Enterobacter, E. coli, Klebsiella, Neisseria, Proteus, Providencia, and Serratia that are resistant to the first generation drugs. Cefotetan, cefoxitin, and, to a lesser extent, cefamandole also have some activity in vitro against B. fragilis. Second generation cephalosporins are inactive against enterococci (e.g., E. faecalis), methicillin-resistant staphylococci, and Pseudomonas.

Third generation drugs are cefotaxime, ceftizoxime, ceftriaxone, moxalactam and cefoperazone. Their activity against gram positive cocci is decreased compared to the older cephalosporins and have greater activity against gram-negative bacilli than 2nd generation cephalosporins. Third generation cephalosporins usually are less active in vitro against susceptible staphylococci than first generation cephalosporins; however, the third generation drugs have an expanded spectrum of activity against gram-negative bacteria compared with the first and second generation drugs. Third generation cephalosporins generally are active in vitro against gram-negative bacteria susceptible to the first and second generation drugs, and most also are active in vitro against Citrobacter, Enterobacter, E. coli, Klebsiella, Neisseria, Proteus, Morganella, Providencia, and Serratia that may be resistant to first and second generation cephalosporins. Third generation cephalosporins are inactive against methicillin-resistant staphylococci and generally are inactive against enterococci (e.g., E. faecalis) and L. monocytogenes.

Fourth generation cephalosporins (e.g. cefepime), like third generation cephalosporins, have an expanded spectrum of activity against gram-negative bacteria compared with the first and second generation drugs. However, fourth generation cephalosporins are active invitro against some gram-negative bacteria, including Pseudomonas aeruginosa and certain Enterobacteriaceae, that generally are resistant to third generation cephalosporins. In addition, fourth generation cephalosporins may be more active against gram-positive bacteria than some third generation drugs. The extended spectrum of activity of cefepime is related to the fact that the drug penetrates the outer membrane of gram-negative bacteria more rapidly than most other cephalosporins and the fact that the drug is more resistant to inactivation by chromosomally and plasmid-mediated beta-lactamases than most other cephalosporins.

Cephalosporins in general have a half life of 1-4 h. The oral drugs are cephalexin, cephradine, cefaclor, cefprozil and cefdinir. The parenteral drugs are cephalothin, cefazolin, cefoxitin, cefotaxime, ceftriaxone and moxalactam. Wide distribution in the body allows treatment of infection at most sites, including bone, soft tissue and muscle. Only low concentrations of first or second generation cephalosporins diffuse into CSF following oral, IM, or IV administration even when meninges are inflamed; however, therapeutic concentrations of cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, or cefuroxime generally are attained in CSF following IM or IV administration, especially if meninges are inflamed. Cefepime also is distributed into CSF following parenteral administration. Cephalosporins readily cross the placenta, and fetal serum concentrations may be 10% or more of maternal serum concentrations. Cephalosporins are distributed in low concentrations into milk. Cephalosoprins are excreted unchanged in the urine. Many are actively secreted by the renal tubule. In general, the dose of cephalosporins should be reduced in patients with poor renal function.

Cephalosporins have a low incidence of adverse effects. The most usual are allergic reactions of the penicillin type. There is cross-allergy between penicillins and cephalosporins involving about 10% of patients. These hypersensitivity reactions include anaphylaxis, skin rash and eosinophilia. Maculopapular or erythematous rash, exfoliative dermatitis, pruritus, urticaria, eosinophilia, fever, and other hypersensitivity reactions have occurred with cefoxitin. Pain may be experienced at the sties of i.v. or i.m. injection. If cephalosporins are continued for more than 2 weeks, thrombocytopenia, neutropenia, interstitial nephritis or abnormal liver function tests may occur; 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. Ceftriaxone achieves high concentrations in bile and as, the calcium salt, may precipitate to cause symptoms resembling cholelithiasis. Moxalactam, cefoperazone and cefamandole have been associated with the development of hypoprothrombinaemia and platelet dysfunction. Renal effects that have occurred occasionally with administration of a cephalosporin include transient increases in BUN and serum creatinine concentrations, renal dysfunction, and toxic nephropathy. Nephrotoxicity has been reported rarely with cephalexin and cefazolin. Genitourinary effects reported with cephalosporin therapy include vaginitis, vaginal candidiasis, genital pruritus, and menstrual irregularities.

Rarely, adverse GI effects including nausea, vomiting, and diarrhea have been reported in patients receiving cefoxitin. Clostridium difficile-associated diarrhea and colitis, caused by toxin-producing clostridia resistant to cefoxitin, has occurred in patients who received multiple doses of the drug for perioperative prophylaxis.

Disulfiram-like reactions have occurred when alcohol was ingested within 48—72 hours after administration of cefamandole, cefoperazone, and cefotetan. Concomitant administration of oral probenecid competitively inhibits tubular secretion resulting in higher and more prolonged serum concentrations of most cephalosporins. Concurrent use of nephrotoxic agents such as aminoglycosides, colistin, polymyxin B, or vancomycin may increase the risk of nephrotoxicity with some cephalosporins and probably should be avoided, if possible.