Chapter: Modern Pharmacology with Clinical Applications: β-Lactam Antibiotics

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The cephalosporins are semisynthetic antibiotics derived from products of various microorganisms, including Cephalosporium and Streptomyces.




The cephalosporins are semisynthetic antibiotics derived from products of various microorganisms, including Cephalosporium and Streptomyces. All cephalosporins have a 7-aminocephalosporanic acid composed of a di-hydrothiazine ring fused to a β-lactam ring (Fig. 45.3). As with the penicillins, the cephalosporin β-lactam ring is the chemical group associated with antibacterial activity. The different pharmacological, pharmacokinetic, and an-tibacterial properties of individual cephalosporins result from substitution of various groups on the basic mole-cule. Cephalosporins also vary in acid stability and β-lactamase susceptibility. Table 45.2 shows the large num-ber of available cephalosporins.


The β-lactamases (penicillinases) inactivate some cephalosporins but are much less efficient than are the cephalosporinases ( β-lactamases specific for the cephalosporins). Resistance to cephalosporins also re-sults from modification of microbial PBPs.


Antibacterial Spectrum


The cephalosporins are classified into generations (Table 45.2) according to their antibacterial spectrum and stability to β-lactamases. The first-generation cephalosporins have in vitro antimicrobial activity against streptococci, methicillin-sensitive S. aureus, and a few gram-negative bacilli. The second-generation cepha-losporins have greater stability against β-lactamase inac-tivation and possess a broader spectrum of activity to in-clude gram-positive cocci, gram-negative organisms, and anaerobes. Among the second-generation cephalo-sporins, the cephamycins (cefoxitin [Mefoxin], cefotetan [Cefotan], and cefmetazole [Zefazone]) have the most activity against Bacteroides fragilis. The extended-spectrum, or third-generation, cephalosporins possess a high degree of in vitro potency and β-lactamase stability and a broader spectrum of action against many common gram-negative bacteria and anaerobes while retaining good activity against streptococci. Third-generation cephalosporins are less active against staphylococci than the earlier generations. The agents with the greatest ac-tivity against P. aeruginosa are cefepime, cefoperazone, and ceftazidime. Cefepime has been called a fourth-gen-eration cephalosporin because of its great in vitro activ-ity against several gram-positive and gram-negative or-ganisms. 

The distinction between third and fourth generation may be irrelevant, however, since clinical outcomes are similar in human trials comparing ce-fepime and other third-generation cephalosporins. None of the cephalosporins adequately treats infections caused by Enterococcus faecalis, E. faecium, MRSA, or L. monocytogenes.


Absorption, Distribution, Metabolism, and Excretion


Most parenteral cephalosporins have good bioavailabil-ity after intramuscular injection, and a few members of each cephalosporin generation have good oral bioavail-ability (Table 45.2). The ester prodrugs cefuroxime ax-etil (Ceftin) and cefpodoxime proxetil (Vantin) are oral formulations in which the ester is hydrolyzed during drug passage through the intestinal mucosa; the free cephalosporin enters the systemic circulation. Con-comitant ingestion of food reduces the bioavailability of some cephalosporins, e.g., cefaclor (Ceclor), and there-fore, these compounds should be administered on an empty stomach.


The cephalosporins distribute in satisfactory con-centrations to most tissues except the central nervous system. Only cefepime, cefuroxime (Zinacef), cefo-taxime (Claforan), ceftriaxone (Rocephin), and cef-tazidime (Fortaz) achieve therapeutic concentrations in cerebrospinal fluid. Cefotaxime and ceftriaxone are an-tibiotics of first choice for the empirical treatment of brain abscess and meningitis.

There is considerable variation in the protein bind-ing among the cephalosporins. Drugs like ceftriaxone that have extensive protein binding (85–95%) may dis-place bilirubin from serum albumin. Consequently, cef-triaxone may increase the risk of kernicterus in jaun-diced neonates.


Urinary excretion is the major elimination path for most cephalosporins. When prescribing cephalosporins to patients with renal failure, practitioners must consider dose reduction or dose interval extension (Table 45.2). Renal tubular secretion contributes to the elimination of some cephalosporins, and an increase in cephalosporin plasma concentrations may occur when probenecid blocks renal tubular secretion of cephalosporins. Biliary elimination is important for some cephalosporins. Cefmetazole, cefoperazone (Cefobid), cefoxitin, and cef-triaxone achieve biliary concentrations greater than those in plasma. After parenteral administration of cef-operazone, 70% of the dose appears in the bile within 24 hours. Practitioners should decrease the dose of cefop-erazone when prescribing for patients with hepatic fail-ure or biliary obstruction. Metabolism is not a major elimination path for most cephalosporins. Cefotaxime is one of the few cephalosporins having an active metabo-lite, desacetyl cefotaxime.


Clinical Uses


The first-generation cephalosporins have activity against most of the bacterial pathogens that colonize skin and infect wounds. Consequently, first-generation cephalosporins are useful in antimicrobial prophylaxis before surgery. Second-generation cephalosporins are used to treat infections caused by susceptible organ-isms. For example, cefoxitin and cefotetan have good anaerobic activity, and they have utility in the treatment and prophylaxis of lower abdominal and gynecological infection. A broad spectrum of antibacterial activity makes third-generation cephalosporins important in the treatment of a wide range of infections, including Lyme disease, pneumonia, peritonitis, and sepsis syn-drome.



Adverse Effects


The cephalosporins have good safety profiles. The overall incidence of adverse events attributed to cephalosporins is between 1 and 10%. The most common adverse drug reactions are rashes (1–5%), eosinophilia (3–10%), gas-trointestinal symptoms (3%), hematological abnormali-ties (1–2%), phlebitis (2%), and fever ( 1%). Ana-phylactic reactions to cephalosporins are rare ( 0.02%).


Because of cross-reactions between cephalosporins and penicillins, caution should be used when prescribing cephalosporins to patients with penicillin allergy. If a patient had anaphylaxis, angioedema, or urticaria fol-

lowing penicillin use, cephalosporins should be avoided. Among patients with morbilliform rashes (resembling measles) after penicillin, the majority (95%) will toler-ate cephalosporins without adverse effects and with no increased risk of anaphylaxis. When evaluating patients with histories of allergic penicillin reactions, practition-ers may order penicillin skin tests to screen potential cephalosporin recipients. The frequency of allergic reac-tions to cephalosporins is 1.7% in patients with histories of type I penicillin reactions and negative penicillin skin tests. Most patients with negative penicillin skin tests may receive cephalosporins safely.


The cephalosporins are valuable because of their broad spectrum of antimicrobial activity. However, their bactericidal action alters gut flora and selects for overgrowth of resistant organisms. Cephalosporins have been associated with superinfections with Clostridium difficile, enterococci, MRSA, coagulase-negative staphylococci, P. aeruginosa, and Candida albi-cans. Overgrowth by toxigenic C. difficile occasionally causes pseudomembranous colitis in patients treated with cephalosporins. Some third-generation cepha-losporins induce production of extended-spectrum β-lactamases (ESBLs) in P. aeruginosa. The ESBLs can transfer to various Enterobacteriaceae and produce or-ganisms resistant to almost all β-lactam antibiotics.


Bleeding is an uncommon but serious side effect of some cephalosporins. The N-methylthiotetrazole (MTT) side chain on the R substituent inhibits production of active vitamin K. Cephalosporins with the MTT side chain (cefamandole, cefmetazole, cefoperazone, cefote-tan) are associated with hypoprothrombinemia, coagu-lation abnormalities, and bleeding. In addition, the MTT cephalosporins increase the effect of oral antico-agulants. Bleeding or coagulation abnormalities caused by MTT cephalosporins can be treated or prevented with supplemental vitamin K. Additional bleeding problems may result from antiplatelet effects. The MTT side chain confers a structure and activity similar to that of disulfiram, so patients taking MTT cephalosporins who also ingest alcohol may develop symptoms similar to the disulfiram reaction.


Children and adults receiving high doses of ceftriax-one may develop gallbladder sludge (pseudolithiasis). While most patients with sludge have no symptoms, oc-casionally the sludge identified by abdominal ultra-sonography has led to laparotomy. Biliary sludge usu-ally disappears after discontinuation of ceftriaxone.


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