___________________________________________________________________________ Antibiotics Review
SIDE EFFECTS/TOXICITY These drugs are usually well tolerated. However, gastrointes- tinal (GI) disturbances may occur with all oral penicillins. Allergy to any of the penicillins is the only absolute contra- indication to use of a penicillin agent. However, studies have found that penicillin allergy is less common than previously thought [22; 23; 24; 25]. Traditionally, allergic reactions were believed to occur in up to 10% of patients; however, more recent studies have found the rate to be much lower. While penicillin-induced anaphylaxis death rate estimates are similar to previous statistics (i.e., approximately 0.002% among the general population), the percentage of individuals with a true penicillin allergy as defined by immunoglobulin E (IgE)- mediated reaction is generally less than 10%, with some stud- ies showing a true penicillin allergy rate of only 0.7% [22; 23; 24; 26]. It is also important to note that approximately 90% of patients previously diagnosed with a penicillin allergy will show no reactivity if not exposed to the antibiotic for 10 years or more, due to the absence of a true allergy or loss of allergy over time [22; 24; 25]. Allergy skin testing is the most reliable way to determine true penicillin allergy and may allow for previously avoided antibiotics to be used as indicated. Reactions commonly misdiagnosed as true allergic responses vary and can include a mild rash (the most common) and urticaria. Rarely, serum sickness, exfoliative dermatitis, and Stevens-Johnson syndrome may develop [6; 20]. These responses were originally thought to develop in response to the beta-lactam ring and its derivatives and, therefore, there is a common misperception that penicillins are cross-reactive with other antibiotics with the same beta-lactam structure (e.g., cephalosporins) [6]. However, the major determinant in the immunologic reaction is now recognized to be the similarity in the side chain of first-generation cephalosporins and penicillins (not the beta-lactam structure), with the reaction nearing 0% in third-generation cephalosporins [22; 23; 24]. Rarely, penicillins may cause hematologic reactions with neutropenia due to reversible bone marrow suppression. Abnormal platelet aggregation may occur, particularly with ticarcillin [27]. Other rare reactions include hepatitis, seizures, interstitial nephritis, and hypokalemia due to local effects in the renal tubules. DRUG INTERACTIONS The penicillins should not be given concurrently with tet- racycline or other bacteriostatic agents. Penicillin works in cells that are actively synthesizing cell wall components, and if metabolism is prevented, then the activity of penicillin is diminished. The antipseudomonal penicillins also may affect warfarin metabolism. Therefore, the prothrombin time, using the international normalized ratio (INR), should be monitored [6; 28].
SPECIAL POPULATIONS The penicillins are pregnancy category B, indicating no adverse events noted in animal studies [6; 29]. These agents are secreted in breast milk, and breastfeeding should be avoided if the infant is allergic to any of the penicillins [30]. Use while breastfeeding may cause modifications of normal intestinal flora and allergic sensitization in the infant [6]. CEPHALOSPORINS Giuseppe Brotzu discovered the first cephalosporin in 1948, observing that the fungus Cephalosporium acremonium produced a substance that inhibited the growth of S. aureus and other bacteria. The initial substance was identified and modified to create the cephalosporins that are now used. The cephamycins were created by adding a methoxy group on the beta-lactam ring of the original compound, based on the structure of cefoxitin, produced by Streptomyces lactamdurans . By altering the chemical groups substituted on the basic molecule, greater antimicrobial activity and longer half-lives have been obtained [31]. MECHANISM OF ACTION Like penicillins, the cephalosporins are beta-lactams in which the beta-lactam ring is joined to a dihydrothiazine ring. Their antimicrobial effect is based on the same mechanism of action as that for the penicillins. The cephalosporins inhibit bacterial cell wall synthesis by blocking the transpeptidases and other PBPs involved in the synthesis and cross-linking of peptido- glycan [32; 33]. Because each bacterial species has a unique chemical structure in its cell wall, the cephalosporins may have different mecha- nisms of action by which they inhibit cell wall synthesis. As with penicillins, resistance to cephalosporins results from mutations in the penicillin-binding proteins (preventing the cephalosporins from binding to them) and from the produc- tion of extended-spectrum beta-lactamases that deactivate the drug [34]. An additional source of resistance in gram-negative bacteria is alteration in the cell-membrane porins that normally allow passage of the cephalosporins into the cell [35]. Of these mechanisms, the production of beta-lactamase is the most clinically significant. This form of resistance may occur through mutations or may be carried on plasmids [36]. PHARMACOKINETICS The cephalosporins have been classified in different ways, based on chemical structure and pharmacologic activities. The conventional classification for clinical purposes groups cephalosporins into “generations” based on when they were developed and similarities in antimicrobial coverage.
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