___________________________________________________________________________ Antibiotics Review
SPECIAL POPULATIONS Cephalosporins are generally considered safe to use in preg- nancy and are designated as category B. They are excreted in breast milk in low concentrations, and the American Academy of Pediatrics (AAP) considers this compatible with breastfeed- ing [6; 56; 57]. CARBAPENEMS Meropenem, imipenem/cilastatin, doripenem, and ertapenem are parenteral synthetic beta-lactams derived from thienamycin, an antibiotic produced by Streptomyces cattleya [58]. They have a lactam ring, like the penicillins and cephalosporins, but have a methylene moiety in the ring. The newest carbapenem is combination imipenem/cilastatin/relebactam [6]. MECHANISM OF ACTION Like other beta-lactams, the carbapenems inhibit mucopeptide synthesis in the bacterial cell wall by binding to PBPs, leading to lysis and cell death. Bacterial resistance may occur due to a specific beta-lactamase that affects carbapenems. Another significant source of resistance is a mutation that results in the absence of the outer membrane porin, thus not allowing transport of the drug into the cell [59]. Cross-resistance may occur between the carbapenems. PHARMACOKINETICS Imipenem and ertapenem have a wide antimicrobial spectrum with excellent activity against enteric gram-negative bacilli and pseudomonas as well as anaerobic bacteria, including Bacteroides species. They also cover many gram-positive cocci, such as Enterococcus and Streptococcus [60]. Meropenem has somewhat greater activity against gram-negative bacteria, which are not affected by most beta-lactamases. Doripenem has good activity against Pseudomonas aeruginosa . Imipenem and ertapenem are approved by the FDA for use in urinary tract infections, pneumonia, intra-abdominal infections, and skin and soft-tissue infections [6]. Meropenem is approved by the FDA for treatment of intra-abdominal infections, skin and skin structure infections, and meningitis in patients older than 3 months of age [6]. Combination meropenem/vaborbactam is approved for the treatment of complicated urinary tract infections caused by susceptible micro-organisms [6; 61]. The combination imipenem/cilastatin/relebactam was approved by the FDA in 2019 for the treatment of complicated urinary tract infections and complicated intra-abdominal infections [6; 62].
Most cephalosporins are eliminated by the kidney. The excep- tion in the oral cephalosporins is cefixime, half of which is excreted in the urine [6]. The remaining half is metabolized in the liver to inactive metabolites and partly excreted in the bile. Cefotaxime is deacetylated by the liver to a bioactive metabolite and inactive forms. The deacetylated metabolites are excreted by the kidney. Cefditoren is excreted predominantly in the bile. In severe hepatic insufficiency, compensatory changes in renal excretion of the hepatically metabolized drugs may occur [47]. In the presence of severe renal and/or hepatic insufficiency, dosage adjustment of cefotaxime is necessary. SIDE EFFECTS/TOXICITY As a group, cephalosporins are relatively well tolerated [48]. The most common complaints are GI upset, resulting in nausea, vomiting, or diarrhea. Thrombophlebitis can occur with intravenous (IV) administration. One to three percent of patients develop an allergic reaction. Rash, fever, eosinophilia, and urticaria can develop. Anaphylaxis is rare. Infrequently, there is some cross-sensitivity with true penicillin allergy (esti- mated nearly 0%to 10% of cases); this occurs mostly with first- generation cephalosporins [21; 22; 23; 24]. If a patient develops urticaria, anaphylaxis, or angioedema with penicillins or a cephalosporin, avoid using any of the other cephalosporins. Although uncommon, nephrotoxicity has been reported [49]. Cephalosporins that contain the methylthiotetrazole (MTT) side chain (cefotetan) may induce a disulfiram-like reaction with alcohol ingestion (e.g., flushing, tachycardia, nausea and vomiting, diaphoresis, dyspnea, hypotension, and confusion). This is due to increased circulating acetaldehyde. Ceftriaxone has been associated with cholelithiasis and chole- static hepatitis due to precipitation in bile [50; 51]. Rare reac- tions include hematologic toxicity with resultant eosinophilia, thrombocytopenia, and leukopenia, all of which resolve after stopping treatment [52]. Rarely, hemolytic anemia develops [53]. Hypoprothrombinemia may occur with cephalosporins with the MTT side chain as a result of interference by the MTT moiety with the synthesis of vitamin-K-dependent clotting factors [54]. For patients at high risk of bleeding, exogenous vitamin K may help alleviate this side effect. False-positive glucosuria testing with a copper reduction test (Clinitest) may occur with many cephalosporins [6; 55]. DRUG INTERACTIONS The serum levels of all the cephalosporins are increased with co-administration of probenecid. The effects of warfarin may be enhanced by co-administration of cefotetan, cefazolin, cefoxitin, and ceftriaxone [6].
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