Antibiotics Review _ __________________________________________________________________________
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]. ABSORPTION/ELIMINATION Imipenem/cilastatin, imipenem/cilastatin/relebactam, meropenem, and ertapenem are given parenterally, as they are unstable in stomach acid. Imipenem is combined with cilastatin, which inhibits dehydropeptidase I in the proximal renal tubular cells. Dehydropeptidase I inactivates imipenem by hydrolysing the beta-lactam ring, so adding the cilastatin allows increased levels of imipenem in the urine and also prevents the production of the nephrotoxic metabolites of imi- penem [63]. The addition of relebactam to imipenem protects imipenem from degradation by certain serine beta-lactamases [6]. Meropenem, doripenem, and ertapenem do not require a dehydropeptidase I inhibitor. Following administration, meropenem penetrates well into body tissues and fluids, including the CSF. Imipenem/cilas- tatin/relebactam and ertapenem are distributed throughout body tissues, but with only low concentrations in the CSF [64]. Most of the imipenem/cilastatin and imipenem/cilastatin/ relebactam doses are excreted in the urine [6]. The remaining 20% to 25% of the dose is excreted through an unknown mechanism. Meropenem is excreted unchanged into the urine by means of glomerular filtration and tubular secretion [65]. Ertapenem is metabolized by hydrolysis of the beta-lactam ring, and then both the metabolite and parent drug are excreted in the urine. The carbapenems require dosage adjustment in patients with renal insufficiency. No changes in dosage are necessary for patients with hepatic insufficiency.
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]. 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.
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MDTX2026
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