Antibiotics Review _ __________________________________________________________________________
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. SIDE EFFECTS/TOXICITY The carbapenems are generally well tolerated. Occasional reactions include nausea and vomiting, phlebitis at the infu- sion site, elevation of liver enzymes, and leukopenia. Seizures may occur. The risk is higher in patients with underlying central nervous system (CNS) disease and in patients with renal disease, which results in high serum levels of the drug [66]. Hypersensitivity reactions may occur, and while there is a degree of cross-sensitivity with penicillins, this risk is lower than previously believed [22; 23; 24]. Carbapenems should be used with caution in patients allergic to the carbapenems or penicillins [6]. DRUG INTERACTIONS There are few drug interactions associated with the car- bapenems, but probenecid may increase the serum levels of meropenem, ertapenem, imipenem/cilastatin, and imipenem/ cilastatin/relebactam and should be avoided. Ertapenem can- not be infused with dextrose or other medications. Meropenem may reduce levels of valproic acid [67].
SPECIAL POPULATIONS Meropenem, doripenem, and ertapenem are pregnancy cat- egory B, with animal studies showing no adverse reactions [68]. Imipenem/cilastatin is pregnancy category C, based on studies in monkeys that showed increased embryonic loss and side effects in the mother [69]. No pregnancy category has been assigned to imipenem/cilastatin/relebactam [6; 70]. No data are available regarding breastfeeding and carbapenem administration. The safety of doripenem use has not been studied in children. Meropenem has been used in children and is indicated by the FDA for the treatment of pediatric meningitis but has not been studied in infants younger than 3 months of age [6; 71]. Ertapenem can be used in infants older than 3 months of age, and imipenem can be used from birth; these agents are useful for treating complicated infections in pediatric patients (e.g., complicated urinary tract infections). MONOBACTAMS Monobactams have a single beta-lactam core, distinguishing them from the other beta-lactam drugs [72]. Aztreonam is the only available example of this class of drugs. Aztreonam was originally extracted from Chromobacterium violaceum . It is now manufactured as a synthetic antibiotic. MECHANISM OF ACTION As with other beta-lactams, aztreonam inhibits mucopeptide synthesis in the bacterial cell wall by binding to the penicillin- binding proteins of gram-negative bacteria, leading to cell lysis and death. Aztreonam is resistant to most beta-lactamases. Treatment in combination with an aminoglycoside appears to be synergistic against Pseudomonas . PHARMACOKINETICS Aztreonam does not have significant activity against gram- positive or anaerobic bacteria and is primarily used as an alternative therapy for gram-negative bacterial infections, including P. aeruginosa and Klebsiella , that are resistant to the first-line beta-lactams or carbapenems. It is indicated for use in pneumonia, soft-tissue infections, urinary tract infections, and intra-abdominal and pelvic infections that are caused by gram-negative aerobic bacteria. There is no oral form of aztreonam, and intravenous is the preferred mode of parenteral administration. It is distributed widely in body tissues and fluids, including inflamed meningeal tissue [6; 73]. Aztreonam is mainly excreted in the urine as an unchanged drug, although there is also minimal hepatic metabolism [6; 74]. Doses must be adjusted for renal insuf- ficiency based on glomerular filtration rate [6; 75].
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