PubMed · 9054330
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S M Shatunov, Iu B Belousov. 1996. [Meropenem].. https://pubmed.ncbi.nlm.nih.gov/9054330/
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The relationship between morphological changes and endotoxin release induced in vitro by carbapenems in a clinical isolate of Pseudomonas aeruginosa was examined. The time-course and magnitude of endotoxin release induced varied among imipenem, panipenem, meropenem and biapenem and related to the morphological changes caused by these agents which variously affected cell shape, cell-wall disintegration and cell lysis. The amount of endotoxin released by carbapenem-treated cells correlated with both the cell-wall morphology and bacterial shape immediately before lysis. Meropenem and biapenem caused markedly increased endotoxin release during cell lysis and cell-wall disintegration, whereas imipenem and panipenem caused much less release of endotoxin.
An important mechanism of bacterial resistance to beta-lactam antibiotics is inactivation by beta-lactam-hydrolyzing enzymes (beta-lactamases). The evolution of the extended-spectrum beta-lactamases (ESBLs) is associated with extensive use of beta-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum beta-lactamases (BDSBLs) are plasmid-mediated class A enzymes produced by gram-negative pathogens, principally Escherichia coli and Klebsiella pneumoniae. MK-0826 was highly potent against all ESBL- and BDSBL-producing K. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 microgram/ml). In E. coli, this activity was associated with high-affinity binding to penicillin-binding proteins 2 and 3. When the inoculum level was increased 10-fold, increasing the amount of beta-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 microgram/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem beta-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) beta-lactamase served as controls. All three carbapenems were subject to an inoculum effect with the majority of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implying some effect of the plasmid-borne enzymes on potency. Importantly, MK-0826 MICs remained at or below 1 microgram/ml under all test conditions.
Pseudomonas aeruginosa is a major problem as a multiresistant nosocomial pathogen, especially in burns and other immunocompromised patients in our hospital. The present prospective study, conducted between June 1996 and December 1997, was aimed at determining the extent of its resistance against highly active antipseudomonal drugs, such as carbapenems (imipenem and meropenem) and ureidopenicillin with beta-lactamase inhibitor (piperacillin/tazobactam); existence of any cross resistance or difference in susceptibility between imipenem and meropenem; and to compare the activity of piperacillin/tazobactam with the two carbapenems against P. aeruginosa. Of the 357 P. aeruginosa isolates tested from 188 patients 37 (10.4%) were resistant to imipenem, 21 (5.9%) to meropenem and 50 (14%) to piperacillin/tazobactam. Cross resistance between the two carbapenems was observed in 5.9% of the isolates. Sixteen (43%) of the imipenem-resistant isolates were susceptible to meropenem but the reverse was observed in none. Amongst the 50 piperacillin/tazobactam-resistant isolates cross resistance with the two carbapenems was observed in 18 (36%) and in 9 (18%) only with imipenem; 23 (46%) were susceptible to both. Our results indicate that P. aeruginosa is least resistant to meropenem followed by imipenem and piperacillin/tazobactam. Cross resistance between the carbapenems and between carbapenems and piperacillin/tazobactam was found. The study further suggests that burns, cardiac-neuro-pediatric surgical, cancer and transplant patients are more susceptible to acquiring infection due to multiresistant P. aeruginosa than other types of patients and common infection sites were wounds, respiratory tract, urine, blood and intravascular lines.