Beta-Lactamase Stability and Inhibitory Activity of Meropenem Combined with a Potent Antibacterial Activity

Antibiotic tolerance, the ability to temporarily sustain viability in the presence of bactericidal antibiotics, constitutes an understudied and yet potentially widespread cause of antibiotic treatment failure. We have previously shown that the Gram-negative pathogen Vibrio cholerae can tolerate exposure to the typically bactericidal β-lactam antibiotics by assuming a spherical morphotype devoid of detectable cell wall material. However, it is unclear how widespread β-lactam tolerance is. Here, we tested a panel of clinically significant Gram-negative pathogens for their response to the potent, broad-spectrum carbapenem antibiotic meropenem. We show that clinical isolates of Enterobacter cloacae, Klebsiella aerogenes, and Klebsiella pneumoniae, but not Escherichia coli, exhibited moderate to high levels of tolerance of meropenem, both in laboratory growth medium and in human serum. Importantly, tolerance was mediated by cell wall-deficient spheroplasts, which readily recovered wild-type morphology and growth upon removal of antibiotic. Our results suggest that carbapenem tolerance is prevalent in clinically significant bacterial species, and we suggest that this could contribute to treatment failure associated with these organisms.

Section: Resultssupporting

confidence: 58%

Spheroplast-Mediated Carbapenem Tolerance in Gram-Negative Pathogens

Cross

Ransegnola

Shin

et al. 2019

“…While being more resistant to ␤-lactamases, meropenem has also been shown to induce ␤-lactamase expression to a greater degree than ceftazidime (12). As shown in Fig.…”

mentioning

confidence: 90%

Mature Pseudomonas aeruginosa Biofilms Prevail Compared to Young Biofilms in the Presence of Ceftazidime

Bowler

Zhanel

Ball

et al. 2012

ABSTRACTPhenotypic tolerances to antibiotics of mature and youngPseudomonas aeruginosaPAO1 biofilms and released planktonic bacteria were compared for four antibiotics. Resistance levels were similar for gentamicin and ciprofloxacin but differed for ceftazidime and meropenem. β-Lactamase mapping showed that, after 5 h of ceftazidime exposure, mature biofilms produced more β-lactamase than young biofilms, facilitating the growth of released planktonic bacteria. This shows the importance of early treatment and choice of antibiotics forP. aeruginosabiofilm infections.

“…The carbapenem class of antimicrobial agents is highly active against the major bacterial pathogens causing meningitis, but in the first clinical trial of such an agent, the use of imipenem-cilastatin was terminated because of an excess of seizures in those receiving the drug (28). Meropenem, a carbapenem structurally related to imipenem, is stable to the majority of ␤-lactamases (23) and is active in vitro against a broad range of gram-negative and gram-positive aerobic and anaerobic bacteria, with several-fold-greater activity than that of imipenem against H. influenzae and N. meningitidis (4). Meropenem is also stable to human renal dehydropeptidase-I and, unlike imipenem, does not need to be combined with a dehydropeptidase inhibitor such as cilastatin (22).…”

mentioning

confidence: 99%

Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Meropenem Meningitis Study Group

Klugman

Dagan

1995

157

Broad-spectrum cephalosporins are drugs of choice for the treatment of meningitis in communities which can afford them. The emergence of cephalosporin-resistant pneumococci demands the clinical trial of alternate agents. Carbapenems are active against the bacteria causing meningitis, but the use of imipenem-cilastatin was frustrated by drug-associated seizures. The safety and efficacy of meropenem, a new carbapenem, were compared to those of cefotaxime in a prospective randomized trial of 190 children with bacterial meningitis. Seizures occurred within 24 h before antibiotic therapy in 16 of 98 patients (16%) randomized to receive meropenem and in 6 of 92 patients (7%) randomized to receive cefotaxime. In patients without seizures before therapy, seizures occurred during therapy in 5 of 82 patients (6%) receiving meropenem and in 1 of 86 patients (1%) receiving cefotaxime (95% confidence interval: ؊0.7%, 10.6%). None were thought to be drug related. Twenty-four meropenem-treated patients (24%) and 11 cefotaxime-treated patients (12%) had neurological abnormalities before therapy. In patients without pretherapy neurological abnormalities, these abnormalities were present after treatment in 4 of 74 meropenem-treated patients (5%) and in 2 of 81 cefotaxime-treated patients (2%) (95% confidence interval: ؊3.2%, 9.1%). Of 75 meropenem-treated and 64 cefotaxime-treated patients with pretherapy positive cerebrospinal-fluid cultures, 68 and 59, respectively, had repeat lumbar punctures. Bacterial eradication was found to be 100% in both groups. Our data suggest that meropenem may be a carbapenem agent that is well tolerated and effective in the treatment of bacterial meningitis.