<p>Simulating moxalactam dosage for extended-spectrum β-lactamase-producing <em>Enterobacteriaceae</em> using blood antimicrobial surveillance network data</p>

Abstract

Objectives: Monte Carlo simulation (MCS) was used to evaluate optimal dosage for cefepime (FEP), moxalactam (MOX), and cefperazone/sulbactam (CFZ/SBT) against extended-spectrum β-lactamase (ESBL) producers isolated from the Blood Bacterial Resistant Investigation Collaborative System. Methods : Minimum inhibitory concentration (MIC) was tested by agar dilution, and ESBL producers were identified by modified Clinical and Laboratory Standards Institute tests. Pharmacokinetic parameters were derived from data on healthy individuals, and probability of target attainment (PTA) and cumulative fraction of response (CFR) %fT >MIC values were estimated by MCS. Results: A total of 2032 Escherichia coli (875 ESBL-producing) and Klebsiella pneumoniae (157 ESBL-producing) strains, and 371 other Enterobacteriaceae strains, were isolated from patients with bloodstream infections (BSIs). MIC 90 values for FEP, MOX, and CFZ/SBT against ESBL-producing E. coli and K. pneumoniae were 64/64 mg/L, 2/32 mg/L, and 64/128 mg/L, respectively. Conventional MOX and CFZ/SBT doses failed to reach 90% PTA against isolates with MICs ≥8 mg/L and ≥4 mg/L, respectively. Against ESBL producers, neither FEP nor CFZ/SBT achieved ≥90% CFR, while CFRs for MOX (1 g iv q6h, 2 g iv q12h, and 2 g iv q8h) exceeded 90% against ESBL-producing E. coli . Simulated CFRs for FEP and MOX were similar (>90%) against non-ESBL-producing Enterobacteriaceae , and higher than CFRs for CFZ/SBT. Conclusion: ESBL producers from BSIs were highly susceptible to MOX, and PTA values were generally higher for MOX than FEP or CFZ/SBT for conventional dosing regimens. This large MCS analysis shows that MOX but not FEP or CFZ/SBT can be used empirically to treat BSIs caused by ESBL-producing E. coli strains.

Beta-Lactam Probability of Target Attainment Success: Cefepime as a Case Study

“…The purpose of this mini review was to briefly survey the techniques and decisions researchers made while performing cefepime PTA. Therefore, only the first 20 titles were reviewed, of which 14 met the inclusion criteria of a PTA study, with at least one evaluation of cefepime alone in adult patients ( Table 1 ) [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. A study by Das et al was excluded because cefepime was studied in combination with a novel beta-lactamase inhibitor, changing the risk benefit from cefepime alone [ 28 ].…”

“…The MIC of interest was generally set at 8 mg/dL, consistent with the breakpoint defined by the Clinical and Laboratory Standards Institute against pseudomonas aeruginosa [ 35 ]. Success was commonly defined as PTA > 90% against a given MIC; however, some authors defined success as CFR > 90% against an observed MIC distribution [ 18 , 20 , 21 , 26 ].…”

“…Pharmacokinetic parameters were most commonly simulated with one or two compartment PK models; however, two authors simulated the %fT based on equations [ 21 , 27 ]. Most authors did not specify the simulated time intervals.…”

Pharmacokinetic and Pharmacodynamic Analysis Using Monte Carlo Simulation of the Oxacephem Antibiotic Flomoxef against Extended-Spectrum β-Lactamase-Producing Enterobacterales from Dogs

“…In recent years, infections caused by the multidrug-resistant extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E) have become a serious issue in companion animals, as well as in humans [1,2]. Carbapenems are frequently used for the treatment of ESBL-E infections in human medicine but there is a risk of developing carbapenem-resistant Enterobacterales (CRE) [3,4]. Although the true prevalence of CRE in companion animals is unknown, there have been several reports on CRE isolation in dogs and cats worldwide [5,6].…”

Pharmacokinetic–pharmacodynamic analysis of cefmetazole against extended-spectrum β-lactamase-producing Enterobacteriaceae in dogs using Monte Carlo Simulation

“…Plasmids encoding ESBLs often carry resistance genes for different classes of antimicrobials; therefore, ESBL-E have developed multidrug resistance with high resistance against β-lactams and other classes of antimicrobials, thus limiting the number of effective antimicrobial agents available for treatment ( 1 ). Carbapenems are recommended as the first-line drugs for treating ESBL-E infections in humans but not in animals owing to the risk of developing carbapenemase-producing Enterobacteriaceae (CPE), which is a more serious threat than ESBL-E ( 4 , 5 ). Therefore, the use of carbapenems is discouraged in veterinary medicine due to the potential risk of zoonotic transmission from companion animals to humans through close contact ( 6 ).…”