Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. METHODS: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen. RESULTS: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ±â€Šstandard deviation parameters were: CL0, 15.21 ±â€Š6.52 L/h; Vc, 10.13 ±â€Š2.26 L; K12, 2.45 ±â€Š1.16 h-1 and K21, 1.76 ±â€Š0.49 h-1 for imipenem, and 6.95 ±â€Š1.34 L/h, 9.81 ±â€Š2.69 L, 2.43 ±â€Š1.13 h-1 and 1.52 ±â€Š0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. CONCLUSIONS: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.

Evaluation of Ceftazidime/Avibactam Administration in Enterobacteriaceae and Pseudomonas aeruginosa Bloodstream Infections by Monte Carlo Simulation.

PURPOSE: To evaluate the administration regimen of ceftazidime/avibactam (CZA) for bloodstream infections caused by Enterobacteriaceae and Pseudomonas aeruginosa. METHODS: The minimal inhibitory concentrations (MICs) of CZA against Enterobacteriaceae and P. aeruginosa isolated from blood cultures at member hospitals in BRICS (Blood Bacterial Resistant Investigation Collaborative System) in 2019 were determined by broth micro-dilution methodology. A 10,000-patient Monte Carlo simulation (MCS) was used to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different CZA dosage regimens to evaluate their efficacies and optimize the best initial dosage regimen. RESULTS: Altogether, 6487 Enterobacteriaceae and P. aeruginosa strains were isolated from the blood cultures. The overall CZA resistance rate was 2.31%, of which the Enterobacteriaceae and P. aeruginosa rates were 1.57% and 14.29%, respectively. The MCS showed that the greater the MIC value, the worse the therapeutic effect. When the CZA MIC was ≤8 mg/L, the standard dose (2.5g iv q8h) achieved 90% PTA in the subset of patients with creatinine clearance (CrCl) values from 51 to 120 mL/min. Although the high-dose regimen (3.75g iv q8h) achieved 90% PTA in patients with CrCl values from 121 to 190 mL/min, implementing the low-dose regimen (1.25g iv q8h) was also effective for patients in the 51-89 mL/min CrCl range. Generally, the high-dose regimen (3.75g iv q8h) reached 90% CFR against all of the strains. Conversely, in patients with CrCl values of 121-190 mL/min, the standard dose (2.5g iv q8h) failed to reach 90% CFR against some Enterobacteriaceae members and P. aeruginosa. When the dose was reduced to the low-dose regimen (1.25g iv q8h), no patients reached 90% CFR against some Enterobacteriaceae members and P. aeruginosa. CONCLUSION: CZA has good antibacterial activity against Enterobacteriaceae and P. aeruginosa in bloodstream infections. Clinicians could make individualized treatment regimens in accordance with the sensitivity of the strains and the level of renal function in their patients to best predict the drug-related clinical responses.

The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital.

PURPOSE: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options. PATIENTS AND METHODS: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June-October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). RESULTS: The most common genotypes of CRKP were blaOXA-48 (53.1%) and blaOXA-48 +blaNDM (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC50 and MIC90 of CZA against CRKP were 2 and >256 µg/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2-3 h every 8 h achieved ≥90% of the target of free ceftazidime plasma concentration over MIC (%fTime >MIC) ≥50% and 100% against isolates MICs of ≤8 and ≤8 µg/mL, respectively. The avibactam regimens also provided 100%fTime at 0.5 µg/mL. Based on CFR ≥90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48. CONCLUSION: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying blaOXA-48 .

Monte Carlo Simulation Methodologies for ß-Lactam/ß-Lactamase Inhibitor Combinations: Effect on Probability of Target Attainment Assessments.

Monte Carlo simulations (MCSs) are used in antibiotic development to predict the probability of pharmacodynamic target attainment (PTA) for a dosing regimen. However, for ß-lactam/ß-lactamase inhibitor combinations (BL-BLICs), methods for linking simulated concentration profiles of the ß-lactam (BL) and ß-lactamase inhibitor (BLI) components are rarely described. Using a previously defined pharmacokinetic model of ceftazidime/avibactam from critically ill patients, we performed four 5000-patient MCSs using different methods of increasing complexity to couple the BL and BLI components and compared PTA for ceftazidime and avibactam targets of >70% fT>MIC and >70% fT>1 mg/L, respectively, at MICs from 1 to 128 mg/L. Method A ignored all covariates and correlations, whereas methods B, C, and D enhanced associations by adding (B) pharmacokinetic parameter correlation within each drug only; (C) pharmacokinetic parameter correlation within each drug and creatinine clearance (CRCL); and (D) pharmacokinetic parameter correlation within each drug, CRCL, and pharmacokinetic parameter correlation between drugs. Method D produced a simulated patient population that best recapitulated the observed relationships between pharmacokinetic parameters in actual patients. Ceftazidime/avibactam PTA at MIC 8 mg/L (the susceptibility break point) and 16 mg/L ranged from 92.4% to 98.3% and 80.2% to 88.4%, respectively. PTA was lowest with method A, whereas PTA estimates were similar for all other methods. Compared with ignoring all pharmacokinetic parameter associations, the inclusion of covariate relationships and parameter correlation between both components of ceftazidime/avibactam leads to fewer patients with discordant pharmacokinetic parameters and results in higher PTA. Consideration of these methodologies should guide future MCS analyses for BL-BLIC.

Assessment of the In Vitro Activities of Ceftolozane/Tazobactam and Ceftazidime/Avibactam in a Collection of Beta-Lactam-Resistant Enterobacteriaceae and Pseudomonas aeruginosa Clinical Isolates at Montpellier University Hospital, France.

Objective: To assess in vitro ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA) activity in beta-lactam-resistant Enterobacteriaceae and Pseudomonas aeruginosa clinical isolates from major carbapenem-using Departments at Montpellier University Hospital, France. Materials and Methods: We tested third-generation cephalosporin-resistant Enterobacteriaceae (by production of extended spectrum ß-lactamase or other mechanisms, mainly AmpC beta-lactamases) and ceftazidime- and/or carbapenem-resistant P. aeruginosa strains isolated from clinical samples of patients hospitalized from January 2017 to May 2017 and August 2016 to July 2017, respectively. We also included all OXA-48 beta-lactamase-producing Enterobacteriaceae strains isolated in the whole hospital from October 2015 to May 2017. We used the 2017 European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines for minimal inhibitory concentration interpretation. Results: Among the 62 cephalosporin-resistant Enterobacteriaceae strains, 60 (97%) were susceptible to CZA and 34 (65%) to C/T. The two CZA-resistant Klebsiella pneumoniae isolates produced (i) NDM-carbapenemase and extended-spectrum beta-lactamase (ESBL) and (ii) ESBL CTXM-15 and OXA-1 associated with impermeability. Moreover, 31 of the 42 P. aeruginosa strains (74%) were susceptible to CZA and 37 (88%) to C/T. Finally, 26/27 (96%) of OXA-48 beta-lactamase-producing Enterobacteriaceae were susceptible to CZA and 8/27 (30%) to C/T. Conclusions: At our hospital, CZA and C/T offer a carbapenem-sparing alternative for resistant gram-negative pathogens and could be a salvage therapy for carbapenem-resistant pathogens.

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

BACKGROUND: The pharmacokinetics, especially the volume of distribution (Vd), of ß-lactam antibiotics can be altered in critically ill patients. This can lead to decreased serum concentrations and a reduction in clinical cures. Ceftazidime/avibactam (CZA) is a new antimicrobial agent utilized in critically ill patients although its pharmacokinetics has not been well defined in these patients. PATIENTS AND METHODS: In this study, the serum concentrations of CZA from adult patients treated in an intensive care unit (ICU) with standard dosing regimens were measured and both pharmacokinetic and pharmacodynamic parameters were computed. The pharmacodynamic analyses included Monte Carlo simulations to determine the probability of target attainment (PTA: free ceftazidime concentrations exceed the minimum inhibitory concentration [MIC] for 50% of the dosing interval; free avibactam concentrations exceed 1 mg/L over the dosing interval) and serum time-kill curves against multi-drug-resistant Enterobacteriaceae susceptible to CZA. Serum concentrations were measured in 10 critically ill patients at two, four, six, and eight hours after multiple doses (infused over two hours) of CZA. RESULTS: A significant linear relation between creatinine clearance and total body clearance was identified for both ceftazidime (R = 0.91) and avibactam (R = 0.88). The mean clearance, volume of distribution, and half-life for ceftazidime were 6.1 ± 3.8 L/h, 35 ± 10.5 L, and 4.8 ± 2.15 h, respectively. For avibactam, these values were 11.1 ± 6.8 L/h, 50.8 ± 14.3 L, and 4.1 ± 2.1 h, respectively. Ceftazidime/avibactam achieved optimal PTA for bacteria with MICs of 16 mg/L or less. Furthermore, time-kill experiments revealed that serum concentrations of CZA, at each collection time, exhibited bactericidal (≥ 3 log10 CFU/mL reduction) activity against each of the study isolates. CONCLUSION: In conclusion, our study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates.

The French addictovigilance network clinical assessment: Z-drugs, true false twins.

INTRODUCTION: In France, an addictovigilance network is responsible for evaluating drug dependence, by drawing on pharmacoepidemiological studies, clinical studies and by assessing healthcare professionals' reports on problematic consumption. METHODS: The aim of this study was to determine whether zolpidem and zopiclone have different dependence profiles, based on healthcare professionals' reports, and to identify various consumer dependence profiles among zolpidem users and among zopiclone users. Dependence in reports was assessed using the EGAP scale; a scale developed using the DSM diagnostic dependence criteria. RESULTS: The comparison of dependence profiles for zolpidem and zopiclone showed differences both in total EGAP score and EGAP item positivity. The descriptive analysis showed that EGAP scores were higher for zolpidem than for zopiclone, suggesting more severe problematic consumption with zolpidem. For zolpidem 2 subpopulations of consumers were identified, with one subpopulation's consumption being more severe than the other, with a significantly higher total EGAP score and more harmful consequences. No subpopulation was highlighted for zopiclone. CONCLUSION: These results were in favour of a higher prevalence of physical and compulsive signs of dependence and of harmful consequences of dependence, with zolpidem than with zopiclone.

Long-term use of zopiclone, zolpidem and zaleplon among Danish elderly and the association with sociodemographic factors and use of other drugs.

PURPOSE: To estimate the degree of long-term use of zopiclone, zolpidem and zaleplon among Danes aged 65 and older and the association with sociodemographic factors and use of other drugs. METHODS: Danish register-based study of 5000 men and 5000 women aged 65 or older on 1 January 2004. Information on sociodemographic factors and drug redemptions were collected for 2003, with follow-up of zopiclone, zolpidem and zaleplon redemptions in 2004. Long-term use was defined as redemptions corresponding to a continuous daily use for more than 4 weeks (based on ½ DDD). The association between long-term use and sociodemographics and drug use was estimated by logistic regression. RESULTS: Ten per cent of all men and 16% of all women had a long-term use for minimum 4 weeks corresponding to 94% of the male and 93% of the female users. Four per cent of the men and 6% of the women had redeemed more than ½ DDD per day in 2004. Long-term use was associated with: Being a woman, high age, widowed or divorced, high education and high gross income. Long-term use was also associated with use of other drugs, the association with ATC group N being the strongest. Restricting the analyses to individuals who had minimum one zopiclone, zolpidem or zaleplon redemption gave similar results. CONCLUSION: The results indicate that the guidance for length of use is not followed. Long-term use of zopiclone, zolpidem and zaleplon is associated with sociodemographic factors and use of other drugs, particularly from ATC group N.

Eszopiclone: a review of its use in the treatment of insomnia.

Eszopiclone (Lunesta), the S-enantiomer of racemic zopiclone, is a nonbenzodiazepine hypnotic agent that is approved in the US as an oral, once-nightly therapy for insomnia in adults; eszopiclone is also currently under review by the European Medicines Agency. Eszopiclone is rapidly absorbed after oral administration without any next-day clinical residual effects being detected. Large, well designed trials of up to 6 months' duration have shown that eszopiclone significantly improves both sleep onset and sleep maintenance compared with placebo in adult and elderly patients with primary insomnia. Eszopiclone for 4-8 weeks also significantly improved sleep parameters compared with placebo in patients with insomnia coexisting with other conditions that also disturb sleep (co-morbid insomnia), and improved certain measures of the co-morbid conditions to a greater extent than the standard therapies alone. Short-term eszopiclone produced improvements in daytime functioning in patients with co-morbid insomnia. Six months' therapy in adults with primary insomnia improved daytime functioning and health-related quality of life. Eszopiclone was generally well tolerated. There was no evidence of tolerance during 12 months' treatment with this agent. On discontinuation of eszopiclone, there was no rebound insomnia or serious withdrawal effects. Well designed, comparative trials with other nonbenzodiazepine hypnotics are needed to determine its relative efficacy and tolerability. A cost-utility analysis suggested that eszopiclone is cost effective for the treatment of primary insomnia in the US. Therefore, eszopiclone is a useful therapeutic option in the management of adult and elderly patients with primary or co-morbid insomnia. Unlike most other hypnotics, eszopiclone is not limited to short-term use.