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Frontiers in Cellular and Infection... 2023Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae pose a huge threat to human health, especially in the context of complicated urinary tract infections...
Efficacy and safety of piperacillin-tazobactam compared with meropenem in treating complicated urinary tract infections including acute pyelonephritis due to extended-spectrum β-lactamase-producing .
INTRODUCTION
Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae pose a huge threat to human health, especially in the context of complicated urinary tract infections (cUTIs). Carbapenems and piperacillin-tazobactam (PTZ) are two antimicrobial agents commonly used to treat cUTIs.
METHODS
A monocentric retrospective cohort study focused on the treatment of cUTIs in adults was conducted from January 2019 to November 2021. Patients with a positive urine culture strain yielding ≥ 103 colony-forming units per milliliter (CFU/mL), and sensitive to PTZ and carbapenems, were included. The primary endpoint was clinical success after antibiotic therapy. The secondary endpoint included rehospitalization and 90-day recurrence of cUTIs caused by ESBL-producing Enterobacteriaceae.
RESULTS
Of the 195 patients included in this study, 110 were treated with PTZ while 85 were administered meropenem. The rate of clinical cure was similar between the PTZ and meropenem groups (80% vs. 78.8%, p = 0.84). However, the PTZ group had a lower duration of total antibiotic use (6 vs. 9; p < 0.01), lower duration of effective antibiotic therapy (6 vs. 8; p < 0.01), and lower duration of hospitalization (16 vs. 22; p < 0.01).
DISCUSSION
In terms of adverse events, the safety of PTZ was higher than that of meropenem in the treatment of cUTIs.
Topics: Adult; Humans; Meropenem; Piperacillin; Retrospective Studies; beta-Lactamase Inhibitors; Penicillanic Acid; Anti-Bacterial Agents; Piperacillin, Tazobactam Drug Combination; Urinary Tract Infections; Pyelonephritis; Enterobacteriaceae; Carbapenems; beta-Lactamases; Enterobacteriaceae Infections
PubMed: 37207190
DOI: 10.3389/fcimb.2023.1093842 -
Antimicrobial Agents and Chemotherapy Oct 2021Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and...
Our study aimed to describe the population pharmacokinetics (PK) of piperacillin and tazobactam in patients on extracorporeal membrane oxygenation (ECMO), with and without renal replacement therapy (RRT). We also aimed to use dosing simulations to identify the optimal dosing strategy for these patient groups. Serial piperacillin and tazobactam plasma concentrations were measured with data analyzed using a population PK approach that included staged testing of patient and treatment covariates. Dosing simulations were conducted to identify the optimal dosing strategy that achieved piperacillin target exposures of 50% and 100% fraction of time free drug concentration is above MIC (%) and toxic exposures of greater than 360 mg/liter. The tazobactam target of percentage of time free concentrations of >2 mg/liter was also assessed. Twenty-seven patients were enrolled, of which 14 patients were receiving concurrent RRT. Piperacillin and tazobactam were both adequately described by two-compartment models, with body mass index, creatinine clearance, and RRT as significant predictors of PK. There were no substantial differences between observed PK parameters and published parameters from non-ECMO patients. Based on dosing simulations, a 4.5-g every 6 hours regimen administered over 4 hours achieves high probabilities of efficacy at a piperacillin MIC of 16 mg/liter while exposing patients to a <3% probability of toxic concentrations. In patients receiving ECMO and RRT, a frequency reduction to every 12 hours dosing lowers the probability of toxic concentrations, although this remains at 7 to 9%. In ECMO patients, piperacillin and tazobactam should be dosed in line with standard recommendations for the critically ill.
Topics: Anti-Bacterial Agents; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Piperacillin; Tazobactam
PubMed: 34460303
DOI: 10.1128/AAC.01438-21 -
Advances in Chronic Kidney Disease Jan 2013Acute kidney injury (AKI) is a common problem in hospitalized patients and is associated with significant morbidity and mortality. Two large trials showed no benefit... (Review)
Review
Acute kidney injury (AKI) is a common problem in hospitalized patients and is associated with significant morbidity and mortality. Two large trials showed no benefit from increased doses of renal replacement therapy (RRT) despite previous clinical data suggesting that increased clearance from RRT has beneficial effects. Since infection is the leading cause of death in AKI, my group and others hypothesized that increased RRT antibiotic clearance might create a competing morbidity. The data from my group, as well as those of other groups, show that many patients are underdosed when routine "1 size fits all" antibiotic dosing is used in patients with AKI receiving continuous RRT (CRRT). Here, concepts of drug distribution and clearance in AKI are briefly discussed and then 1 antibiotic (piperacillin) is discussed in depth to illustrate the challenges in applying the medical literature to clinical practice. The fact that published data on drug dosing in AKI and dialysis reflect the evolution of practice patterns and often do not apply to present prescribing habits is also discussed. A more general approach to drug dosing facilitates situation-specific prescribing by the nephrologist and critical care specialist.
Topics: Acute Kidney Injury; Anti-Bacterial Agents; Antifungal Agents; Biological Availability; Critical Care; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Piperacillin; Practice Guidelines as Topic; Renal Replacement Therapy; Tissue Distribution
PubMed: 23265600
DOI: 10.1053/j.ackd.2012.10.004 -
The Journal of Antimicrobial... Apr 2022To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen...
OBJECTIVES
To explore extracorporeal membrane oxygenation (ECMO)-related alterations of the pharmacokinetics (PK) of piperacillin/tazobactam and determine an optimal dosage regimen for critically ill adult patients.
METHODS
Population PK models for piperacillin/tazobactam were developed using a non-linear mixed effect modelling approach. The percentage of time within 24 h for which the free concentration exceeded the MIC at a steady-state (50%fT>MIC, 100%fT>MIC, and 100%fT>4×MIC) for various combinations of dosage regimens and renal function were explored using Monte-Carlo simulation.
RESULTS
A total of 226 plasma samples from 38 patients were used to develop a population PK model. Piperacillin/tazobactam PK was best described by two-compartment models, in which estimated glomerular filtration rate (eGFR), calculated using CKD-EPI equation based on cystatin C level, was a significant covariate for total clearance of each piperacillin and tazobactam. ECMO use decreased the central volume of distribution of both piperacillin and tazobactam in critically ill patients. Patients with Escherichia coli or Klebsiella pneumoniae infection, but not those with Pseudomonas aeruginosa infection, exhibited a PK/pharmacodynamic target attainment >90% when the target is 50%fT>MIC, as a result of applying the currently recommended dosage regimen. Prolonged or continuous infusion of 16 g/day was required when the treatment goal was 100%fT>MIC or 100%fT>4×MIC, and patients had an eGFR of 130-170 mL/min/1.73 m2.
CONCLUSIONS
ECMO use decreases piperacillin/tazobactam exposure. Prolonged or continuous infusion can achieve the treatment target in critically ill patients, particularly when MIC is above 8 mg/L or when patients have an eGFR of 130-170 mL/min/1.73 m2.
Topics: Adult; Anti-Bacterial Agents; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Republic of Korea; Tazobactam
PubMed: 35224630
DOI: 10.1093/jac/dkac059 -
Molecules (Basel, Switzerland) Jan 2022β-Lactam antibiotics are most commonly used in the critically ill, but their effective dosing is challenging and may result in sub-therapeutic concentrations that can...
Quantitative Determination of Unbound Piperacillin and Imipenem in Biological Material from Critically Ill Using Thin-Film Microextraction-Liquid Chromatography-Mass Spectrometry.
β-Lactam antibiotics are most commonly used in the critically ill, but their effective dosing is challenging and may result in sub-therapeutic concentrations that can lead to therapy failure and even promote antimicrobial resistance. In this study, we present the analytical tool enabling specific and sensitive determination of the sole biologically active fraction of piperacillin and imipenem in biological material from the critically ill. Thin-film microextraction sampling technique, followed by rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, was optimized and validated for the quantitative determination of antibiotics in blood and bronchoalveolar lavage (BAL) specimens collected from intensive care unit (ICU) patients suffering from ventilation-associated pneumonia (n = 18 and n = 9, respectively). The method was optimized and proved to meet the criteria of US Food and Drug Administration (FDA) guidelines for bioanalytical method validation. Highly selective, sensitive, accurate and precise analysis by means of thin-film microextraction-LC-MS/MS, which is not affected by matrix-related factors, was successfully applied in clinical settings, revealing poor penetration of piperacillin and imipenem from blood into BAL fluid (reflecting the site of bacterial infection), nonlinearity in antibiotic binding to plasma-proteins and drug-specific dependence on creatinine clearance. This work demonstrates that only a small fraction of biologically active antibiotics reach the site of infection, providing clinicians with a high-throughput analytical tool for future studies on personalized therapeutic drug monitoring when tailoring the dosing strategy to an individual patient.
Topics: Anti-Bacterial Agents; Chromatography, Liquid; Imipenem; Limit of Detection; Mass Spectrometry; Piperacillin; Solid Phase Microextraction
PubMed: 35164191
DOI: 10.3390/molecules27030926 -
Emerging Microbes & Infections Dec 2022The excessive use of piperacillin/tazobactam (P/T) has promoted the emergence of P/T-resistant . We reported that in , P/T contributes to the development of...
BACKGROUND
The excessive use of piperacillin/tazobactam (P/T) has promoted the emergence of P/T-resistant . We reported that in , P/T contributes to the development of extended-spectrum resistance to β-lactam/β-lactamase inhibitor (BL/BLI) (ESRI) in isolates that are P/T susceptible but have low-level resistance to BL/BLI. Currently, the detection of P/T resistance relying on conventional methods is time-consuming. To overcome this issue, we developed a cost-effective test based on MALDI-MS technology, called MALDIpiptaz, which aims to detect P/T resistance and ESRI developers in .
METHODS
We used automated Clover MS Data Analysis software to analyse the protein profile spectra obtained by MALDI-MS from a collection of 248 isolates (91 P/T-resistant, 81 ESRI developers and 76 P/T-susceptible). This software allowed to preprocess all the spectra to build different peak matrices that were analysed by machine learning algorithms.
RESULTS
We demonstrated that MALDIpiptaz can efficiently and rapidly (15 min) discriminate between P/T-resistant, ESRI developer and P/T-susceptible isolates and allowed the correct classification between ESRI developers from their isogenic resistance to P/T.
CONCLUSION
The combination of excellent performance and cost-effectiveness are all desirable attributes, allowing the MALDIpiptaz test to be a useful tool for the rapid determination of P/T resistance in clinically relevant isolates.
Topics: Anti-Bacterial Agents; Escherichia coli; Escherichia coli Infections; Humans; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; beta-Lactamases
PubMed: 35972021
DOI: 10.1080/22221751.2022.2113746 -
Clinical Pharmacology and Therapeutics Oct 2014Pulmonary infections in critically ill patients are common and are associated with high morbidity and mortality. Piperacillin-tazobactam is a frequently used therapy in... (Clinical Trial)
Clinical Trial
Pulmonary infections in critically ill patients are common and are associated with high morbidity and mortality. Piperacillin-tazobactam is a frequently used therapy in critically ill patients with pulmonary infection. Antibiotic concentrations in the lung reflect target-site antibiotic concentrations in patients with pneumonia. The aim of this study was to assess the plasma and intrapulmonary pharmacokinetics (PK) of piperacillin-tazobactam in critically ill patients administered standard piperacillin-tazobactam regimens. A population PK model was developed to describe plasma and intrapulmonary piperacillin and tazobactam concentrations. The probability of piperacillin exposures reaching pharmacodynamic end points and the impact of pulmonary permeability on piperacillin and tazobactam pulmonary penetration was explored. The median piperacillin and tazobactam pulmonary penetration ratios were 49.3 and 121.2%, respectively. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated with pulmonary permeability. Current piperacillin-tazobactam regimens may be insufficient to treat pneumonia caused by piperacillin-tazobactam-susceptible organisms in some critically ill patients.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Drug Combinations; Drug Resistance, Bacterial; Female; Humans; Lung; Male; Middle Aged; Monte Carlo Method; Penicillanic Acid; Permeability; Piperacillin; Tazobactam
PubMed: 24926779
DOI: 10.1038/clpt.2014.131 -
Antimicrobial Agents and Chemotherapy Jul 2023We conducted antimicrobial susceptibility testing of 267 isolates for 16 antibiotics from 2017 to 2022. The highest susceptibility was found for...
We conducted antimicrobial susceptibility testing of 267 isolates for 16 antibiotics from 2017 to 2022. The highest susceptibility was found for piperacillin-tazobactam (70%) and ceftazidime-avibactam (62%). Between 30% and 49% of strains were susceptible to tigecycline, ceftazidime, and meropenem. We applied species-specific Achromobacter xylosoxidans breakpoints for piperacillin-tazobactam, meropenem, and trimethoprim-sulfamethoxazole and EUCAST pharmacokinetic/pharmacodynamic (PK/PD) breakpoints for the others. A. xylosoxidans was the most frequently isolated species, followed by Achromobacter insuavis and Achromobacter ruhlandii.
Topics: Humans; Meropenem; Cystic Fibrosis; Microbial Sensitivity Tests; Anti-Bacterial Agents; Achromobacter; Piperacillin; Tazobactam
PubMed: 37310234
DOI: 10.1128/aac.00379-23 -
Journal of Clinical Microbiology Apr 2023In this issue of the , C. Manuel, R. Maynard, A. Abbott, K. Adams, et al. (J Clin Microbiol 61:e01617-22, 2023, https://doi.org/10.1128/JCM.01617-22) describe a...
In this issue of the , C. Manuel, R. Maynard, A. Abbott, K. Adams, et al. (J Clin Microbiol 61:e01617-22, 2023, https://doi.org/10.1128/JCM.01617-22) describe a multisite study evaluation of piperacillin-tazobactam (TZP) MIC testing on three U.S. Food and Drug Administration (FDA)-cleared antimicrobial susceptibility testing (AST) devices compared to the reference broth microdilution method for organisms belonging to . Although overall performance of each of the three devices was comparable when applying either FDA or Clinical and Laboratory Standards Institute (CLSI) TZP breakpoints, failure to update to the current CLSI breakpoints may result in falsely categorizing as many as 20% of the TZP-resistant isolates as susceptible. The impact of not updating clinical breakpoints and strategies for implementation of updated breakpoints are discussed.
Topics: Humans; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Reference Standards; Anti-Bacterial Agents; Pseudomonas aeruginosa
PubMed: 36920195
DOI: 10.1128/jcm.00042-23 -
Antimicrobial Agents and Chemotherapy Sep 2022Carbapenems are recommended for the treatment of urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing, multidrug-resistant Escherichia coli however, due...
Pharmacodynamics of Piperacillin-Tazobactam/Amikacin Combination versus Meropenem against Extended-Spectrum β-Lactamase-Producing Escherichia coli in a Hollow Fiber Infection Model.
Carbapenems are recommended for the treatment of urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing, multidrug-resistant Escherichia coli however, due to selection of carbapenem resistance, there is an increasing interest in alternative treatment regimens including the use of β-lactam-aminoglycoside combinations. We compared the pharmacodynamic activity of piperacillin-tazobactam and amikacin as mono and combination therapy versus meropenem monotherapy against extended-spectrum β-lactamase (ESBL)-producing, piperacillin-tazobactam resistant E. coli using a dynamic hollow fiber infection model (HFIM) over 7 days. Broth-microdilution was performed to determine the MIC of E. coli isolates. Whole genome sequencing was conducted. Four E. coli isolates were tested in HFIM with an initial inoculum of ~10 CFU/mL. Dosing regimens tested were piperacillin-tazobactam 4.5 g, 6-hourly, plus amikacin 30 mg/kg, 24-hourly, as combination therapy, and piperacillin-tazobactam 4.5 g, 6-hourly, amikacin 30 mg/kg, 24-hourly, and meropenem 1 g, 8-hourly, each as monotherapy. We observed that piperacillin-tazobactam and amikacin monotherapy demonstrated initial rapid bacterial killing but then led to amplification of resistant subpopulations. The piperacillin-tazobactam/amikacin combination and meropenem experiments both attained a rapid bacterial killing (~4-5 log) within 24 h and did not result in any emergence of resistant subpopulations. Genome sequencing demonstrated that all ESBL-producing E. coli clinical isolates carried multiple antibiotic resistance genes including , , , , and . These results suggest that the combination of piperacillin-tazobactam/amikacin may have a potential role as a carbapenem-sparing regimen, which should be tested in future urosepsis clinical trials.
Topics: Amikacin; Anti-Bacterial Agents; Carbapenems; Escherichia coli; Meropenem; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination; beta-Lactamases; beta-Lactams
PubMed: 35924928
DOI: 10.1128/aac.00162-22