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European Journal of Drug Metabolism and... May 2021Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVE
Standard piperacillin-tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients.
METHODS
Those receiving standard-dose P-T with BMI ≥ 30 kg/m weighing 105-139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% fT > 16/4 mg/L) on various P-T regimens was calculated using each patient's own pharmacokinetic values.
RESULTS
Piperacillin and tazobactam half-lives ranged from 0.5-10.6 to 0.9-15.0 h, while volumes of distribution ranged from 13.6-54.8 to 11.5-60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T.
CONCLUSION
Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. CLINICAL TRIAL REGISTRATION (CLINICALTRIALS.GOV): NCT01923363.
Topics: Adult; Aged; Anti-Bacterial Agents; Creatinine; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Middle Aged; Models, Biological; Obesity; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Renal Dialysis; Tissue Distribution; Young Adult
PubMed: 33743171
DOI: 10.1007/s13318-021-00677-1 -
Therapeutic Drug Monitoring Aug 2019Therapeutic drug monitoring (TDM) is increasingly used to optimize the dosing of beta-lactam antibiotics in critically ill patients. However, beta-lactams are inherently...
BACKGROUND
Therapeutic drug monitoring (TDM) is increasingly used to optimize the dosing of beta-lactam antibiotics in critically ill patients. However, beta-lactams are inherently unstable and degrade over time. Hence, patient samples need to be appropriately handled and stored before analysis to generate valid results for TDM. The appropriate handling and storage conditions are not established, with few and conflicting studies on the stability of beta-lactam antibiotics in clinical samples. The aim of this study was to assess the preanalytical stability of piperacillin, tazobactam, meropenem, and ceftazidime in human plasma and whole blood using a liquid chromatography-tandem mass spectrometry method for simultaneous quantification.
METHODS
A reverse phase liquid chromatography-tandem mass spectrometry method for the quantification of piperacillin, tazobactam, meropenem, and ceftazidime in plasma after protein precipitation was developed and validated. The preanalytical stability of these beta-lactams was assessed in EDTA- and citrate-anticoagulated plasma at 24, 4, and -20°C. The whole blood stability of the analytes in EDTA-anticoagulated tubes was assessed at 24°C. Stability was determined by nonlinear regression analysis defined by the lower limit of the 95th confidence interval of the time to 15% of degradation.
RESULTS
Based on the lower limit of the 95th confidence interval of the time to 15% of degradation, piperacillin, tazobactam, meropenem, and ceftazidime were stable in EDTA-anticoagulated plasma for at least 6 hours at 24°C, 3 days at 4°C, and 4 days at -20°C. Stability in EDTA- and citrate-anticoagulated plasma was similar. Stability in whole blood was similar to plasma at 24°C.
CONCLUSIONS
Plasma samples for the TDM of piperacillin, tazobactam, meropenem, and ceftazidime should be processed within 6 hours if kept at room temperature and within 3 days if kept at 4°C. All long-term storage of samples should be at -80°C.
Topics: Anti-Bacterial Agents; Ceftazidime; Chromatography, High Pressure Liquid; Drug Monitoring; Humans; Meropenem; Piperacillin; Plasma; Tandem Mass Spectrometry; Tazobactam
PubMed: 31306394
DOI: 10.1097/FTD.0000000000000650 -
Journal of Medical Microbiology Feb 2023Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents...
activity of imipenem/relebactam against piperacillin/tazobactam-resistant and meropenem-resistant non- and collected from patients with bloodstream, intra-abdominal and urinary tract infections in Western Europe: SMART 2018-2020.
Piperacillin/tazobactam and carbapenems are important agents for the treatment of serious Gram-negative infections in hospitalized patients. Resistance to both agents is a significant concern in clinical isolates of and ; new agents with improved activity are needed. Publication of current, region-specific data describing the activity of newer agents such as imipenem/relebactam (IMR) against piperacillin/tazobactam-resistant and carbapenem-resistant and are needed to support their clinical use. To describe the activity of IMR against non- (NME) and isolated from bloodstream, intra-abdominal and urinary tract infection samples by hospital laboratories in Western Europe with a focus on the activity of IMR against piperacillin/tazobactam-resistant and meropenem-resistant isolates. From 2018 to 2020, 29 hospital laboratories in six countries in Western Europe participated in the SMART global surveillance programme and contributed 9487 NME and 1004 . isolates. MICs were determined by CLSI broth microdilution testing and interpreted by EUCAST (2021) breakpoints. β-Lactamase genes were identified in selected isolate subsets (2018-2020) and sequenced in molecularly characterized (2020). IMR (99.4 % susceptible), amikacin (98.0 %), meropenem (97.7 %) and imipenem (97.6 %) were the most active agents against NME; 83.1 % of NME were piperacillin/tazobactam-susceptible. Relebactam increased imipenem susceptibility of NME from Italy by 8.3 %, from Portugal by 2.9 %, and from France, Germany, Spain and the UK by <1 %. In total, 96.4 % of piperacillin/tazobactam-resistant (=1601) and 73.7 % of meropenem-resistant (=152) NME were IMR-susceptible. Also, 0.4 % of NME were MBL-positive, 0.9 % OXA-48-like-positive (MBL-negative) and 1.5 % KPC-positive (MBL-negative). Amikacin (95.4 % susceptible) and IMR (94.1 %) were the most active agents against ; 81.7 % of isolates were imipenem-susceptible and 79.6 % were piperacillin/tazobactam-susceptible. Relebactam increased susceptibility to imipenem by 12.5 % overall (range by country, 4.3-17.5 %); and by 30.7 % in piperacillin/tazobactam-resistant and 24.3 % in meropenem-resistant . In total, 1.6 % of isolates were MBL-positive. Seven of eight molecularly characterized IMR-resistant isolates from 2020 were -deficient. IMR may be a potential treatment option for bloodstream, intra-abdominal and urinary tract infections caused by NME and in Western Europe, including infections caused by piperacillin/tazobactam-resistant and meropenem-resistant isolates.
Topics: Humans; Meropenem; Pseudomonas aeruginosa; Amikacin; Anti-Bacterial Agents; Imipenem; Urinary Tract Infections; Piperacillin, Tazobactam Drug Combination; Europe; Microbial Sensitivity Tests; Pseudomonas Infections; Cephalosporins
PubMed: 36763081
DOI: 10.1099/jmm.0.001645 -
The Journal of Antimicrobial... May 2020Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic...
BACKGROUND
Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases.
OBJECTIVES
To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies.
METHODS
(i) Male Sprague-Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®.
RESULTS
Urinary output increased from Day -1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P < 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P < 0.001, KIM-1; P < 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin.
CONCLUSIONS
All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.
Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Drug Therapy, Combination; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Rats; Rats, Sprague-Dawley; Retrospective Studies; Vancomycin
PubMed: 32011685
DOI: 10.1093/jac/dkz563 -
Indian Journal of Medical Microbiology 2023The CLSI annual update of its M100 document is eagerly awaited every year. This year's update, the M100-Ed33, was published in February, and will significantly affect... (Review)
Review
BACKGROUND
The CLSI annual update of its M100 document is eagerly awaited every year. This year's update, the M100-Ed33, was published in February, and will significantly affect clinical practices.
OBJECTIVE
To highlight and explain the rationale of the changes and their clinical impact.
CONTENT
The major changes this year are mostly focused on PK/PD data, selective and cascade reporting of the antibiotics and therapy related comments. The CLSI has moved away from its classical grouping of antibiotics (A, B, U, O) to a tier-based approach (Tier 1, 2, 3, 4) which will aid in cascade reporting during an antibiotic susceptibility testing (AST). Rather than non-fastidious, fastidious and anaerobe grouping, the tables have been made organism specific. The aminoglycosides breakpoints have been changed for both Enterobacterales and Pseudomonas aeruginosa while for P. aeruginosa, the breakpoints of piperacillin - tazobactam (TZP) are also updated. These updates are mostly based on attainment of drug plasma level for bacterial stasis rather than bactericidal effect of the antibiotics. It is noteworthy, that these breakpoint changes are made, keeping in view that the aminoglycosides for all organisms should be used in combination therapy. For P. aeruginosa, gentamicin has been removed, while amikacin has been restricted for urinary isolates only.
Topics: Humans; Anti-Bacterial Agents; Amikacin; Pseudomonas aeruginosa; Piperacillin, Tazobactam Drug Combination; Microbial Sensitivity Tests
PubMed: 37945125
DOI: 10.1016/j.ijmmb.2023.100432 -
British Journal of Clinical Pharmacology Apr 2023A common approach to assess the efficacy of piperacillin is to first measure the total concentration and afterwards apply a theoretical unbound fraction of 70% to obtain...
A common approach to assess the efficacy of piperacillin is to first measure the total concentration and afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction, therefore we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on the dosing recommendations of piperacillin. Unbound factors of 70%, 75%, 80% and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fractions caused minimal impact on piperacillin clearance and target attainment but seemed to influence model validity.
Topics: Humans; Piperacillin; Anti-Bacterial Agents; Critical Illness; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination
PubMed: 36445340
DOI: 10.1111/bcp.15619 -
Journal of the Formosan Medical... May 2022The Taiwan Acute Kidney Injury (AKI) Task Force conducted a review of data and developed a consensus regarding nephrotoxins and AKI. This consensus covers: (1)... (Review)
Review
The Taiwan Acute Kidney Injury (AKI) Task Force conducted a review of data and developed a consensus regarding nephrotoxins and AKI. This consensus covers: (1) contrast-associated AKI; (2) drug-induced nephrotoxicity; (3) prevention of drug-associated AKI; (4) follow up after AKI; (5) re-initiation of medication after AKI. Strategies for the avoidance of contrast media related AKI, including peri-procedural hydration, sodium bicarbonate solutions, oral N-acetylcysteine, and iso-osmolar/low-osmolar non-ionic iodinated contrast media have been recommended, given the respective evidence levels. Regarding anticoagulants, both warfarin and new oral anticoagulants have potential nephrotoxicity, and dosage should be reduced if renal pathology exam proves renal injury. Recommended strategies to prevent drug related AKI have included assessment of 5R/(6R) reactions - risk, recognition, response, renal support, rehabilitation and (research), use of AKI alert system and computerized decision support. In terms of antibiotics-associated AKI, avoiding concomitant administration of vancomycin and piperacillin-tazobactam, monitoring vancomycin trough level, switching from vancomycin to teicoplanin in high-risk patients, and replacing conventional amphotericin B with lipid-based amphotericin B have been shown to reduce drug related AKI. With respect to non-steroidal anti-inflammatory drug associated AKI, it is recommended to use these drugs cautiously in the elderly and in patients receiving renin-angiotensin-aldosterone system inhibitors/diuretics triple combinations.
Topics: Acute Kidney Injury; Aged; Amphotericin B; Anti-Bacterial Agents; Anticoagulants; Consensus; Contrast Media; Drug Therapy, Combination; Female; Humans; Male; Piperacillin; Retrospective Studies; Taiwan; Vancomycin
PubMed: 34998658
DOI: 10.1016/j.jfma.2021.12.007 -
Antimicrobial Agents and Chemotherapy Dec 2022We aimed to develop a piperacillin population pharmacokinetic (PK) model in critically ill children receiving continuous renal replacement therapy (CRRT) and to optimize...
We aimed to develop a piperacillin population pharmacokinetic (PK) model in critically ill children receiving continuous renal replacement therapy (CRRT) and to optimize dosing regimens. The piperacillin plasma concentration was quantified by high-performance liquid chromatography. Piperacillin PK was investigated using a nonlinear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration according to the target of 100% interdose interval time in which concentration is one to four times above the MIC (100% fT > 1 to 4× MIC). A total of 32 children with a median (interquartile range [IQR]) postnatal age of 2 years (0 to 11), body weight (BW) of 15 kg (6 to 38), and receiving CRRT were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. BW and residual diuresis () explained some between-subject variabilities on volume of distribution (), where [Formula: see text], and clearance (CL), where [Formula: see text], where CL and are 6.78 L/h and 55.0 L, respectively, normalized to a 70-kg subject and median residual diuresis of 0.06 mL/kg/h. Simulations with intermittent and continuous administrations for 4 typical patients with different rates of residual diuresis (0, 0.1, 0.25, and 0.5 mL/kg/h) showed that continuous infusions were appropriate to attain the PK target for patients with residual diuresis higher than 0.1 mL/kg/h according to BW and MIC, while for anuric patients, less frequent intermittent doses were mandatory to avoid accumulation. Optimal exposure to piperacillin in critically ill children on CRRT should be achieved by using continuous infusions with escalating doses for high-MIC bacteria, except for anuric patients who require less frequent intermittent doses.
Topics: Humans; Child; Child, Preschool; Piperacillin; Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Piperacillin, Tazobactam Drug Combination; Renal Replacement Therapy
PubMed: 36342152
DOI: 10.1128/aac.01135-22 -
Antimicrobial Agents and Chemotherapy May 2024Japan is a country with an approximate 10% prevalence rate of carbapenem-resistant (CRPA). Currently, a comprehensive overview of the genotype and phenotype patterns of...
Japan is a country with an approximate 10% prevalence rate of carbapenem-resistant (CRPA). Currently, a comprehensive overview of the genotype and phenotype patterns of CRPA in Japan is lacking. Herein, we conducted genome sequencing and quantitative antimicrobial susceptibility testing for 382 meropenem-resistant CRPA isolates that were collected from 78 hospitals across Japan from 2019 to 2020. CRPA exhibited susceptibility rates of 52.9%, 26.4%, and 88.0% against piperacillin-tazobactam, ciprofloxacin, and amikacin, respectively, whereas 27.7% of CRPA isolates was classified as difficult-to-treat resistance . Of the 148 sequence types detected, ST274 (9.7%) was predominant, followed by ST235 (7.6%). The proportion of urine isolates in ST235 was higher than that in other STs ( = 0.0056, χ test). Only 4.1% of CRPA isolates carried the carbapenemase genes: (2) and (13). One ST235 isolate carried the novel variant in the chromosome. Regarding chromosomal mutations, 87.1% of CRPA isolates possessed inactivating or other resistance mutations in , and 28.8% showed mutations in the regulatory genes (, , and ) for the MexAB-OprM efflux pump. Additionally, 4.7% of CRPA isolates carried a resistance mutation in the PBP3-encoding gene . The findings from this study and other surveillance studies collectively demonstrate that CRPA exhibits marked genetic diversity and that its multidrug resistance in Japan is less prevailed than in other regions. This study contributes a valuable data set that addresses a gap in genotype/phenotype information regarding CRPA in the Asia-Pacific region, where the epidemiological background markedly differs between regions.
Topics: Pseudomonas aeruginosa; Japan; Microbial Sensitivity Tests; Carbapenems; Anti-Bacterial Agents; Humans; Bacterial Proteins; Pseudomonas Infections; beta-Lactamases; Genome, Bacterial; Piperacillin, Tazobactam Drug Combination; Whole Genome Sequencing; Meropenem; Drug Resistance, Multiple, Bacterial; Amikacin
PubMed: 38564665
DOI: 10.1128/aac.01669-23 -
The Australian Journal of Rural Health Jun 2023The aim of this study was to investigate the type, indication and duration of restricted antibiotics prescribed to inpatients who had undergone antimicrobial stewardship... (Observational Study)
Observational Study
OBJECTIVE
The aim of this study was to investigate the type, indication and duration of restricted antibiotics prescribed to inpatients who had undergone antimicrobial stewardship (AMS) review by the infectious diseases specialist and to assess the effectiveness of the AMS program in a rural hospital.
DESIGN
This was an observational retrospective study.
SETTING
The study was conducted at a rural referral hospital in NSW.
PARTICIPANTS
Inpatients from the medical, surgical and intensive care units were included.
MAIN OUTCOME MEASURES
The main outcome measure was the type, indication and average duration of restricted antibiotics that were reviewed in the AMS rounds. The rate of adherence to AMS advice and the rate of step-down of antibiotics after AMS advice were other outcome measures. Data on participant characteristics were also collected.
RESULTS
The most commonly prescribed restricted antibiotic in medicine and surgery was amoxicillin-clavulanic acid (28%), followed by ceftriaxone (15%) and piperacillin-tazobactam (10%), with the most common indication being intra-abdominal infection (37%). In intensive care, ceftriaxone (16.7%) and piperacillin-tazobactam (16.7%) were most prescribed, and the most common indication was community-acquired pneumonia (24.5%). The adherence rate to AMS advice was 86% in medicine and surgery and 83% in intensive care. AMS rounds managed to cease or step down antibiotics 60% of the time.
CONCLUSION
The AMS program in a rural hospital was effective with an overall AMS advice adherence rate of 84.5% which measures well against tertiary-level centres. Continued AMS and advocacy of such programs in rural regions are fundamental to optimising patient outcomes in the rural community.
Topics: Humans; Anti-Bacterial Agents; Antimicrobial Stewardship; Australia; Ceftriaxone; Hospitals, Rural; Piperacillin, Tazobactam Drug Combination; Retrospective Studies
PubMed: 36939285
DOI: 10.1111/ajr.12979