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Journal of Clinical Pharmacy and... Aug 2022Timely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement... (Review)
Review
Pharmacokinetics of piperacillin and tazobactam in critically Ill patients treated with continuous kidney replacement therapy: A mini-review and population pharmacokinetic analysis.
WHAT IS KNOWN AND OBJECTIVE
Timely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement therapy (CKRT) often have physiologic derangements that affect pharmacokinetics (PK) of antibiotics and dosing may be challenging. We sought to aggregate previously published piperacillin and tazobactam (pip-tazo) pharmacokinetic data in critically ill patients undergoing CKRT to better understand pharmacokinetics of pip-tazo in this population and better inform dosing.
METHODS
The National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn.
RESULTS AND DISCUSSION
Median and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA.
WHAT IS NEW AND CONCLUSION
Pip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.
Topics: Anti-Bacterial Agents; Critical Illness; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Renal Replacement Therapy; Tazobactam
PubMed: 35352374
DOI: 10.1111/jcpt.13657 -
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 -
British Journal of Clinical Pharmacology Mar 2022Early-onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for...
AIMS
Early-onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model-based dosing regimen of piperacillin/tazobactam in EOS patients.
METHODS
A prospective, single-centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg , q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected.
RESULTS
A total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14-41.29) weeks. Forty-seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2-305.8) hours and 31 (30, 5-123) days. There were no obvious adverse events and no infection-related deaths occurred in the first month of life.
CONCLUSIONS
A model-based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment.
Topics: Anti-Bacterial Agents; Humans; Infant; Infant, Newborn; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Sepsis
PubMed: 34450681
DOI: 10.1111/bcp.15058 -
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 -
Journal of Thrombosis and Thrombolysis Jul 2019Drug-induced thrombocytopenia (DITP) has been described as a sudden and severe hematologic complication of piperacillin/tazobactam. The proposed mechanism by which...
Drug-induced thrombocytopenia (DITP) has been described as a sudden and severe hematologic complication of piperacillin/tazobactam. The proposed mechanism by which piperacillin/tazobactam causes DITP involves the formation of a covalent bond to platelet membrane protein thereby inducing a humoral immune response. Given the immunogenic nature of this adverse event and the structural similarities across beta-lactam antibiotics, the potential for cross-reactivity between agents within the class should be considered. However, the structural moiety of piperacillin/tazobactam responsible for this immunogenic response has not been identified-the relationship between structure and activity for this phenomenon remains unknown. Data on the safety and cross-reactivity of other beta-lactam agents in this setting is lacking. We report the first case of piperacillin/tazobactam DITP successfully challenged by the use of cefepime for the treatment of aspiration pneumonia. Further studies are needed to determine the structural moiety of piperacillin/tazobactam responsible for this immunogenic response and evaluate the safety of other beta-lactam antibiotics in this clinical setting.
Topics: Adult; Anti-Bacterial Agents; Cefepime; Female; Humans; Immunity, Humoral; Male; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Aspiration; Tazobactam; Thrombocytopenia
PubMed: 30968302
DOI: 10.1007/s11239-019-01848-3 -
Journal of Critical Care Dec 2019Increased renal elimination is the leading cause for subtherapeutic concentrations of renally cleared antibiotics and it has been hypothesized that brain damaged...
PURPOSE
Increased renal elimination is the leading cause for subtherapeutic concentrations of renally cleared antibiotics and it has been hypothesized that brain damaged patients in the intensive care unit (ICU) are particularly at risk. The objective of this study is to determine the prevalence of subtherapeutic piperacillin concentrations in neurocritical patients and to investigate if having a neurocritical diagnosis is a risk factor for this.
MATERIALS AND METHODS
Single center retrospective analysis of a prospective cohort study of adult ICU patients receiving continuous infusion piperacillin/tazobactam. Patients were categorized as either having a neurocritical diagnosis or not. An unbound piperacillin concentration > 4× the epidemiologic cut-off value (ECOFF) of Pseudomonas aeruginosa was selected as the PKPD target of choice. Multivariable logistic regression was performed to identify risk factors for subtherapeutic piperacillin concentrations.
RESULTS
356 patients had a measured creatinine clearance (mCrCl) and matched piperacillin concentration, 52 of which had a neurocritical diagnosis. Subtherapeutic piperacillin concentrations were reported significantly more frequent in neurocritical patients. In multivariate analysis, the only risk factor identified for subtherapeutic piperacillin concentration was an increasing mCrCl.
CONCLUSION
Subtherapeutic piperacillin concentrations are common in neurocritical patients yet having a neurocritical admission diagnosis was not identified as an independent risk factor.
Topics: Adult; Aged; Anti-Bacterial Agents; Critical Care; Critical Illness; Female; Humans; Intensive Care Units; Kidney; Kidney Function Tests; Male; Middle Aged; Multivariate Analysis; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas aeruginosa; Retrospective Studies; Risk Factors
PubMed: 31349159
DOI: 10.1016/j.jcrc.2019.07.007 -
Acta Anaesthesiologica Scandinavica Aug 2023Piperacillin/tazobactam or meropenem are often used to treat patients with severe bacterial infections. We aimed to compare the desirable and undesirable effects of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Piperacillin/tazobactam or meropenem are often used to treat patients with severe bacterial infections. We aimed to compare the desirable and undesirable effects of empirical and/or definitive piperacillin/tazobactam versus carbapenems in patients with severe bacterial infections.
METHODS
We searched PubMed, Embase, CENTRAL, Epistemonikos, and trial registers for randomised clinical trials of empirical and/or definitive piperacillin/tazobactam versus carbapenems in adult patients with severe bacterial infection (i.e., any bacterial infection requiring hospitalisation). The primary outcome was all-cause short-term mortality within 90 days. Secondary outcomes were all-cause long-term mortality, adverse events, quality of life, days alive without or duration of life support, secondary infections, selection of fungi or resistant bacteria, and days alive and out of hospital or hospital length of stay. We calculated relative risks (RRs) using random effects and fixed effect meta-analyses along with trial sequential analyses.
RESULTS
We included 31 trials (n = 8790 patients) with overall high risk of bias. The RR for all-cause short-term mortality was 1.16 (95% confidence interval [CI]: 0.94-1.43, low certainty evidence), for adverse events 1.00 (98% CI: 0.96-1.04, moderate certainty evidence), for secondary infections 1.13 (98% CI: 0.76-1.68, very low certainty evidence), and for selection of fungi or resistant bacteria 1.61 (98% CI: 0.89-2.89, very low certainty evidence). There were no or limited data for the remaining outcomes.
CONCLUSIONS
Based on very low or low certainty evidence, piperacillin/tazobactam may be associated with less favourable outcomes in patients with severe bacterial infections as compared with carbapenems, but the information size for a robust conclusion has not been reached.
Topics: Adult; Humans; Carbapenems; Coinfection; Quality of Life; Piperacillin, Tazobactam Drug Combination; Bacterial Infections; Bacteria
PubMed: 36919866
DOI: 10.1111/aas.14239 -
Pediatric Research Mar 2023Antibiotics are commonly used in human neonates, but their impact on neonatal T cell immunity remains poorly understood. The aim of this study was to investigate the...
BACKGROUND
Antibiotics are commonly used in human neonates, but their impact on neonatal T cell immunity remains poorly understood. The aim of this study was to investigate the impact of the antibiotic piperacillin with the beta-lactamase inhibitor tazobactam on neonatal CD4+ and CD8+ T cell responses to Streptococcus pneumoniae.
METHODS
Splenic and lung cells were isolated from the neonatal mice receiving piperacillin and tazobactam or saline (sham) and cultured with S. pneumoniae to analyze T cell cytokine production by ELISA and flow cytometry.
RESULTS
Antibiotic exposure to neonatal mice resulted in reduced numbers of CD4+/CD8+ T cells in the spleen and lungs compared to control mice. Upon in vitro stimulation with S. pneumoniae, splenocytes and lung cells from antibiotic-exposed mice produced lower levels of IFN-γ (Th1)/IL-17A (Th17) and IL-17A cytokines, respectively. Flow cytometric analysis revealed that S. pneumoniae-stimulated splenic CD4+ T cells from antibiotic-exposed mice expressed decreased levels of IFN-γ and IL-17A compared to control mice, whereas lung CD4+ T cells produced lower levels of IL-17A. However, no significant difference was observed for IL-4 (Th2) production.
CONCLUSIONS
Neonatal mice exposure to piperacillin and tazobactam reduces the number of CD4+ and CD8+ T cells, and suppresses Th1 and Th17, but not Th2, responses to S. pneumoniae.
IMPACT
Exposure of neonatal mice with a combination of piperacillin and tazobactam reduces CD4+/CD8+ T cells in the spleen and lungs. Antibiotic exposure suppresses neonatal Th1 and Th17, but not Th2, responses to Streptococcus pneumoniae. Our findings may have important implications for developing better therapeutic strategies in the neonatal intensive care unit.
Topics: Humans; Animals; Mice; Interleukin-17; Animals, Newborn; Anti-Bacterial Agents; Cytokines; Th17 Cells; Streptococcus pneumoniae; Piperacillin; Tazobactam; Th1 Cells
PubMed: 35778498
DOI: 10.1038/s41390-022-02115-7 -
Journal of Clinical Microbiology Feb 2023species are anaerobic, Gram-negative bacilli increasingly recognized as pathogens capable of causing invasive infections such as bloodstream infection (BSI),... (Review)
Review
species are anaerobic, Gram-negative bacilli increasingly recognized as pathogens capable of causing invasive infections such as bloodstream infection (BSI), particularly among immunocompromised patients. However, there is a paucity of data regarding epidemiology, antimicrobial susceptibility, optimal treatment, and clinical outcomes among patients with bacteremia. Patient risk factors, treatment approaches, and outcomes of a retrospective cohort of adult patients with BSI at a tertiary medical center (Mayo Clinic Rochester [MCR]) were evaluated. Concurrently, species, temporal trends, and antimicrobial susceptibility testing (AST) results of isolates submitted to a reference laboratory (Mayo Clinic Laboratories) over the past 10 years were examined. We identified 224 blood culture isolates of species, with 26 isolates from patients treated at MCR. The most frequent species included L. trevisanii (49%), L. buccalis (24%), and L. wadei (16%). species demonstrated >90% susceptibility to penicillin, metronidazole, ertapenem, and piperacillin-tazobactam. However, 96% (74/77) of isolates were resistant to moxifloxacin. For patients treated at MCR, the mean patient age was 55 years (standard deviation [SD], 17), with 9 females (35%), and all were neutropenic at the time of BSI. The primary sources of infection were gastrointestinal (58%), intravascular catheter (35%), and odontogenic (15%). Patients were treated with metronidazole (42%), piperacillin-tazobactam (27%), or carbapenems (19%). The mean duration of treatment was 11 days (SD, 4.5), with a 60-day all-cause mortality of 19% and no microbiologic relapse. species are rare but important causes of BSI in neutropenic patients. Due to evolving antimicrobial susceptibility profiles, a review of AST results is necessary when selecting optimal antimicrobial therapy.
Topics: Adult; Female; Humans; Middle Aged; Metronidazole; Leptotrichia; Retrospective Studies; Bacteremia; Anti-Infective Agents; Piperacillin, Tazobactam Drug Combination; Gram-Negative Bacteria; Sepsis; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 36715514
DOI: 10.1128/jcm.01733-22 -
BMC Infectious Diseases Sep 2023Many factors determine empirical antibiotic treatment of community-acquired pneumonia (CAP). We aimed to describe the empirical antibiotic treatment CAP patients with an...
Empirical antibiotic treatment for community-acquired pneumonia and accuracy for Legionella pneumophila, Mycoplasma pneumoniae, and Clamydophila pneumoniae: a descriptive cross-sectional study of adult patients in the emergency department.
BACKGROUND
Many factors determine empirical antibiotic treatment of community-acquired pneumonia (CAP). We aimed to describe the empirical antibiotic treatment CAP patients with an acute hospital visit and to determine if the current treatment algorithm provided specific and sufficient coverage against Legionella pneumophila, Mycoplasma pneumoniae, and Clamydophila pneumoniae (LMC).
METHODS
A descriptive cross-sectional, multicenter study of all adults with an acute hospital visit in the Region of Southern Denmark between January 2016 and March 2018 was performed. Using medical records, we retrospectively identified the empirical antibiotic treatment and the microbiological etiology for CAP patients. CAP patients who were prescribed antibiotics within 24 h of admission and with an identified bacterial pathogen were included. The prescribed empirical antibiotic treatment and its ability to provide specific and sufficient coverage against LMC pneumonia were determined.
RESULTS
Of the 19,133 patients diagnosed with CAP, 1590 (8.3%) patients were included in this study. Piperacillin-tazobactam and Beta-lactamase sensitive penicillins were the most commonly prescribed empirical treatments, 515 (32%) and 388 (24%), respectively. Our analysis showed that 42 (37%, 95% CI: 28-47%) of 113 patients with LMC pneumonia were prescribed antibiotics with LMC coverage, and 42 (12%, 95% CI: 8-15%) of 364 patients prescribed antibiotics with LMC coverage had LMC pneumonia.
CONCLUSION
Piperacillin-tazobactam, a broad-spectrum antibiotic recommended for uncertain infectious focus, was the most frequent CAP treatment and prescribed to every third patient. In addition, the current empirical antibiotic treatment accuracy was low for LMC pneumonia. Therefore, future research should focus on faster diagnostic tools for identifying the infection focus and precise microbiological testing.
Topics: Humans; Adult; Legionella pneumophila; Mycoplasma pneumoniae; Cross-Sectional Studies; Retrospective Studies; Anti-Bacterial Agents; Piperacillin, Tazobactam Drug Combination; Emergency Service, Hospital; Pneumonia; Community-Acquired Infections
PubMed: 37670282
DOI: 10.1186/s12879-023-08565-6