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Antimicrobial Agents and Chemotherapy Mar 2021There is insufficient data on the relationship between antibiotic dosing and plasma concentrations in patients treated with continuous renal replacement therapy (CRRT).... (Observational Study)
Observational Study
There is insufficient data on the relationship between antibiotic dosing and plasma concentrations in patients treated with continuous renal replacement therapy (CRRT). In this prospective observational study, we explored the variability in plasma concentrations of meropenem and piperacillin in critically ill patients treated with CRRT and the correlation between concentrations and CRRT intensity. Antibiotic concentrations were measured at the middle and end of the dosing interval and repeated after 2 to 3 days when feasible. Measured concentrations were compared to the clinical susceptible breakpoints for , 16 and 2 mg/liter for piperacillin and meropenem, respectively. CRRT intensity was estimated by delivered, time-averaged, total effluent flow (), corrected for predilution. Concentrations were also compared between patients with different residual diuresis. We included 140 meropenem concentrations from 98 patients and 47 piperacillin concentrations from 37 patients. Concentrations at the middle of the dosing interval were above target at all occasions for both antibiotics. For meropenem, 6.5% of trough concentrations were below target, and for piperacillin, 22%. Correlations between and antibiotic concentrations or the concentration half-life () were either statistically not significant or weak. Meropenem concentrations and values differed between patients with different residual diuresis. Thus, when treating intensive care patients with CRRT and recommended doses of meropenem or piperacillin, both low, suboptimal plasma concentrations and unnecessarily high, potentially toxic, plasma concentrations are common. Plasma concentrations cannot be predicted from CRRT intensity. Residual diuresis is associated with lower meropenem concentrations, but the correlation is weak. Concentration measurement is probably the most useful approach to avoid suboptimal treatment.
Topics: Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Piperacillin; Renal Replacement Therapy
PubMed: 33495227
DOI: 10.1128/AAC.02029-20 -
Clinical Pharmacokinetics Jun 2022Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and... (Observational Study)
Observational Study
BACKGROUND AND OBJECTIVES
Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine.
METHODS
In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin-tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function.
RESULTS
A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively.
CONCLUSIONS
A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases.
GOV IDENTIFIER
NCT03738683.
Topics: Adult; Anti-Bacterial Agents; Critical Illness; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Tazobactam
PubMed: 35377133
DOI: 10.1007/s40262-022-01113-6 -
Antimicrobial Agents and Chemotherapy Nov 2019Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of...
Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.
Topics: Anti-Bacterial Agents; Child; Child, Preschool; Cross Infection; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas Infections; Pseudomonas aeruginosa; Tazobactam
PubMed: 31427292
DOI: 10.1128/AAC.01260-19 -
The Journal of Antimicrobial... Sep 2023Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care.
The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.
BACKGROUND
Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care.
OBJECTIVES
The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing.
METHODS
NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval.
RESULTS
For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively).
CONCLUSIONS
NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.
Topics: Infant, Newborn; Humans; Child; Adolescent; Piperacillin; Floxacillin; Amoxicillin; Prospective Studies; Anti-Bacterial Agents; Penicillins; Microbial Sensitivity Tests
PubMed: 37531085
DOI: 10.1093/jac/dkad196 -
Pediatrics International : Official... Jan 2022Drug utilization evaluation (DUE) is a systematic, criteria-based assessment of medicine that aims to optimize the appropriateness of antibiotic prescription. This study...
BACKGROUND
Drug utilization evaluation (DUE) is a systematic, criteria-based assessment of medicine that aims to optimize the appropriateness of antibiotic prescription. This study aimed to evaluate the performance of the DUE on prescriptions of two commonly used antibiotics in a pediatric population, cefepime and piperacillin/tazobactam, in a tertiary care hospital.
METHODS
This quasi-experimental study was conducted at the Department of Pediatrics, Ramathibodi Hospital, between March 2020 and August 2021. All hospitalized children aged 1 month to 20 years who received at least one dose of cefepime or piperacillin/tazobactam were enrolled. Before implementing the DUE, cefepime and piperacillin/tazobactam prescriptions were retrospectively evaluated using the DUE criteria. During the 6 month DUE implementation period, physicians voluntarily chose to use DUE to assess the prescriptions' appropriateness. Demographic data, antibiotic use, and clinical data were recorded.
RESULTS
There were 304 prescriptions of cefepime and piperacillin/tazobactam, with 108 empirical prescriptions (72 patients) in the DUE group and 158 prescriptions (138 patients) in the non-DUE group. The appropriateness of empirical prescriptions of cefepime and piperacillin/tazobactam was significantly higher in the DUE group (93.5% vs. 83.5%; P = 0.003). Drug utilization evaluation was significantly associated with appropriate empirical prescriptions (adjusted OR 5.32: 95% CI 1.80-15.73; P = 0.003). Prescriptions in critical care wards and urinary tract infections (UTIs) were associated with not fulfilling the DUE criteria for appropriateness.
CONCLUSIONS
Drug utilization evaluation could improve the appropriateness of empirical use of cefepime and piperacillin/tazobactam in pediatric patients. Patients in critical care units and with UTIs appeared to be associated with inappropriate empirical treatment.
Topics: Child; Humans; Cefepime; Retrospective Studies; Cephalosporins; Piperacillin, Tazobactam Drug Combination; Anti-Bacterial Agents; Drug Utilization Review
PubMed: 36257611
DOI: 10.1111/ped.15276 -
Medicine Jul 2023The objective was to compare the clinical efficacy of cefoperazone-sulbactam with piperacillin-tazobactam in the treatment of severe community-acquired pneumonia (SCAP)....
The objective was to compare the clinical efficacy of cefoperazone-sulbactam with piperacillin-tazobactam in the treatment of severe community-acquired pneumonia (SCAP). The retrospective study was conducted from March 1, 2018 to May 30, 2019. Clinical outcomes were compared for patients who received either cefoperazone-sulbactam or piperacillin-tazobactam in the treatment of SCAP. A total of 815 SCAP patients were enrolled. Among them, 343 received cefoperazone-sulbactam, and 472 received piperacillin-tazobactam. Patients who received cefoperazone-sulbactam presented with higher Charlson Comorbidity Index scores. (6.20 ± 2.77 vs 5.72 ± 2.61; P = .009). The clinical cure rates and effectiveness for patients receiving cefoperazone-sulbactam and piperacillin-tazobactam were 84.2% versus 80.3% (P = .367) and 85.4% versus 83.3% (P = .258), respectively. In addition, the overall mortality rate of the cefoperazone-sulbactam group was 16% (n = 55), which was also comparable to the piperacillin-tazobactam group (17.8%, n = 84, P = .572). The primary clinical outcomes for patients receiving cefoperazone-sulbactam were superior compared to those receiving piperacillin-tazobactam after adjusting disease severity status. The clinical efficacy of cefoperazone-sulbactam in the treatment of adult patients with SCAP is comparable to that of piperacillin-tazobactam. After adjusting for disease severity, cefoperazone-sulbactam tended to be superior to piperacillin-tazobactam.
Topics: Humans; Cefoperazone; Sulbactam; Anti-Bacterial Agents; Piperacillin; Retrospective Studies; Penicillanic Acid; Piperacillin, Tazobactam Drug Combination; Treatment Outcome; Microbial Sensitivity Tests; Community-Acquired Infections; Pneumonia
PubMed: 37443505
DOI: 10.1097/MD.0000000000034284 -
The Journal of Antimicrobial... Nov 2023The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For...
BACKGROUND
The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable β-lactams, standard and high dosages have been proposed for short-infusion regimens only.
OBJECTIVES
To evaluate dosages for β-lactams administered by prolonged infusion (PI) and continuous infusion (CI).
METHODS
Monte Carlo simulations were performed for seven injectable β-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable.
RESULTS
Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam.
CONCLUSIONS
These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.
Topics: Humans; Cefepime; Aztreonam; Anti-Bacterial Agents; Ceftazidime; Piperacillin; Microbial Sensitivity Tests; Monte Carlo Method
PubMed: 37796958
DOI: 10.1093/jac/dkad300 -
Clinical Pharmacokinetics Jul 2021Piperacillin-tazobactam is a potent β-lactam/β-lactamase inhibitor antibiotic commonly prescribed in the intensive care unit setting. Admitted patients often show... (Review)
Review
Piperacillin-tazobactam is a potent β-lactam/β-lactamase inhibitor antibiotic commonly prescribed in the intensive care unit setting. Admitted patients often show large variability in treatment response due to multiple pathophysiological changes present in this population that alter the drug's pharmacokinetics. This review summarizes the population pharmacokinetic models developed for piperacillin-tazobactam and provides comprehensive data on current dosing strategies while identifying significant covariates in critically ill patients. A literature search on the PubMed database was conducted, from its inception to July 2020. Relevant articles were retained if they met the defined inclusion/exclusion criteria. A total of ten studies, published between 2009 and 2020, were eligible. One- and two-compartment models were used in two and eight studies, respectively. The lowest estimated piperacillin clearance value was 3.12 L/h, and the highest value was 19.9 L/h. The estimations for volume of distribution varied between 11.2 and 41.2 L. Tazobactam clearance values ranged between 5.1 and 6.78 L/h, and tazobactam volume of distribution values ranged between 17.5 and 76.1 L. The most frequent covariates were creatinine clearance and body weight, each present in four studies. Almost all studies used an exponential approach for the interindividual variability. The highest variability was observed in piperacillin central volume of distribution, at a value of 75.0%. Simulations showed that continuous or extended infusion methods performed better than intermittent administration to achieve appropriate pharmacodynamic targets. This review synthesizes important pharmacokinetic elements for piperacillin-tazobactam in an intensive care unit setting. This will help clinicians better understand changes in the drug's pharmacokinetic parameters in this specific population.
Topics: Anti-Bacterial Agents; Critical Illness; Humans; Intensive Care Units; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Prospective Studies; Tazobactam
PubMed: 33876381
DOI: 10.1007/s40262-021-01013-1 -
The Journal of Antimicrobial... Jan 2021Piperacillin/tazobactam combined with vancomycin has been associated with a decline in renal function when compared with monotherapy. Teicoplanin is a glycopeptide...
OBJECTIVES
Piperacillin/tazobactam combined with vancomycin has been associated with a decline in renal function when compared with monotherapy. Teicoplanin is a glycopeptide similar to vancomycin. We investigated whether piperacillin/tazobactam combined with teicoplanin is associated with a decline in renal function as well.
METHODS
We conducted a single-centre retrospective cohort study with data from our electronic health records from 9 August 2013 to 15 November 2019, including all adult patients that received either piperacillin/tazobactam, teicoplanin or piperacillin/tazobactam + teicoplanin. The incidence of acute kidney injury (AKI) at 48-72 h served as the primary outcome, whereas change in serum creatinine served as a secondary outcome.
RESULTS
Of the 4202 included patients, 3188 (75.9%) received piperacillin/tazobactam, 791 (18.8%) received teicoplanin and 223 (5.3%) received piperacillin/tazobactam + teicoplanin. The incidence of AKI at 48-72 h after commencement of antibiotic therapy was 5.4% for piperacillin/tazobactam, 3.4% for teicoplanin and 11.7% for piperacillin/tazobactam + teicoplanin (P < 0.001). However, mean serum creatinine at 48-72 h was slightly higher in the piperacillin/tazobactam + teicoplanin group therapy compared with baseline [+1.61% (95% CI -2.25 to 5.70)], indicating a slight decrease in renal function, and decreased for piperacillin/tazobactam [-1.98% (95% CI -2.73 to -1.22)] and teicoplanin [-8.01% (95% CI -9.54 to -6.45)]. After correcting for significant confounders in a multivariate linear regression analysis, these patterns remained.
CONCLUSIONS
Our study suggests that piperacillin/tazobactam + teicoplanin is associated with a higher prevalence of AKI compared with monotherapy. However, as the overall decline in renal function with piperacillin/tazobactam + teicoplanin is very small, its clinical relevance is likely limited. Therefore, piperacillin/tazobactam + teicoplanin can probably be safely combined.
Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Drug Therapy, Combination; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Teicoplanin; Vancomycin
PubMed: 32944771
DOI: 10.1093/jac/dkaa385 -
Journal of Pediatric Surgery Oct 2023Antibiotic overutilization in the neonatal intensive care unit (NICU) has many adverse effects, and necrotizing enterocolitis (NEC) is one of the most common indications...
BACKGROUND
Antibiotic overutilization in the neonatal intensive care unit (NICU) has many adverse effects, and necrotizing enterocolitis (NEC) is one of the most common indications for antibiotics in premature infants. Evidence for a preferred antibiotic regimen for NEC is lacking. This project aims to reduce piperacillin-tazobactam use and overall antibiotic duration in neonates with NEC through the implementation of an antibiotic stewardship pathway based on the modified Bell stage classification system.
METHODS
A multidisciplinary team consisting of neonatology, pharmacy, infectious disease, and surgery developed an antibiotic protocol for the management of NEC based on Bell stage. Recommendations included 48 h of ampicillin/gentamicin (AG) for stage I, 5-10 days of AG for stage II, the addition of metronidazole for stage IIIA, and 7-14 days of piperacillin-tazobactam (PT) for stage IIIB. We evaluated overall antibiotic and PT exposure, progression to surgical NEC, NEC recurrence, antibiotic resistance, bacteremia/fungemia, and mortality 1 year pre- and post-protocol implementation.
RESULTS
27 patients pre-intervention and 44 post-intervention were analyzed. Antibiotic exposure was reduced from a median 119.19 to 80.65 days of therapy (DOT) per 1000 patient days (p = 0.11). PT exposure decreased after protocol implementation (median 68.78 vs. 7.97 DOT per 1000 patient days, p = 0.002). There were no significant differences in morbidity or mortality outcomes.
CONCLUSIONS
Antibiotic stewardship strategies can be implemented in the NICU without compromising outcomes in patients with NEC. Bell stage stratification appears to be an effective method for antibiotic selection. Further studies are needed in a larger population to optimize regimens and ensure safety.
TYPE OF STUDY
Retrospective comparative study.
LEVEL OF EVIDENCE
Level III.
Topics: Infant; Female; Infant, Newborn; Humans; Enterocolitis, Necrotizing; Antimicrobial Stewardship; Quality Improvement; Retrospective Studies; Infant, Premature; Anti-Bacterial Agents; Ampicillin; Fetal Diseases; Infant, Newborn, Diseases; Piperacillin, Tazobactam Drug Combination
PubMed: 37479571
DOI: 10.1016/j.jpedsurg.2023.06.009