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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 -
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 -
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... 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 -
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 -
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 -
Orthopaedics & Traumatology, Surgery &... Dec 2022Antibiotics differ in their elution characteristics from bone cement. But no such data is available on piperacillin and tazobactam. Therefore, we performed an in vitro... (Observational Study)
Observational Study
BACKGROUND
Antibiotics differ in their elution characteristics from bone cement. But no such data is available on piperacillin and tazobactam. Therefore, we performed an in vitro observational study to examine (1) in vitro elution characteristics of piperacillin and tazobactam from bone cement, (2) their biological activity using minimum inhibitory concentration and (3) elution characteristics and biological activity when combined with gentamicin in bone cement.
HYPOTHESIS
The null hypothesis was that piperacillin and tazobactam after elution from bone cement can achieve concentrations higher than minimum inhibitory concentration.
MATERIAL AND METHODS
Forty milligrams bone cement was mixed with the following combination of antibiotics: without any antibiotic (sample A, control), 4g/0.50g piperacillin/tazobactam (sample B), 6g/0.75g piperacillin/tazobactam (sample C), 8g/1.0g piperacillin/tazobactam (sample D) and 4g/0.50g piperacillin/tazobactam and 400mg gentamicin (sample E). Samples were analysed on reverse-phase ultra-high-performance liquid chromatography. Antibacterial activity in the elute were tested against standard American Type Culture Collection (ATCC) strains.
RESULTS
Detectable drug elution for piperacillin and tazobactam was seen till 21days. Peak drug levels for all formulations were seen at 48hours (140.8 & 297.5μg/mL for samples B of piperacillin and tazobactam respectively). About 0.83-1.24% of piperacillin and 23.17-29.17% of tazobactam were released from the samples. Gentamicin improved elution of piperacillin and tazobactam: 140.8 vs. 919.9μg/mL (p=0.000) for samples B & E of piperacillin respectively and 297.5 & 1138.4μg/mL (p=0.001) for samples B & E of tazobactam respectively at 2days. Sample E showed complete inhibition of tested microorganisms, while B sample was microbiologically less active compared to E on day 5.
CONCLUSIONS
Piperacillin and tazobactam eluted successfully from bone cement and also retained antimicrobial activity after elution. Maximum elution was seen up to day 2 after which it reduced drastically. Antimicrobial action was seen up to 7days.
LEVEL OF EVIDENCE
III; comparative study.
Topics: Humans; Gentamicins; Polymethyl Methacrylate; Penicillanic Acid; Bone Cements; Piperacillin; Tazobactam; Piperacillin, Tazobactam Drug Combination; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 35123032
DOI: 10.1016/j.otsr.2022.103230 -
JAMA Network Open May 2022There is a lack of studies comparing the intended and unintended consequences of prospective review and feedback (PRF) with computerized decision support systems (CDSS),...
IMPORTANCE
There is a lack of studies comparing the intended and unintended consequences of prospective review and feedback (PRF) with computerized decision support systems (CDSS), especially in the longer term in antimicrobial stewardship.
OBJECTIVE
To examine the outcomes associated with the sequential implementation of PRF and CDSS and changes to these interventions with long-term use of antibiotics for and incidence of multidrug resistant organisms (MDROs) and other unintended outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study used an interrupted time series with segmented regression analysis of data from January 2007 to December 2018. Data were extracted from the electronic medical records of patients admitted at a large university teaching hospital with high rates of antibiotic resistance in Singapore. Data were analyzed from June 2019 to June 2020.
EXPOSURES
PRF of piperacillin-tazobactam and carbapenems (intervention 1, April 2009), with the addition of hospital-wide CDSS (intervention 2, April 2011), and lifting of CDSS for half of the hospital wards for 6 months (intervention 3, March 2017).
MAIN OUTCOMES AND MEASURES
Monthly antimicrobial use was measured in defined daily doses (DDDs) per 1000 patient-days. The monthly incidence of MDROs was calculated as number of clinical isolates detected per 1000 inpatient-days over a 6-month period. Unintended outcomes examined included in-hospital mortality and age-adjusted length of stay (LOS).
RESULTS
The number of inpatients increased from 56 263 in 2007 to 63 572 in 2018. During the same period, the mean monthly patient days increased from 33 929 in 2007 to 45 603 in 2018, and the proportion of patients older than 65 years increased from 45.5% in 2007 to 56.6% in 2018. After intervention 1, there were 0.33 (95% CI, 0.18 to 0.48) more DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and -11.05 (95% CI, -15.55 to -6.55) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 2, there were -0.22 (95% CI, -0.33 to -0.10) fewer DDDs per 1000 patient-days per month of piperacillin-tazobactam and carbapenems and -2.10 (95% CI, -3.13 to -1.07) fewer DDDs per 1000 patient-days per month for other broad-spectrum antibiotics. After intervention 3, use of piperacillin-tazobactam and carbapenem increased by 0.28 (95% CI, 0.02 to 0.55) DDDs per 1000 patient-days per month. After intervention 2, incidence of Clostridioides difficile decreased (estimate, -0.02 [95% CI, -0.03 to -0.01] cases per 1000 patient-days per month).
CONCLUSIONS AND RELEVANCE
In this cohort study, concurrent PRF and CDSS were associated with limiting the use of piperacillin-tazobactam and carbapenems while reducing use of other antibiotics.
Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; Carbapenems; Cohort Studies; Drug Resistance, Microbial; Humans; Piperacillin; Prospective Studies; Tazobactam
PubMed: 35503216
DOI: 10.1001/jamanetworkopen.2022.10180 -
Deutsches Arzteblatt International May 2018Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is... (Review)
Review
BACKGROUND
Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance.
METHODS
This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature.
RESULTS
Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems.
CONCLUSION
The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.
Topics: Aminoglycosides; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Ceftazidime; Cephalosporins; Colistin; Drug Therapy, Combination; Escherichia coli; Fluoroquinolones; Fosfomycin; Germany; Gram-Negative Bacteria; Humans; Klebsiella pneumoniae; Piperacillin; Pseudomonas aeruginosa; Tigecycline
PubMed: 29914612
DOI: 10.3238/arztebl.2018.0345 -
Antimicrobial Agents and Chemotherapy Jan 2016The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an...
The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.
Topics: Age Factors; Anti-Bacterial Agents; Area Under Curve; Child; Child, Preschool; Computer Simulation; Critical Illness; Drug Administration Schedule; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Glomerular Filtration Rate; Half-Life; Humans; Infant; Intensive Care Units; Male; Microbial Sensitivity Tests; Monte Carlo Method; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Sex Factors
PubMed: 26552978
DOI: 10.1128/AAC.02089-15