Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

ABSTRACTSufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC forPseudomonas aeruginosa(16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR(>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50%fTMIC) and 0.125 mg/liter (100%fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

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Pharmacodynamic Attainment of the Synergism of Meropenem and Fosfomycin Combination againstPseudomonas aeruginosaProducing Metallo-β-Lactamase

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00126-19 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 10

Author(s):

James Albiero ◽

Josmar Mazucheli ◽

Juliana Pimenta dos Reis Barros ◽

Marcia Maria dos Anjos Szczerepa ◽

Sheila Alexandra Belini Nishiyama ◽

...

Keyword(s):

Drug Concentration ◽

Multidrug Resistant ◽

Free Drug ◽

Synergistic Action ◽

Free Drug Concentration ◽

Target Attainment ◽

Time Curve ◽

Content Type ◽

Dosing Regimens

ABSTRACTFosfomycin combined with other antimicrobials has shown good efficacy against multidrug-resistant (MDR) bacteria in bothin vitroand clinical studies; however, the activity of fosfomycin combined with other antimicrobials against metallo-β-lactamase (MBL)-producingPseudomonas aeruginosastrains has not been tested. The objective of this study was to determine the synergism and optimal intravenous dosing regimens of fosfomycin with meropenem against MDR and MBL-producingP. aeruginosastrains. The MICs of both antimicrobials were determined by the checkerboard method and analyzed by two synergism tests with 19 clones ofP. aeruginosaisolates, 10 of which were MBL producers. A pharmacodynamic (PD) analysis was performed for meropenem (administered at 1 g every 8 h [q8h], 1.5 g every 6 h [q6h], and 2 g q8h) and fosfomycin (administered at 4 g q8h, 4 g q6h, 6 g q8h, and 8 g q8h) regimens with a dose reduction for renal impairment by determining the probability of target attainment (PTA) for target PD indices of meropenem (the percentage of the time in a 24-h duration at which the free drug concentration remains above the MIC [fT>MIC], ≥40%) and fosfomycin (the ratio of the area under the free drug concentration-versus-time curve over 24 h and the MIC [fAUC/MIC], ≥40.8). The combination reduced the MIC50and MIC90by 8-fold. Seven (44%) isolates with MICs in the intermediate or resistant ranges became sensitive to meropenem. For the MBL-producing isolates, the combination resulted in 40% of isolates becoming sensitive to meropenem. The meropenem regimens reached a PTA of ≥90% (MIC = 4 μg/ml) in 6 (32%) isolates when they were used as monotherapy and 13 (68%) isolates when they were combined with fosfomycin. None of the fosfomycin monotherapy regimens reached the PTA of ≥90% (MIC = 16 μg/ml). When combined with meropenem, the fosfomycin regimens reached the PTA of ≥90% in 14 (74%) isolates. The increase in pharmacodynamic activities resulting from the synergistic action of meropenem with fosfomycin demonstrates the potential relevance of this combination to fight infections caused by MDR and MBL-producingP. aeruginosastrains.

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Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00988-17 ◽

2017 ◽

Vol 61 (10) ◽

Cited By ~ 12

Author(s):

Timothy J. Bensman ◽

Joshua Wang ◽

Jordanna Jayne ◽

Lynn Fukushima ◽

Adupa P. Rao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Drug Concentration ◽

Free Drug ◽

Free Drug Concentration ◽

Beta Lactam ◽

Target Attainment ◽

Cumulative Percentage ◽

Optimal Dosing ◽

Exposure Target ◽

Pulmonary Exacerbations

ABSTRACT Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT >MIC) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT >1 mg/liter) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 ± 1.28 liters/h; AVI CL, 12.30 ± 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 ± 6.54 liters; AVI V, 25.30 ± 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT >MIC, 50%) of >0.9 for MICs of ≤16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.)

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Identification of Optimal Renal Dosage Adjustments for Traditional and Extended-Infusion Piperacillin-Tazobactam Dosing Regimens in Hospitalized Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00296-09 ◽

2009 ◽

Vol 54 (1) ◽

pp. 460-465 ◽

Cited By ~ 37

Author(s):

N. Patel ◽

M. H. Scheetz ◽

G. L. Drusano ◽

T. P. Lodise

Keyword(s):

Monte Carlo Simulation ◽

Free Drug ◽

Population Pharmacokinetic ◽

Target Attainment ◽

Population Pharmacokinetic Modeling ◽

Dosing Interval ◽

Drug Concentrations ◽

Dosing Regimens ◽

Dosing Strategies ◽

Extended Infusion

ABSTRACT This study examined the effect of various levels of renal impairment on the probability of achieving free drug concentrations that exceed the MIC for 50% of the dosing interval (50% fT > MIC) for traditional and extended-infusion piperacillin-tazobactam (TZP) dosing strategies. It also identified optimal renal dosage adjustments for traditional and extended-infusion dosing schemes that yielded probability of target attainment (PTA) and exposure profiles that were isometric to those of the parent regimens. Data from 105 patients were analyzed using the population pharmacokinetic modeling program BigNPAG. To assess the effect of creatinine clearance (CLCR) on overall clearance, TZP clearance was made proportional to the estimated CLCR. A Monte Carlo simulation (9,999 subjects) was performed for the traditional dosing scheme (4.5 g infused during 30 min every 6 h) and the extended-infusion TZP dosing scheme (3.375 g infused during 4 h every 8 h). The fraction of simulated subjects who achieved 50% fT > MIC was calculated for the range of piperacillin MICs from 0.25 to 32 mg/liter and stratified by CLCR. The traditional TZP regimen displayed the greatest variability in PTA across MIC values, especially for MIC values exceeding 4 mg/liter, when stratified by CLCR. In contrast, the PTA for the extended-infusion TZP regimen exceeded ≥80% for MIC values of ≤8 mg/liter across all CLCR strata. All regimens were associated with suboptimal PTA for MIC values of ≥32 mg/liter irrespective of the CLCR. The CLCR adjustments for traditional and extended-infusion TZP dosing regimens should be considered at a CLCR of ≤20 ml/min.

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Pharmacodynamic Target Attainment for Various Ceftazidime Dosing Schemes in High-Flux Hemodialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00474-13 ◽

2013 ◽

Vol 57 (12) ◽

pp. 5854-5859 ◽

Cited By ~ 17

Author(s):

Angela S. Loo ◽

Michael Neely ◽

Evan J. Anderson ◽

Cybele Ghossein ◽

Milena M. McLaughlin ◽

...

Keyword(s):

Joint Probability ◽

High Flux ◽

Target Attainment ◽

Once Daily ◽

Content Type ◽

Optimal Dosing ◽

Improved Outcomes ◽

Dosing Regimens ◽

High Level ◽

Joint Probability Density

ABSTRACTCeftazidime is a broad-spectrum cephalosporin with high-level activity against a variety of Gram-negative pathogens, includingPseudomonas aeruginosa. Improved outcomes are associated with cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) of >45 to 70% of the dosing interval. Optimal dosing to achieve a 90% probability of target attainment (PTA) in patients receiving high-flux hemodialysis (HFHD) is unknown. We used existing data from six anephric adults receiving hemodialysis to construct a population model with the Pmetrics package for R. From the final model's joint probability density, we simulated the PTA for various ceftazidime dosing regimens, HFHD schedules, and organism MICs. For HFHD every 48 h and 1 g of ceftazidime given posthemodialysis, the PTA exceeds 90% for all isolates with MICs of ≤8 μg/ml, assuming a goal of 70%TMIC. For 72-h dialysis intervals, postdialysis dosing of 1 g is adequate for achievement of the 70%TMICgoal only for organisms with MICs of ≤4 μg/ml, while 2 g is adequate for organisms with MICs of ≤8 μg/ml. A dose of 500 mg once daily, regardless of HFHD schedule, has a 90% PTA for organisms with MICs of ≤16 μg/ml, while 1 g once daily may achieve 100% PTA even for resistant organisms with a MIC of 32 μg/ml. Therefore, to ensure maximal ceftazidime activity, once-daily dosing of 500 mg to 1 g ceftazidime in patients receiving HFHD may be preferable for critically ill patients when MIC data are unavailable and for more resistant organisms with ceftazidime MICs of 16 to 32 μg/ml.

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Pharmacodynamics of a Long-Acting Echinocandin, CD101, in a Neutropenic Invasive-Candidiasis Murine Model Using an Extended-Interval Dosing Design

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02154-17 ◽

2017 ◽

Vol 62 (2) ◽

Cited By ~ 17

Author(s):

Alexander J. Lepak ◽

Miao Zhao ◽

Brian VanScoy ◽

Paul G. Ambrose ◽

David R. Andes

Keyword(s):

Invasive Candidiasis ◽

Half Life ◽

Intraperitoneal Administration ◽

Time Curve ◽

Content Type ◽

Elimination Half ◽

Dosing Regimens ◽

Dosing Strategies ◽

Long Acting

ABSTRACT Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans, making it possible to design once-weekly dosing strategies. The present study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select Candida albicans (n = 4), C. glabrata (n = 3), and C. parapsilosis (n = 3) strains. The CD101 MIC ranged from 0.03 to 1 mg/liter. Plasma pharmacokinetic measurements were performed using uninfected mice after intraperitoneal administration of 1, 4, 16, and 64 mg/kg. The elimination half-life was prolonged at 28 to 41 h. Neutropenic mice were infected with each strain by lateral tail vein injection, treated with a single dose of CD101, and monitored for 7 days, at which time the organism burden was enumerated from the kidneys. Dose-dependent activity was observed for each organism. The pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC index) correlated well with efficacy (R 2, 0.74 to 0.93). The median stasis 24-h free-drug AUC/MIC targets were as follows: for C. albicans, 2.92; for C. glabrata, 0.07; and for C. parapsilosis, 2.61. The PK/PD targets for 1-log10 kill endpoint were 2- to 4-fold higher. Interestingly, the aforementioned PK/PD targets of CD101 were numerically lower for all three species than those of other echinocandins. In summary, CD101 is a promising, novel echinocandin with advantageous pharmacokinetic properties and potent in vivo pharmacodynamic activity.

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1535. Pharmacokinetic (PK) and Pharmacodynamic (PD) Evaluation of Cefepime (CPM) in Obese and Non-Obese Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1399 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S559-S559

Author(s):

Taylor Morrisette ◽

Nichole Neville ◽

Scott W Mueller ◽

Abbie Britton ◽

Gabrielle Jacknin ◽

...

Keyword(s):

Patient Outcomes ◽

High Performance ◽

Reversed Phase ◽

Simulated Patients ◽

Obese Patients ◽

Target Attainment ◽

Optimal Dosing ◽

Significant Difference ◽

Chi Squared ◽

Dosing Strategies

Abstract Background Appropriate application of antimicrobial PK/PD properties is crucial to optimizing patient outcomes. Although β-lactams are among the most utilized and effective antibiotics, optimal dosing strategies in obese populations are largely unknown. The objective of this study was to compare PK/PD of CPM in non-obese (NO, weight 80–100 kg) and obese (O, weight > 100 kg) patients. Methods A prospective comparative PK/PD analysis was conducted in NO and O patients receiving CPM. Blood samples were obtained at 30, 60, 120, 240, 360, and 480 minutes after CPM infusion. CPM concentrations were determined by reversed-phase high-performance liquid chromatography. Non-compartmental PK analyses were performed, followed by Monte Carlo simulations (Oracle Crystal Ball®, 5,000 simulated patients) to estimate probability of target attainment (PTA) against common Gram-negative pathogens. The desired PD target for CPM was % time above MIC of unbound drug (%fT > MIC) ≥ 60%. Chi-squared and Mann–Whitney U tests were used for analysis. Results Seventeen patients were enrolled and most (94%) received CPM 2 g q8h. A significant difference in actual body weight and body mass index was observed (P < 0.001). There were no differences in other baseline or PK characteristics between the two groups. Utilizing CPM 2 g q8h, PTA ≥ 90% was not observed for organisms with an MIC of 8 μg/mL, the current CLSI breakpoint for P. aeruginosa and A. baumannii (PTA = 88% vs. 81% in NO and O groups, respectively). With a 6 g continuous infusion (CI), however, ≥ 90% PTA was achieved in both groups (PTA = 100%) for organisms with an MIC of 8 μg/mL, while a regimen of 2 g q8h (infused over 3 hours [EI]) also provided PTA of ≥ 90% in both groups (PTA = 98% vs. 92% in NO and O groups, respectively). Goal PTA was not obtained in either group for organisms with an MIC of 4 μg/mL with CPM 1 g q8h or 2 g q12h (i.e., CLSI recommended dosing for organisms with MICs of 4 μg/mL). Conclusion Optimizing PK/PD parameters through novel dosing strategies are essential in both the NO and O populations for optimal CPM exposure in susceptible pathogens with higher MICs. CPM 6 grams/day by either CI or EI provides more optimal PK/PD characteristics in obese patients for pathogens with MICs at or near the current CLSI-recommended breakpoint. Disclosures All authors: No reported disclosures.

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Evaluation of Voriconazole and Posaconazole Dosing in Patients with Thermal Burn Injuries

Journal of Burn Care & Research ◽

10.1093/jbcr/irab200 ◽

2021 ◽

Author(s):

Kaitlin L Musick ◽

Savannah L Jones ◽

Ashlyn M Norris ◽

Lauren J Hochstetler ◽

Felicia N Williams ◽

...

Keyword(s):

Fungal Infections ◽

Patient Specific ◽

Burn Patients ◽

Therapeutic Level ◽

Thermal Burn ◽

Adequate Treatment ◽

Treatment Regimens ◽

Optimal Dosing ◽

Dosing Regimens ◽

Dosing Strategies

Abstract Fungal infections are a recognized cause of increased morbidity and mortality in thermal burn patients. Adequate treatment regimens remain a challenge due to unpredictable pharmacokinetic/pharmacodynamic changes caused by a hypermetabolic state and individual patient factors. A retrospective evaluation of adult thermal burn patients from April 2014 to April 2020 was conducted to assess voriconazole and posaconazole antifungal dosing regimens. The primary outcome was the incidence of attaining a therapeutic steady-state trough level on the patient’s initial voriconazole or posaconazole regimen. Of the 35 patients analyzed, 28 (80.0%) patients achieved a therapeutic level during azole therapy. However, only 13 (46.4%) patients achieved a therapeutic level on their first azole regimen. The median time to therapeutic level was 8.0 + 21.1 days from the start of azole therapy. Optimal dosing strategies for azole therapy in patients with thermal burns remains undefined. Further assessment is needed to delineate patient-specific factors that can contribute to subtherapeutic azole levels in thermal burn patients and the overall clinical impact of population-specific dosing regimens.

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Is One Sample Enough? β-Lactam Target Attainment and Penetration into Epithelial Lining Fluid Based on Multiple Bronchoalveolar Lavage Sampling Time Points in a Swine Pneumonia Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01922-18 ◽

2018 ◽

Vol 63 (2) ◽

pp. e01922-18 ◽

Cited By ~ 1

Author(s):

Ana Motos ◽

Joseph L. Kuti ◽

Gianluigi Li Bassi ◽

Antoni Torres ◽

David P. Nicolau

Keyword(s):

Antimicrobial Agents ◽

Free Drug ◽

Sampling Time ◽

Epithelial Lining ◽

Target Attainment ◽

Epithelial Lining Fluid ◽

Time Points ◽

Optimal Dosing ◽

Exposure Target ◽

Investigational Agents

ABSTRACTDescribing the disposition of antimicrobial agents at the site of infection is crucial to guide optimal dosing for investigational agents. For antibiotics in development for the treatment of nosocomial pneumonia, concentrations in the epithelial lining fluid (ELF) of the lung are frequently determined from a bronchoscopy at a single time point. The influence of profiles constructed from a single ELF concentration point for each subject has never been reported. This study compares the pharmacokinetics of two β-lactams, ceftolozane and piperacillin, among different ELF sampling approaches using simulated human regimens in a swine pneumonia model. Plasma and ELF concentration-time profiles were characterized in two-compartment models by the use of robustly sampled ELF concentrations and by the random selection of one or two ELF concentrations from each swine. A 5,000-subject Monte Carlo simulation was performed for each model to define the ELF penetration, as described by the ratio of the area under the concentration curve (AUC) for ELF to the AUC for free drug in plasma (AUCELF/fAUCplasma) and the probability of target attainment (PTA). Given the intersubject variability of the ELF penetrations observed, differences between the models developed using robust numbers of ELF samples versus one or two ELF samples per swine were minimal for both drugs (maximum dispersion < 20%). Using a threshold exposure target of 60% of the time that the free drug concentration remains above the MIC target, the ceftolozane and piperacillin regimens achieved PTAs of ≥90% at MICs of up to 4 and 1 μg/ml, respectively, among the different ELF sampling strategies. These models suggest that the ELF models constructed with concentrations from sparse ELF sampling time points result in exposure estimates similar to those constructed from robustly sampled ELF profiles.

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Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03086-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2888-2894 ◽

Cited By ~ 15

Author(s):

Daniel Gonzalez ◽

Paula Delmore ◽

Barry T. Bloom ◽

C. Michael Cotten ◽

Brenda B. Poindexter ◽

...

Keyword(s):

Volume Of Distribution ◽

Safety Study ◽

Term Infants ◽

Content Type ◽

Acid Glycoprotein ◽

Optimal Dosing ◽

Population Pk ◽

Postmenstrual Age ◽

Dosing Regimens ◽

State Concentration

ABSTRACTClindamycin may be active against methicillin-resistantStaphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC forS. aureusof 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)

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Simplifying Piperacillin/Tazobactam Dosing: Pharmacodynamics of Utilizing Only 4.5 or 3.375 g Doses for Patients With Normal and Impaired Renal Function

Journal of Pharmacy Practice ◽

10.1177/0897190016684453 ◽

2016 ◽

Vol 30 (6) ◽

pp. 593-599 ◽

Cited By ~ 1

Author(s):

Abrar K. Thabit ◽

Mordechai Grupper ◽

David P. Nicolau ◽

Joseph L. Kuti

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Renal Function ◽

Impaired Renal Function ◽

Inhibitory Concentration ◽

Prolonged Infusion ◽

Target Attainment ◽

Dosing Regimens ◽

Function Range ◽

Prescribing Information

Objectives: To evaluate the pharmacodynamic exposure of piperacillin/tazobactam across the renal function range using 4.5 or 3.375 g dosing regimens. Methods: A 5000-patient Monte Carlo simulation was conducted to determine the probability of achieving 50% free time above the minimum inhibitory concentration ( fT > MIC) for piperacillin. Proposed regimens, using solely 4.5 or 3.375 g strengths, were compared with regimens listed in piperacillin/tazobactam prescribing information over creatinine clearance (CrCl) ranges of 120 mL/min to hemodialysis. The probability of target attainment (PTA) at MICs ≤ 16 μg/mL was compared between proposed and standard regimens. Results: At CrCl 41 to 120 mL/min, prolonged infusions of 4.5 g (3 hours) and 3.375 g (4 hours) every 6 hours resulted in ≥95% PTA versus ≥76% for standard regimens (0.5 hour). At CrCl 20 to 40 mL/min, 4.5 and 3.375 g every 8 hours as prolonged infusions achieved slightly higher PTA (≥98%) versus standard regimens (≥93%). Similarly, PTA achieved with prolonged infusions of 4.5 and 3.375 g every 12 hours (≥93%) was comparable with those of standard regimens (≥91%) at CrCl 1 to 19 mL/min. In hemodialysis, 100% PTA was achieved with prolonged infusion regimens. Conclusion: Piperacillin/tazobactam regimens designed around the 4.5 or 3.375 g dose and prolonged infusions provided similar or better PTA at MICs ≤ 16 μg/mL compared with standard regimens. These observations may support the stocking and use of a single piperacillin/tazobactam strength to simplify dosing.

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