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Objectives: Piperacillin (PIP)/tazobactam is a frequently prescribed antibiotic; however, over- or underdosing may contribute to toxicity, therapeutic failure, and development of antimicrobial resistance. An external evaluation of 24 published PIP-models demonstrated that model-informed precision dosing (MIPD) can enhance target attainment. Employing various candidate models, this study aimed to assess the predictive performance of different MIPD-approaches comparing (i) a single-model approach, (ii) a model selection algorithm (MSA) and (iii) a model averaging algorithm (MAA)., Methods: Precision, accuracy and expected target attainment, considering either initial (B1) or initial and secondary (B2) therapeutic drug monitoring (TDM)-samples per patient, were assessed in a multicentre dataset (561 patients, 11 German centres, 3654 TDM-samples)., Results: The results demonstrated a slight superiority in predictive performance using MAA in B1, regardless of the candidate models, compared to MSA and the best single models (MAA, MSA, best single models: inaccuracy ±3%, ±10%, ±8%; imprecision: <25%, <31%, <28%; expected target attainment >77%, >71%, >73%). The inclusion of a second TDM-sample notably improved precision and target attainment for all MIPD-approaches, particularly within the context of MSA and most of the single models. The expected target attainment is maximized (up to >90%) when the TDM-sample is integrated within 24 h., Conclusions: In conclusion, MAA streamlines MIPD by reducing the risk of selecting an inappropriate model for specific patients. Therefore, MIPD of PIP using MAA implicates further optimisation of antibiotic exposure in critically ill patients, by improving predictive performance with only one sample available for Bayesian forecasting, safety, and usability in clinical practice., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Piperacillin/tazobactam is extensively used off-label to treat late-onset neonatal sepsis, but safety and pharmacokinetic data in this population are limited. Additionally, the organic immaturity of the newborns contributes to a high piperacillin pharmacokinetic variability. This affects the clinical efficacy of the antibiotic treatment and increases the probability of developing drug resistance. This study aimed to evaluate the predictive performance of reported piperacillin population pharmacokinetic models for their application in a model-informed precision dosing strategy in preterm and term Mexican neonatal intensive care patients., Methods: Published population pharmacokinetic models for piperacillin which included neonates in their study population were identified. From the reference models, structured models, population pharmacokinetic parameters, and interindividual and residual variability data were extracted to be replicated in pharmacokinetic software (NONMEM ® version 7.4). For the clinical study, a sampling schedule was designed, and 2-3 blood samples of 250 µL were taken from neonates who met the inclusion criteria. Piperacillin plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. The clinical treatment data were collected, and piperacillin plasma concentrations were estimated using reference pharmacokinetic models for an a priori or Bayesian approach. Statistical methods were used in terms of bias and precision to evaluate the differences between observed and estimated neonatal piperacillin plasma concentrations with the different approaches and to identify the pharmacokinetic model that best fits the neonatal data., Results: A total of 70 plasma samples were collected from 25 neonatal patients, of which 15 were preterm neonates. The overall median value (range) postnatal age, gestational age, body weight, and serum creatinine at the sampling collecting day were 12 (3-26) days, 34.2 (26-41.1) weeks, 1.78 (0.08-3.90) Kg, 0.47 (0.20-0.90) mg/dL, respectively. Three population pharmacokinetic models for piperacillin in infants up to 2 months were identified, and their predictive performance in neonatal data was evaluated. No pharmacokinetic model was suitable for our population using an a priori approach. The model published by Cohen-Wolkowiez et al. in 2014 with a Bayesian approach showed the best performance of the pharmacokinetic models evaluated in our neonatal data. The procedure requires two blood samples (predose and postdose), and, when applied, it predicted 66.6% of the observations with a relative median absolute predicted error of less than 30%., Conclusions: The population pharmacokinetic model developed by Cohen-Wolkowiez et al. in 2014 demonstrated superior performance in predicting the plasma concentration of piperacillin in preterm and term Mexican neonatal intensive care patients. The Bayesian approach, including two different piperacillin plasma concentrations, was clinically acceptable regarding bias and precision. Its application for model-informed precision dosing can be an option to optimize the piperacillin dosage in our population., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objective: Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF)., Methods: Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cl eff ) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days., Results: HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (β = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (β = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cl eff for each antibiotic (meropenem β = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (β = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (β = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cl eff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (β = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (β = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type., Conclusion: MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Pathophysiological changes post-liver transplantation impact the pharmacokinetics and pharmacodynamics of antibiotics. Piperacillin, often used in combination with tazobactam, is a key antibiotic after transplantation to its broad-spectrum activity, but there is a lack of specific pharmacokinetic data in this population. This study aims to describe the pharmacokinetic parameters and target attainment of piperacillin in pediatric liver transplant recipients., Methods: Patients with preserved renal function (estimated glomerular filtration rate > 50 mL/min/1.73 m 2 ) receiving intravenous piperacillin-tazobactam at 112.5 mg/kg every 8 h (100 mg piperacillin/12.5 mg tazobactam), with a rapid infusion (0.5-1 h), were included. Two blood samples per child were collected during the same interval within 48 h of starting therapy. A Bayesian approach was applied to estimate individual pharmacokinetic parameters and perform dosing recommendations against Enterococcus spp., Enterobacterales and Pseudomonas aeruginosa., Results: Eight patients with median age of 8 months were included. Median piperacillin clearance and central volume of distribution for the cohort were 11.11 L/h/70 kg and 9.80 L/70 kg, respectively. Seven patients (87.5%) presented with concentrations below the target of 100% fT > MIC. Simulations suggested that these patients required more frequent dosing and extended duration of infusion to ensure target attainment. One patient (12.5%) had trough concentrations that exceed 16 mg/L and could receive a lower daily dose., Conclusions: This case series highlights the importance of personalized therapy in pediatric liver transplant recipients due to the unpredictable and highly variable piperacillin pharmacokinetics in this population., (© 2024 Wiley Periodicals LLC.)

Objectives: WCK 4282 is a novel combination of cefepime 2 g and tazobactam 2 g being developed for the treatment of infections caused by piperacillin/tazobactam-resistant ESBL infections. The dosing regimen for cefepime/tazobactam needs to be optimized to generate adequate exposures to treat infections caused by ESBL-producing pathogens resistant to both cefepime and piperacillin/tazobactam., Methods: We developed pharmacokinetic population models of cefepime and tazobactam to evaluate the optimal dose adjustments in patients, including those with augmented renal clearance as well as various degrees of renal impairment, and also for those on intermittent haemodialysis. Optimal doses for various degrees of renal function were identified by determining the PTA for a range of MICs. To cover ESBL-producing pathogens with an cefepime/tazobactam MIC of 16 mg/L, a dosing regimen of 2 g q8h infused over 1.5 h resulted in a combined PTA of 99% for the mean murine 1 log10-kill target for the cefepime/tazobactam combination., Results: We found that to adjust for renal function, doses need to be reduced to 1 g q8h, 500 mg q8h and 500 mg q12h for patients with CLCR of 30-59, 15-29 and 8-14 mL/min (as well as patients with intermittent haemodialysis), respectively. In patients with high to augmented CLR (estimated CLCR 120-180 mL/min), a prolonged 4 h infusion of standard dose is required., Conclusions: The suggested dosing regimens will result in exposures of cefepime and tazobactam that would be adequate for infections caused by ESBL-producing pathogens with a cefepime/tazobactam MICs up to 16 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Antibiotic treatment is crucial for patients with chronic bacterial infections. Suspected drug allergies often lead to inconsistent therapies and challenging clinical management for patients and caregivers. The objective of this study was to evaluate the value of lymphocyte transformation tests in comparison to skin tests for the prediction of delayed-type allergic reactions., Methods: This prospective, observational study tested the diagnostic value of skin prick tests, intradermal tests (reading: 15 min and 72 h) and lymphocyte transformations tests for the prediction of allergic reactions in CF patients with physician reported allergy to piperacillin/tazobactam, meropenem and ceftazidime. The tests were performed directly before a 14d intravenous drug challenge., Results: We performed 33 drug challenges in 29 subjects. 21 drug challenges were negative (63 %); 12 lead to a reaction (37 %), of those 2 were immediate and 10 were delayed-type. 100 % of the skin prick tests were negative. 97 % (33/34) of the intradermal tests with early reading and 100 % of the intradermal tests with late reading yielded negative results. 5/11 patients who experienced a delayed-type reaction during the drug challenge had a positive lymphocyte transformations test. All 17 patients who did not react had a negative lymphocyte transformations test. For piperacillin/tazobactam, 4/5 patients who experienced a delayed-type reaction during the drug challenge had positive lymphocyte transformations tests. Hence, for piperacillin/tazobactam, the sensitivity of the lymphocyte transformation test for prediction of reactions was 80.0 % and the specificity 100 %., Conclusion: We demonstrate that the lymphocyte transformation test predicts delayed-type allergy to piperacillin/tazobactam in contrast to skin tests., Competing Interests: Declaration of Competing Interest JR has received payments for lectures from Vertex Pharmaceuticals outside of the submitted work. MAM received grants from Vertex Pharmaceuticals; and personal fees for participation in advisory boards, consultancy and lectures from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Enterprise Therapeutics, Kither Biotech, and Antabio outside of the submitted work. DJN has received research grants from Merck, AstraZeneca, GSK, and Janssen Pharmaceuticals to study mechanisms of drug hypersensitivity. However, this funding does not directly relate to the research described in this manuscript. Other authors have no conflicts to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To evaluate the predictive performance of population pharmacokinetic models for piperacillin (PIP) available in the software MwPharm, TDMx and ID-ODs for initial dosing selection and therapeutic drug monitoring (TDM) purposes., Methods: This is a prospective observational study in adult patients with severe infections receiving PIP treatment. Plasma concentrations were quantified by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. The differences between predicted and observed PIP concentrations were evaluated with Bland-Altman plots; additionally, the relative and absolute bias and precision of the models were determined., Results: A total of 145 PIP plasma concentrations from 42 patients were analysed. For population prediction, MwPharm showed the best predictive performance with a mean relative difference of 34.68% (95% CI -197% to 266%) and a root mean square error (RMSE) of 60.42 µg/mL; meanwhile TDMx and ID-ODs under-predicted PIP concentrations. For individual prediction, the TDMx model was found to be the most precise with a mean relative difference of 7.61% (95% CI -57.63 to 72.86%), and RMSE of 17.86 µg/mL., Conclusion: Current software for TDM is a valuable tool, but it may also include different population pharmacokinetic models in patients with severe infections, and should be evaluated before performing a model-based TDM in clinical practice. Considering the heterogeneous characteristics of patients with severe infections, this study demonstrates the need for therapy personalisation for PIP to improve pharmacokinetic/pharmacodynamic target attainment., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Medical errors associated with IV preparation and administration procedures in a hospital workflow can even cost human lives due to the direct effect they have on patients. A large number of such incidents, which have been reported in bibliography up to date, indicate the urgent need for their prevention. This study aims at proposing an analytical methodology for identifying and quantifying IV drugs before their administration, which has the potential to be fully harmonized with clinical practices. More specifically, it reports on the analysis of a piperacillin (PIP) and tazobactam (TAZ) IV formulation, using Raman spectroscopy. The simultaneous analysis of the two APIs in the same formulation was performed in three stages: before reconstitution in the form of powder without removing the substance out of the commercial glass bottle (non-invasively), directly after reconstitution in the same way, and just before administration, either the liquid drug is placed in the infusion set (on-line analysis) or a minimal amount of it is transferred from the IV bag to a Raman optic cell (at-line analysis). Except for the successful identification of the APIs in all cases, their quantification was also achieved through calibration curves with correlation coefficients ranging from 0.953 to 0.999 for PIP and from 0.965 to 0.997 for TAZ. In any case, the whole procedure does not need more than 10 min to be completed. The current methodology, based on Raman spectroscopy, outweighs other spectroscopic (UV/Vis, FT-IR/ATR) or chromatographic (HPLC, UHPLC) protocols, already applied, which are invasive, costly, time-consuming, not environmentally friendly, and require specialized staff and more complex sample preparation procedures, thus exposing the staff to hazardous materials, especially in cases of cytotoxic drugs. Such an approach has the potential to bridge the gap between experimental setup and clinical implementation through exploitation of already developed handheld devices, along with the presence of digital spectral libraries.

Rationale: Listeria monocytogenes (L. monocytogenes) is a compatible intracellular bacterial pathogen that can invade different mammalian cells and reach the central nervous system (CNS), leading to meningoencephalitis and brain abscesses. In the diagnosis of L. monocytogenes meningoencephalitis (LMM), conventional tests are often reported as negative due to antibiotic therapy or low bacterial content in cerebrospinal fluid. To date, prompt diagnosis and accurate treatment remain a challenge for patients with Listeria infections., Patient Concerns: Here, we report a case of a 64-year-old male diagnosed with LMM by using metagenomics next-generation sequencing (mNGS)., Diagnosis: LMM was confirmed by mNGS analysis of cerebrospinal fluid., Interventions: The patient was treated with piperacillin and sensitive antibiotics., Outcomes: The patient could walk independently about 1 month after admission and was discharged from the hospital., Lessons: This case highlights the value of mNGS in the diagnosis of LMM and emphasizes the inadequate sensitivity of conventional diagnostic methods for Listeria infection., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Pharmacokinetic interaction of high-dose methotrexate (MTX) and other concomitantly administered renally secreted medicinal products may lead to insufficient methotrexate serum level decrease and significant MTX toxicity., Case Report: We report the case of an 18-year-old male patient treated with high-dose MTX for an osteosarcoma and with high-dose piperacillin-tazobactam at the same time. MTX serum levels were severely elevated 24 hours after the MTX infusion and did not decrease in accordance with the specific calcium folinate rescue protocol. The patient experienced renal failure accompanied by neurological symptoms, most consistent with MTX-related renal and CNS toxicity. Management and outcome: After discontinuation of piperacillin-tazobactam, intensified calcium folinate rescue therapy, and IV hydration, the MTX serum levels decreased appropriately, and toxicity symptoms resolved., Discussion: Severe MTX-related toxicity, caused by drug-drug interaction, suggests that the concomitant use of high-dose MTX and high-dose piperacillin-tazobactam should be avoided generally.

To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CL R ) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CL R post-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CL R was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CL int,OAT1,3,invivo ) and its ontogeny. CL int,OAT1,3,invivo ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CL R predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months-15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CL int,OAT1,3,invivo that yields accurate CL R predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.

Purpose: Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays., Methods: Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire., Results: The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly., Conclusion: German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To adapt an antibiotic dose adjustment software initially developed in English, to Portuguese and to the Brazilian context., Methods: This was an observational, descriptive study in which the Delphi method was used to establish consensus among specialists from different health areas, with questions addressing the visual and operational aspects of the software. In a second stage, a pilot experimental study was performed with the random comparison of patients for evaluation and adaptation of the software in the real environment of an intensive care unit, where it was compared between patients who used the standardized dose of piperacillin/tazobactam, and those who used an individualized dose adjusted through the software Individually Designed and Optimized Dosing Strategies., Results: Twelve professionals participated in the first round, whose suggestions were forwarded to the software developer for adjustments, and subsequently submitted to the second round. Eight specialists participated in the second round. Indexes of 80% and 90% of concordance were obtained between the judges, characterizing uniformity in the suggestions. Thus, there was modification in the layout of the software for linguistic and cultural adequacy, minimizing errors of understanding and contradictions. In the second stage, 21 patients were included, and there were no differences between doses of piperacillin in the standard dose and adjusted dose Groups., Conclusion: The adapted version of the software is safe and reliable for its use in Brazil.

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (V p ) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (K m ) and the maximum elimination rate for Michaelis-Menten elimination (V max ) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for K m and V max were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for K m lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Gram-negative rod (GNR) infections adversely affect the outcome of patients with malignancies and following hematopoietic stem cell transplantation (HSCT). This retrospective observational study aimed to describe the epidemiology, outcome, and resistance patterns of GNR bacteremia in children with hematologic malignancies (HM) and after HSCT during the period spanning from 2010 to 2014 in a tertiary children's hospital. A total of 270 children were included in the analysis; 65 (24%) developed 85 episodes of GNR bacteremia; the rate was 36/122 (29.5%) in post-HSCT and 29/178 (16.3%) in HM patients (P<0.05). Overall, 10% of the GNRs were carbapenem resistant. In multivariate analysis, prolonged neutropenia (≥7 d; odds ratio: 19.5, 95% confidence interval: 2.6-148.4) and total hospitalization for a duration of >30 days in the last 3 months (odds ratio: 17.5, 95% confidence interval: 1.4-224.4) were associated with carbapenem-resistant GNR bacteremia. Thirty-day mortality following GNR bacteremia was 0% in HM and 7/52 episodes (13.5%) in HSCT patients (P<0.05). Carbapenem-resistant versus carbapenem-sensitive bacteremia was associated with longer duration of bacteremia (mean: 3.8 vs. 1.7 d), higher risk for intensive care unit hospitalization (44.4% vs. 10.1%), and higher mortality rate (33% vs. 5.8%) (P<0.05). To summarize, GNR bacteremia was frequent, especially in post-HSCT children. Carbapenem resistance adversely affects patients' outcome, increasing morbidity and mortality. Empirical antibiotic therapy must be adjusted to the local resistance patterns.

Background: We analyzed the impact of continuous/extended infusion (C/EI) vs intermittent infusion of piperacillin-tazobactam (TZP) and carbapenems on 30-day mortality of patients with liver cirrhosis and bloodstream infection (BSI)., Methods: The BICRHOME study was a prospective, multicenter study that enrolled 312 cirrhotic patients with BSI. In this secondary analysis, we selected patients receiving TZP or carbapenems as adequate empirical treatment. The 30-day mortality of patients receiving C/EI or intermittent infusion of TZP or carbapenems was assessed with Kaplan-Meier curves, Cox-regression model, and estimation of the average treatment effect (ATE) using propensity score matching., Results: Overall, 119 patients received TZP or carbapenems as empirical treatment. Patients who received C/EI had a significantly lower mortality rate (16% vs 36%, P = .047). In a Cox-regression model, the administration of C/EI was associated with a significantly lower mortality (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.11-0.936; P = .04) when adjusted for severity of illness and an ATE of 25.6% reduction in 30-day mortality risk (95% CI, 18.9-32.3; P < .0001) estimated with propensity score matching. A significant reduction in 30-day mortality was also observed in the subgroups of patients with sepsis (HR, 0.21; 95% CI, 0.06-0.74), acute-on-chronic liver failure (HR, 0.29; 95% CI, 0.03-0.99), and a model for end-stage liver disease score ≥25 (HR, 0.26; 95% CI, 0.08-0.92). At competing risk analysis, C/EI of beta-lactams was associated with significantly higher rates of hospital discharge (subdistribution hazard [95% CI], 1.62 [1.06-2.47])., Conclusions: C/EI of beta-lactams in cirrhotic patients with BSI may improve outcomes and facilitate earlier discharge., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target., Objectives: To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights., Methods: Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights., Results: A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT > 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2-3 (q6h) or 3-4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT > 1×MIC due to the rapid piperacillin elimination., Conclusions: The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC)., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Febrile neutropenia (FN) is the most common complication in pediatric oncology patients. Appropriate empirical antibiotics treatment is essential for treatment outcome. Methods: This study was a randomized prospective controlled study to demonstrate the efficacy of piperacillin/tazobactam (PIP/TZO) monotherapy compared with ceftazidime/amikacin in children with FN. Pediatric oncology patients at Chiang Mai University Hospital, diagnosed with FN, were randomized to receive either PIP/TZO 320 mg/kg/day divided every 8 hours or ceftazidime 100 mg/kg/ day divided every 8 hours plus amikacin 15 mg/kg/day once daily. Treatment responses were compared between the two groups. Results: One-hundred and eighteen febrile neutropenic episodes in 70 patients (42 males and 28 females) were enrolled. The median age was 7 (3-10) years. The early response and complete response to initial treatment were achieved in 48/59 (81.4%) episodes and 41/59 (69.5%) episodes in PIP/TZO group compared with 40/59 (67.8%) episodes and 33/59 (55.9%) episodes in ceftazidime/amikacin group (p-value 0.091 and 0.128, respectively). Treatment modification in PIP/TZO group was required in 18/59 (30.5%) compared with 26/59 (44.1%) patients in ceftazidime/amikacin group (p-value 0.128). Similarly, the duration of fever, duration of neutropenia and duration of antibiotics treatment were not significantly different between two groups. No serious adverse events were observed. Conclusion: The treatment responses of PIP/TZO monotherapy and ceftazidime/amikacin therapy were not significantly different. Both therapies were effective for FN in pediatric oncology patients.

There is mounting evidence that combination of antibiotic therapy with vancomycin and piperacillin/tazobactam (pip/tazo) is associated with acute kidney injury (AKI). To determine whether vancomycin plus pip/tazo is associated with higher rates of AKI compared to vancomycin plus cefepime among pediatric hematology/oncology (heme/onc) patients, we examined 121 heme/onc patients receiving at least two consecutive days of therapy with vancomycin and either pip/tazo or cefepime. Rate of AKI was higher in the pip/tazo than the cefepime group (4/27 [14.8%] vs 2/94 [2.1%], P = 0.022)., (© 2019 Wiley Periodicals, Inc.)

Background: Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens., Procedure: This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. MIC 50 and MIC 90 were defined based on an intrainstitutional MIC range., Results: A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC 50 (2.0 mg/L), MIC 90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4× MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC ≤ 8 mg/L., Conclusions: Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA., (© 2019 Wiley Periodicals, Inc.)

Piperacillin-tazobactam has been proposed as an alternative to carbapenems for the treatment of infections caused by extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae However, limited understanding of optimal dosing strategies for this combination may curtail its utility. In this study, we correlated various exposures of piperacillin-tazobactam to efficacy, using a modified pharmacokinetic/pharmacodynamic index. Using a clinical Klebsiella pneumoniae isolate expressing CTX-M-15, piperacillin MIC values were determined with increasing tazobactam concentrations and fitted to a sigmoid inhibitory maximum effect ( E max ) model. A hollow-fiber infection model (HFIM) was used to evaluate the efficacy of escalating tazobactam dosing with a fixed piperacillin exposure. Simulated drug concentrations from the HFIM were incorporated in the E max model to determine the percentage of free time above instantaneous MIC (% f T>MICi) associated with each experimental exposure. The target % f T>MICi associated with growth suppression was prospectively validated using an SHV-12-producing isolate of Escherichia coli and 2 other CTX-M-15-producing K. pneumoniae isolates. Based on our reference isolate, piperacillin-tazobactam exposures of % f T>MICi of ≥55.1% were associated with growth suppression. Despite underlying differences, these findings were consistent with prospective observations in 3 other clinical isolates. Our modeling approach can be applied relatively easily in the clinical setting, and it appeared to be robust in predicting the effectiveness of various piperacillin-tazobactam exposures. This modified pharmacokinetic/pharmacodynamic index could be used to characterize response to other β-lactam/β-lactamase inhibitor combinations., (Copyright © 2019 American Society for Microbiology.)

The authors present a case of bilateral femoral emphysematous osteomyelitis caused by Escherichia coli in a 60-year-old woman with rheumatoid arthritis who was receiving long-term prednisone therapy. The infection in both femoral shafts was eradicated with surgical debridement, followed by insertion of intramedullary rods composed of culture-specific antibiotic cement into the femoral canals in conjunction with 6 weeks of intravenous antibiotics. The rods were subsequently removed, and no signs of further osteomyelitis were recognized at follow-up. To the authors' knowledge, this is the first case of its kind reported in the orthopedic literature. Emphysematous osteomyelitis, a rare and dangerous entity, can be successfully managed by intramedullary antibiotic delivery in the subacute setting. [Orthopedics. 2019; 42(1):e128-e130.]., (Copyright 2018, SLACK Incorporated.)

We aimed to clarify prophylactic antimicrobial effects of single-dose piperacillin (PIPC) for perioperative infections in the transurethral resection of bladder tumor (TURBT) in comparison with those of single-dose tazobactam/piperacillin (TAZ/PIPC) through a retrospective analysis. We analyzed data from 192 TURBT patients treated with single-dose (4 g) intravenous PIPC (P group) between April 2015 and April 2017. For comparison, we analyzed data from 50 TURBT patients treated with single-dose (4.5 g) intravenous TAZ/PIPC (T/P group) between June 2013 and April 2014. We compared the perioperative incidences of fever (≥38 °C) and bacteriuria in the two groups. The number of febrile patients was four (2.1%) in the P group and one (2.0%) in the T/P group, without significant difference (p = 0.970). Among these febrile patients, urine and blood samples of two patients in the P group tested positive for bacterial cultures of Citrobacter koseri and Enterococcus faecalis, respectively. None of the patients in the T/P group tested positive for urine culture, postoperatively. However, 22 patients (18.2%) in the P group tested positive for urine culture, and Staphylococcus epidermidis (six patients), E. faecalis (three patients), Escherichia coli (three patients), Streptococcus agalactiae (two patients), Staphylococcus aureus (two patients), and C. koseri (one patient) were isolated. There was no significant difference in the incidence of bacteriuria in these two groups (p = 0.055). Based on these results, single-dose PIPC administration for the prevention of perioperative infections in TURBT was as effective as TAZ/PIPC., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Combination therapy with vancomycin and piperacillin/tazobactam (TZP) has been associated with increased risk of acute kidney injury (AKI) compared with monotherapy with either agent. This retrospective, matched cohort study was conducted to assess the comparative incidence of AKI due to combination therapy in patients receiving vancomycin and TZP in combination or as monotherapy. Patients aged ≥18 years admitted to Albany Medical Center (Albany, NY) between September 2013 and August 2014 who had received therapy for at least two consecutive days were included. Patients who were pregnant, neutropenic, had AKI on admission or with cystic fibrosis were excluded. Patients were matched on baseline risk of AKI. The main outcome of interest was AKI, defined as an increase in serum creatinine of ≥0.3 mg/L or ≥50% within 48 h. Secondary outcomes evaluated were length of hospital and ICU stay and inpatient mortality associated with AKI. The risk of AKI was 7.0%, 8.5% and 26.8% in the vancomycin monotherapy, TZP monotherapy and combination groups, respectively (P < 0.001). In the multivariate analysis, combination therapy was independently associated with an increased odds of AKI (adjusted odds ratio = 4.406, 95% confidence interval 1.472-13.188) compared with vancomycin monotherapy. The excess risk of combination therapy was 11.3%. In this matched cohort study, there was an increased incidence of AKI in patients receiving vancomycin and TZP combination therapy. Further research is needed to determine the individual strategies to best prevent inpatient AKI in patients receiving this combination therapy., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Background: Sustained low-efficiency dialysis (SLED), is increasingly being used in intensive care units (ICUs) but studies informing drug dosing for such patients is lacking., Objective: To describe the population pharmacokinetics (PKs) of piperacillin/tazobactam in critically ill adults receiving SLED and to provide dosing recommendations., Methods: This prospective population PK study was conducted in adult ICU patients prescribed piperacillin/tazobactam while receiving SLED; 321 blood samples were obtained from 34 participants during and between approximately 50 SLED treatments for quantification of piperacillin and tazobactam concentrations in plasma. A population PK model was developed. Monte Carlo simulation was used to determine the probability of target attainment and pathogen-specific fractional target attainment at different doses., Results: From a 2-compartment linear model with zero-order input, the mean (SD) clearance of piperacillin on SLED and off SLED were 4.81 (8.48) and 1.42 (1.54) L/h, respectively. Tazobactam concentrations were not sufficient for analysis. For the target of 50% fT>MIC (unbound concentrations of drug are above the minimum inhibitory concentration for >50% of the dosing interval), 3-g of piperacillin infused over 0.5 hours every 8 hours was appropriate for susceptible organisms with MIC ≤16 mg/L. For life-threatening infections where the target of 100% fT>MIC is preferred, a 9-g dose administered as a continuous infusion every 24 hours was appropriate for susceptible organisms with MIC ≤32 mg/L., Conclusions and Relevance: In critically ill patients receiving SLED, piperacillin doses need to be guided by the frequency of SLED treatments and susceptibility of the known or suspected pathogen.

Purpose: The development of surgical site infection (SSI) after biliary reconstruction is highly influenced by the presence of preoperative bacteria in the bile juice. We selected vancomycin and piperacillin/tazobactam (VCM + PIPC/TAZ) as perioperative prophylactic antibiotics for patients undergoing pancreaticoduodenectomy. This study aimed to retrospectively analyze the effectiveness of VCM + PIPC/TAZ compared to cefmetazole., Methods: Seventy-two patients who underwent pancreaticoduodenectomy between April 2015 and March 2017 at our department were evaluated. Forty patients were administered cefmetazole as the perioperative prophylactic antibiotic, and 32 were administered VCM + PIPC/TAZ. The intraoperative VCM blood concentration (incision, biliary reconstruction, and wound closure) was measured during surgery to confirm the hemodynamics., Results: The frequency of SSIs was significantly lower in the VCM + PIPC/TAZ group (8/32 patients) than in the cefmetazole group (20/40 patients, P = 0.031). Postoperatively, significantly fewer patients in the VCM + PIPC/TAZ group (4/32 patients) required ≥ 15 days of additional antibiotic administration compared to those in the cefmetazole group (14/40 patients, P = 0.033). Six of 32 patients in the VCM + PIPC/TAZ group showed redneck syndrome symptoms. There was no significant difference in the VCM blood concentration between patients with and without SSIs., Conclusions: The use of VCM + PIPC/TAZ can reduce the incidence of SSI after pancreaticoduodenectomy and also reduce the need for the additional administration of antibiotics for ≥ 15 days after surgery.

Aims: Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble time-dependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates - creatinine clearance (Cl cr ) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/tazobactam (PIP/TZB)., Methods: In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry., Results: The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Cl cr ≥130 mL/min/1.73 m 2 . Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vd me =70.3 L (41.9-101.5), Vd pip = 46.8 L (39.7-60.0). 100%fT me >MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFB pip with Vd pip (P=0.021)., Conclusion: Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vd pip across subjects at each and every time point.

Background: Although survival of children with hematological diseases and cancer has increased dramatically, life-threatening complications due to bacterial infections occur in 5-10% of febrile episodes in pediatric cancer patients. A prospective randomized study was performed to clarify the usefulness of meropenem (MEPM) and piperacillin/tazobactam (PIPC/TAZ) with or without intravenous immunoglobulin (IVIG) as second-line therapy for pediatric patients with febrile neutropenia (FN)., Procedure: As first-line therapy for FN, 105 patients with 434 episodes were randomly assigned to receive MEPM or PIPC/TAZ. A total of 71 pediatric patients and 144 episodes were judged as failures and enrolled for second-line treatment. In second-line treatment, patients were randomized to a group of MEPM and PIPC/TAZ with or without IVIG. MEPM was given to patients who received PIPC/TAZ as first-line treatment, and PIPC/TAZ was given to patients who received MEPM as first-line treatment., Results: The total success rate of second-line therapy was 49.3%. MEPM with or without IVIG was effective in 44.3% of cases, and PIPC/TAZ with or without IVIG was effective in 55.3%; this difference was not significant. The success rate in patients with serum IgG under 1000 mg/dl was 41.3% in the MEPM or PIPC/TAZ group and 64.3% in the MEPM + IVIG or PIPC/TAZ + IVIG group (p = 0.028)., Conclusions: The present results suggest that PIPC/TAZ is as effective as MEPM and safe for second-line treatment of FN in pediatric patients. Furthermore, IVIG appears very effective for patients with low serum IgG levels., (Copyright © 2017. Published by Elsevier B.V.)

Background: The appropriate use of broad-spectrum antibiotics, including appropriate de-escalation, is essential to reduce the emergence of antibiotic resistance. In surgical floors antibiotics are prescribed for prophylaxis (mostly, single dose), empirical treatment (started if infection is suspected till bacteria are identified with its sensitivity to antibiotics), or treatment of well-defined infection of previously isolated bacteria with its sensitivity to antibiotics. In this study, we aimed to evaluate the use of broad-spectrum antibiotics based on requests for cultures and de-escalation based on sensitivity results of culture tests at tertiary care hospital., Method: A retrospective cohort study was conducted to evaluate the utilization of broad-spectrum antibiotics on surgical floors at a tertiary care center in Jeddah, Saudi Arabia. Patients who are admitted to surgical floors were included if they received any of three broad-spectrum antibiotics (piperacillin-tazobactam, imipenem-cilastatin or meropenem) from 1 June 2014 to 31 August 2014. Data were collected on whether culture and sensitivity test requests were made within 24h of starting antibiotics, the duration of antibiotic therapy and the number of days to de-escalation after receiving culture and sensitivity results., Results: Of the 163 patients who received broad-spectrum antibiotics, culture tests were requested in 112. Before receiving culture results, one patient was discharged and one died. The results of culture tests justified continuation of broad-spectrum antibiotics in only 22 patients, whereas 24 showed no microbial growth in any culture. De-escalation was delayed >24h after culture results became available in 33 out of 64 eligible patients. On the other hand, 51 patients continued receiving broad spectrum antibiotics without any culture test during the whole treatment course., Conclusion: The use of broad-spectrum antibiotics in surgical floors at a tertiary care hospital in Saudi Arabia was largely unjustified by culture-test result. Interventions are needed to enforce culture and sensitivity test requests within 24h of starting the broad spectrum antibiotics therapy with further follow up to ensure appropriate de-escalation and discontinuation whenever indicated., (Copyright © 2017. Published by Elsevier Ltd.)

Rationale: Superior mesenteric venous thrombosis (SMVT) is a rare condition that carries high mortality. Very few cases have been reported of SMVT, complicating acute appendicitis. Early recognition requires a high index of suspicion and is crucial in successful treatment of such a life-threatening condition., Patient Concerns: A 33-year-old male presents with a 4-day history of right lower abdominal pain, nausea and subjective fever. CT scan showed acute appendicitis and a central filling defect in the superior mesenteric vein., Diagnoses: Acute appendicitis complicated by SMVT., Interventions: Intravenous antibiotics, appendectomy, and anticoagulation., Outcomes: Repeat CT scan showed successful resolution of the SMVT at a 3-month follow up., Lessons: Clinical awareness and high index of suspicion are essential to diagnose and manage SMVT, a serious complication of acute appendicitis.

Background: Piperacillin-tazobactam is common empiric antibiotic therapy. Hematologic laboratory test abnormalities were documented but rare in premarketing studies, and whether these alterations are of clinical significance has been studied little. Very few cases of piperacillin-induced bleeding, thrombocytopenia, or both have been reported; aberrations in platelet function have not been implicated., Case Description: A 55-year old Vietnamese man with hypertension presented for treatment of an Intracranial hemorrhage. Platelet function assays (PFAs) at the time of external ventricular drain and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. The patient was later started on empiric piperacillin-tazobactam due to high suspicion for aspiration pneumonia. After removal of the quad-lumen bolt and external ventricular drain on separate days, both follow-up computed tomography scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. Repeat PFAs were abnormally prolonged, representing a distinct change from baseline. A trend toward normalization of PFAs was observed 6 hours after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter., Conclusions: This is unique in that the significant bleeding that occurred was attributable to platelet dysfunction rather than thrombocytopenia. This is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Pericardial effusion can develop during any stage of pericarditis, and small effusions that appear rapidly can cause cardiac tamponade. Pyopericardium is a rare aetiology for tamponade. This is a case of an elderly diabetic lady, on steroid therapy for immune thrombocytopenia, who presented with fever and acute dyspnoea. She developed cardiac tamponade due to pyopericardium with Staphylococcus as the causative organism. Staphylococcus pyopericardium, in the absence of a primary focus of infection, progressing to tamponade is an uncommon scenario., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Severe infections of the respiratory tracts of critically ill patients are common and associated with excess morbidity and mortality. Piperacillin is commonly used to treat pulmonary infections in critically ill patients. Adequate antibiotic concentration in the epithelial lining fluid (ELF) of the lung is essential for successful treatment of pulmonary infection., Objectives: To compare piperacillin pharmacokinetics/pharmacodynamics in the serum and ELF of healthy volunteers and critically ill patients., Methods: Piperacillin concentrations in the serum and ELF of healthy volunteers and critically ill patients were compared using population methodologies., Results: Median piperacillin exposure was significantly higher in the serum and the ELF of critically ill patients compared with healthy volunteers. The IQR for serum piperacillin exposure in critically ill patients was six times greater than for healthy volunteers. The IQR for piperacillin exposure in the ELF of critically ill patients was four times greater than for healthy volunteers. The median pulmonary piperacillin penetration ratio was 0.31 in healthy volunteers and 0.54 in critically ill patients., Conclusions: Greater variability in serum and ELF piperacillin concentrations is observed in critically ill patients compared with healthy adult subjects and must be considered in the development of dosage regimens. Pulmonary penetration of antimicrobial agents should be studied in critically ill patients, as well as healthy volunteers, during drug development to ensure appropriate dosing of patients with pneumonia.

Importance: Meropenem-vaborbactam is a combination carbapenem/beta-lactamase inhibitor and a potential treatment for severe drug-resistant gram-negative infections., Objective: To evaluate efficacy and adverse events of meropenem-vaborbactam in complicated urinary tract infection (UTI), including acute pyelonephritis., Design, Setting, and Participants: Phase 3, multicenter, multinational, randomized clinical trial (TANGO I) conducted November 2014 to April 2016 and enrolling patients (≥18 years) with complicated UTI, stratified by infection type and geographic region., Interventions: Eligible patients were randomized 1:1 to receive meropenem-vaborbactam (2g/2g over 3 hours; n = 274) or piperacillin-tazobactam (4g/0.5g over 30 minutes; n = 276) every 8 hours. After 15 or more doses, patients could be switched to oral levofloxacin if they met prespecified criteria for improvement, to complete 10 days of total treatment., Main Outcomes and Measures: Primary end point for FDA criteria was overall success (clinical cure or improvement and microbial eradication composite) at end of intravenous treatment in the microbiologic modified intent-to-treat (ITT) population. Primary end point for European Medicines Agency (EMA) criteria was microbial eradication at test-of-cure visit in the microbiologic modified ITT and microbiologic evaluable populations. Prespecified noninferiority margin was -15%. Because the protocol prespecified superiority testing in the event of noninferiority, 2-sided 95% CIs were calculated., Results: Among 550 patients randomized, 545 received study drug (mean age, 52.8 years; 361 [66.2%] women; 374 [68.6%] in the microbiologic modified ITT population; 347 [63.7%] in the microbiologic evaluable population; 508 [93.2%] completed the trial). For the FDA primary end point, overall success occurred in 189 of 192 (98.4%) with meropenem-vaborbactam vs 171 of 182 (94.0%) with piperacillin-tazobactam (difference, 4.5% [95% CI, 0.7% to 9.1%]; P < .001 for noninferiority). For the EMA primary end point, microbial eradication in the microbiologic modified ITT population occurred in 128 of 192 (66.7%) with meropenem-vaborbactam vs 105 of 182 (57.7%) with piperacillin-tazobactam (difference, 9.0% [95% CI, -0.9% to 18.7%]; P < .001 for noninferiority); microbial eradication in the microbiologic evaluable population occurred in 118 of 178 (66.3%) vs 102 of 169 (60.4%) (difference, 5.9% [95% CI, -4.2% to 16.0%]; P < .001 for noninferiority). Adverse events were reported in 106 of 272 (39.0%) with meropenem-vaborbactam vs 97 of 273 (35.5%) with piperacillin-tazobactam., Conclusions and Relevance: Among patients with complicated UTI, including acute pyelonephritis and growth of a baseline pathogen, meropenem-vaborbactam vs piperacillin-tazobactam resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Further research is needed to understand the spectrum of patients in whom meropenem-vaborbactam offers a clinical advantage., Trial Registration: clinicaltrials.gov Identifier: NCT02166476.

Objectives: We sought to evaluate clinical outcomes of intensive care unit (ICU) patients following a hospital-wide initiative of prolonged piperacillin/tazobactam (PIP/TAZ) infusion., Methods: Retrospective observational study of patients >18 years old who was hospitalized in the ICU receiving PIP/TAZ for >72 hours during the preimplementation (June 1, 2010 to May 31, 2011) and postimplementation (July 7, 2011 to June 30, 2014) periods., Results: There were 124 and 429 patients who met inclusion criteria with average age of 54.3 and 56.9 years, and average duration of PIP/TAZ therapy was 6.1 ± 2.8 days and 5.9 ± 3.4 days in the pre- and postimplementation period, respectively. Intensive care unit and hospital length of stay (LOS) following initiation of PIP/TAZ were 8.0 ± 8.4 days versus 6.4 ± 6.8 days and 26.3 ± 22.8 days versus 20.4 ± 16.1 days among patients in the pre- and postimplementation periods, respectively. Compared to patients who received intermittent PIP/TAZ infusion, the adjusted difference in ICU and hospital LOS was 0.6 ± 0.8 days (95% confidence interval [CI]: -0.9 to 2.1 days) and 5.6 ± 2.1 days (95% CI: 1.4 - 9.7 days) shorter among patients who received prolonged PIP/TAZ infusion. At hospital discharge, 19 (15.3%) intermittent infusion and 74 (17.2%) prolonged infusion recipients had died. In comparison to intermittent infusion recipients, the adjusted odds ratio for mortality was 1.17 (95% CI: 0.65-2.1) with prolonged infusion., Conclusion: Our study demonstrated a reduction in hospital LOS with prolonged PIP/TAZ infusion among critically ill patients. Randomized trials are needed to further validate these findings.

Tazobactam/piperacillin (TAZ/PIPC) is an antimicrobial drug agent with a broad spectrum of antibacterial activity and is recommended as first-line therapy for hospital-acquired pneumonia, nursing- and healthcare-associated pneumonia, and other severe pneumonias. Nevertheless, in clinical settings, TAZ/PIPC is not fully effective in the treatment of pneumonia in the elderly. In the present study, we retrospectively investigated the efficacy of TAZ/PIPC for pneumonia in elderly patients and identified factors that reduced its efficacy. Ninety-nine patients (mean age of 83.4 years and no significant difference in the sex ratio) were included in the present study. The efficacy rate of TAZ/PIPC for pneumonia in elderly patients was 81.8%, which was approximately 7 to 10% lower than that in domestic phase III trials. A multivariate analysis identified the complications of chronic respiratory disease as a significant factor attenuating the therapeutic effects of TAZ/PIPC [odds ratio 4.050, 95% confidence interval (CI) 1.008-16.271]. In conclusion, TAZ/PIPC may not be sufficiently effective for pneumonia in elderly patients with the complications of chronic respiratory disease as a background.

Raoultella planticola is rarely associated with clinical infection, and a limited number of pediatric cases have been reported. Herein we report a case of bacteremia presumptively secondary to bilateral conjunctivitis in an infant caused by R. planticola which was successfully treated with piperacillin-tazobactam. It should be kept in mind that R. planticola can be a pathogen in pediatric age groups., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Burn patients are prone to infections which often necessitate broad antibiotic coverage. Vancomycin is a common antibiotic after burn injury and is administered alone (V), or in combination with imipenem-cilastin (V/IC) or piperacillin-tazobactam (V/PT). Sparse reports indicate that the combination V/PT is associated with increased renal dysfunction. The purpose of this study was to evaluate the short-term impact of the three antibiotic administration types on renal dysfunction., Methods: All pediatric and adult patients admitted to our centers between 2004 and 2016 with a burn injury were included in this retrospective review if they met the criteria of exposition to either V, V/IC, or V/PT for at least 48 h, had normal baseline creatinine, and no pre-existing renal dysfunction. Creatinine was monitored for 7 days after initial exposure; the absolute and relative increase was calculated, and patient renal outcomes were classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria depending on creatinine increases and estimated creatinine clearance. Secondary endpoints (demographic and clinical data, incidences of septicemia, and renal replacement therapy) were analyzed. Antibiotic doses were modeled in logistic and linear multivariable regression models to predict categorical KDIGO events and relative creatinine increase., Results: Out of 1449 patients who were screened, 718 met the inclusion criteria, 246 were adults, and 472 were children. Between the study cohorts V, V/IC, and V/PT, patient characteristics at admission were comparable. V/PT administration was associated with a statistically higher serum creatinine, and lower creatinine clearance compared to patients receiving V alone or V/IC in adults and children after burn injury. The incidence of KDIGO stages 1, 2, and 3 was higher after V/PT treatment. In children, the incidence of KDIGO stage 3 following administration of V/PT was greater than after V/IC. In adults, the incidence of renal replacement therapy was higher after V/PT compared with V or V/IC. Multivariate modeling demonstrated that V/PT is an independent predictor of renal dysfunction., Conclusion: Co-administration of vancomycin and piperacillin-tazobactam is associated with increased renal dysfunction in pediatric and adult burn patients when compared to vancomycin alone or vancomycin plus imipenem-cilastin. The mechanism of this increased nephrotoxicity remains elusive and warrants further scientific evaluation.

Purpose of Review: Acute kidney injury (AKI) is a common complication in the critically ill population, is multifactorial and associated with increased mortality. Drug-induced kidney injury is a significant contributor to the development of AKI. The purpose of this review is to provide updates in the epidemiology, susceptibility and management of drug-induced kidney disease (DIKD)., Recent Findings: Recent changes in guidelines for the management of serious infections in the critically ill have resulted in an increased frequency of DIKD. Varying definitions employed in clinical trials has complicated the awareness of this adverse event. Causality assessment is often missing from studies as it is complicated by the need to evaluate competing AKI risk factors. This has led to uncertainty in the nephrotoxic risk of commonly used drugs., Summary: Standard criteria for DIKD should be applied in clinical trials to improve our understanding of the frequency of these events. Adjudication of these events will improve the clinician's ability to evaluate the causal relationship and relative contribution of specific drugs to the AKI event.

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.

Diabetic foot infections are a common and serious problem for all health systems worldwide. The aim of this study was to examine the resistance to antibiotics of microorganisms isolated from infected soft tissues of diabetic foot ulcers, using tissue cultures. We included 113 consecutive patients (70 men, 43 women) with a mean age of 66.4 ± 11.2 years and a mean diabetes duration of 14.4 ± 7.6 years presenting with diabetic foot soft tissue infections. Generally, no high antibiotic resistance was observed. Piperacillin-tazobactam exhibited the lowest resistance in Pseudomonas, as well as in the other Gram-negative pathogens. In methicillin-resistant Staphylococcus aureus isolates, there was no resistance to anti-Staphylococcus agents. Of note, clindamycin, erythromycin, and amoxycillin/clavulanic acid exhibited high resistance in Gram-positive cocci. These results suggest that antibiotic resistance in infected diabetic foot ulcers in our area is not high and they are anticipated to prove potentially useful in the initial choice of antibiotic regimen.

Early administration of appropriate empiric antibiotics is essential for achieving the best possible outcomes in sepsis. Yet the choice of antibiotic therapy has become more challenging due to recent reports of nephrotoxicity with the combination of vancomycin and piperacillin/tazobactam, the "workhorse" regimen at many institutions. In this article we assess the evidence for nephrotoxicity and its possible mechanisms, provide recommendations for risk mitigation, address the advantages and disadvantages of alternative antibiotic choices, and suggest areas for future research., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent., Objective: To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients., Methods: This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] <25 kg/m 2 ), obesity class I and II (BMI 30-39.9kg/m 2 ), and obesity class III (BMI≥40 kg/m 2 ) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated., Results: Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively ( P=0.002). Longer durations of therapy ( P<0.0001), higher initial maintenance doses in both total milligrams/day ( P=0.0137) and milligrams/kilogram ( P=0.0307), and any trough level >20 mg/L ( P<0.0001) were identified as predictors of development of nephrotoxicity. Concomitant administration of piperacillin/tazobactam, diuretics, and IV contrast were associated with development of nephrotoxicity ( P<0.005, all). Patients with class III obesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75)., Conclusions: Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity.

The purpose of this study was to evaluate the observed incidence of acute kidney injury (AKI) in adult patients receiving either piperacillin-tazobactam (PT) and vancomycin or meropenem and vancomycin for at least 48h. In this retrospective cohort study, we included adult patients with no known renal dysfunction who received either the combination of PT-vancomycin or meropenem-vancomycin for at least 48h. The study's primary outcome was the incidence of acute kidney injury (AKI), defined by the Kidney Disease: Improving Global Outcomes (KDIGO) in patients with baseline normal renal function as an increase in serum creatinine (Scr) by ≥0.3mg/dl within 48h. A total of 183 patients were evaluated for AKI. The incidence of AKI was higher but not statistically different in the PT-vancomycin group (7.41%) compared with the meropenem-vancomycin group (5.33%). This study was not able to detect a statistically significant difference in AKI between the two treatment groups. A larger prospective study is warranted., (Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.)

Background: Piperacillin (PIP) in combination with tazobactam is commonly used for anti-infective treatment in cancer patients. PIP exerts a time-dependent killing. Thus, the maintenance of plasma concentrations above a pre-defined target concentration for a pre-defined time may be relevant for optimal efficacy. It is assumed that PIP-plasma concentrations above the clinical breakpoint of the target pathogen [Pseudomonas aeruginosa, clinical breakpoint at minimal inhibitory concentration (MIC) 16 mg/L] should be reached for 100% of the dosing interval or >4xMIC (64 mg/L) for 50% of the dosing interval. Whereas studies in the intensive-care setting have shown underdosing in patients with sepsis, little is known about PIP-plasma concentrations in cancer patients., Methods: Data of 56 cancer patients who received piperacillin/tazobactam (PIP/TAZ, 4.5 g three times daily) as empiric therapy for suspected infection were analysed at baseline and 4 h after the infusion., Results: Median trough concentrations in steady state [median 3 days (IQR 3-5) after start of PIP/TAZ] were 4.6 mg/L (95% CI 0.3-136.3) and median PIP-plasma concentrations 4 h after infusion were 46.2 mg/L (95% CI 10.1-285.6). A second evaluation 5 days (IQR 4-7) after start of PIP/TAZ confirmed these results: trough concentrations were 2.7 mg/L (95% CI 0.5-6.3), concentrations after 4 h 28.0 mg/L (95% CI 1.7-47.3). A good renal function was associated with lower plasma concentrations (r = -0.388, p < 0.003). Detailed pharmacokinetic measurements in six patients showed low maximum plasma concentration (median 165 mg/L) and a rapid decline of plasma concentrations (median plasma half time 1.38 h)., Conclusion: In conclusion, piperacillin plasma concentrations in cancer patients are below target levels warranting prospective trials to investigate therapeutic drug monitoring.

Vancomycin use is often associated with nephrotoxicity. It remains uncertain, however, to what extent vancomycin is directly responsible, as numerous potential risk factors for acute kidney injury frequently coexist. Herein, we critically examine available data in adult patients pertinent to this question. We review the pharmacokinetics/pharmacodynamics of vancomycin metabolism. Efficacy and safety data are discussed. The pathophysiology of vancomycin nephrotoxicity is considered. Risk factors for nephrotoxicity are enumerated, including the potential synergistic nephrotoxicity of vancomycin and piperacillin-tazobactam. Suggestions for clinical practice and future research are given., (© 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)