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Purpose: This study aimed to present real-life data on the use, effectiveness, and safety of administering Ceftolozane/Tazobactam (C/T) through elastomeric pumps (EP) in the outpatient setting., Methods: This case series study was conducted from January 2022 to July 2023 in a large University Hospital in Rome, Italy. Patients receiving continuous infusion of C/T via EP were included up to a follow-up period of 90 days after the end of antibiotic therapy. The primary endpoint was the infection's clinical cure rate. Secondary endpoints were adverse events attributable to continuous home infusion of Ceftolozane/Tazobactam via elastomeric pumps., Results: Seven patients received C/T continuously infused via EP and were included in the final analysis. Three patients suffered from prosthetic joint infection ( n  = 3/7; 43%), two patients from osteomyelitis ( n  = 2/7; 29%), one patient from otomastoiditis ( n  = 1/7; 15%) and one from pneumonia ( n  = 1/7; 15%). All infection were sustained by P. aeruginosa. Five strains had MDR-type susceptibility profiles ( n  = 5/7; 71%) and two of these were DTR ( n  = 2/7; 29%). The infection cure rate reached 86% ( n  = 6/7). Two patients reported a complication related to the vascular catheter for drug infusion ( n  = 2/7; 29%)., Conclusions: Continuous infusion of Ceftolozane/Tazobactam by elastomeric pumps has been shown to be safe and effective in practice representing a viable option of intravenous treatment in outpatient setting for infection sustained by P. aeruginosa especially for multidrug-resistant strains.

Introduction: Ceftolozane is a cephalosporin similar to ceftazidime in its structure, which is marketed in combination with tazobactam, a well-known β-lactamase inhibitor., Areas Covered: After a brief introduction on the drug characteristics and efficacy, we focused on available data from randomized controlled trials and post-marketing observational studies pertaining to the safety of ceftolozane/tazobactam (C/T) for the treatment of complicated urinary tract infections (cUTI). A search was conducted in PubMed from January 2010 to February 2023., Expert Opinion: The use of C/T for the treatment of cUTI is supported by solid efficacy and safety data, especially for the treatment of those pathogens where it can represent a first-line approach due to some peculiar characteristics: (i) treatment of cUTI caused by multidrug-resistant Pseudomonas aeruginosa , in view of its frequent activity against carbapenem-resistant isolates when resistance mechanisms other than production of carbapenemases are concerned; (ii) treatment of cUTI caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacterales in those settings where the selective pressure for carbapenem resistance needs to be relieved, as a suitable and effective carbapenem-sparing option. Although development of resistance to C/T during or after treatment has been reported, this has been reported very rarely in patients receiving C/T for the treatment of cUTI.

Background: Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections (cIAI). The safety and efficacy of ceftolozane/tazobactam in pediatric participants with cIAI were assessed., Methods: This phase 2 study (NCT03217136) randomized participants to either ceftolozane/tazobactam+metronidazole or meropenem for treatment of cIAI in pediatric participants (<18 years). The primary objective was to assess the safety and tolerability of intravenous ceftolozane/tazobactam+metronidazole. Clinical cure at end of treatment (EOT) and test of cure (TOC) visits were secondary end points., Results: The modified intent-to-treat (MITT) population included 91 participants (ceftolozane/tazobactam+metronidazole, n = 70; meropenem, n = 21). Complicated appendicitis was the most common diagnosis (93.4%); Escherichia coli was the most common pathogen (65.9%). Adverse events (AEs) occurred in 80.0% and 61.9% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, drug-related AEs occurred in 18.6% and 14.3% and serious AEs occurred in 11.4% and 0% of participants receiving ceftolozane/tazobactam+metronidazole and meropenem, respectively. No drug-related serious AEs or discontinuations due to drug-related AEs occurred. Rates of the clinical cure for ceftolozane/tazobactam+metronidazole and meropenem at EOT were 80.0% and 95.2% (difference: -14.3; 95% confidence interval: -26.67 to 4.93) and at TOC were 80.0% and 100.0% (difference: -19.1; 95% confidence interval: -30.18 to -2.89), respectively; 6 of the 14 clinical failures for ceftolozane/tazobactam+metronidazole at TOC were indeterminate responses imputed as failures per protocol., Conclusion: Ceftolozane/tazobactam+metronidazole was well tolerated in pediatric participants with cIAI and had a safety profile similar to the established safety profile in adults. In this descriptive efficacy analysis, ceftolozane/tazobactam+metronidazole appeared efficacious., Competing Interests: J.L., F.-H.S, J.A.H., M.B., M.G.J., C.D.A., E.G.R., and C.J.B. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. M.W.P. was an employee of MSD at the time of the study conduct. C.-C.A.J. received consulting fees from MSD and holds stock in Merck & Co., Inc., Rahway, NJ, USA. J.N. reports funding to conduct the study from MSD to his institution. N.D. has no potential conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Ceftolozane/tazobactam, a cephalosporin-β-lactamase inhibitor combination, active against multidrug-resistant Gram-negative pathogens, is approved for treatment of adults with complicated urinary tract infections (cUTI). Safety and efficacy of ceftolozane/tazobactam in pediatric participants with cUTI, including pyelonephritis, were assessed., Methods: This phase 2 study (NCT03230838) compared ceftolozane/tazobactam with meropenem for treatment of cUTI in participants from birth to <18 years of age. The primary objective was safety and tolerability. Key secondary end points included clinical cure and per-participant microbiologic response rates at end of treatment (EOT) and test of cure (TOC) visits., Results: The microbiologic modified intent-to-treat (mMITT) population included 95 participants (ceftolozane/tazobactam, n = 71; meropenem, n = 24). The most common diagnosis and pathogen were pyelonephritis (ceftolozane/tazobactam, 84.5%; meropenem, 79.2%) and Escherichia coli (ceftolozane/tazobactam, 74.6%; meropenem, 87.5%); 5.7% (ceftolozane/tazobactam) and 4.8% (meropenem) of E. coli isolates were extended-spectrum β-lactamase-producers. Rates of adverse events were similar between treatment groups (any: ceftolozane/tazobactam, 59.0% vs. meropenem, 60.6%; drug-related: ceftolozane/tazobactam, 14.0% vs. meropenem, 15.2%; serious: ceftolozane/tazobactam, 3.0% vs. meropenem, 6.1%). Rates of clinical cure for ceftolozane/tazobactam and meropenem at EOT were 94.4% and 100% and at TOC were 88.7% and 95.8%, respectively. Rates of microbiologic eradication for ceftolozane/tazobactam and meropenem at EOT were 93.0% and 95.8%, and at TOC were 84.5% and 87.5%, respectively., Conclusions: Ceftolozane/tazobactam had a favorable safety profile in pediatric participants with cUTI; rates of clinical cure and microbiologic eradication were high and similar to meropenem. Ceftolozane/tazobactam is a safe and effective new treatment option for children with cUTI, especially due to antibacterial-resistant Gram-negative pathogens., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP)., Methods: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups., Results: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001)., Conclusions: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T., Competing Interests: Potential conflicts of interest. M. J. R. has received grant support, consulted, or spoken on behalf of AbbVie, Melinta, Merck, Paratek, Shionogi, and Tetraphase and is partially supported by the National Institutes of Health (R21 Al163726). W. D. K. has received grant support from Merck. S. A. is an employee of Seres Therapeutics. C. Y., D. H., D. L., E. C., G. S., I. S., W. J. M., J. T., J. W., K. M., L. A., M. B., M. J. R., M. M., M. P., M. R., M. V., N. F., N. R., N. T., P. W., R. P., S. D., S. J., S. S., T. M., and V. V. have nothing to disclose. G. S. has received speaking honoraria from AbbVie, Paratek, and Sunovion, consulting fees from Octapharma, Ferring, AbbVie and Paratek, and Research funding from Octapharma. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Piperacillin/tazobactam, a commonly used antibiotic, is associated with acute kidney injury (AKI). The relationship between piperacillin concentrations and AKI remains unknown., Objective: Estimate piperacillin exposures in critically ill children and young adults administered piperacillin/tazobactam to identify concentrations and clinical factors associated with piperacillin-associated AKI., Patients and Methods: We assessed piperacillin pharmacokinetics in 107 patients admitted to the paediatric ICU who received at least one dose of piperacillin/tazobactam. Piperacillin AUC, highest peak (Cmax) and highest trough (Cmin) in the first 24 hours of therapy were estimated. Piperacillin-associated AKI was defined as Kidney Disease: Improving Global Outcomes (KDIGO) Stage 2/3 AKI present >24 hours after initial piperacillin/tazobactam dose. Likelihood of piperacillin-associated AKI was rated using the Naranjo Adverse Drug Reaction Probability Scale. Multivariable logistic regression was performed to identify patient and clinical predictors of piperacillin-associated AKI., Results: Out of 107 patients, 16 (15%) were rated as possibly or probably having piperacillin-associated AKI. Estimated AUC and highest Cmin in the first 24 hours were higher in patients with piperacillin-associated AKI (2042 versus 1445 mg*h/L, P = 0.03; 50.1 versus 10.7 mg/L, P < 0.001). Logistic regression showed predictors of piperacillin-associated AKI included higher Cmin (OR: 5.4, 95% CI: 1.7-23) and age (OR: 1.13, 95% CI: 1.05-1.25)., Conclusions: We show a relationship between estimated piperacillin AUC and highest Cmin in the first 24 hours of piperacillin/tazobactam therapy and piperacillin-associated AKI, suggesting total piperacillin exposure early in the course is associated with AKI development. These data could serve as the foundation for implementation of model-informed precision dosing to reduce AKI incidence in patients given piperacillin/tazobactam., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Ceftolozane-tazobactam is a novel cephalosporin/β-lactamase inhibitor combination with activity against Gram-negative bacteria (GNB). We aimed to comprehensively evaluate the clinical efficacy and safety of ceftolozane-tazobactam in treating GNB infections in adult patients., Research Design and Methods: PubMed, Embase, and Cochrane databases were retrieved until August 2022. Randomized trials and non-randomized controlled studies evaluating ceftolozane-tazobactam and its comparators in adult patients with GNB infections were included., Results: A total of 13 studies were included. Overall, patients receiving ceftolozane-tazobactam had significant advantages in clinical cure (odds ratio [OR], 1.62; 95% CI, 1.05-2.51) and microbiological eradication (OR, 1.43; 95% CI, 1.19-1.71), especially in Pseudomonas aeruginosa -infected patients. Ceftolozane-tazobactam had a significant advantage in clinical success or microbial eradication compared with polymyxin/aminoglycosides (PL/AG) or levofloxacin. There were no significant differences in adverse events (AEs), Clostridium difficile infection (CDI), and mortality between ceftolozane-tazobactam and comparators. Notably, ceftolozane-tazobactam showed a significantly lower risk of acute kidney injury compared with PL/AG., Conclusions: Ceftolozane-tazobactam showed excellent clinical and microbiological efficacy in treating GNB, especially P. aeruginosa -induced infections. The overall safety profile of ceftolozane-tazobactam was comparable to other antimicrobials, with no increased risk of CDI and obvious advantage over antibacterial agents with high nephrotoxicity.

Objectives: This study aimed to evaluate the efficacy and safety of ceftolozane/tazobactam (C/T) plus metronidazole versus meropenem plus placebo for the treatment of complicated intra-abdominal infection (cIAI) in Chinese adult participants., Methods: In this phase III clinical trial (NCT03830333), Chinese adult participants with cIAI were randomized 1:1 to receive C/T plus metronidazole or meropenem plus placebo. The primary objective was to assess C/T plus metronidazole for noninferiority versus meropenem for clinical response rate at the test of cure (TOC; 28 ± 2 days after study start) visit in the clinically evaluable population. Secondary endpoints included clinical and microbiologic responses at the TOC and end-of-treatment (≤24 hours after last dose) visits and adverse event rates., Results: Clinical cure at the TOC visit in the clinically evaluable population was 95.2% and 93.1% for C/T plus metronidazole and meropenem, respectively (between-treatment difference: 2.1% [95% confidence interval: -4.7%, 8.8%]); thus, noninferiority was met. Clinical responses at the TOC and end-of-treatment visits and microbiologic responses at the TOC visit were consistent with the primary efficacy endpoint. Safety was comparable between study treatment groups., Conclusion: In Chinese adult participants with cIAI, C/T plus metronidazole was noninferior to meropenem, with comparable safety., Competing Interests: Declarations of competing interest XD, YW, and FS are employees of MSD, China. XC and HW are former employees of MSD, China. MGJ, MB, JAH, and CJB are employees of MSD. MSD, China and MSD employees may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. YS, JF, and GC have no competing interests to declare., (Copyright © 2022 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc.,, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, idiosyncratic reaction to a drug which presents after a prolonged latency period. Although it most commonly occurs with aromatic anticonvulsants, antibiotics are also occasionally implicated. A 50-year-old male was admitted for left pyopneumothorax. He was started on intravenous piperacillin-tazobactam (Pip/Taz) and clindamycin. After 10 days of treatment, he developed high grade fever with maculopapular rashes with areas of scaling. He had elevated WBC counts with eosinophils of 21% and raised serum transaminases. After excluding other possible etiologies for febrile illness, a possibility of DRESS was considered. Naranjo scale, used for causality assessment, yielded a total score of 6, pointing toward probable adverse drug reaction. Also, the patient had 6 out of the 7 inclusion criteria for DRESS as per European Registry of Severe Cutaneous Adverse Reaction (RegiScar) scoring. Pip/Taz was found to be causative drug and was discontinued. He was conservatively managed with antipyretics and topical steroids. Fever subsided the day after stopping Pip/Taz and his rashes resolved gradually. In conclusion the possibility of antibiotics-induced DRESS should be considered and high index of vigilance is advised.

Objective: New treatments are needed for multidrug-resistant (MDR) gram-negative infections in neonates. Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination that has broad-spectrum activity against most common gram-negative bacteria, including MDR strains. We evaluated pharmacokinetics (PK) and safety of ceftolozane/tazobactam in term and premature neonates and young infants., Study Design: This is a subgroup analysis of a phase 1, noncomparative, open-label, multicenter study that characterized the PK, safety, and tolerability of a single intravenous (IV) dose of ceftolozane/tazobactam in pediatric patients with proven/suspected gram-negative infection or receiving perioperative prophylaxis., Results: Seven patients were enrolled in Group A (birth [7 days postnatal] to < 3 months, > 32 weeks gestation) and six patients were enrolled in Group B (birth [7 days postnatal] to < 3 months, ≤ 32 weeks gestation). PK profiles in neonates and young infants were generally comparable to those of older children receiving a single IV dose of ceftolozane/tazobactam. No serious adverse events (AEs), treatment-related AEs, severe AEs, or clinically significant laboratory abnormalities were reported., Conclusion: Among term and premature neonates and young infants, PK was comparable to older children and ceftolozane/tazobactam was generally well tolerated. An adaptable and flexible study design is necessary for enrollment in neonatal PK trials., Competing Interests: J.Y.A. has received institutional research funding and honoraria from Merck & Co., Inc., Kenilworth, NJ. A.A. has received institutional research funding from Merck & Co., Inc.. J.S.B. participated as an investigator in this trial, and his employer received funding for institutional research and protocol design from Merck & Co., Inc.. Z.Z., B.Y., M.L.R., M.G.J., and E.G.R. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, and may own stock and/or hold stock options in Merck & Co., Inc., Kenilworth, NJ., (Thieme. All rights reserved.)

The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.

Objective: To determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection., Methods: ARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated., Results: Mean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V ss ) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V ss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate., Conclusions: In patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam. CLINICALTRIALS., Gov Identifier: NCT02387372., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The clinical use, safety and effectiveness of ceftolozane/tazobactam among 13 patients 3 months to 19 years of age infected with multidrug-resistant Pseudomonas aeruginosa are described. All but one patient achieved clinical cure after initial treatment. Adverse drug events attributed to treatment included transaminitis and neutropenia which occurred in 2 patients and resolved upon dose reduction.

The aim of this systematic review was to assess AKI (acute kidney injury) in adult patients, treated with vancomycin (V) + piperacillin/tazobactam (PT) compared to V monotherapy. Studies were found in Pubmed, Web of Science and Scopus databases. Articles not in English, pediatric studies and case reports were excluded. A study is eligible for inclusion if the adjusted Odds ratio (aOR) for AKI in V + PT compared to V monotherapy groups, could be extracted or determined from available data. Six retrospective cohort studies were eligible for inclusion criteria and so they were included in the analysis. All studies separately showed a significant higher risk of developing AKI (OR > 1, p < 0.05) in V + PT group compared to V monotherapy group. Considering the methodological difference of included studies, a random effect model was preferred. The model showed a pooled significant higher risk of developing AKI [OR 2.77 (95% CI 1.94, 3.96), p < 0.0001] in V + PT group compared to V group. Association of V and PT appears to be associated with a greater risk of AKI compared to V in monotherapy. These results may serve as the impetus for further evaluation into true mechanisms behind this additive nephrotoxic effect and its potential implications on mortality.

Objectives : Limited evidence has suggested that cefoperazone-sulbactam causes coagulation disorders and bleeding. Methods : The authors conducted a retrospective study to compare patients receiving cefoperazone-sulbactam versus those treated with cefoperazone-tazobactam or ceftazidime. Propensity-score matching was used to explore whether treatment with cefoperazone-sulbactam increased the risk of prothrombin time (PT) prolongation, coagulation disorders, and bleeding, or decreased platelets (PLT). Results : The cohort included 23,242 patients. Among patients receiving cefoperazone-sulbactam, the risk of PT prolongation, coagulation disorders, decreased PLT, and bleeding was 5.3%, 9.2%, 15.7%, and 4.2%, respectively. Propensity-score matching analyses suggested that cefoperazone-sulbactam increased the risk of PT prolongation (aOR 2.26, 95% CI 1.61-3.18), coagulation disorders (aOR 1.81, 95% CI 1.43-2.30), and decreased PLT (aOR 1.46, 95% CI 1.25-1.72), but not increase bleeding (aOR 1.05, 95% CI 0.79-1.40) compared with ceftazidime. Patients receiving cefoperazone-sulbactam had higher risk of PT prolongation (aOR 1.53, 95% CI 1.11-2.10), coagulation disorders (aOR 1.53, 95% CI 1.21-1.95), but not decreased PLT (aOR 0.93, 95% CI 0.81-1.07) or bleeding (aOR 1.11, 95% CI 0.87-1.42), compared with those receiving cefoperazone-tazobactam. Conclusion : Cefoperazone-sulbactam may be associated with a higher risk of PT prolongation and coagulation disorders compared with cefoperazone-tazobactam and ceftazidime.

Background: This study investigated predominant microorganisms causing community-onset bacteraemia at the medical emergency department (ED) of a tertiary-care university hospital in Germany from 2013 to 2018 and their antimicrobial susceptibility patterns., Methods: Antimicrobial resistance patterns in patients with positive blood cultures presenting to an internal medicine ED were retrospectively analysed., Results: Blood cultures were obtained at 5191 of 66,879 ED encounters, with 1013 (19.5%) positive results, and true positive results at 740 encounters (diagnostic yield, 14.3%). The most frequently isolated relevant microorganisms were Enterobacterales (n = 439, 59.3%), Staphylococcus aureus (n = 92, 12.4%), Streptococcus pneumoniae (n = 34, 4.6%), Pseudomonas aeruginosa (n = 32, 4.3%), Streptococcus pyogenes (n = 16, 2.2%), Enterococcus faecalis (n = 18, 2.4%), and Enterococcus faecium (n = 12, 1.6%). Antimicrobial susceptibility testing revealed a high proportion of resistance against ampicillin-sulbactam in Enterobacterales (42.2%). The rate of methicillin-resistant Staphylococcus aureus was low (0.4%). Piperacillin-tazobactam therapy provided coverage for 83.2% of all relevant pathogens using conventional breakpoints. Application of the new European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations increased the percentage of susceptible isolates to high-dose piperacillin-tazobactam to 92.8% (p < 0.001). Broad-spectrum carbapenems would only cover an additional 4.8%. The addition of vancomycin or linezolid extended coverage by just 1.7%., Conclusions: Using an ureidopenicillin-beta-lactamase inhibitor combination at the high dose suggested by the new EUCAST recommendations provided nearly 93% coverage for relevant pathogens in patients with suspected bloodstream infection in our cohort. This might offer a safe option to reduce the empiric use of carbapenems. Our data support the absence of a general need for glycopeptides or oxazolidinones in empiric treatment.

Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions., (Copyright © 2019 American Society for Microbiology.)

Drug-induced thrombocytopenia (DITP) has been described as a sudden and severe hematologic complication of piperacillin/tazobactam. The proposed mechanism by which piperacillin/tazobactam causes DITP involves the formation of a covalent bond to platelet membrane protein thereby inducing a humoral immune response. Given the immunogenic nature of this adverse event and the structural similarities across beta-lactam antibiotics, the potential for cross-reactivity between agents within the class should be considered. However, the structural moiety of piperacillin/tazobactam responsible for this immunogenic response has not been identified-the relationship between structure and activity for this phenomenon remains unknown. Data on the safety and cross-reactivity of other beta-lactam agents in this setting is lacking. We report the first case of piperacillin/tazobactam DITP successfully challenged by the use of cefepime for the treatment of aspiration pneumonia. Further studies are needed to determine the structural moiety of piperacillin/tazobactam responsible for this immunogenic response and evaluate the safety of other beta-lactam antibiotics in this clinical setting.

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.)

This study describes the largest clinical experience using ceftolozane/tazobactam (C/T) for different Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy (June 2016-March 2018). All adult patients treated with ≥4 days of C/T were enrolled. Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin-structure infection (20.8%), complicated UTI (13.9%), complicated IAI (12.9%), bone infection (8.9%) and primary bacteraemia (5.9%). Over one-half of P. aeruginosa strains were XDR (50.5%), with 78.2% of isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (38.6%). When used as second-line or later, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P. aeruginosa and clinical failure of previous therapy. Concomitant antibiotics were reported in 35.6% of patients. C/T doses were 1.5 g q8h in 70 patients (69.3%) and 3 g q8h in 31 patients (30.7%); median duration of C/T therapy was 14 days. Overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or receiving continuous renal replacement therapy (CRRT). Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the infection type. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving CRRT., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Tazobactam/ceftolozane, a novel antimicrobial therapy, is active against Pseudomonas aeruginosa and most extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. We report the results of the efficacy and safety of tazobactam/ceftolozane in Japanese patients with complicated intra-abdominal infections (cIAI). A multicenter, open-label, noncomparative study (MK-7625A Protocol 013, ClinicalTrials.gov Identifier: NCT02739997) to investigate the efficacy and safety of tazobactam/ceftolozane used in combination with metronidazole in Japanese patients with cIAI was conducted. One hundred Japanese patients with cIAI received tazobactam/ceftolozane 1.5 g (tazobactam 0.5 g/ceftolozane 1 g) plus metronidazole 500 mg intravenously every 8 h for 60 min for 4-14 days. The clinical response rate at the Test-of-Cure visit (TOC; Day 28 ± 2 days) was 92.0% (81/88 subjects). By disease type, the clinical response rates were 92.3% (24/26) for cholecystitis, 100% (6/6) for liver abscess, 93.5% (58/62) for intra-abdominal abscess and 90.2% (55/61) for peritonitis. The per-subject microbiological response rate at the TOC was 90.2% (55/61). Per-pathogen microbiological response rates in the most common baseline pathogens were Escherichia coli 90.2% (37/41), Kebsiella pneumoniae 91.7% (11/12), Streptococcus anginosus 100% (11/11), Streptococcus constellatus 90.0% (9/10) and Bacteroides fragilis 95.2% (20/21). The most common drug-related AEs were aspartate aminotransferase increased (11.0%) and alanine aminotransferase increased (9.0%). No serious drug-related AE was reported during the study. The favorable effect of tazobactam/ceftolozane in the treatment of cIAI suggests that the agent will be useful in clinical practice in Japan., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report efficacy and safety results for a combination of a novel cephalosporin class antibiotic and a β-Lactamase inhibitor, tazobactam/ceftolozane (1:2) at a dose of 1.5 g intravenously every 8 h in Japanese patients with uncomplicated pyelonephritis and complicated urinary tract infection. This study design was a nonrandomized, multicenter, open-label trial, and the treatment period was 7 days. Of 115 patients enrolled in this study, 114 received tazobactam/ceftolozane, and 90 were included in the efficacy analyses. Ninety-nine isolates (bacterial count ≥10 5  CFU/mL) were identified by urine culture. The main baseline uropathogens were Escherichia coli (80 isolates), Klebsiella pneumoniae (8 isolates), and Proteus mirabilis (3 isolates). Of these, 13 isolates were ESBL-producers. The favorable per-patient microbiological response rate at 7 days after the final administration of tazobactam/ceftolozane was 80.7% (71/88). The response rate in uncomplicated pyelonephritis was 90.0% (36/40), complicated pyelonephritis 63.6% (14/22), and complicated cystitis 80.8% (21/26). The favorable clinical response rate was 96.6% (86/89), and composite response rate (based on microbiological and clinical response) was 80.7% (71/88). The eradication rate by uropathogen was 83.5% (66/79) in E. coli, 42.9% (3/7) in K. pneumoniae, and 100% (3/3) in P. mirabilis. The incidence of drug-related adverse events was 17.5% (20/114 patients). The most common drug-related adverse events were diarrhea and alanine aminotransferase increased in 5.3% (6/114 patients each). Drug-related serious adverse events and deaths were not observed. These results support the safety and efficacy of tazobactam/ceftolozane and suggest it will be a useful treatment for uncomplicated pyelonephritis and complicated urinary tract infection., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We present our experience in patients with hematologic malignancy and Pseudomonas aeruginosa infection treated with ceftolozane-tazobactam. We performed a single-center case-control study comparing patients with hematologic malignancy and P. aeruginosa infection treated with ceftolozane-tazobactam (study group) with similar patients not treated with ceftolozane-tazobactam (control group) to assess safety and efficacy. Nineteen cases and 38 controls were analyzed. Cases were younger (45.6 years versus 57.6 years; P  = 0.012) and less frequently had bacteremia (52.6% versus 86.8%; P  = 0.008). They also had worse Multinational Association for Supportive Care in Cancer (MASCC) scores (10.2 versus 16.1; P  = 0.0001), more hospital-acquired infections (78.9% versus 47.4%; P  = 0.013), and more extremely drug-resistant (XDR) P. aeruginosa infections (47.4% versus 21.1%; P  = 0.015). Cases received a median of 14 days (7 to 18 days) of ceftolozane-tazobactam (monotherapy in 11 cases [57.9.6%]). Ceftolozane-tazobactam was mostly used as targeted therapy (16 cases; 84.2%) because of resistance (9 cases; 47.4%), failure (4 cases; 21.1%), and toxicity (3 cases; 15.8%). Ten cases had bacteremia (52.6%). The sources were pneumonia (26.3%), catheter-related bacteremia (21.1%), primary bacteremia (21.1%), and perianal/genital (15.7%), urinary (10.5%), and skin/soft tissue (5.3%) infection. No toxicity was attributed to ceftolozane-tazobactam. More than 60% had neutropenia, and 15.8% fulfilled the criteria for sepsis. There were no significant differences in clinical cure at day 14 (89.5% versus 71.1%; P  = 0.183) or recurrence (15.8% versus 10.5%; P  = 0.675). Thirty-day mortality was lower among cases (5.3% versus 28.9%; P  = 0.045). Ceftolozane-tazobactam was well tolerated and at least as effective as other alternatives for P. aeruginosa infection in patients with hematologic malignancy, including neutropenic patients with sepsis caused by XDR strains., (Copyright © 2019 American Society for Microbiology.)

Introduction: Vancomycin (VAN) is associated with an increased risk of acute kidney injury (AKI). Evidence is conflicting regarding the risk of AKI when VAN is combined with an antipseudomonal β-lactam., Objectives: To determine the comparative incidence of AKI when VAN is combined with piperacillin-tazobactam (PTZ) or meropenem (MER)., Methods: This was a retrospective cohort study of acutely ill adults receiving the combination of VAN and PTZ or MER for at least 48 hours between November 1, 2014, and October 31, 2016, in a tertiary care hospital. Critically ill patients and those with baseline renal dysfunction were excluded. The primary outcome was the incidence of AKI during or within 72 hours of completing antibiotic therapy, defined as an absolute increase in serum creatinine (S cr ) of 0.5 mg/dl or higher or a 50% or more increase in S cr from baseline. Secondary outcomes included time to AKI development, duration of AKI, and length of hospitalization. Continuous variables were assessed using the Wilcoxon rank sum or the Student t test; categorical variables were assessed using χ 2 or Fisher exact tests. Independent risk factors for the development of AKI were also examined., Results: A total of 169 patients were evaluated. A significantly higher incidence of AKI was observed in the PTZ group compared with MER (16.5% vs 3.6%; p=0.009). The median time to AKI onset was significantly shorter with PTZ compared with MER (3 vs 7 days; p=0.009). After adjusting for baseline differences, VAN/PTZ was associated with a 6.8-fold increased risk of developing AKI (odds ratio [OR] 6.8, 95% confidence interval [CI] 1.5-30.9) compared with VAN/MER. VAN doses higher than 4 g/day and trough levels higher than 20 μg/ml were independent risk factors for developing AKI (OR 8.7, 95% CI 1.04-72.94, and OR 9.01, 95% CI 1.44-56.21, respectively)., Conclusion: The combination of VAN/PTZ increases the risk of AKI when compared with VAN/MER in acutely ill adults., (© 2018 Pharmacotherapy Publications, Inc.)

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: Drug-resistant Gram-negative bacteria are a growing threat to children; thus new antibiotics are needed to treat infections caused by these pathogens. Ceftolozane/tazobactam is active against many Gram-negative pathogens and is approved for treatment of complicated intra-abdominal and urinary tract infections in adults, but has not been evaluated in children., Methods: This phase 1, noncomparative, open-label, multicenter study characterized the pharmacokinetics (by noncompartmental analysis), safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients (birth [7 days postnatal] to < 18 years of age) with proven/suspected Gram-negative infection or receiving perioperative prophylaxis (clinicaltrials.gov NCT02266706). Patients were enrolled into 1 of 6 age groups to receive a single, age-based ceftolozane/tazobactam dose, with timed blood sample collection for determining plasma concentrations of ceftolozane and tazobactam. Safety and tolerability were also evaluated., Results: Thirty-seven patients received study drug; 34 were included in the pharmacokinetic population. Ceftolozane and tazobactam pharmacokinetic parameters were generally comparable for patients 3 months to < 18 years of age. Patients from birth (7 days postnatal) to < 3 months of age had lower clearance than older children, likely due to the immature renal function of these young infants. No deaths, study drug-related serious adverse events, or clinically significant laboratory abnormalities were observed after administration of ceftolozane/tazobactam., Conclusions: The doses evaluated in this study yielded ceftolozane/tazobactam exposure levels generally comparable with those in adults. Single doses of ceftolozane/tazobactam were well-tolerated, and no safety concerns were identified. These data informed pharmacokinetic/pharmacodynamic models to derive pediatric dose recommendations for phase 2 ceftolozane/tazobactam clinical trials.

Ceftolozane/tazobactam is an antibacterial approved at 1.5 g (1g/0.5 g) every 8 hours (q8h); higher doses may provide additional benefits in difficult-to-treat infections. We conducted a phase I trial in healthy adults evaluating safety, tolerability, and pharmacokinetics of 3 g (2 g/1 g) ceftolozane/tazobactam administered q8h for 10 days. Sixteen participants were randomized (2:1:1) to 3 g ceftolozane/tazobactam, 1.5 g ceftolozane/tazobactam, or placebo. Participants underwent regular safety and plasma drug level assessments, with a follow-up safety visit 7 days after completion. No adverse events (AEs) were reported with placebo; 75% of participants in the 1.5-g and 50% in the 3-g arm experienced AEs. AE types were similar between the ceftolozane/tazobactam groups; all AEs were mild. No participants experienced clinically meaningful laboratory assessment or electrocardiogram abnormalities. Both ceftolozane and tazobactam exhibited dose-proportional pharmacokinetics without accumulation and without substantial differences in clearance and volume of distribution between groups. In the 3-g group, mean ceftolozane parameters were: peak concentration 104 μg/mL (day 1), 112 μg/mL (day 10); half-life 3 hours (day 10); area under the concentration-time curve (AUC (0-t) ) 272 μg·h/mL (day 1), 300μg·h/mL (day 10). Mean tazobactam parameters were: peak concentration 28 μg/mL (day 1), 26 μg/mL (day 10); half-life 1 hour (day 10); AUC (0-t) 47μg·h/mL (day 1), 41μg·h/mL (day 10). Administration of 3 g ceftolozane/tazobactam q8h for 10 days was safe and well tolerated in healthy volunteers., (© 2018, The American College of Clinical Pharmacology.)