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Introduction Colistin is used to treat severe antibiotic-resistant Gram-negative infections (GNIs). With the rise of antibiotic resistance, colistin has been used increasingly as a ‘last-line’ therapy for multidrug-resistant GNIs. We evaluated the incidence of acute kidney injury (AKI) and mortality among patients receiving colistin or one of the new β-lactam/β-lactamase inhibitors (βL + βLI) (ceftazidime/avibactam, ceftolozane/tazobactam, or meropenem/vaborbactam). Methods This retrospective cohort study used data from the Premier Healthcare Database. The cohort included propensity score-matched adults with an inpatient stay between January 2016 and December 2018. Patients given both colistin and BL + BLI as treatment for ≥ 72 h were excluded. AKI was defined as acute renal failure or dialysis during hospitalization with antibiotic administration. Propensity score matching was used to control for selection bias and confounding. Logistic regression evaluated associations between treatment, AKI, and in-hospital mortality. Results The total number of patients in the matched cohorts were 256 in each. Overall, 23.8% and 13.3% of patients receiving colistin or new βL + βLI agents, respectively, experienced AKI during hospitalization (p = 0.002); odds of AKI for colistin were 3.0 (95% CI 1.71, 5.21). Following propensity score-matching, patients without baseline renal disease experienced AKI during hospitalization to a higher degree in the colistin group compared to the βL + βLI group (17.1% vs. 6.8%); colistin use was associated with 3.7 times higher odds (95% CI 1.84, 7.42) of AKI compared to βL + βLI agents. The odds of mortality in patients on colistin developing AKI were more than three times that of patients receiving a BL + BLI agent who developed AKI. Among patients receiving colistin, incident AKI was associated with 6.1 times higher odds (95% CI 2.53, 14.71) of mortality. Conclusions Patients receiving colistin for GNIs had significantly higher odds of AKI and mortality than those receiving βL + βLI. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00556-x.

Introduction Gram-negative nosocomial pneumonia (NP), including hospital-acquired bacterial pneumonia (HABP), ventilated HABP (vHABP), and ventilator-associated bacterial pneumonia (VABP), is a significant cause of morbidity and mortality. Common pathogens, including Enterobacterales and Pseudomonas aeruginosa, are prevalent in healthcare settings and have few effective treatment options due to high rates of antibacterial resistance. Resistant pathogens are associated with significantly worse outcomes, relative to patients with susceptible infections. Ceftolozane/tazobactam (C/T) has established efficacy in clinical trials of patients with NP. This review aims to collate data on C/T use for HABP/vHABP/VABP infections in real-world clinical practice. Methods This systematic literature review searched online biomedical databases for real-world studies of C/T used to treat Gram-negative respiratory tract infections (RTIs) between January 2009 and June 2020. Results Thirty-three studies comprising 658 patients were identified. Pneumonia was the most common infection treated with C/T (85%), with a smaller number of unspecified RTIs (9%) and tracheobronchitis (5%) reported. The majority of patients had respiratory infections caused by P. aeruginosa (92.8%), of which 88.1% were multidrug-resistant. Examination of these studies demonstrated an increase in the percentage of patients receiving the recommended dose of C/T for respiratory infections (3 g q8h or renal impairment-adjusted) over time (36.8% of patients in 2017 to 71.5% in 2020). Clinical success rates ranged from 51.4 to 100%, with 10 studies (55.6% of studies reporting clinical success) reporting clinical success rates of > 70%; microbiological success rates ranged from 57.0 to 100.0%, with three studies (60.0% of studies reporting microbiological success) reporting microbiological success rates of > 70%. Thirty-day mortality ranged from 0.0 to 33.0%, with nine studies (90% of studies reporting mortality) reporting 30-day mortality of

Introduction The clinical efficacy and safety of ceftolozane/tazobactam for the treatment of ventilated hospital-acquired bacterial pneumonia (vHABP) and ventilator-associated bacterial pneumonia (VABP) has been demonstrated in the phase III randomised controlled trial ASPECT-NP. However, there are no published data on the cost-effectiveness of ceftolozane/tazobactam for vHABP/VABP. These nosocomial infections are associated with high rates of morbidity and mortality, and are increasingly complicated by growing rates of resistance and the inappropriate use of antimicrobials. This study is to assess the cost-effectiveness of ceftolozane/tazobactam compared with meropenem for the treatment of vHABP/VABP in a US hospital setting. Methods A short-term decision tree followed by a long-term Markov model was developed to estimate lifetime costs and quality-adjusted life-years associated with ceftolozane/tazobactam and meropenem in the treatment of patients with vHABP/VABP. Pathogen susceptibility and clinical efficacy were informed by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database and ASPECT-NP, respectively. A US healthcare sector perspective was adopted, capturing direct costs borne by third-party payers or integrated health systems, and direct health effects for patients. Results In the confirmed treatment setting (post-susceptibility results), the incremental cost-effectiveness ratio for ceftolozane/tazobactam compared to meropenem was US$12,126 per quality-adjusted life-year (QALY); this reduced when used in the early treatment setting (before susceptibility results) at $4775/QALY. Conclusion Ceftolozane/tazobactam represents a highly cost-effective treatment option for patients with vHABP/VABP versus meropenem when used in either the confirmed or early treatment setting; with increased cost-effectiveness shown in the early setting. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00436-4.

Introduction Hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP) are associated with significant healthcare resource utilization (HCRU). This a priori, exploratory, secondary analysis from the ASPECT-NP clinical trial evaluated resource utilization among patients with ventilated HABP (vHABP)/VABP treated with ceftolozane/tazobactam or meropenem. Methods This analysis used data from the randomized, double-blind, noninferiority phase 3 ASPECT-NP trial of patients with vHABP/VABP randomized to receive ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) or meropenem 1 g for 8–14 days. Day 28 outcomes included hospital length of stay (LOS), intensive care unit (ICU) LOS, and time to mechanical ventilation extubation in the microbiological intention-to-treat (mITT) population and in an HCRU population. The HCRU population, a subset of patients from the mITT population that were alive at day 28, was used to remove resource use bias influenced by mortality rates. Results Ceftolozane/tazobactam-treated versus meropenem-treated patients, respectively, had fewer deaths (20.1% vs. 25.5%), fewer hospital discharges (30.7% vs. 32.4%), and higher ICU discharges (60.0% vs. 58.3%) and extubations (51.9% vs. 48.2%) by day 28. In the HCRU population, adjusted LOS differences (95% confidence intervals) for ceftolozane/tazobactam compared with meropenem were 0.1 (− 1.4 to 1.6) hospitalization days, − 1.4 (− 2.9 to 0.2) ICU days, and − 0.9 (− 2.4 to 0.7) mechanical ventilation days. Patterns were similar among the VABP and Pseudomonas aeruginosa subgroups. Conclusion Similar 28-day resource utilization outcomes were observed between ceftolozane/tazobactam and meropenem in the mITT population of patients from ASPECT-NP with vHABP/VABP due to gram-negative pathogens. ASPECT-NP was not powered to detect differences in resource utilization outcomes between treatment groups; however, numerical differences in ICU LOS and duration of mechanical ventilation were noted. Further study is needed to assess resource utilization in the real-world practice setting, especially among patients excluded from ASPECT-NP, including those with resistant P. aeruginosa infections. Trial Registrations ClinicalTrials.gov: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11. Electronic supplementary material The online version of this article (10.1007/s40121-020-00343-0) contains supplementary material, which is available to authorized users.

Introduction Mucoid Pseudomonas aeruginosa (MP) strains in cystic fibrosis (CF) patients are thought to initiate the chronic infection stage of CF and are associated with pulmonary function decline. Objectives The purpose of this study was to assess the susceptibility of MP strains to ceftolozane/tazobactam and the efficacy of ceftolozane/tazobactam against MP strains compared with those for standard-of-care antipseudomonal antibiotics. Methods Ten clinical isolates of MP from CF patients were tested for susceptibility with Etest and time–kill analysis with ceftolozane/tazobactam compared with ceftazidime, cefepime, ciprofloxacin, meropenem, tobramycin, and polymyxin B. The physiologic free peak concentrations were used in the time–kill experiments. Results Ceftolozane/tazobactam minimum inhibitory concentrations ranged from 0.032 to 1.5 mg/L. In the time–kill analysis, the mean starting inoculum for the isolates was 6.29 ± 0.22 log10 colony forming units (CFU) per milliliter. On average, ceftolozane/tazobactam, cefepime, ciprofloxacin, meropenem, tobramycin, and polymyxin B all demonstrated bactericidal activity. With all isolates taken into account, polymyxin B, tobramycin, meropenem, and ceftolozane/tazobactam 3 g were the most potent, with reductions in inoculum of 5.07 ± 0.45, 4.58 ± 2.2, 4.76 ± 0.71, and 4.17 ± 0.94 log10 CFU/mL, respectively. Ceftolozane/tazobactam 1.5 g, cefepime, and ciprofloxacin reduced the starting inoculum by 3.74 ± 0.99, 3.42 ± 1.4, and 3.23 ± 2.0 log10 CFU/mL, respectively. Despite 90% susceptibility, ceftazidime was bactericidal against seven of ten strains, with an average reduction in starting inoculum of 2.91 ± 2.2 log10 CFU/mL. Conclusion Ceftolozane/tazobactam activity against MP strains derived from CF patients was comparable to that of standard-of-care agents at both the 1.5-g dose and the 3-g dose. Further in vitro modeling and clinical trials are warranted.

Introduction Ceftolozane/tazobactam is an antibacterial agent with potent in vitro activity against Gram-negative pathogens, including many extended-spectrum β-lactamase-producing Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa. Because ceftolozane/tazobactam is primarily excreted renally, appropriate dose adjustments are needed for patients with renal impairment. Monte Carlo simulations were used to determine the probability of pharmacokinetic/pharmacodynamic target attainment for patients with varying degrees of renal function, including augmented renal clearance (ARC) and end-stage renal disease (ESRD) with hemodialysis. Methods Monte Carlo simulations were conducted for 1000 patients with ARC and normal renal function, mild renal impairment, moderate renal impairment, or severe renal impairment, and for 5000 patients with ESRD. Simulated dosing regimens were based on approved doses for each renal function category. Attainment targets for ceftolozane were 24.8% (bacteriostasis), 32.2% (1-log kill; bactericidal), and 40% (2-log kill) fT > minimum inhibitory concentration (MIC). The target for tazobactam was to achieve a 20% fT > minimum effective concentration (MEC) at an MEC of 1 mg/L, which was derived from a neutropenic mouse thigh infection model and was confirmed by efficacy data from clinical studies for complicated intraabdominal infections and complicated urinary tract infections. Results In patients with ARC or normal renal function, ≥91% achieved bactericidal activity (32.2% fT > MIC) up to an MIC of 4 mg/L with a 1000-mg ceftolozane dose. In patients with renal impairment (mild, moderate, severe, ESRD), ≥93% achieved bactericidal activity up to an MIC of 8 mg/L. In patients of all renal function categories, the approved dosing regimens of tazobactam achieved ≥91% target attainment against a target of 20% fT > MEC. Conclusions At the approved dosing regimens for ceftolozane/tazobactam, ≥91% of patients in all renal function categories, including ARC (up to 200 mL/min) and ESRD, reached target attainment for bactericidal activity at MICs that correspond to susceptibility breakpoints for Enterobacteriaceae and P. aeruginosa.

Introduction Ceftolozane/tazobactam (C/T) is a novel antibiotic approved for complicated intra-abdominal and urinary tract infections caused by Gram-positive and Gram-negative organisms, including some MDR strains. Little is known about the use of this agent for treatment of bacteremia and even less so about the appropriateness of the renally defined regimens. We describe a case of a 66-year-old man with a history of chronic kidney disease (baseline Cr = 3–4 mg/dl) and recurrent nephrolithiasis with bilateral stents who had positive concurrent urine and blood cultures for MDR Pseudomonas aeruginosa (PSA), susceptible only to amikacin and colistin. Due to the MDR phenotype and his underlying kidney disease, the 375 mg (250 mg/125 mg) dose of C/T was given as monotherapy every 8 h for his bloodstream infection. Methods Once steady state was anticipated, blood was obtained at the end of infusion (1 h), and at 3, 5 and 8 h for drug concentration determination using a validated high-performance liquid chromatography method at the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford. Results The minimum inhibitory concentration (MIC) for the PSA was 2/4 for C/T, indicating susceptibility. Concentration of ceftolozane of 21.87 µg/ml at 8 h indicated that serum concentrations were maintained above the MIC throughout the dosing interval. The patient was given 25 days of C/T and experienced a successful clinical outcome. Blood cultures obtained at 1 and 3 weeks after completion of treatment remained sterile. No adverse events were attributed to C/T. Conclusion In this patient, the renally adjusted dose of C/T was safe and provided sufficiently high drug concentrations that exceeded the MIC of the infecting organism over the course of therapy. More data are required to determine the clinical utility of C/T in the setting of MDR PSA bacteremia.

Introduction Gram-negative multi-drug resistance is an emerging threat among pediatric patients with cystic fibrosis (CF). Ceftolozane/tazobactam (C/T) is an extended-spectrum cephalosporin/beta-lactamase inhibitor combination that has been shown to maintain activity against MDR P. aeruginosa isolates. The understanding of C/T effectiveness in pediatric patients is extremely limited. Minimum inhibitory concentration (MIC) testing and time-kill analyses were performed to better understand the antimicrobial susceptibility and potential role of C/T. Methods Non-duplicate clinical respiratory MDR P. aeruginosa isolates (n = 5) from four pediatric CF patients were identified. MICs were determined for these isolates using CLSI broth microdilution methods. Time-kill analyses were performed using multiples of C/T alone, and combinations of C/T 2× and 8× the MIC with 30 mg/L tobramycin or 80 mg/L amikacin for all isolates. Cell counts were determined by serial dilution plating. Results Isolates had variable susceptibilities to C/T (range 0.5–8 mg/L), tobramycin (range 2 to >64 mg/L) and amikacin (range 8 to >256 mg/L). Time-kill analyses revealed an average of 0.71 (range −0.6 to 4.4), 1.50 (range 0.8–2.0) and 2.1 (range 1.2–3.4) log-kill at 4×, 8× and 16× the C/T MIC, respectively. At a tobramycin MIC of 32 mg/L, combination therapy showed synergistic benefit when the isolate was C/T susceptible. C/T and amikacin combination therapy showed synergistic activity at an amikacin MIC >256 mg/L when C/T MIC was 2 mg/L (4.7 log-kill at 2× C/T MIC and 4.0 log-kill at 8× C/T MIC). Conclusion C/T appears to be a promising treatment option for treatment of MDR P. aeruginosa in pediatric CF patients, both alone and in combination with tobramycin or amikacin. Interestingly, the benefit of C/T combination therapy with amikacin may be more pronounced than with the addition of tobramycin. Further evaluation of such combination regimens in pediatric CF patients is warranted.