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Background Ceftolozane/tazobactam and ceftazidime/avibactam are commonly used in patients with MDR- Pseudomonas aeruginosa (PSA) pneumonia (PNA). This study compared outcomes between non-COVID-19 hospitalized patients with MDR-PSA PNA who received ceftolozane/tazobactam or ceftazidime/avibactam. Methods The study included non-COVID-19 adult hospitalized patients with MDR-PSA PNA in the PINC AI Healthcare Database (2016–22) who received ceftolozane/tazobactam or ceftazidime/avibactam within 3 days of index culture for ≥2 days. Outcomes were mortality, recurrent MDR-PSA PNA, discharge destination, post-index culture day length of stay (LOS) and costs (in US dollars, USD), and hospital readmission. Results The final sample included 197 patients (117 ceftolozane/tazobactam, 80 ceftazidime/avibactam). No significant differences were observed in mortality and post-index culture LOS and costs between groups. In the multivariable analyses, patients who received ceftolozane/tazobactam versus ceftazidime/avibactam had lower recurrent MDR-PSA PNA (7.9% versus 18.0%, P  = 0.03) and 60 day PNA-related readmissions (11.1% versus 28.5%, P  = 0.03) and were more likely to be discharged home (25.8% versus 9.8%, P  = 0.03). Compared with ceftazidime/avibactam patients, ceftolozane/tazobactam patients had lower adjusted median total antibiotic costs (5052 USD versus 8099 USD, P  = 0.003) and lower adjusted median comparator (ceftolozane/tazobactam or ceftazidime/avibactam) antibiotic costs (3938 USD versus 6441 USD, P  = 0.005). In the desirability of outcome ranking (DOOR) analysis, a ceftolozane/tazobactam-treated patient was more likely to have a more favourable outcome than a ceftazidime/avibactam-treated patient [DOOR probability: 59.6% (95% CI: 52.5%–66.8%)]. Conclusions Early treatment with ceftolozane/tazobactam may offer some clinical and cost benefits over ceftazidime/avibactam in patients with MDR-PSA PNA. Further large-scale studies are necessary to comprehensively understand the outcomes associated with these treatments for MDR-PSA PNA. [ABSTRACT FROM AUTHOR]

Objectives We aimed to compare the stability of the newly developed β-lactams (cefiderocol) and β-lactam/β-lactamase inhibitor combinations (ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam) against the most clinically relevant mechanisms of mutational and transferable β-lactam resistance in Pseudomonas aeruginosa. Methods We screened a collection of 61 P. aeruginosa PAO1 derivatives. Eighteen isolates displayed the most relevant mechanisms of mutational resistance to β-lactams. The other 43 constructs expressed transferable β-lactamases from genes cloned in pUCP-24. MICs were determined by reference broth microdilution. Results Cefiderocol and imipenem/relebactam exhibited excellent in vitro activity against all of the mutational resistance mechanisms studied. Aztreonam/avibactam, cefepime/taniborbactam, cefepime/zidebactam, meropenem/vaborbactam, meropenem/nacubactam and meropenem/xeruborbactam proved to be more vulnerable to mutational events, especially to overexpression of efflux operons. The agents exhibiting the widest spectrum of activity against transferable β-lactamases were aztreonam/avibactam and cefepime/zidebactam, followed by cefepime/taniborbactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam. However, some MBLs, particularly NDM enzymes, may affect their activity. Combined production of certain enzymes (e.g. NDM-1) with increased MexAB-OprM-mediated efflux and OprD deficiency results in resistance to almost all agents tested, including last options such as aztreonam/avibactam and cefiderocol. Conclusions Cefiderocol and new β-lactam/β-lactamase inhibitor combinations show promising and complementary in vitro activity against mutational and transferable P. aeruginosa β-lactam resistance. However, the combined effects of efflux pumps, OprD deficiency and efficient β-lactamases could still result in the loss of all therapeutic options. Resistance surveillance, judicious use of new agents and continued drug development efforts are encouraged. [ABSTRACT FROM AUTHOR]

Ceftolozane, a novel cephalosporin, combined with tazobactam, a known β-lactamase inhibitor, shows robust antipseudomonal activity, although it doesn't cover carbapenemases. Our review of data from 2012 to 2021 in Taiwan highlights TOL/TAZ's in-vitro performance.TOL/TAZ is most effective against Pseudomonas aeruginosa (91.3–94.4 % susceptible, with an MIC

An important intermediate product in the synthesis of ceftolozane, tert-butyl N-(2-{[({1-methyl-5-[(triphenylmethyl)amino]-1H-pyrazol-4-yl}amino)carbonyl]amino}ethyl)carbamate, was obtained in an overall yield of 59.5% via amination, reduction, esterification, trityl protection, and condensation steps starting from 1-methyl-1H-pyrazol-5-amine. The structures of the target product and intermediates in each step were characterized by mass spectrometry, 1H and 13C NMR, and FT-IR spectroscopy. [ABSTRACT FROM AUTHOR]

This single-center study evaluated the efficacy and safety of tazobactam/ceftolozane (TAZ/CTLZ) in combination with metronidazole for intraabdominal infection in a hepato-biliary-pancreatic field in clinical practice. This study included 50 patients, including 35 with intraabdominal abscess or peritonitis, 5 with liver abscess, 4 with cholecystitis, and 6 with cholangitis with sepsis. Of the 50 patients, 29 received TAZ/CTLZ and metronidazole after a prior antibacterial therapy failure, including tazobactam/piperacillin, cefmetazole, and levofloxacin. Source control was performed in 36 patients. The clinical response could be evaluated in 49 patients. The clinical cure rate at end-of-therapy was 91.8% (45 of 49 patients) and that at test-of-cure was 89.6% (43 of 48 patients). Of 5 patients in whom clinical response at test-of-cure was a failure, 1 developed infectious disease during chemoradiotherapy for recurrent cancer and 4 after liver resection or pancreatoduodenectomy. Three of the 4 patients were associated with pancreatic juice leakage. Isolated pathogens were eradicated or presumably eradicated in 27 of 31 (87.1%) patients in whom microbiological response at test-of-cure could be evaluated. The response rate for AmpC-producing Enterobacteriaceae was 87.5%. Nausea was observed in two patients. Aspartate and alanine aminotransferase activities were increased in 3 of the 50 (6.0%) patients. The activities improved after the antibiotic discontinuation. This observational study demonstrated that TAZ/CTLZ in combination with metronidazole has a favorable effect without major drug-related adverse events for intraabdominal infection in the hepato-biliary-pancreatic field in clinical practice although the efficacy of TAZ/CTLZ may decrease in compromised patients. [ABSTRACT FROM AUTHOR]

ABSTRACT: 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.

Background: Gram-negative rods are one of the most commonly isolated bacteria within human infections. These microorganisms are typically opportunistic pathogens that pose a serious threat to public health due to the possibility of transmission in the human population. Resistance to carbapenems is one of the most important antimicrobial resistance mechanisms amongst them. The aim of this study was to evaluate ceftolozane–tazobactam in vitro activity against carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae clinical strains. Information on the antimicrobial activity of this antimicrobial against Gram-negative rods was also supplemented with a brief review of the relevant literature. Methods: The research involved 316 strains of Gram-negative rods: P. aeruginosa—206 and K. pneumoniae—110. Results: Of the tested strains, 86.0% P. aeruginosa and 30.0% K. pneumoniae remained susceptible to ceftolozane–tazobactam. Conclusions: Therefore, ceftolozane–tazobactam might be a good option in the treatment of infections caused by carbapenem-resistant P. aeruginosa strains, including those in ICU patients. Meanwhile, due to dissemination of ESBLs among K. pneumoniae strains, infections with this etiology should not be treated with the ceftolozane–tazobactam combination. [ABSTRACT FROM AUTHOR]

BackgroundOvercoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa.MethodsIn this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer β-lactam/β-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO).ResultsWe found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA).ConclusionsThe diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.

Introduction: Recently, complicated intra-abdominal infections (cIAI) have been caused not only by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa, but also by extended-spectrum β-lactamase-producing Enterobacterales members. Ceftolozane–tazobactam (CTLZ–TAZ) is considered to exhibit therapeutic effects against cIAI. Studies on the concentrations of antibiotics in abdominal tissues directly affected by cIAI are limited. Therefore, in this study, we investigated the pharmacokinetics of CTLZ–TAZ in abdominal tissue and simulated the administration regimen required to achieve the pharmacodynamic target for cIAI-causing bacteria. Methods: Patients scheduled for elective lower gastrointestinal surgery were intravenously administered preoperative CTLZ–TAZ (1 g CTLZ and 0.5 g TAZ). Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected during the surgery, and CTLZ as well as TAZ concentrations were measured. The noncompartmental and compartmental pharmacokinetic parameters were then estimated. Site-specific pharmacodynamic target attainment analysis using 1.5 g of CTLZ–TAZ was performed. Results: CTLZ–TAZ was administered to nine patients (once to five patients and twice to four patients). The mean peritoneal fluid-to-plasma ratio (one dose/two doses) for CTLZ was 0.74/1.15, which was slightly higher than the mean peritoneal fluid-to-plasma ratio for TAZ (0.95/1.13). The ratio for subcutaneous adipose was lower than those for peritoneal fluid and peritoneum tissues. We also discovered that the average ratio of CTLZ and TAZ concentrations in all tissues was maintained at or above 2:1. In our investigation of pharmacodynamic target attainment in each tissue, the desired bactericidal effect was attained with all CTLZ–TAZ (1.5 g) administration regimens [q12h (3 g/day), q8h (4.5 g/day), and q6h (6 g/day)]. Conclusion: To the best of our knowledge, this is the first study investigating the optimal pharmacodynamic level of CTLZ–TAZ in the abdominal tissue against cIAI-causing bacteria. This study also serves as a guideline for designing an optimal administration regimen based on pharmacodynamic target attainment for cIAI-causing bacteria. Details of the trial registration: The institutional review board of Hiroshima University Hospital, CRB6180006. The Japan Registry of Clinical Trials, jRCTs061190025. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background: High-dose cefepime-tazobactam (WCK 4282) is currently under clinical development at a dosage of 2 grams/2 grams every 8 hours with prolonged infusion (90 minutes). Objective: To evaluate the in vitro activity of high-dose cefepime-tazobactam. Methods: A total of 23, 246 gram-negative organisms were collected from 133 medical centers (34 countries) in 2018-2019 and susceptibility was tested by broth microdilution method against cefepime-tazobactam (tazobactam at fixed 8 mg/L) and comparator agents. Results: Cefepime-tazobactam and cefepime inhibited 97.6% and 85.4% of Enterobacterales isolates (n = 18,143) at ≤8 mg/L, respectively. Cefepime-tazobactam activity against Enterobacterales was comparable with meropenem (97.0% susceptible) and greater than ertapenem (95.2% susceptible) or piperacillin-tazobactam (88.0% susceptible). Moreover, cefepime-tazobactam retained potent activity against meropenem-susceptible Enterobacterales isolates that were nonsusceptible to ceftazidime, ceftriaxone, and piperacillin-tazobactam (96.3% inhibited at ≤8 mg/L) or ceftolozane-tazobactam (96.2% inhibited at ≤8 mg/L). Against P. aeruginosa (n = 4,553), the percentage of isolates inhibited at ≤8 mg/L of cefepime-tazobactam (82.7%) was higher than meropenem (76.0%) or piperacillin-tazobactam (76.4%), and the percentage inhibited at the proposed pharmacokinetic/pharmacodynamic breakpoint of ≤16 mg/L (92.2%) was comparable with ceftolozane-tazobactam (93.5%). Conclusions: The results of this in vitro study support the clinical development of cefepime-tazobactam as a carbapenem-sparing option to treat infections caused by Enterobacterales and P. aeruginosa, including multidrug-resistant isolates.

• Phase III study of ceftolozane/tazobactam (C/T) plus metronidazole for complicated intra-abdominal infection in China. • C/T plus metronidazole was noninferior to meropenem for clinical response. • Safety was comparable between C/T plus metronidazole and meropenem groups. • C/T plus metronidazole had efficacy against extended-spectrum β-lactamase-positive Enterobacterales. 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. 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. 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. In Chinese adult participants with cIAI, C/T plus metronidazole was noninferior to meropenem, with comparable safety. [ABSTRACT FROM AUTHOR]

Background: Gram-negative rods are one of the most commonly isolated bacteria within human infections. These microorganisms are typically opportunistic pathogens that pose a serious threat to public health due to the possibility of transmission in the human population. Resistance to carbapenems is one of the most important antimicrobial resistance mechanisms amongst them. The aim of this study was to evaluate ceftolozane–tazobactam in vitro activity against carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae clinical strains. Information on the antimicrobial activity of this antimicrobial against Gram-negative rods was also supplemented with a brief review of the relevant literature. Methods: The research involved 316 strains of Gram-negative rods: P. aeruginosa—206 and K. pneumoniae—110. Results: Of the tested strains, 86.0% P. aeruginosa and 30.0% K. pneumoniae remained susceptible to ceftolozane–tazobactam. Conclusions: Therefore, ceftolozane–tazobactam might be a good option in the treatment of infections caused by carbapenem-resistant P. aeruginosa strains, including those in ICU patients. Meanwhile, due to dissemination of ESBLs among K. pneumoniae strains, infections with this etiology should not be treated with the ceftolozane–tazobactam combination.

• High-dose cefepime-tazobactam is under clinical development • A total of 23,246 organisms from 133 medical centers in 34 countries were tested • Cefepime-tazobactam inhibited 97.6% of Enterobacterales at ≤8 mg/L • Cefepime-tazobactam activity against Enterobacterales was comparable with meropenem • Cefepime-tazobactam inhibited 96.2% of P. aeruginosa at ≤8 mg/L High-dose cefepime-tazobactam (WCK 4282) is currently under clinical development at a dosage of 2 grams/2 grams every 8 hours with prolonged infusion (90 minutes). To evaluate the in vitro activity of high-dose cefepime-tazobactam. A total of 23, 246 gram-negative organisms were collected from 133 medical centers (34 countries) in 2018-2019 and susceptibility was tested by broth microdilution method against cefepime-tazobactam (tazobactam at fixed 8 mg/L) and comparator agents. Cefepime-tazobactam and cefepime inhibited 97.6% and 85.4% of Enterobacterales isolates (n = 18,143) at ≤8 mg/L, respectively. Cefepime-tazobactam activity against Enterobacterales was comparable with meropenem (97.0% susceptible) and greater than ertapenem (95.2% susceptible) or piperacillin-tazobactam (88.0% susceptible). Moreover, cefepime-tazobactam retained potent activity against meropenem-susceptible Enterobacterales isolates that were nonsusceptible to ceftazidime, ceftriaxone, and piperacillin-tazobactam (96.3% inhibited at ≤8 mg/L) or ceftolozane-tazobactam (96.2% inhibited at ≤8 mg/L). Against P. aeruginosa (n = 4,553), the percentage of isolates inhibited at ≤8 mg/L of cefepime-tazobactam (82.7%) was higher than meropenem (76.0%) or piperacillin-tazobactam (76.4%), and the percentage inhibited at the proposed pharmacokinetic/pharmacodynamic breakpoint of ≤16 mg/L (92.2%) was comparable with ceftolozane-tazobactam (93.5%). The results of this in vitro study support the clinical development of cefepime-tazobactam as a carbapenem-sparing option to treat infections caused by Enterobacterales and P. aeruginosa, including multidrug-resistant isolates. [ABSTRACT FROM AUTHOR]

We describe a case of a 48 years old male with left sided endocarditis and septic emboli secondary to a Pseudomonas aeruginosa strain that developed resistance to other β-lactam antibiotics during therapy resulting in prolonged bacteremia. Blood cultures sterilized within 1 day of initiating ceftolozane/tazobactam 3 g every 8 hours in combination with ciprofloxacin. Steady state free ceftolozane plasma Cmax and Cmin concentrations were calculated to be 122.2μg/mL and 24.3μg/mL, respectively. The multidrug-resistant strain harbored chromosomal β-lactamases OXA-486 and PDC-3, mutations in ampD and dacB predicted to lead to ampC over-expression, and mutations in OprD predicted to decrease outer membrane permeability. Following completion of a 42 day course and aortic valve replacement, the patient was deemed clinically cured without recurrence of infection at follow up 2 years later. To our knowledge, this is the first reported case to measure ceftolozane concentrations during the treatment of endocarditis which supports dose optimization approaches of severe endovascular disease due to multidrug resistant pathogens. [ABSTRACT FROM AUTHOR]

Cephalosporins are beta-lactam antibiotics classified into five generations. The newest generation has three representatives: ceftaroline fosamile, the combination ceftolozane/tazobactam (cephalosporin/beta-lactamase inhibitor), and ceftobiprole medocaril. These new cephalosporins are valuable anti-infective agents, with potent activity against multidrug-resistant bacteria, and with a positive balance between benefits and side effects. However, the fifth-generation cephalosporins should be judiciously used to prevent the occurrence of bacterial resistance phenomenon.

Abstract Background Extracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units and can modify drug pharmacokinetics and lead to under-exposure associated with treatment failure. Ceftolozane/tazobactam is an antibiotic combination used for complicated infections in critically ill patients. Launched in 2015, sparse data are available on the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam. The aim of the present study was to determine the influence of ECMO on the pharmacokinetics of ceftolozane-tazobactam. Methods An ex vivo model (closed-loop ECMO circuits primed with human whole blood) was used to study adsorption during 8-h inter-dose intervals over a 24-h period (for all three ceftolozane/tazobactam injections) with eight samples per inter-dose interval. Two different dosages of ceftolozane/tazobactam injection were studied and a control (whole blood spiked with ceftolozane/tazobactam in a glass tube) was performed. An in vivo porcine model was developed with a 1-h infusion of ceftolozane–tazobactam and concentration monitoring for 11 h. Pigs undergoing ECMO were compared with a control group. Pharmacokinetic analysis of in vivo data (non-compartmental analysis and non-linear mixed effects modelling) was performed to determine the influence of ECMO. Results With the ex vivo model, variations in concentration ranged from − 5.73 to 1.26% and from − 12.95 to − 2.89% respectively for ceftolozane (concentrations ranging from 20 to 180 mg/l) and tazobactam (concentrations ranging from 10 to 75 mg/l) after 8 h. In vivo pharmacokinetic exploration showed that ECMO induces a significant decrease of 37% for tazobactam clearance without significant modification in the pharmacokinetics of ceftolozane, probably due to a small cohort size. Conclusions Considering that the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam is not clinically significant, normal ceftolozane and tazobactam dosing in critically ill patients should be effective for patients undergoing ECMO.

Background: The emergence of antibiotic resistance is increasing and there are few effective antibiotics to treat infections caused by resistant and multidrug resistant bacterial pathogens. This study aimed to evaluate the in vitro activity of ceftolozane–tazobactam against clinical bacterial isolates from Brazil. Methods: A total of 673 Gram-negative bacterial isolates including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and other Enterobacterales collected from 2016 to 2017 were tested, most of them isolated from patients in intensive care units. Minimum inhibitory concentrations (MIC50/90) were determined by broth microdilution for amikacin, aztreonam, cefepime, cefotaxime, cefoxitin, ceftolozane–tazobactam, ceftazidime, ceftriaxone, ciprofloxacin, colistin, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam using dried panels. Antimicrobial susceptibility results were interpreted according to Clinical and Laboratory Standards Institute criteria. Results: Susceptibility rates to ceftolozane–tazobactam ranged from 40.4% to 94.9%. P. aeruginosa susceptibility rate to ceftolozane–tazobactam was 84.9% (MIC50/90, 1/16 μg/mL) and 99.2% to colistin. For E. coli, ceftolozane–tazobactam inhibited 94.9% (MIC50/90, 0.25/1 μg/mL) of the microorganisms. The susceptibility rate of K. pneumoniae to ceftolozane–tazobactam was 40.4% (MIC50/90, 16/>32 μg/mL). Other Enterobacterales have shown susceptibility rates of 81.1% (MIC50/90, 0.5/16 μg/mL) to ceftolozane–tazobactam, 93.9% to meropenem, 90.9% to amikacin (90.9%), and 88.6% to ertapenem. In non-carbapenemase producing isolates, AmpC mutations were found three isolates. Conclusions: Ceftolozane–tazobactam has shown relevant activity against a large variety of the analyzed microorganisms collected from multiple centers in Brazil, showing promising results even in multidrug resistant strains.

Objective: To evaluate the cost-effectiveness of ceftolozane/tazobactam + metronidazole (C/T+M) and ceftolozane/tazobactam (C/T) compared with 8 alternatives used in the treatment of complicated intraabdominal infection (cIAI) and complicated urinary tract infection (cUTI) respectively. Methods: A Monte Carlo simulation decision model was used for the estimation and comparison of treatment-related costs, and quality adjusted life years for patients with cIAI treated with C/T+M in comparison with cefepime + metronidazole, ciprofloxacin + metronidazole, doripenem, levofloxacin + metronidazole, meropenem, piperacillin/tazobactam, ceftazidime + metronidazole or imipenem/cilastatin and patients with cUTI treated with C/T in comparison with cefepime, ciprofloxacin, doripenem, levofloxacin, meropenem, piperacillin/tazobactam, ceftazidime or imipenem/cilastatin. Local costs were estimated using base cases identified by experts and consulting local databases. Sensitivity values of the PACTS (Program to Assess Ceftolozane/Tazobactam Susceptibility) study in Latin America were used in the model. Results: C/T+M and C/T obtained incremental cost-effectiveness ratios (ICER) that were below the Colombian cost-effectiveness threshold (3 GDP per capita) in most comparisons, and were dominated by meropenem, considering only gram-negative microorganisms. Sensitivity assessments were also carried out, in which only the population with P. aeruginosa infections was considered, showing positive results for C/T+M and C/T (cost-effective or dominant with regards to all comparators). Conclusions: C/T+M and C/T could be cost-effective alternatives in the treatment of CIAI and CUTI in Colombia, when there is an adequate and rational use of antibiotics. The results of the sensitivity analyses showed dominance and cost-effectiveness with regards to every comparator in patients infected with P. aeruginosa

Ceftolozane, a novel cephalosporin, combined with tazobactam, a known β-lactamase inhibitor, shows robust antipseudomonal activity, although it doesn't cover carbapenemases. Our review of data from 2012 to 2021 in Taiwan highlights TOL/TAZ's in-vitro performance. TOL/TAZ is most effective against Pseudomonas aeruginosa (91.3-94.4 % susceptible, with an MIC <4 μg/mL). It also demonstrates good activity against Enterobacterales , including Escherichia coli (88-94.3 % susceptible), Klebsiella pneumoniae (72.6-84.1 % susceptible), Citrobacter koseri (93.3 % susceptible), Klebsiella oxytoca (98.1-100 % susceptible), and Proteus mirabilis (100 % susceptible). However, its efficacy varies among species typically associated with chromosomally-mediated AmpC production, such as Morganella morganii (100 % susceptible), Serratia marcescens (81.3-90.0 % susceptible), Enterobacter cloacae species complex (76.6-76.7 % susceptible), Klebsiella aerogenes (66.7-89.6% susceptible), and Citrobacter freundii (60.0 % susceptible). For carbapenem-nonsusceptible isolates, TOL/TAZ is less effective against K. pneumoniae and E. coli (susceptibility <10 %) but remains useful for P. aeruginosa (susceptibility 81.3-91.8 %). In conclusion, TOL/TAZ shows potent activity against P. aeruginosa and carbapenem-susceptible Enterobacterales in Taiwan., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Extended‐spectrum β‐lactamase (ESBL)‐producing Enterobacterales are a global threat to public health due to their antimicrobial resistance profile and, consequently, their limited available treatment options. Tazobactam is a sulfone β‐lactamase inhibitor with in vitro inhibitory activity against common ESBLs in Enterobacterales, including CTX‐M. However, the role of tazobactam‐based combinations in treating infections caused by ESBL‐producing Enterobacterales remains unclear. In the United States, two tazobactam‐based combinations are available, piperacillin‐tazobactam and ceftolozane‐tazobactam. We evaluated and compared the roles of tazobactam‐based combinations against ESBL‐producing organisms with emphasis on pharmacokinetic/pharmacodynamic exposures in relation to MIC distributions and established breakpoints, clinical outcomes data specific to infection site, and considerations for downstream effects with these agents regarding antimicrobial resistance development. While limited data with ceftolozane‐tazobactam are encouraging for its potential role in infections due to ESBL‐producing Enterobacterales, further evidence is needed to determine its place in therapy. Conversely, currently available microbiologic, pharmacokinetic, pharmacodynamic, and clinical data do not suggest a role for piperacillin‐tazobactam, and we caution clinicians against its usage for these infections. [ABSTRACT FROM AUTHOR]