fr-264205 and Pneumonia

Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients.. This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by non-compartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: ≥30% and ≥20% of the dosing interval, respectively).. Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam Tmax (6 and 2 h, respectively) were delayed in ELF compared with plasma (1 h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1 mg/L, respectively, for 100% of the dosing interval. There were no deaths or adverse event-related study discontinuations.. In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens.

Topics: Anti-Bacterial Agents; Cephalosporins; Critical Illness; Humans; Lung; Pneumonia; Tazobactam

Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.

Topics: Adult; Anti-Bacterial Agents; Bronchoalveolar Lavage Fluid; Cephalosporins; Cross Infection; Drug Combinations; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Penicillanic Acid; Pneumonia; Tazobactam; Young Adult

To evaluate the in-vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and comparator agents against contemporary Pseudomonas aeruginosa isolates from US hospitals.. In total, 3184 isolates were collected consecutively from 71 US medical centres in 2020-2021, and susceptibility tested by reference broth microdilution. Clinical Laboratory Standard Institute breakpoints were applied.. Ceftazidime-avibactam [97.0% susceptible (S)], ceftolozane-tazobactam (98.0%S), imipenem-relebactam (97.3%S) and tobramycin (96.4%S) were the most active agents against the aggregate P. aeruginosa isolate collection, and retained good activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and multi-drug-resistant (MDR) isolates. All other antimicrobials tested showed limited activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and MDR isolates. The most common infections were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (17.0%) and bloodstream infections (11.7%); ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam showed consistent activity against isolates from these infection types. Susceptibility to piperacillin-tazobactam and meropenem was lower among isolates from pneumonia compared with other infection types.. Ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam were highly active, and exhibited similar coverage against a large contemporary collection of P. aeruginosa isolates from US hospitals. Cross-resistance among the newer β-lactams/β-lactam inhibitors (BL/BLIs) varied markedly; ≥72.1% of isolates resistant to one of the three newer BL/BLIs approved for P. aeruginosa treatment remained susceptible to at least one of the other two BL/BLIs, indicating that all three should be tested in the clinical laboratory. These three BL/BLIs represent valuable therapeutic options for P. aeruginosa infection.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporins; Drug Combinations; Hospitals; Humans; Imipenem; Lactams; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To report on the activity of ceftolozane-tazobactam and comparators against Pseudomonas aeruginosa isolates collected from hospitalized patients with pneumonia in US intensive care units (ICUs) between 2015 and 2018. Activity against all P. aeruginosa and common resistant phenotypes are described to better inform decision-making and support antimicrobial stewardship efforts.. In total, 781 P. aeruginosa isolates were collected from 28 US hospitals. These isolates were tested for susceptibility to ceftolozane-tazobactam and comparators by Clinical and Laboratory Standards Institute (CLSI) broth microdilution methodology using CLSI (2020) breakpoints. Phenotypes analysed included piperacillin-tazobactam-non-susceptible (NS), cefepime-NS, ceftazidime-NS, meropenem-NS and difficult-to-treat resistance (DTR).. Ceftolozane-tazobactam was the most potent agent tested (minimum inhibitory concentration to inhibit 50% and 90% of isolates of 0.5 and 2 mg/L, respectively, inhibiting 97.2% at the susceptible breakpoint of ≤4 mg/L). Traditional first-line antipseudomonal β-lactam antibiotics (piperacillin-tazobactam, cefepime and ceftazidime) demonstrated <33% susceptibility when P. aeruginosa was NS to one or more agent. Although escalation of therapy to meropenem is commonly employed clinically, meropenem susceptibility ranged from 33.6% to 44.9% if P. aeruginosa was NS to any traditional first-line antipseudomonal β-lactam agent. Conversely, ceftolozane-tazobactam remained active against isolates that were NS to other agents, inhibiting 88.4% of isolates NS to piperacillin-tazobactam, 85.0% of isolates NS to cefepime and ceftazidime, and 90.3% of isolates NS to meropenem. Ceftolozane-tazobactam also maintained activity against 73.0% of DTR isolates.. Ceftolozane-tazobactam maintained high activity against P. aeruginosa isolated from hospitalized patients with pneumonia in US ICUs, and had the greatest activity against isolates NS to one or more antipseudomonal β-lactams and DTR isolates.

Topics: Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Humans; Intensive Care Units; Microbial Sensitivity Tests; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; United States

Topics: Cephalosporins; Cross Infection; Double-Blind Method; Humans; Meropenem; Pneumonia; Tazobactam