fr-264205 and Gram-Negative-Bacterial-Infections

Decisions regarding empirical antimicrobial therapy for complicated intra-abdominal infections (cIAIs) are increasingly difficult because of the threat of antimicrobial resistance. Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are a particular challenge, as is multidrug-resistant (MDR) Pseudomonas aeruginosa, both of which are encountered in cIAI. Ceftolozane/tazobactam is a new antimicrobial that provides an effective solution for treating cIAI.. Evidence concerning the mechanism of action of ceftolozane/tazobactam, its in vitro activity against common cIAI pathogens, and pharmacokinetic and pharmacodynamic properties are reviewed. The clinical efficacy and safety of ceftolozane/tazobactam plus metronidazole, as determined by the Phase II and III clinical trials in hospitalized adults with cIAI, are discussed.. Ceftolozane/tazobactam has demonstrated efficacy and safety in patients with cIAI, including those who are infected with ESBL-producing Enterobacteriaceae and P. aeruginosa. High rates of clinical cure by ceftolozane/tazobactam in Phase II and III trials suggest that this antimicrobial will be valuable for treating infections caused by MDR Gram-negative bacteria. In recent years, clinicians have become dependent on carbapenems for treating MDR infections. There is concern that this could lead to emergence of carbapenem-resistant strains, emphasizing the importance of antimicrobial stewardship. Ceftolozane/tazobactam appears to be an effective carbapenem-sparing alternative for treating cIAI.

Topics: Anti-Bacterial Agents; Cephalosporins; Clinical Trials, Phase III as Topic; Drug Combinations; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Intraabdominal Infections; Penicillanic Acid; Tazobactam

Ceftolozane is a novel cephalosporin currently being developed with the β-lactamase inhibitor tazobactam for the treatment of complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), and ventilator-associated bacterial pneumonia (VABP). The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity. As a β-lactam, its mechanism of action is the inhibition of penicillin-binding proteins (PBPs). Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases (e.g., TEM-1 and SHV-1), but, similar to other oxyimino-cephalosporins such as ceftazidime and ceftriaxone, it is compromised by extended-spectrum β-lactamases (ESBLs) and carbapenemases. The addition of tazobactam extends the activity of ceftolozane to include most ESBL producers as well as some anaerobic species. Ceftolozane is distinguished from other cephalosporins by its potent activity versus Pseudomonas aeruginosa, including various drug-resistant phenotypes such as carbapenem, piperacillin/tazobactam, and ceftazidime-resistant isolates, as well as those strains that are multidrug-resistant (MDR). Its antipseudomonal activity is attributed to its ability to evade the multitude of resistance mechanisms employed by P. aeruginosa, including efflux pumps, reduced uptake through porins and modification of PBPs. Ceftolozane demonstrates linear pharmacokinetics unaffected by the coadministration of tazobactam; specifically, it follows a two-compartmental model with linear elimination. Following single doses, ranging from 250 to 2,000 mg, over a 1-h intravenous infusion, ceftolozane displays a mean plasma half-life of 2.3 h (range 1.9-2.6 h), a steady-state volume of distribution that ranges from 13.1 to 17.6 L, and a mean clearance of 102.4 mL/min. It demonstrates low plasma protein binding (20 %), is primarily eliminated via urinary excretion (≥92 %), and may require dose adjustments in patients with a creatinine clearance <50 mL/min. Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic-pharmacodynamic index that is best correlated with ceftolozane's in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen (%fT >MIC), as expected of β-lactams

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacterial Infections; Humans; Penicillanic Acid; Tazobactam

High rates of morbidity and mortality have been linked to the emergence of antimicrobial-resistant Gram-negative pathogens, especially in the hospital setting. Infections due to extended-spectrum-β-lactamase producing Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae) and multidrug-resistant Pseudomonas aeruginosa pose a major health threat and dramatically reduce the therapeutic options to achieve an appropriate treatment. There is a need for novel antimicrobials that could provide clinical efficacy toward multidrug-resistant Gram-negative pathogens, including extended-spectrum-β-lactamase and carbapenemase producers. Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin associated with a well-established β-lactamase inhibitor currently in clinical development for the treatment of complicated intra-abdominal infections, complicated urinary tract infections and nosocomial pneumonia. Phase II and III trials have shown high efficacy and good tolerability in complicated urinary and intra-abdominal infections compared with standard therapy. A study for the treatment of nosocomial pneumonia is planned.

Topics: Animals; beta-Lactamase Inhibitors; Cephalosporins; Clinical Trials as Topic; Enterobacteriaceae; Escherichia coli; Gram-Negative Bacterial Infections; Humans; Intraabdominal Infections; Investigational New Drug Application; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Penicillanic Acid; Pseudomonas aeruginosa; Tazobactam; Treatment Outcome; Urinary Tract Infections

We evaluated in vitro activity of ceftolozane-tazobactam (TOL-TAZ), formerly CXA-201, against recent clinical anaerobic isolates with emphasis on the Bacteroides fragilis group. Ceftolozane-tazobactam showed good activity against B. fragilis species and intermediate to limited activity against other species of Bacteroides. Ceftolozane-tazobactam showed very good activity against Prevotella spp., Fusobacterium spp., and Propionibacterium spp., varying activities against Gram-positive cocci, and limited activity against Clostridium spp.

Topics: Anaerobiosis; Anti-Bacterial Agents; Bacteroides fragilis; Cephalosporins; Clostridium; Drug Combinations; Fusobacterium; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Prevotella; Propionibacterium; Tazobactam