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Abstract
During the mid-nineties, 95–97% of intra-abdominal infection (IAI)- associated microbes were susceptible to commonly used antibiotics. Nowadays, in Gram-negative bacilli, β-lactam resistance and the associated co-resistance to other antibiotics leading to multidrug resistance is reaching crisis proportions. This is a critical issue in the treatment of IAIs, especially for complicated IAIs and for those of nosocomial origin in severely ill patients. In this setting, this article reviews the place in the therapeutic armamentarium of ceftolozane/tazobactam, a new cephalosporin/β-lactamase inhibitor with good activity against extended spectrum β-lactamase producing Enterobacteriaceae, with stability to AmpC β-lactamases and good anti-pseudomonal activity being stable against the most common resistance mechanisms driven by mutation in Pseudomonas aeruginosa. A profound review of its in vitro activity, in vivo efficacy in animal models, pharmacodynamics, pharmacokinetics, clinical efficacy in clinical trials in complicated IAIs and safety data is performed.
Financial & competing interests disclosure
E Maseda has received payments for lectures from Astellas Pharma, Pfizer and Merck Sharp and Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
In Gram-negative bacilli, β-lactam resistance and the associated co-resistance to other antibiotics leading to multidrug resistance is reaching crisis proportions. This is a critical issue in the treatment of intra-abdominal infections (IAIs), especially for complicated IAIs and for those of nosocomial origin in severely ill patients.
Ceftolozane/tazobactam is a new cephalosporin/β-lactamase inhibitor with good activity against extended spectrum β-lactamase-producing Enterobacteriaceae, with stability to AmpC β-lactamases and good antipseudomonal activity being stable against the most common resistance mechanisms driven by mutation in Pseudomonas aeruginosa.
The longer half-life of ceftolozane compared with other cephalosporins is a potential advantage for achieving longer t > MIC. The standard 1000/500 mg every 8 h dosing regimen achieved free-drug t > MIC ≥32.2% for P. aeruginosa with MIC = 8 µg/ml in >90% of simulated patients, supporting the proposed in vitro susceptibility breakpoint of 8 µg/ml.
Phase III trials in cIAI comparing ceftolozane/tazobactam plus metronidazole versus meropenem showed noninferiority with respect to clinical cure rates and bacterial eradication.
Based on safety data from Phase I to Phase III clinical trials, the adverse effect profile of ceftolozane/tazobactam does not appear to be different to that of other β-lactams.
In the treatment of complicated IAIs, combined therapy is needed to extend the coverage of ceftolozane/tazobactam to anaerobes (as in the clinical trials performed) and to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci in specific patients at risk.
The use of ceftolozane/tazobactam as alternative treatment may help in reducing carbapenem use, thus possibly delaying carbapenemase selection and diffusion.