Ceftolozane/Tazobactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination with Activity Against Multidrug-Resistant Gram-Negative Bacilli

Abstract

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. Two phase II clinical trials have been conducted to evaluate ceftolozane ± tazobactam in the settings of cUTIs and cIAIs. One trial compared ceftolozane 1,000 mg every 8 h (q8h) versus ceftazidime 1,000 mg q8h in the treatment of cUTI, including pyelonephritis, and demonstrated similar microbiologic and clinical outcomes, as well as a similar incidence of adverse effects after 7-10 days of treatment, respectively. A second trial has been conducted comparing ceftolozane/tazobactam 1,000/500 mg and metronidazole 500 mg q8h versus meropenem 1,000 mg q8h in the tre...

Alternatives to antibiotics—a pipeline portfolio review

“…For example, the recently approved combination of ceftolozane and tazobactam, for cIAI, cUTI and pyelonephritis, has clinical efficacy data for 10 pathogens including Klebsiella spp, Escherichia coli and Pseudomonas aeruginosa with clinical microbiology suggesting potential against another 20 pathogens. 136,137 Multiple alternative therapies would be required to provide similar spectrum of coverage. In the first instance, A2As are likely to focus on the most prevalent infections and may provide sufficient clinical benefit to ensure a return on investment.…”

Targeting Antibiotic Resistance

“…It maintains the aminothiadiazole ring and oxime functional groups of ceftaroline and ceftobiprole, which confer enhanced activity against Gram‐negative bacilli and stability against β‐lactamases, respectively 151. Additionally the appended dimethylacetic acid moiety provides improved antipseudomonal activity 146, 151.…”

“…Additionally the appended dimethylacetic acid moiety provides improved antipseudomonal activity 146, 151. On the eastern side, a highly substituted pyrazole ring provides the steric bulk necessary to reduce hydrolysis by β‐lactamases 151. The SAR of the substitution pattern of the pyrazole ring was studied in detail, and a 5‐amino‐1‐methyl‐1 H ‐pyrazol‐2‐ium moiety was found to confer the highest antipseudomonal activity 146.…”

“…Ceftolozane shows broad‐spectrum activity, including against drug‐ and multidrug‐resistant Pseudomonas aeruginosa , along with potent antipseudomonal activity 151, 152. Unfortunately, like other oxyimino cephalosporins, it is sensitive to extended‐spectrum β‐lactamases (ESBL) and carbapenemases.…”

“…Unfortunately, like other oxyimino cephalosporins, it is sensitive to extended‐spectrum β‐lactamases (ESBL) and carbapenemases. For this reason, ceftolozane is marketed in conjunction with the β‐lactamase inhibitor tazobactam (see Section 4), which broadens its spectrum to include ESBL‐producing strains of P. aeruginosa and Bacteroides fragilis 151, 153…”