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Ceftolozane-tazobactam effectively treats MDR P. aeruginosa infections

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November 4, 2018

Ceftolozane-tazobactam effectively treats multidrug-resistant Pseudomonas aeruginosa infections, especially when initiated early on, findings from a retrospective study showed.

Writing in Open Forum Infectious Diseases, Jason C. Gallagher, PharmD, FCCP, FIDP, FIDSA, clinical professor at the Temple University School of Pharmacy and a clinical pharmacy specialist in infectious diseases at Temple University Hospital, and colleagues explained that the two agents work well in combination because ceftolozane is stable against AmpC enzymes produced by P. aeruginosa — allowing for improved activity — while tazobactam protects ceftolozane from being destroyed by most extended-spectrum beta-lactamases.

“At present, the combination is indicated for the treatment of complicated urinary tract infections and complicated intra-abdominal infections, the latter with concomitant metronidazole,” Gallagher and colleagues wrote. “Despite potent in vitro activity against strains of Pseudomonas aeruginosa that are resistant to other anti-pseudomonal beta-lactam agents, few of these isolates were in clinical trials, and clinical evidence supporting ceftolozane-tazobactam for these infections is lacking.”

The researchers conducted a multicenter, retrospective observational study, collecting patient data from 20 hospitals across the United States. They included adults infected with P. aeruginosa from any source between December 2014 and February 2018 who received ceftolozane-tazobactam treatment for at least 24 hours. According to the study, a composite of 30-day and inpatient mortality was the primary outcome, with secondary outcomes including clinical success (signs and symptoms improved from baseline to the end of treatment) and microbiological cure (negative culture at the end of treatment).

Among the 205 patients included in the study, severe illness and comorbidities were common, with pneumonia affecting 59%, Gallagher and colleagues said. They reported a median 9-day delay from culture collection to the initiation of ceftolozane-tazobactam.

Of the 139 isolates tested for susceptibility, 89.9% (n = 125) were susceptible to ceftolozane-tazobactam. Overall, 19% (n = 39) of the patients died, 73.7% (n = 151) experienced clinical success and 70.7% (n = 145) experienced microbiological cure, according to the study.

Upon analysis, Gallagher and colleagues found that survival was associated with an earlier initiation of ceftolozane-tazobactam therapy. Specifically, when ceftolozane-tazobactam was started within 4 days of culture collection, there were improve odds of survival (aOR = 5.55; 95% CI, 2.14-14.4), clinical success (aOR = 2.93; 95% CI, 1.4-6.1) and microbiological cure (aOR = 2.59; 95% CI, 1.24-5.38).

Gallagher and colleagues highlighted the need for stewardship programs and practitioners “to strike a difficult balance between early use of agents such as ceftolozane-tazobactam in appropriate patients who may benefit from it with the economic and microbiological consequences of overuse.”

“The finding that earlier initiation of ceftolozane-tazobactam after culture collection was associated with lower mortality, greater clinical success, and greater microbiological cure is significant,” Gallagher and colleagues wrote. “While de-escalation approaches are commonly recommended by clinical guidelines in many syndromes, the elevated costs associated with new antimicrobials agents and a desire to reserve these agents for highly-resistant organisms may lead to a reversion to an “escalation” approach in patients with these organisms.” – by Marley Ghizzone

Disclosures: Gallagher reports having received grant funding from Merck and serving as a consultant to Achaogen, Astellas, Merck, Paratek, Shionogi, and Tetraphase. He reports currently serving on speaker’s bureaus for Allergan, Astellas, Melinta, and Merck. Please see the study for all other authors’ relevant financial disclosures.

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Perspective

This retrospective study from 20 hospitals in the United States provides a real-world snapshot on how ceftolozane-tazobactam is being used in the treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections. Patients identified in the study had high mortality, significant comorbidities, prolonged hospitalization, a very high percentage of carbapenem resistance and ceftolozane-tazobactam was largely being used off-label for pneumonia. Mortality in the study was 19% and 73.7% of patients achieved clinical success. Starting ceftolozane-tazobactam within 4 days of obtaining cultures was associated with survival on multivariate analysis. Limitations of the study include its retrospective design, the lack of a control group and the fact that ceftolozane-tazobactam susceptibility test results were not available for 32% of the patients.

This study informs the literature on how ceftolozane-tazobactam is being used to treat MDR P. aeruginosa infections and indicates this is a potentially valuable option for patients. There is much that is still unknown about the optimal use of ceftolozane-tazobactam in this setting, including what is the optimal dosing, the role of combination therapy, its effectiveness relative to other antimicrobials and the extent to which the emergence of resistance is a concern. More studies are needed to inform the most optimal use of ceftolozane-tazobactam for patients with MDR Pseudomonas aeruginosa infections.

Michael P. Stevens, MD, MPH, FACP, FIDSA, FSHEA

Associate professor of internal medicine
Associate chair, division of infectious diseases
Director, antimicrobial stewardship program
Associate hospital epidemiologist
Director, travel and tropical medicine clinic
Virginia Commonwealth University School of Medicine

Disclosure: Stevens reports no relevant financial disclosures.