In the Journals

Trial for MRSA combination therapy discontinued over safety concerns

The addition of an antistaphylococcal beta-lactam antibiotic to standard of care — IV vancomycin or daptomycin — did not improve outcomes for patients with MRSA bloodstream infections and increased the risk for acute kidney injury, leading to the early termination of the study, researchers reported in JAMA.

“MRSA bloodstream infections are difficult to treat, with associated mortality of approximately 25% per episode,” Steven Y.C. Tong, MBBS, PhD, associate professor at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, told Healio.

“The most commonly used therapy, vancomycin, has a number of shortcomings and this may be related to the poor outcomes,” Tong said. “We wanted to test the combination of standard therapy — usually vancomycin — plus a beta-lactam compared to standard therapy alone.”

According to Tong, although the combination has strong supportive data from laboratory and animal studies, there has been no clinical trial evidence to determine if it would improve clinical outcomes.

To determine the efficacy of the combination compared with standard therapy alone, Tong and colleagues performed an open-label, randomized clinical trial of 352 adults hospitalized with MRSA bacteremia at 27 hospitals in four countries from August 2015 to July 2018. According to the study, 121 of the 352 patients completed the trial.

Fifty-nine patients (35%) randomly assigned to receive combination therapy met the primary endpoint — a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse and microbiological treatment failure — compared with 68 patients (39%) assigned to receive standard therapy.

The researchers found that all-cause 90-day mortality occurred in 35 (21%) of patients in the combination therapy group vs. 28 (16%) in the standard-therapy group, a difference of 4.5% (95% CI, 3.7% to 12.7%). Additionally, persistent bacteremia at day 5 was observed in 19 of 166 patients (11%) in the combination group vs. 35 of 172 (20%) in the standard group, for a difference of –8.9% (95% CI, 16.6% to 1.2%). Acute kidney injury occurred in 34 of 145 patients (23%) in the combination group vs. nine of 145 (6%) in the standard therapy group, a difference of 17.2% (95% CI, 9.3%-25.2%).

Based on these results, the data and safety monitoring board recommended early termination of the study before the enrollment of 440 patients.

“There was no evidence of improved clinical outcomes using the pre-specified primary endpoint,” Tong said. “Although the combination did reduce the duration of bacteremia, we did not see any reduction in mortality at 90 days. The surprising finding was that acute kidney injury was much more common in the combination therapy group.”

Tong noted the importance of clinical trials, saying “this finding would not have been apparent without a rigorous clinical trial.” – by Caitlyn Stulpin

Disclosures: Tong reported no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

The addition of an antistaphylococcal beta-lactam antibiotic to standard of care — IV vancomycin or daptomycin — did not improve outcomes for patients with MRSA bloodstream infections and increased the risk for acute kidney injury, leading to the early termination of the study, researchers reported in JAMA.

“MRSA bloodstream infections are difficult to treat, with associated mortality of approximately 25% per episode,” Steven Y.C. Tong, MBBS, PhD, associate professor at the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia, told Healio.

“The most commonly used therapy, vancomycin, has a number of shortcomings and this may be related to the poor outcomes,” Tong said. “We wanted to test the combination of standard therapy — usually vancomycin — plus a beta-lactam compared to standard therapy alone.”

According to Tong, although the combination has strong supportive data from laboratory and animal studies, there has been no clinical trial evidence to determine if it would improve clinical outcomes.

To determine the efficacy of the combination compared with standard therapy alone, Tong and colleagues performed an open-label, randomized clinical trial of 352 adults hospitalized with MRSA bacteremia at 27 hospitals in four countries from August 2015 to July 2018. According to the study, 121 of the 352 patients completed the trial.

Fifty-nine patients (35%) randomly assigned to receive combination therapy met the primary endpoint — a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse and microbiological treatment failure — compared with 68 patients (39%) assigned to receive standard therapy.

The researchers found that all-cause 90-day mortality occurred in 35 (21%) of patients in the combination therapy group vs. 28 (16%) in the standard-therapy group, a difference of 4.5% (95% CI, 3.7% to 12.7%). Additionally, persistent bacteremia at day 5 was observed in 19 of 166 patients (11%) in the combination group vs. 35 of 172 (20%) in the standard group, for a difference of –8.9% (95% CI, 16.6% to 1.2%). Acute kidney injury occurred in 34 of 145 patients (23%) in the combination group vs. nine of 145 (6%) in the standard therapy group, a difference of 17.2% (95% CI, 9.3%-25.2%).

Based on these results, the data and safety monitoring board recommended early termination of the study before the enrollment of 440 patients.

“There was no evidence of improved clinical outcomes using the pre-specified primary endpoint,” Tong said. “Although the combination did reduce the duration of bacteremia, we did not see any reduction in mortality at 90 days. The surprising finding was that acute kidney injury was much more common in the combination therapy group.”

Tong noted the importance of clinical trials, saying “this finding would not have been apparent without a rigorous clinical trial.” – by Caitlyn Stulpin

Disclosures: Tong reported no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.