Drug Combo No Better in MRSA Blood Infections, Ups Risk

Veronica Hackethal, MD

February 11, 2020

Adding a β-lactam antibiotic to standard antibiotic therapy for blood infections caused by methicillin-resistant Staphylococcus aureus (MRSA) did not improve outcomes but increased risk for acute kidney injury (AKI), according to results from the randomized controlled CAMERA2 (Combination Antibiotics for Methicillin Resistant Staphylococcus aureus) trial.

Because of an increase in the incidence of AKI, the trial was stopped early, report Steven Y. C. Tong, MBBS, PhD, and colleagues with the Australasian Society for Infectious Diseases Clinical Research Network. The results were published online today in JAMA.

"In patients with MRSA bacteremia, the addition of 7 days of an antistaphylococcal β-lactam to standard therapy did not statistically significantly reduce the occurrence of a composite of 90-day mortality, microbiological persistence, relapse, or treatment failure," write Tong, who is affiliated with the Institute for Infection and Immunity in Melbourne, Australia, and colleagues.

"Given the early termination, the trial may have been underpowered to demonstrate an improvement in the composite primary end point; however, it is likely that any potential gains in efficacy with combination therapy would be offset by the increased toxicity," they add.

MRSA infections are associated with a mortality rate of 20% to 25%. The preferred treatment for MRSA blood infections is vancomycin or daptomycin.

Laboratory and animal studies suggest that adding a β-lactam to standard therapy may kill bacteria better than standard therapy alone. A few human studies seem to back this up, but those studies were limited by small size and/or observational design.

Outside of research studies, combined therapy is generally reserved for treatment-resistant MRSA infections. Few high-quality, randomized controlled trials have evaluated whether this practice improves outcomes and is safe for patients with MRSA blood infections.

To evaluate the issue, researchers conducted an open-label, randomized clinical trial at 27 hospitals in Australia, Singapore, Israel, and New Zealand covering the period from August 2015 to July 2018. The study enrolled 352 adults who had been hospitalized for MRSA blood infections. The participants' mean age was 62.2 years; 34.4% (n = 121) were women, and most came from Australia and New Zealand.

Researchers randomly assigned 178 participants to receive standard therapy plus 7 days of an antistaphylococcal β-lactam antibiotic; they assigned 178 to receive standard therapy alone. Standard therapy consisted of intravenous vancomycin or daptomycin. Antistaphylococcal β-lactams included intravenous flucloxacillin, cloxacillin, or cefazolin. Choice of antibiotic and total duration of therapy was left up to the treating clinician.

After enrollment of 80% of the planned 440 participants, the data and safety monitoring board recommended early termination of the study, owing to increased rates of AKI in the combined therapy group.

There were no significant differences in mortality between the two groups at any time point during the study.

Likewise, there was no significant difference in the percentage of participants who met the primary endpoint, a 90-day composite of mortality, persistent bacteremia at day 5, relapsed MRSA infection 72 hours after a culture proved positive, and antibiotic treatment failure at day 14 (absolute difference, –4.2%; 95% confidence interval [CI], –14.3% to 6.0%; P = .42). Only 35% (n = 59) of the combined therapy group and 39% (n = 68) of the standard therapy group met the primary endpoint.

Also between the two groups there was no significant difference for 7 of 9 secondary endpoints, including 90-day all-cause mortality (risk difference, 4.5%; 95% CI, –3.7% to 12.7%; P = .28), relapsed MRSA infection (risk difference, –2.0; 95% CI, –8.1 to 4.1; P = .52), and antibiotic treatment failure (risk difference, –0.3; 95% CI, –6.5 to 5.9; P = .92 )

Analyses that excluded individuals who were receiving dialysis at enrollment showed that the incidence of AKI was significantly higher in the combined therapy group compared to the standard therapy group (23% vs 6%; risk difference, 17.2%; 95% CI, 9.3% – 25.2%; P < .001).

Among the combined therapy group there was significantly less bacteremia at day 5 compared to the standard therapy group (11% vs 20%; risk difference, −8.9%; 95% CI, −16.6 to −1.2%; P = .02).

"The study by Tong and colleagues is an elegant addition to a paucity of high-quality clinical trials informing optimal therapy for MRSA bacteremia," write Tejal N. Gandhi, MD, and Preeti N. Malani, MD, MSJ, in an accompanying editorial. Both Gandhi and Malani are affiliated with the University of Michigan, Ann Arbor. Malani is the associate editor of JAMA.

However, they note that there are many unanswered questions regarding the study. For example, only 3.6% (13/352) of participants received daptomycin, and most participants in the combined group received vancomycin with flucloxacillin or cloxacillin as their β-lactam instead of cefazolin. An exploratory post hoc analysis found that fewer participants who received cefazolin developed AKI in comparison with patients who received flucloxacillin or cloxacillin (3.7% [1/27] vs 27.0% [30/111]).

That raises the question as to whether cefazolin or other combinations of antibiotics not included in the study may be yield improved outcomes for MRSA patients without increasing toxicity.

"[The] applicability of the results to other combination treatment strategies (including vancomycin plus cefazolin, daptomycin plus cefazolin, and daptomycin plus an antistaphylococcal penicillin) is limited," Gandhi and Malani write.

Other questions concern the cost-effectiveness of regimens and whether age and the source of infection affect outcomes. The average age of the patients in this study was 64 years. Outcomes may be different for younger individuals who have relatively good kidney function. Only 15 participants had MRSA endocarditis, which carries a higher mortality rate than bacteremia of other causes.

"Until such data are available, routine combination therapy with a β-lactam as initial treatment for MRSA bacteremia should be avoided," Gandhi and Malani conclude. "Even in refractory cases, a cautious approach is warranted given that the results of Tong and colleagues add to several prior randomized clinical trials that demonstrated that initial combination therapy did not result in improved clinical outcomes but was associated with increased toxicity."

The study was supported by grants from the Australian National Health and Medical Research Council, the Singapore National Medical Research Council, and the Ramiciotti Foundation. The original article contains a listing of the study authors' relevant financial relationships. Gandi and Malani have disclosed no relevant financial relationships.

JAMA. 2020;323:515-516, 527-537.

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