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CAMERA2: Combination Therapy for MRSA Bacteremia Effective but Linked to Higher Mortality, AKI Rates

In vitro, animal models, and observational studies in humans have demonstrated that combination therapy comprising vancomycin, the current standard treatment, with a β-lactam appears to be more effective than monotherapy in treating methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.

But results from the largest clinical trial to date have raised concerns over the effects of combination therapy on mortality and rates of acute kidney injury (AKI).
The CAMERA2 study, presented at the European Congress of Clinical Microbiology and Infectious Disease (ECCMID 2019), sought to evaluate combination therapy through an investigator-initiated randomized controlled trial of patients with MRSA bacteremia.

Between August 2015 and July 2018, the trial enrolled 352 participants across 27 sites in 4 countries (Australia, New Zealand, Singapore, and Israel) who were diagnosed with MRSA bacteremia within 72 hours of index blood culture draw, who were aged 18 years and older, and who were likely to remain an inpatient for ≥7 days. Participants were randomized to either the standard treatment, vancomycin or daptomycin, or the standard treatment plus an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin).

The primary endpoint was a composite outcome at 90 days of all-cause mortality, persistent bacteremia at day 5 or beyond, microbiological relapse, or microbiological treatment failure, and assessed by a blinded adjudication committee. Secondary endpoints included individual elements of the composite primary endpoint, bacteremia at day 2, and acute kidney injury or need for renal replacement therapy.

Two hundred fifty two of the participants were from New Zealand or Australia, 56 from Singapore, and 44 from Israel. The median age of participants was 64 years, 34% were female, and 64% had a health care-associated infection. Fifteen percent were receiving haemodialysis. Three hundred forty four participants (standard care n = 174, combination n = 170) were included in the modified intention-to-treat analysis. The trial was stopped early on the recommendation of the data and safety monitoring board.

“The main result was that we found no difference in the primary endpoint, which was a composite of 90-day mortality, persistent bacteremia at day 5, and microbiological failure and relapse,” Steven Tong, PhD, associate professor at the Doherty Institute and the Menzies School of Research, and presenter of the CAMERA2 study, told Contagion® (see video). “However, what we did find was that there was a markedly increased risk of acute kidney injury in the combination arm. Of patients who received combination therapy, 30% developed acute kidney injury vs 9% in the standard therapy arm.”

Investigators found increased mortality in the combination arm where 21% of patients died vs 16% in the standard therapy arm, although the number of patients with persistent bacteremia at day 5 in the combination arm was significantly reduced compared with standard therapy.

In a post-hoc exploratory analysis, 7 patients in the combination group ended up on renal replacement therapy vs only 2 in the standard therapy group.

“In retrospect now, we’re really pleased in some ways that we found something out. Something unexpected but that, I think, has clinical impact,” Tong said (see video). “It’s very clear to me that we should not be using a combination of vancomycin plus flucloxacillin for treatment of MRSA bacteremia. We ended up doing more harm to patients through that combination than the standard therapy group. I think this should actually give us pause in our enthusiasm for combination therapy for Staphylococcus bacteremia.”

“The other key message is the duration of bacteremia may not be a good surrogate endpoint,” Tong said. “We reduced the duration of bacteremia, that was very clear, with combination therapy but that had no impact on overall results, which was no difference in the composite primary endpoint.”

The study, “Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: The CAMERA2 Randomized Controlled Trial,” was presented in an oral session on Tuesday, April 16, 2019, at ECCMID 2019 in Amsterdam, the Netherlands.
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