By Richard R. Watkins, MD, MS, FACP, FIDSA

Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports no financial relationships relevant to this field of study.

SYNOPSIS: In a randomized clinical trial conducted at 27 hospitals in four countries, researchers found that the addition of an antistaphylococcal beta-lactam to vancomycin or daptomycin (99% received vancomycin) did not lead to improved outcomes in MRSA bacteremia. The trial was stopped early because of safety concerns, including a higher risk of acute kidney injury in the combination group.

SOURCE: Tong SYC, Lye DC, Yahav D, et al. Effect of vancomycin or daptomycin with vs without an antistaphylococcal β-lactam on mortality, bacteremia, relapse, or treatment failure in patients with MRSA bacteremia: A randomized clinical trial. JAMA 2020;323:527-537.

The treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with vancomycin or daptomycin (currently the standard of care) leads to death in approximately 20% of cases. Thus, better treatment regimens are needed urgently. Tong and colleagues sought to determine whether adding a beta-lactam agent with antistaphylococcal activity to vancomycin or daptomycin would lead to improved outcomes.

The study was a multicenter, open label, randomized, clinical trial powered to detect superiority. Patients were included if they had a positive blood culture for MRSA, were randomized within 72 hours of the first positive blood culture, were 18 years of age or older, and were likely to remain hospitalized for at least seven days following randomization. They were randomized in a 1:1 ratio to standard therapy, which was intravenous vancomycin dosed to maintain trough levels of 15 to 20 mcg/mL, or daptomycin dosed at 6 to 10 mg/kg per day, or to combination therapy that included vancomycin or daptomycin plus a seven-day course of an intravenous beta-lactam drug (i.e., flucloxacillin, cloxacillin, or cefazolin).

The primary outcome, assessed 90 days after randomization, was a composite measure with four components, including all-cause mortality, persistent bacteremia at day 5, microbiological relapse defined as a positive blood culture for MRSA at least 72 hours following a negative blood culture, and microbiological treatment failure defined as a positive sterile site culture for MRSA at least 14 days after randomization. Participants were recruited between August 2015 and July 2018 from 27 hospitals in Australia, New Zealand, Singapore, and Israel.

Of the 352 patients included in the analysis, 174 were randomized to combination therapy and 178 to standard therapy. The median age was 64 years and most (349/352) received vancomycin. The primary composite outcome at day 90 was met by 59 of 170 patients in the combination group (35%) vs. 68 of 175 in the standard therapy group (39%; difference, -4.2%; 95% confidence interval [CI], -14.3% to 6.0%; P = 0.42). For the secondary outcomes, mortality did not differ significantly at any point between the groups. However, persistent bacteremia at day 5 was less common in the combination group (19/166 [11%]) vs. the standard therapy group (35/172 [20%]; difference, -8.9%; 95% CI, -16.6 to -1.2; P = 0.02). Acute kidney injury (AKI) occurred significantly more often in the combination group (34/145 [23%]) than in the standard therapy group (9/145 [6%]; difference, 17.2%; 95% CI, 9.3%-25.2%; P < 0.001). The trial was stopped early because of the higher AKI incidence in the combination group.

The investigators conducted a post hoc analysis for the AKI cases. Of the 34 patients in the combination therapy group who developed AKI, six required hemodialysis (HD). By day 90, two still required HD and seven had died. In contrast, of the nine patients with AKI in the standard therapy group, two required HD. By day 90, neither was still receiving HD, and three of the nine had died. Furthermore, the severity of the AKI was higher in the combination group. Finally, AKI was associated more with flucloxacillin (28%) and cloxacillin (24%) than with cefazolin (4%).

COMMENTARY

Clinicians need better therapies for MRSA bacteremia. As the study by Tong and colleagues demonstrates, combination therapy that includes seven days of an antistaphylococcal beta-lactam does not seem to be the answer. The only advantage for combination therapy was a reduction in persistent bacteremia at day 5. However, the benefit was far outweighed by the higher incidence of AKI, which notably led to the trial being stopped early. This is similar to previous studies that examined aminoglycosides or rifampin in combination with standard therapy for MRSA bacteremia, both of which led to increased toxicity without a discernible benefit. Moreover, a reduction in the duration of MRSA bacteremia has not been shown to lead to better outcomes in prospective studies.

The incidence of AKI with cefazolin was much less than with the antistaphylococcal penicillins. Indeed, the trial left open the possibility that the combination of vancomycin with cefazolin might be effective and not harmful. Further studies to investigate this hypothesis are warranted.

The study was well-designed overall. However, there are a few limitations worth noting. First, other antistaphylococcal penicillins (e.g., nafcillin or oxacillin) might not be as nephrotoxic in combination compared to the ones used in the trial. Second, few patients were prescribed daptomycin, which is less nephrotoxic than vancomycin. Third, vancomycin dosing was based on maintaining trough levels between 15 and 20 mcg/mL, which has been associated with a higher risk for nephrotoxicity compared to using area-under-the-curve (AUC)-guided dosing.

Fourth, the median age of the patients was 64 years, which raises the issue of whether combination therapy might be safer in younger patients and perhaps beneficial in certain populations, such as patients who use intravenous drugs. Finally, 98% of the patients received antibiotics in the preceding 72 hours before randomization, which might have been a confounding variable.

Using combination therapy for MRSA bacteremia is a tempting concept because of its theoretical benefits and positive results from animal models. We have a good understanding of what does not work, based on previous studies and now the one by Tong and colleagues. Yet, while the study by Tong and colleagues has provided new answers, it also has generated further questions that deserve to be studied using a similar rigorous scientific approach.