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

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 retrospective cohort study, investigators found the addition of a β-lactam antibiotic to daptomycin led to less clinical failure (60-day all-cause mortality and/or 60-day recurrence) in patients with methicillin-resistant Staphylococcus aureus bacteremia.

SOURCE: Jorgensen SCJ, Zasowski EJ, Trinh TD, et al. Daptomycin plus β-lactam combination therapy for methicillin-resistant Staphylococcus aureus bloodstream infections: A retrospective, comparative cohort study. Clin Infect Dis 2020;71:1-10.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia causes significant morbidity and mortality despite the availability of antibiotics that demonstrate good in vitro activity. Thus, the optimal treatment of MRSA bacteremia remains unclear. Based on data from smaller studies and case reports, Jorgensen and colleagues sought to determine whether the combination of daptomycin plus a β-lactam antibiotic improved outcomes for MRSA bacteremia compared to daptomycin alone.

The study was a retrospective, observational, cohort study conducted at two medical centers in Detroit. Inclusion criteria were age 18 years and older, one or more blood cultures positive for MRSA, and daptomycin started within 120 hours of initial blood culture collection and continued for at least 72 hours. Patients who received any β-lactam for at least 24 hours and within 24 hours of the initiation of daptomycin were included in the daptomycin plus β-lactam group. Patients who had a pulmonary source for their MRSA bacteremia or cases of polymicrobial bacteremia were excluded. The authors adjusted for confounding variables by employing an inverse probability treatment weighting approach.

There were 157 patients in the daptomycin monotherapy group and 72 patients in the daptomycin plus β-lactam group. The groups were mostly well balanced, although heart failure and chronic kidney disease were more prevalent in monotherapy recipients. Moreover, a greater proportion of patients who received combination therapy had an osteoarticular or skin source as the etiology of their MRSA bacteremia, while an intravenous (IV) catheter-related bacteremia was a more common source in the monotherapy group. Most (61%) were treated initially with vancomycin and were switched to daptomycin because of a vancomycin minimum inhibitory concentration (MIC) of 2 mg/L. The reasons for adding the β-lactam drug included empirical coverage (45.8%), anticipated synergy (34.7%), or another concurrent infection (19.4%). The most commonly used β-lactam agents were cephalosporins (cefepime n = 31 [43%], cefazolin n = 18 [25%], ceftaroline n = 7 [9.7%], and ceftriaxone n = 7 [9.7%]). Of the 52 patients who experienced clinical failure, 43 were in the monotherapy group and nine were in the combination group (P = 0.013). There was a significant reduction in the odds of clinical failure in the combination group vs. the monotherapy group (adjusted odds ratio [aOR] 0.386; 95% confidence interval [CI], 0.175-0.853).

Acute kidney injury (AKI) was significantly higher in the combination group compared to the monotherapy group (10.8% vs. 2.9%, respectively;  P = 0.046). Nine of the 10 patients in the monotherapy group who developed AKI received at least one dose of a nephrotoxic drug within 72 hours prior to the onset of AKI. There were six reported cases of Clostridioides difficile infection, four in the combination group and two in the monotherapy group (P = 0.08). Finally, creatinine phosphokinase elevation occurred in 10 patients, which was not significantly different between the two groups.

COMMENTARY

The argument for and against combination therapy for MRSA bacteremia has long been debated. The study by Jorgensen and colleagues adds to the evidence base on combination therapy and likely will be cited often in future studies. However, it raises about as many questions as it answers. On one hand, combination therapy was associated with significantly reduced 60-day mortality and/or 60-day recurrence of MRSA bacteremia. On the other hand, significantly more AKI occurred in the combination therapy group, despite a lower baseline proportion of patients with chronic kidney disease (CKD) compared to the monotherapy group. Moreover, when the 60-day mortality and/or 60-day recurrence measurement was divided further into 60-day mortality, 30-day mortality, 60-day recurrence, and 30-day recurrence, there were no significant differences between the combination and monotherapy groups.

Both the authors and an accompanying editorial raise an important issue from the recent CAMERA2 study.1 This randomized clinical trial for MRSA bacteremia compared monotherapy (vancomycin or daptomycin) to combination therapy (vancomycin or daptomycin plus seven days of an antistaphylococcal penicillin or cefazolin). It was stopped early after an interim analysis found no effect on death or complications at 90 days, but a four-fold increase in AKI among patients who received combination therapy.2 Notably, patients who received cefazolin had a lower rate of AKI (7%) compared to those who received flucloxacillin (35%).

Should all patients with MRSA bacteremia receive combination therapy? The short answer is no. In the vast majority of instances, in vitro and observational studies should not be relied on for making clinical decisions. It has become evident, based on the study by Jorgensen and colleagues and previous ones such as CAMERA2, that additional antibiotics increase the risk for adverse events. Thus, while there is a suggestion of benefit, it currently is not enough to recommend that combination therapy be used in most cases of MRSA bacteremia.

This is a good example of where definitive randomized trials, in addition to CAMERA2, are needed. Indeed, the addition of cefazolin to vancomycin or daptomycin might be safer than other β-lactams, and it seems reasonable to investigate this hypothesis. Another important goal will be to identify subgroups of patients for whom the benefits of combination therapy outweigh the risks. Until then, the debate over combination therapy will remain unsettled.

REFERENCES

  1. Holland TL, Davis JS. Combination therapy for MRSA bacteremia: To β or not to β? Clin Infect Dis 2020;71:11-13.
  2. Tong SYC, Nelson J, Paterson DL, et al. CAMERA2 - Combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: Study protocol for a randomised controlled trial. Trials 2016;17:170.