Combination Therapy for Staphylococcus aureus Bacteremia: Hopes Dashed Again Free

(See the Major Article by Cheng et al on pages e196–203.)

Staphylococcusaureus bacteremia is both common and deadly. In the United States, there are more than 100 000 episodes per year with approximately 20 000 deaths. Given the relative paucity of randomized, controlled trial data to inform management decisions, publication of the Daptomycin as Adjunctive Therapy for Staphylococcus aureus Bacteremia in Hospital (DASH) study by Cheng and colleagues in this issue of Clinical Infectious Diseases is a welcome contribution [REF Cheng CID 2020].

The study was a double-blind, placebo-controlled, randomized clinical trial of adjunctive daptomycin (or saline placebo) administered for 5 days in combination with standard-of-care β-lactam therapy for 104 adults with methicillin-susceptible S. aureus (MSSA) bacteremia. Conducted at 2 hospitals in Montreal, Canada, the primary outcome was duration of bacteremia. Adjunctive daptomycin did not reduce the duration of bacteremia (median of 3.1 days in the daptomycin group vs 3.0 days in the placebo group in the modified intention-to-treat populations [and 2.04 days and 1.65 days, respectively, in the entire intention-to-treat populations]) nor was there a difference in 90-day mortality (18.9% in the daptomycin group vs 17.7% in the placebo group).

Many of the therapeutic clinical studies have focused on methicillin-resistant S. aureus (MRSA) bacteremia. However, while the incidence of MRSA bacteremia has declined in the past decade in the United States, the incidence of MSSA bacteremia has increased [1]. For most of the world, MSSA bacteremia contributes to a greater burden of disease than MRSA bacteremia [1–4]. Also, MSSA bacteremia is by no means a benign disease. The 90-day mortality rate in DASH (18% [19/104]) was similar to that in the Combination Antibiotics for Methicillin Resistant Staphylococcus aureus 2 (CAMERA2) trial (18% [63/344]), which only included MRSA bacteremia [5]. Although patients with MSSA and MRSA bacteremia are often assumed to be quite different, the baseline characteristics between the DASH and CAMERA2 patients, respectively, of median ages (67 years and 64 years), sex (35% and 34% female), and median Charlson comorbidity index (5 and 5) were strikingly similar. Given the greater burden of disease, research efforts to improve the management of MSSA bacteremia are important, arguably, more so than for MRSA bacteremia.

In addition to a focus on MSSA, the DASH study has many methodological strengths. As a placebo-controlled trial with blinding of investigators and participants and an objective primary outcome, bias was minimized. There were also no missing data, with daily blood cultures obtained until blood cultures were negative or death had occurred. On the other hand, although the study achieved the prespecified sample size, the overall numbers were relatively small to be able to robustly assess clinical outcomes. For example, the incidence of nephrotoxicity was 48% compared with 29% in the daptomycin and placebo treatment groups, respectively. This was not statistically different but hints at a concerning signal. A similar indication of potential increased toxicity was present in the CAMERA1 trial of 60 patients [6] but only conclusively borne out in the larger CAMERA2 study of 352 patients [5].

What clinical implications do the DASH findings have? Given that clinicians are unlikely to have been using the combination of daptomycin and a β-lactam for MSSA bacteremia, there is no need to change current clinical guidelines or practice as a results of the DASH trial. In terms of up-front combination therapy for MSSA bacteremia, the ARREST (Adjunctive Rifampicin for Staphylococcus aureus Bacteraemia) study, which assessed the role of adjunctive rifampicin, also found no benefit in combination therapy among 711 patients with MSSA bacteremia [7]. Thus, at this stage, up-front combination therapy for MSSA bacteremia should only be considered in the setting of a clinical trial. We would argue that the same principle applies to MRSA bacteremia.

What do the results of the DASH trial mean for the broader research agenda of combination therapy for S. aureus bacteremia? Although the sample size of the DASH trial was small, there was not even a signal of efficacy of daptomycin combination therapy. Thus, a larger subsequent trial is unlikely to change its conclusion. We can now add the combination of daptomycin with a β-lactam for MSSA to a growing list of combination therapies that have proven in randomized clinical trials to not be of clinical benefit for S. aureus bacteremia: i) The addition of gentamicin to backbone antibiotic therapy [8, 9]; ii) The addition of rifampicin to backbone antibiotic therapy for MSSA in the ARREST trial (only 6% in this trial had MRSA) [7]; and iii) The addition of an anti-staphylococcal penicillin to vancomycin for MRSA bacteremia in the CAMERA2 trial [5].

There do, however, remain some glimmers of hope. One possible reason why the promise of β-lactam combination therapy for MRSA from in vitro and observational studies [10] has not translated into net clinical benefit in clinical trials is nephrotoxicity. In the CAMERA2 trial, cefazolin (as opposed to flucloxacillin or cloxacillin) appeared to have no nephrotoxicity signal when added to backbone therapy, but the numbers were small. Furthermore, a recent pilot clinical trial of adding ceftaroline to backbone antibiotic therapy for MRSA bacteremia showed no signal of nephrotoxicity [11]. Hence, it is possible that future trials of combination therapy for S. aureus bacteremia using β-lactams that are less nephrotoxic may show a net benefit.

Looking further afield, nonclassic antimicrobials are being developed. In a first-in-class phase 2 study, exebacase, which is a direct lytic agent, when combined with standard antibiotic therapy, was found to be safe and improved clinical response at day 14 in an exploratory MRSA subgroup of 43 patients. However, there was no evidence of improved clinical response when all 116 patients were assessed in the primary efficacy analysis [12].

While combination therapies may be attractive, more is not always better. Perhaps the clinical research focus should prioritize determining which of the available single agents is most effective and least harmful. For MSSA bacteremia, should we use cefazolin or anti-staphylococcal β-lactams, such as nafcillin? For MRSA bacteremia, should we use vancomycin or daptomycin or ceftaroline?

In order to answer the outstanding questions about optimal antibiotic therapies for S. aureus bacteremia, we need large, well-designed clinical trials. Given that most of the antibiotics proposed to be tested in such trials are off-patent, it is unlikely that industry will fund such studies. Enter investigator-initiated trials. The DASH, CAMERA2, and ARREST trials are examples of comparative effectiveness trials for S. aureus bacteremia that have been done relatively cheaply but with rigorous study design and strong internal and external validity. Ongoing and increased support for such studies by research funding agencies is essential if we are to improve outcomes from this devastating infection.

Notes

Acknowledgments. S. Y. C. T. and J. S. D. are supported by National Health and Medical Research Council Career Development Fellowships (1145033 and 1160331). S. Y. C. T. and J. S. D. were joint principal investigators for the CAMERA2 trial and are planning future collaborations with authors from the article they have commented upon.

Potential conflicts of interest. The authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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