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Editorial

September 25, 2018

Treatment Algorithms for Staphylococcal Bacteremia: Improving Clinical Care and Enhancing Antimicrobial Stewardship

Eli N. Perencevich, Preeti N. Malani

JAMA. 2018;320(12):1243-1244. doi:10.1001/jama.2018.13315

Antimicrobial resistance is among the most important threats to human health. Lost in the episodic outbreaks of emerging pathogens such as 2009 H1N1 influenza, Ebola, and Zika virus has been the steady increase in resistance to commonly used antibiotics in frequently seen bacterial infections. Confronting antimicrobial resistance requires investment in 3 critical areas including (1) antimicrobial discovery, (2) rapid diagnostics, and (3) infection prevention and antimicrobial stewardship. In particular, algorithms based on clinical practice guidelines, that promote appropriate antibiotics and durations of therapy and limit unnecessary treatment, have the potential to enhance care for individual patients and improve public health more broadly.

In this issue of JAMA, Holland and colleagues report the findings of a multicenter randomized trial of an algorithm compared with usual care for the treatment of staphylococcal bacteremia. The study was conducted at 16 academic medical centers, predominately in the United States, over 6 years. Patients were randomly assigned to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm-based therapy group, whereas care in the usual practice group was determined by the treating clinicians. Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. Patients with known or suspected complicated infection at the time of randomization were excluded.

Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 assigned to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, −6.2% to ∞). Serious adverse events were reported among 32.5% of patients in the algorithm-based therapy group and 28.3% of those in the usual practice group (difference, 4.2%; 95% CI, −3.8% to 12.2%). In a per-protocol analysis, among patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days in the algorithm-based therapy group vs 6.2 days in the usual practice group (difference, −1.8 days [95% CI, −3.1 to −0.6). Although interpretation was limited by wide confidence intervals, the rates of serious adverse events were not significantly different between the groups.

Staphylococcal bacteremia encompasses 2 clinically distinct pathogens. Staphylococcus aureus causes both health care–associated and community-acquired bacteremia, with an annual incidence ranging as high as 38.2 per 100 000 person-years in the United States and mortality rates of approximately 20% .Staphylococcus aureus is typically divided into methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains, the latter of which have been associated with higher mortality. The heterogeneous species group of coagulase-negative staphylococci, apart from Staphylococcus lugdunensis, are much less virulent than S aureus and together comprise the most common cause of health care–associated bacteremia.

Optimal care of patients with S aureus bacteremia includes source control (eg, device removal or surgical drainage), echocardiography to evaluate for possible endocarditis, infectious disease consultation, and appropriate antibiotic selection once susceptibilities are known. Even though optimal therapy selection for MSSA bacteremia has not been well established with randomized trials, parenteral cefazolin or an antistaphylococcal penicillin are preferred. The majority of coagulase-negative staphylococci are methicillin resistant and, similar to MRSA, are treated with vancomycin or daptomycin, an approach based on limited clinical trial evidence.

Despite the recognized severity of S aureus bacteremia, the optimal duration of therapy has not been established with prospective clinical trials. Current recommendations, based on low-quality evidence, recommend 4 to 6 weeks for complicated S aureus bacteremia and a minimum of 14 days after the first negative surveillance blood culture result for uncomplicated bacteremia. Similarly, the therapeutic duration for coagulase-negative staphylococcus bacteremia is based on limited evidence but ranges from 0 to 3 days for simple bacteremia (often a contaminant), 5 to 7 days for uncomplicated bacteremia in the setting of a removable central venous catheter, and multiple weeks of therapy for complicated bacteremia in the setting of persistent positive blood culture results, retained foreign bodies, or endocarditis.

Given limited evidence supporting treatment (both drug choice and duration), it may be surprising to see a clinical trial evaluating an algorithm with formalized clinical definitions and guidance on antibiotic selection and treatment duration. Furthermore, the algorithm evaluated by Holland et al addresses bacteremia caused both by S aureus (typically undertreated and associated with relatively poor outcomes) and coagulase-negative staphylococci (frequently overtreated and associated with minimal morbidity). Current antimicrobial stewardship guidelines recommend targeted improvements in antibiotic use for clinical syndromes such as S aureus bacteremia. Although stewardship guidelines do not specifically mention coagulase-negative staphylococci, some programs report success using rapid diagnostics to differentiate coagulase-negative staphylococci from S aureus.

Despite uncertainties around optimal treatment, Holland et al successfully implemented a treatment algorithm for 5 related clinical syndromes. Importantly, they achieved the primary outcome of noninferiority for clinical success while demonstrating a nearly 2-day reduction in antibiotic duration overall, including a 3-day reduction in therapy for uncomplicated coagulase-negative staphylococcus bacteremia. Given that vancomycin is the most commonly prescribed antibiotic in US acute care hospitals, a 3-day reduction for a high-incidence condition such as uncomplicated coagulase-negative staphylococcus bacteremia could have a sizable public health effect.

A particular strength of this study was the use of a blinded adjudication committee of infectious diseases experts that confirmed primary outcomes, bacteremia-attributable mortality, and possible bias introduced by nonstudy antibiotics. Although bacteremia-related mortality was not a prespecified outcome, it is reassuring that despite reduced therapeutic duration, the adjudication committee identified lower attributable mortality among patients treated with the algorithm. Another key exploratory finding was the higher clinical success among patients with complicated S aureus bacteremia treated with the algorithm compared with usual practice (82.6% vs 35.7%). This observation adds to existing evidence that bundled processes of care for this serious infection can improve outcomes. The authors use their results to further highlight an important caveat—2 weeks of therapy for uncomplicated S aureus bacteremia should be used with caution and only after careful evaluation for metastatic infection.

Although the results reported by Holland et al are intriguing, the study also has several potential limitations. First, while the study was multicenter and multiyear, there were only an average of 5 patients contributed per hospital per year and about 1 case of S aureus bacteremia per year. Thus, this small subsample might not be generalizable to all acute care settings.

Second, the study sites all had access to infectious diseases consultants. While infectious diseases consultation has been associated with improved outcomes in S aureus bacteremia, many hospitals currently lack on-site access to infectious diseases expertise, potentially limiting the generalizability of these findings in resource-limited or rural settings. It is possible that this clinical algorithm could be more efficacious in those settings, but further research is needed.

Third, as noted by the authors, the algorithm was randomized at the individual patient level within hospitals, suggesting the potential for contamination among clinicians treating patients in both study groups. This could result in the usual practice group being treated similarly to the algorithm-based therapy group over time and would bias the results toward the null. As such, it would have been interesting to evaluate the results over time. If contamination was determined to significantly bias the results, future studies could reduce contamination through hospital-level cluster randomization.

The report by Holland et al is an elegant addition to the evidence base of how to best manage staphylococcal bacteremia, and these results will likely influence the next iteration of treatment guidelines. The algorithm-defined antibiotic duration targets should be considered for inclusion in antimicrobial stewardship programs and guidelines. However, algorithms cannot simply be applied in a vacuum without ongoing monitoring and adjustment based on an individual patient’s clinical course. Moreover, algorithms can only be as good as the clinical evidence supporting their recommendations. The limited quality of evidence used in this algorithm, through no fault of the investigators, is an important reminder that future investment in clinical trials targeting optimal antibiotic selection and duration are essential to continued progress. Successful response to the antimicrobial resistance crisis demands better evidence and dedicated resources to support future investigations.

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