Highlighted Study: Kale‐Pradhan, P.B., Giuliano, C., Jongekrijg, A. and Rybak, M.J. (2020), Combination of Vancomycin or Daptomycin and Beta‐lactam Antibiotics: A Meta‐analysis. Pharmacotherapy, 40: 648-658. doi:10.1002/phar.2437.
Methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of community-acquired and healthcare-acquired infections. Serious infections caused by MRSA include bacteremia and endocarditis, both of which are associated with high rates of morbidity and mortality. First line agents for treatment of these infections are vancomycin and daptomycin. However, concern for clinical failure, particularly in the setting of high-grade bacteremia or evidence of elevated vancomycin minimum inhibitory concentrations (MICs), may lead clinicians to consider combination therapy with each agent rather than monotherapy. The role of combination therapy with β-lactams in particular has become of increasing clinical interest in recent years given its potential to augment innate host immunity and because of the observed “seesaw effect.”1 Evidence for use of β-lactam combination therapy for MRSA has been demonstrated in in-vitro laboratory trials, in-vivo animal analyses, clinical observational studies, and randomized-controlled trials.
A recent meta-analysis by Kale-Pradhan et al. aimed to analyze available data to guide clinical decision making on the role of β-lactam combination therapy with vancomycin or daptomycin for treatment of MRSA bacteremia and endocarditis.2 This meta-analysis evaluated the outcomes described in 9 studies (n = 1636) published between January 1966 and February 2020, characterizing the clinical and microbiologic impact associated with both vancomycin and daptomycin monotherapy as well as in combination with β-lactams. Three trials were randomized and controlled, while the remaining were retrospective cohort studies. The most frequent sites of primary infection were endovascular, infective endocarditis, or catheter-related blood stream infection. Non-endovascular sites leading to bacteremia or endocarditis commonly included skin and soft tissue, osteoarticular, genitourinary, and lower respiratory tract.
Of the six cohort studies, two evaluated daptomycin and four evaluated vancomycin both in combination and as monotherapy. Vancomycin was most commonly dosed using a trough-based strategy and daptomycin dosing was not explicitly discussed. However, review of the individual studies utilizing daptomycin indicated an average daily dose of 8 mg/kg (range 6-10 mg/kg) in three of the four studies.3-5 The fourth study described dosing as a range of 6-10 mg/kg adjusted for renal function.1 Various β-lactams were used in the individual studies. With respect to initiation and duration of combination therapy, all studies reported initiation of combination therapy within 24-72 hours of bacteremia onset. Adjunctive β-lactam therapy continuation ranged between 2 and 9 days. The total duration of antimicrobial therapy throughout the studies varied based on the primary treatment indication.
Upon collective study analysis, Kale-Pradhan et al. found that combination therapy with either vancomycin or daptomycin plus a β-lactam was associated with significantly lower rates of clinical failure, compared to monotherapy with vancomycin or daptomycin alone (12.5-35% vs. 27.4-39%; OR 0.56; 95% CI, 0.39–0.79; I2 = 26.22%; P = .001). Outcome differences were primarily driven by the reduced rates of persistent bacteremia (OR 0.56; 95% CI, 0.43–0.75; I2 = 0.0%, P = .01) or bacteremia relapse (OR, 0.63; 95% CI, 0.43–0.92; I2 = 0.0%, P = .02) among patients who received combination therapy compared to those who received monotherapy. There was no difference in mortality identified between groups (12.5-35% combination vs 7.8-26% monotherapy, OR 0.98; 95% CI, 0.70-1.39; I2 = 0.0%; P = .93). Mortality was used to define clinical failure in four of the nine studies that did not report alternative outcomes. Despite variations among studies, heterogeneity with respect to the clinical outcomes of interest was generally low. With respect to nephrotoxicity, a post-hoc analysis did not identify significant differences between groups (OR, 1.83; 95% CI, 0.75–4.48, I2 = 68.87%, P = .18).
It is helpful to consider these findings within the scope of the analysis. Nine studies were included among the over 4,000 studies that were reviewed, demonstrating selective inclusion criteria. Notably, studies in which combination therapy was initiated after prior clinical failure were excluded. Although differences in nephrotoxicity rates between combination and monotherapy groups were not observed in this analysis, individual studies including the CAMERA 2 trial suggest that risk may be more prevalent with select agents in combination therapy (e.g. flucloxacillin, cloxacillin).1 Therefore, caution should be exercised with use of these agents in particular until more data become available.
Ultimately, findings from this meta-analysis largely support consideration of combination therapy in patients with MRSA bacteremia or endocarditis that are at substantial risk of recurrence or clinical failure, such as in the setting of high-grade metastatic infection. Routine use of combination therapy may not be necessary, though patients who receive combination therapy for multiple indications (e.g. vancomycin for MRSA bacteremia plus cefepime for hospital-acquired pneumonia) may experience some degree of added benefit. Data from this analysis do not support use of one particular β-lactam over another, though caution should be exercised when utilizing agents associated with nephrotoxicity in other studies. Combination therapy with a β-lactam does not appear to be required for the entire duration of treatment for clinical benefit, but the optimal duration has yet to be determined. Impending IDSA guidelines, scheduled for release in the Fall of 2020, will hopefully provide additional insight and guidance on the role of combination therapy for patients with serious MRSA infections.