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Double Trouble: Assessing the Impact of Combining Daptomycin and Fosfomycin for MRSA Bacteremia

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This highlighted study looks at using these 2 therapies concurrently for this infection.

Highlighted Study: Pujol M, Miró JM, Shaw E, et al. Daptomycin plus Fosfomycin versus Daptomycin Alone for Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis. A Randomized Clinical Trial [published online ahead of print, 2020 Jul 29]. Clin Infect Dis. 2020;ciaa1081. doi:10.1093/cid/ciaa1081

Morbidity and mortality associated with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections have remained a long-standing concern for clinicians. While national incidence of MRSA bacteremia has decreased compared to prior decades,1 lingering consequences including recurrence and complications of the index infection remain concerningly prevalent.2

Vancomycin has been established as the standard of care for MRSA bacteremia, although favor is steadily shifting elsewhere due to difficulty in achieving optimal pharmacokinetic targets, rise in clinical failures, and reports of resistance. Daptomycin has since come into the limelight as an alternative agent due to demonstrated non-inferiority3 to and possible advantage4,5 over vancomycin while maintaining a predictable pharmacokinetic profile and favorable rates of adverse effects. Unfortunately, surfacing reports of clinical failures associated with daptomycin monotherapy6 further implore clinicians to investigate novel avenues of therapy.

Interests in using daptomycin in combination with other agents like fosfomycin have increased in light of synergistic in vitro activity and positive outcomes in animal models.7 Until recently, clinical efficacy of daptomycin with fosfomycin was limited to retrospective case series8,9 demonstrating promising rates of cure compared to current standards of care. With this in mind, Pujol and colleagues sought to further explore this particular combination for the treatment of MRSA bacteremia in the only prospective and randomized trial to date.

In this open-label trial, patients with MRSA bacteremia within 72 hours of randomization were enrolled in a 1:1 fashion to receive either daptomycin 10mg/kg IV daily or daptomycin 10mg/kg IV daily with fosfomycin 2g IV q6h. Pertinent exclusion criteria included patients with a life expectancy less than 24 hours, those who require antimicrobial coverage beyond MRSA, pneumonia as a source of bacteremia, and presence of prosthetic valve endocarditis. Following randomization, patients were treated for a total of 10-14 days for uncomplicated bacteremia and 28-42 days for complicated bacteremia.

The primary outcome of interest was the rate of treatment success (i.e. negative blood cultures with clinical resolution) at the test of cure visit, determined at 6 weeks following the end of therapy. Secondary outcomes include presence of MRSA bacteremia at multiple points throughout the study period, progression to complicated bacteremia, all-cause mortality, and adverse events.

Ultimately, 74 patients received the combination of daptomycin plus fosfomycin, and 81 patients received daptomycin alone. Baseline characteristics between the two treatment groups were similar. Patients were, on average, 73 years old and 67% of patients were male. Patients in both arms had relatively low Charlson comorbidity and Pitt bacteremia scores and were treated for a median of 14 days, indicating less severe and uncomplicated cases of bacteremia. The main source of bacteremia was from intravascular catheters, but other sources included skin and soft tissue infections, surgical site infections, and urinary tract infections.

Treatment success was achieved in more patients receiving both daptomycin and fosfomycin, compared with patients receiving daptomycin alone; however, this difference was not statistically significant (Table 1). However, statistical significance was achieved in favor of combination therapy in many of their secondary microbiological endpoints including time to blood culture clearance, rates of microbiological failure, and rates of complicated bacteremia.

Although the incidence of all adverse effects was similar between groups, patients receiving both agents were significantly more likely to experience adverse effects that lead to treatment discontinuation commonly due to cardiac failure and hypokalemia.

Despite no statistical difference in the rates of treatment success, authors suggest there may still be a clinical benefit with combination therapy due to significantly shorter time to blood sterilization and higher rates of microbiological cure. While these results are promising, this study may be difficult to apply externally.

Combination therapy with daptomycin is often indicated in the setting of salvage therapy for MRSA bacteremia. In the United States, this is most commonly done with β-lactam antibiotics such as ceftaroline, the only β-lactam with activity against MRSA.10, 11, 12

Given that patients in the current study were clinically stable and not always candidates for salvage therapy, the clinical applicability and place in therapy for daptomycin and fosfomycin is unclear compared to the data available with daptomycin and β-lactams. Additionally, IV fosfomycin does not have FDA-approval at the time of writing this article.

At a time when isolates of S aureus are displaying increasing MICs for vancomycin, there is certainly a need for more treatment options when vancomycin becomes less of a viable option. This study illustrates a potential role for the combination of daptomycin and fosfomycin, and shows that the combination warrants further study in larger prospective trials.

Lapin is a PGY-1 pharmacy resident at the Hospital of the University of Pennsylvania. His clinical interests are in infectious diseases and antimicrobial stewardship, and he plans to pursue a PGY-2 residency in infectious diseases.

Lee is an infectious diseases clinical pharmacy specialist at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania. Her practice areas include inpatient antimicrobial stewardship, as well as the transition & monitoring of patients receiving outpatient parenteral antimicrobial therapy.

References:

  1. Kourtis AP, Hatfield K, Baggs J, et al. Vital Signs: Epidemiology and Recent Trends in Methicillin-Resistant and in Methicillin-Susceptible Staphylococcus aureus Bloodstream Infections — United States. MMWR Morb Mortal Wkly Rep. 2019;68:214—219.
  2. Inagaki K, Lucar J, Blackshear C, Hobbs C V. Methicillin-susceptible and methicillin-resistant Staphylococcus aureus bacteremia: Nationwide estimates of 30- day readmission, in-hospital mortality, length of stay, and cost in the United States. Clin Infect Dis. 2019; 69:2112—2118.
  3. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355(7):653-665.
  4. Murray KP, Zaho JJ, David SL, et al. Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study. Clin Infect Dis. 2013;56(11):1562-9.
  5. Claeys KC, Zasowski EJ, Casapao AM, et al. Daptomycin improves outcomes regardless of vancomycin MIC in a propensity-matched analysis of methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother. 2016;60(10):5841-48.
  6. Gasch O, Camoez M, Dominguez MA, et al. Emergence of resistance to daptomycin in a cohort of patients with methicillin-resistant Staphylococcus aureus persistent bacteraemia treated with daptomycin. J Antimicrob Chemother. 2014;69:568—571.
  7. García-de-la-Mària C, Gasch O, García-Gonzalez J, et al. The combination of daptomycin and fosfomycin has synergistic, potent, and rapid bactericidal activity against methicillin-resistant Staphylococcus aureus in a rabbit model of experimental endocarditis. Antimicrob Agents Chemother. 2018;62:e02633-17.
  8. Chen LY, Huang CH, Kuo SC, et al. High-dose daptomycin and fosfomycin treatmet of a patient with endocarditis caused by daptomycin-nonsusceptible Staphylococcus aureus: case report. BMC Infect Dis. 2011;11:152.
  9. Miró JM, Entenza JM, del Río A, et al. High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 2012;56:4511— 4515.
  10. Geriak M, Haddad F, Rizvi K, et al. Clinical Data on Daptomycin plus Ceftaroline versus Standard of Care Monotherapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia. Antimicrob Agents Chemother. 2019;63(5):e02483-18. Published 2019 Apr 25.
  11. 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):1-10.
  12. Sakoulas G, Nonejuie P, Nizet V, Pogliano J, Crum-Cianflone N, Haddad F. Treatment of high-level gentamicin-resistant Enterococcus faecalis endocarditis with daptomycin plus ceftaroline. Antimicrob Agents Chemother. 2013;57(8):4042-4045.