Daptomycin plus Fosfomycin versus Daptomycin alone

Klinik für Infektiologie & Spitalhygiene

Daptomycin plus Fosfomycin versus Daptomycin alone
   for methicillin-resistant Staphylococcus aureus
            bacteremia and endocarditis:
              a randomized clinical trial

Miquel Pujol et al. for the MRSA Bacteremia (BACSARM) Trial Investigators
                            CID 2021;72(9):1517–25

                         Journal Club 31.05.2021
                            Andreas Neumayr

Background:
• Mortality of S. aureus bacteremia is high: 20 – 30%1
• Mortality of MRSA bacteremia is double that of MSSA bacteremia
• Available monotherapies not optimal:
  − Vancomycin: slow bactericidal activity, poor tissue penetration,
                potential toxicity
  − Daptomycin: clin. failure up to 30%2, emergence of resistance
• 2020: CAMERA2: Vanco. or Dapto. monotherapy VS Vanco. or
  Dapto. + a β-lactame for MRSA bacteremia3
   no mortality benefit of combination therapy
   higher rate and more severe AKI with combination therapy
• Daptomycin + fosfomycin is synergistic and rapidly bactericidal
  against MRSA in vitro and in the rabbit endocarditis model4
1   Kourtis et al. MMRW 2019;68:214-9.   3   Tong et al. JAMA 2020;doi:10.1001
2   Karchmer. CID 2021;72(9):1526–8.     4   Garcia-de-la-Maria et al. Antimicrob Agents Chemother. 2018;62:e02633-17.

• Study design:      Randomized (1:1) phase 3 superiority, open-label trial
• Study sites:       18 Spanish hospitals
• Recruitment:       12/2013 – 11/2017
• Participants:      Adult inpatients ≥18y
• Inclusion criteria: MRSA bacteremia (Def.: ≥1 pos. blood culture ≤72 hours)
• Exlusion criteria: Life expectancy ≤24 hours, polymicrobial bacteremia,
                     pneumonia as a source of bacteremia, prosthetic valve
                     endocarditis, NYHA III/IV, severe end-stage liver disease
                     (Child-Pugh C), any clinical condition requiring additional
                     antibiotics active against MRSA, prior history of eosinoph.
                     pneumonia, allergy to daptomycin or fosfomycin
• Study arms:        I: Daptomycin 1x 10 mg/kg/d i.v.
                     II: Daptomycin 1x 10mg/kg/d + Fosfomycin 4x 2g/d i.v.
                     10 – 14 days for uncomplicated bacteremia
                     28 – 42 days for complicated bacteremia

• Sample size calc.: 81 patients per arm to detect a 20% differences between
                     arms with a power of 80% and an α-level of 0.05
• Primary endpoint: Test of cure (TOC) at 6 weeks after the end of therapy
                    (Def.: alive + resolution of symptoms + neg. blood cultures)
• 2ndary endpoints:   -- bacteremia at day 3, day 7, and at week 6
                      -- microbiological failure*; complicated bacteremia
                      -- AEs leading to treatment discontinuation
                      -- mortality due to any cause at day 7 and at week 6
                         [* persistent bacteremia, recurrent bacteremia,
                            emergence of resistance to study drugs]
• Analysis: (i) modified intention-to-treat analysis, including all appropriately
                 randomized patients who received ≥24h of antibiotic therapy
            (ii) subgroup homogeneity analysis of the treatment effect
                         -- age
                         -- presence of endocarditis
                         -- Pitt Bacteremia Score

Pitt Bacteremia Score

Review on the Pitt Bacteremia Score:
Al-Hasan MN , Baddour LM. Resilience of the Pitt Bacteremia Score: 3 Decades and Counting. CID 2020;9:1834–36.

Sample size
 ~ reached

PBS

p = 0.133

                                             p < 0.001
                        *                    p = 0.022

                                             p = 0.012

                                             p = 0.687

* complicated bacteremia:
            - spread of infection
            - suppurative thrombophlebitis
            - endocarditis
            - infection involving a foreign material that could not be removed in

Conclusions:
• The 12% higher treatment success rate did not reach statistical significance
• Combination therapy prevents microbiological failure but is more often
  associated with adverse events
• Combination therapy may possibly be more effective than monotherapy in
  younger patients and in those with more severe disease
Strengths/limitations:
• Strength: solid design & analysis, low drop-out rate (enrolment challenging)
• Limitation: - no blinding; may have impacted discontinuation due to clinical
                 worsening or suspected AEs or escalation of treatment
              - low number of patients with endocarditis & critically ill patients
Outlook:
• A One-fits-all treatment approach is unlikely: e.g. putative benefit of CT in a
  young IVDU with MRSA endocarditis vs. AE-related disadvantage of CT in an
  old comorbid patient with catheter-related MRSA bacteremia
• Limiting combination therapy to clearance of bacteremia?

Thanks!