Efficacy of Daptomycin Plus Fosfomycin Versus Daptomycin for Treatment of MRSA Bacteremia

Staph Aureus Methicillin Resistant Bacteremia Clinical Trial

Official title:

Randomized Multicenter Study to Assess Efficacy of Daptomycin Plus Fosfomycin Versus Daptomycin Monotherapy for Treatment of Methicillin Resistant Staphylococcus Aureus Bacteremia in Hospitalized Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01898338
• Other study ID #: BACSARM
• Secondary ID: 2013-000586-37
• Status: Completed
• Phase: Phase 3
• First received: July 2, 2013
• Last updated: January 16, 2018
• Start date: December 2013
• Est. completion date: January 10, 2018

Study information

• Verified date: January 2018
• Source: Spanish Network for Research in Infectious Diseases
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To demonstrate that the combination of daptomycin and fosfomycin is superior to daptomycin alone in the treatment of methicillin resistant Staphylococcus aureus (MRSA) bacteremia.

Description:

The mortality associated to MRSA bacteremia remains higher than 30% of episodes despite the availability of new antibiotics. Objective: To demonstrate that the combination of daptomycin and fosfomycin is superior to daptomycin alone in the treatment of methicillin resistant Staphylococcus aureus (MRSA) bacteremia. Design: Randomized, open-label and multicenter study. Intervention: Patients with MRSA bacteremia will be randomized (1:1) in Group 1: daptomycin 10mg/Kg/24h intravenous (iv) and Group 2: daptomycin 10 mg/kg/24 iv plus fosfomycin and 2g/6h iv. Duration of therapy will be 10-14 days for uncomplicated bacteremia and up to 42 days for complicated bacteremia. Follow up: There will be a clinical and microbiological evaluation at baseline, during treatment and at week 6 after the end of therapy (test of cure visit, TOC). Complicated bacteremia was considered if: a) persistence of a positive blood culture at 72-96 h from the start of antibiotic, b) evidence of spread of infection (metastatic infection) c) infection involving a non-removable device in less than 4 days. Sample size: Assuming 60% cure rate with daptomycin and a 20% difference in cure rates between both groups, we estimated that 103 patients will be needed for each group (α:0.05, ß: 0.2). Main endpoint: clinical and microbiological response at the TOC visit. Treatment success was defined as the resolution of clinical signs and symptoms and negative blood culture. Treatment failure was defined if any of the following situations: a) lack of clinical response at 72 h or more after initiation of the study therapy b) persistent bacteremia (positive blood culture on day 7 after randomization), c) withdrawal of treatment due to adverse effects or for any other reason based on clinical judgment. d) relapse of MRSA bacteremia before the TOC visit e) death for any reason before the TOC visit. Secondary endpoints: evaluation in both groups of clinical and microbiological response at end of therapy (EOT visit); mortality at EOT and TOC visit; persistent MRSA bacteremia; recurrence of MRSA bacteremia (positive blood culture when previous ones were negative); emergence of daptomycin or fosfomycin resistance and severe adverse effects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 167
• Est. completion date: January 10, 2018
• Est. primary completion date: January 10, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Patients with at least 1 positive blood culture to MRSA within 72h up to randomization

• Adult patients, equal or older than 18 years old

• Signed informed consent

• Mandatory use of contraception methods for fertile women during the study period and for 6 months after stopping antibiotic therapy

Exclusion Criteria:

• Polymicrobial bacteremia

• Pneumonia associated to the bacteremia

• Severe clinical status with expected survival of less than 24 hours

• Allergy to daptomycin or fosfomycin

• A positive pregnancy test at the time of inclusion

• Any clinical condition that requires additional antibiotic therapy with microbiological activity against MRSA

• Patient already included in another clinical trial

• Prior history of eosinophilic pneumonia

Related Conditions & MeSH terms

• Bacteremia
• Staph Aureus Methicillin Resistant Bacteremia

Intervention

Drug:
• Fosfomycin 2gr/6h iv

• Daptomycin 10mg/kg/24h iv

Locations

Country	Name	City	State
Spain	Hospital Universitario de Cruces	Barakaldo
Spain	Hospital Clinic	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital del Mar- Parc de Salut Mar	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital Universitari de Bellvitge	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Hospital Universitario Lucus Augusti	Lugo
Spain	Hospital General Gregorio Marañon	Madrid
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Complejo Asistencial Son Espases	Palma de Mallorca
Spain	Hospital Parc Taulí	Sabadell	Barcelona
Spain	Hospital Virgen Macarena	Sevilla
Spain	Hospital Universitari Joan XXIII	Tarragona
Spain	Hospital de Terrassa	Terrassa	Barcelona
Spain	Hospital Universitari Mútua de Terrassa	Terrassa	Barcelona

Sponsors (2)

Lead Sponsor	Collaborator
Miquel Pujol	Hospital Universitari de Bellvitge

Country where clinical trial is conducted

Spain, 

References & Publications (16)

Chang FY, Peacock JE Jr, Musher DM, Triplett P, MacDonald BB, Mylotte JM, O'Donnell A, Wagener MM, Yu VL. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltimore). 2003 Sep;82(5):333-9. — View Citation

Chen LY, Huang CH, Kuo SC, Hsiao CY, Lin ML, Wang FD, Fung CP. High-dose daptomycin and fosfomycin treatment of a patient with endocarditis caused by daptomycin-nonsusceptible Staphylococcus aureus: case report. BMC Infect Dis. 2011 May 26;11:152. doi: 10.1186/1471-2334-11-152. — View Citation

Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003 Jan 1;36(1):53-9. Epub 2002 Dec 13. — View Citation

Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fätkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE; S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006 Aug 17;355(7):653-65. — View Citation

Garrigós C, Murillo O, Lora-Tamayo J, Verdaguer R, Tubau F, Cabellos C, Cabo J, Ariza J. Fosfomycin-daptomycin and other fosfomycin combinations as alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2013 Jan;57(1):606-10. doi: 10.1128/AAC.01570-12. Epub 2012 Oct 22. — View Citation

Gasch O, Ayats J, Angeles Dominguez M, Tubau F, Liñares J, Peña C, Grau I, Pallarés R, Gudiol F, Ariza J, Pujol M. Epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection: secular trends over 19 years at a university hospital. Medicine (Baltimore). 2011 Sep;90(5):319-27. doi: 10.1097/MD.0b013e31822f0b54. — View Citation

Gasch O, Camoez M, Dominguez MA, Padilla B, Pintado V, Almirante B, Molina J, Lopez-Medrano F, Ruiz E, Martinez JA, Bereciartua E, Rodriguez-Lopez F, Fernandez-Mazarrasa C, Goenaga MA, Benito N, Rodriguez-Baño J, Espejo E, Pujol M; REIPI/GEIH Study Groups. Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy. Clin Microbiol Infect. 2013 Nov;19(11):1049-57. doi: 10.1111/1469-0691.12108. Epub 2013 Jan 17. — View Citation

Gudiol F, Aguado JM, Pascual A, Pujol M, Almirante B, Miró JM, Cercenado E, Domínguez Mde L, Soriano A, Rodríguez-Baño J, Vallés J, Palomar M, Tornos P, Bouza E; Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. [Consensus document for the treatment of bacteremia and endocarditis caused by methicillin-resistent Staphylococcus aureus. Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica]. Enferm Infecc Microbiol Clin. 2009 Feb;27(2):105-15. doi: 10.1016/j.eimc.2008.09.003. Epub 2009 Feb 11. Review. Spanish. — View Citation

Kastoris AC, Rafailidis PI, Vouloumanou EK, Gkegkes ID, Falagas ME. Synergy of fosfomycin with other antibiotics for Gram-positive and Gram-negative bacteria. Eur J Clin Pharmacol. 2010 Apr;66(4):359-68. doi: 10.1007/s00228-010-0794-5. Epub 2010 Feb 26. — View Citation

Kullar R, Davis SL, Levine DP, Zhao JJ, Crank CW, Segreti J, Sakoulas G, Cosgrove SE, Rybak MJ. High-dose daptomycin for treatment of complicated gram-positive infections: a large, multicenter, retrospective study. Pharmacotherapy. 2011 Jun;31(6):527-36. doi: 10.1592/phco.31.6.527. — View Citation

Lai CC, Sheng WH, Wang JT, Cheng A, Chuang YC, Chen YC, Chang SC. Safety and efficacy of high-dose daptomycin as salvage therapy for severe gram-positive bacterial sepsis in hospitalized adult patients. BMC Infect Dis. 2013 Feb 4;13:66. doi: 10.1186/1471-2334-13-66. — View Citation

Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011 Feb 1;52(3):285-92. doi: 10.1093/cid/cir034. — View Citation

Miró JM, Entenza JM, Del Río A, Velasco M, Castañeda X, Garcia de la Mària C, Giddey M, Armero Y, Pericàs JM, Cervera C, Mestres CA, Almela M, Falces C, Marco F, Moreillon P, Moreno A; Hospital Clinic Experimental Endocarditis Study Group. High-dose daptomycin plus fosfomycin is safe and effective in treating methicillin-susceptible and methicillin-resistant Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 2012 Aug;56(8):4511-5. Epub 2012 May 29. — View Citation

Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis. 2010 Feb;29(2):127-42. doi: 10.1007/s10096-009-0833-2. Epub 2009 Nov 14. Review. — View Citation

Rehm SJ, Boucher H, Levine D, Campion M, Eisenstein BI, Vigliani GA, Corey GR, Abrutyn E. Daptomycin versus vancomycin plus gentamicin for treatment of bacteraemia and endocarditis due to Staphylococcus aureus: subset analysis of patients infected with methicillin-resistant isolates. J Antimicrob Chemother. 2008 Dec;62(6):1413-21. doi: 10.1093/jac/dkn372. Epub 2008 Sep 8. — View Citation

Wu G, Abraham T, Rapp J, Vastey F, Saad N, Balmir E. Daptomycin: evaluation of a high-dose treatment strategy. Int J Antimicrob Agents. 2011 Sep;38(3):192-6. doi: 10.1016/j.ijantimicag.2011.03.006. Epub 2011 May 6. Review. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Therapy response	Therapy response is considered if clinical and microbiological response is achieved at week 6 after end of therapy	at week 6 after end of therapy (an average of 8 to 12 weeks from the beginnig of therapy)
Secondary	Mortality		participants will be followed an average of 8 to 12 weeks from the begining of therapy
Secondary	Severe adverse effects	whatever	participants will be followed an average of 8 to 12 weeks from the begining of therapy
Secondary	Number of persistent bacteremia	Defined as a positive blood culture on day 7 after starting the study therapy	participants will be followed an average of 8 to 12 weeks from the begining of therapy
Secondary	Bacteremia recurrence	Defined as a positive blood culture to MRSA when previous ones were negative	participants will be followed an average of 8 to 12 weeks from the begining of therapy
Secondary	Therapy response at end of therapy (EOT visit)	Success is considered if clinical resolution and negative blood culture at end of therapy.	at end of therapy