IL-10 Stratifying Tool for Towards Antibiotic Selection for MRSaB

Bacteremia Clinical Trial

Official title:

A Multi-center Prospective Randomized Open Label Study of Utilizing Interleukin 10 (IL-10) Levels as a Guide for Antibiotic Selection for Methicillin Resistant Staphylococcus Aureus Bacteremia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02660346
• Other study ID #: IL-10 MRSaB
• Status: Completed
• Phase: Phase 4
• First received: October 21, 2015
• Last updated: January 30, 2018
• Start date: November 2015
• Est. completion date: January 30, 2018

Study information

• Verified date: January 2018
• Source: Sharp HealthCare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Patients with MRSaB have high therapeutic failure rates and mortality rates. Recent studies have shown that an elevated IL-10 level is an independent risk factor of mortality. It may also serve as biomarker for very early risk stratification. The aim of this study is to compare the outcomes for patients with elevated IL-10 levels (≥8 pg/ml) when treated with standard antibiotic therapy (daptomycin or vancomycin) versus early aggressive therapy (daptomycin with ceftaroline) for the treatment of MRSaB.

Description:

Patients with MRSaB have primary therapeutic failure rates of 40-50% and high mortality rate of 10-50% when treated with the recommended standard antimicrobial therapy. (Sharp) local data for MRSaB for 2014 shows an all-cause mortality rate of 29%. Recent studies have been published that utilize the predictive biomarker, IL-10, aiding the understanding for the wide variability in mortality. Further studies are needed to elucidate the clinical relevance of utilizing IL-10 levels to optimize MRSaB management and whether or not patient outcomes are enhanced.

Under current standard treatment strategies, vancomycin 15 mg/kg IVPB every 12 hrs following a 30 mg/kg IVPB loading dose is the first line of antibiotic therapy initiated with known or suspected MRSaB. Only when patients have showed an unsatisfactory clinical response such as prolonged bacteremia and/or continued clinical signs of uncontrolled infection are more potent/aggressive and more expensive antibiotic choices considered in most cases. Even the time for consideration of such a switch is a matter of controversy, with current MRSA treatment guidelines recommending a switch after 7-days of failure.

Several recent studies have shown that an elevated IL-10 level is an independent risk factor of mortality. In animal models, it has been shown that the bacterial cell wall of Staphylococcus aureus stimulates the production of IL-10. A small study by Rose et al. showed that this observation is consistent in humans. In another study, the authors concluded that elevated IL-10 at the time of presentation is a predictive value of mortality in patients with MRSaB4. In addition, the authors concluded that IL-10 may serve as a biomarker for very early risk stratification, with selection of standard therapy for low-risk patients and more potent, expensive, and cumbersome antibiotic therapies reserved for the high-risk patients. Furthermore, it is postulated that treating high risk patients with aggressive/intensified therapy earlier may improve economic and microbiological outcomes, such as a decreased length of treatment, decreased time in the Intensive Care Unit, decreased length of stay in the hospital, and decreased duration of bacteremia.

The aim in this study is to compare the outcomes for patients with elevated IL-10 levels (≥ 8 pg/mL) when treated with standard antibiotic therapy versus early aggressive therapy for the treatment of MRSaB. Aggressive therapy is defined in study to be daptomycin (6-8mg/kg/day) with ceftaroline (600 mg q8hr).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: January 30, 2018
• Est. primary completion date: September 15, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult (= 18 years of age) men or women.

• Diagnosis of MRSaB

• Has not been treated with antibiotics for MRSaB within 7 days of admission

• Has been on standard antibiotics for < 72hrs prior to randomization

• In the opinion of the investigator, the subject must require and be a suitable candidate for IV antibiotic therapy.

Exclusion Criteria:

• Medical history of hypersensitivity or allergic reaction to vancomycin, or vancomycin derivatives, daptomycin or ceftaroline

• Severe allergy to cephalosporins, i.e. Type 1 reaction, especially IgE mediated anaphylaxis

• Comfort care patients

• Death within 72hrs of the start of antibiotic therapy

• Polymicrobial bacteremia: Staphylococcus aureus and another gram positive, gram negative or anaerobic pathogen

• Burns covering = 10% of body.

• Pt currently enrolled in an investigational study

Related Conditions & MeSH terms

• Bacteremia

Intervention

Drug:
• Daptomycin
Control Arm Treatment if used as monotherapy. Study Arm Treatment if used in combination with ceftaroline.
• Vancomycin
Control Arm Treatment
• Ceftaroline
Study Arm Treatment

Locations

Country	Name	City	State
United States	Sharp Grossmont Hospital	La Mesa	California
United States	Sharp Memorial Hospital	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
Sharp HealthCare

Country where clinical trial is conducted

United States, 

References & Publications (15)

Barber KE, Werth BJ, Rybak MJ. The combination of ceftaroline plus daptomycin allows for therapeutic de-escalation and daptomycin sparing against MRSA. J Antimicrob Chemother. 2015 Feb;70(2):505-9. doi: 10.1093/jac/dku378. Epub 2014 Sep 22. — View Citation

Dhand A, Bayer AS, Pogliano J, Yang SJ, Bolaris M, Nizet V, Wang G, Sakoulas G. Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: role of enhanced daptomycin binding. Clin Infect Dis. 2011 Jul 15;53(2):158-63. doi: 10.1093/cid/cir340. — View Citation

Fabre V, Ferrada M, Buckel WR, Avdic E, Cosgrove SE. Ceftaroline in Combination With Trimethoprim-Sulfamethoxazole for Salvage Therapy of Methicillin-Resistant Staphylococcus aureus Bacteremia and Endocarditis. Open Forum Infect Dis. 2014 Jul 8;1(2):ofu046. doi: 10.1093/ofid/ofu046. eCollection 2014 Sep. Erratum in: Open Forum Infect Dis. 2015 Apr;2(2):ofv058. — View Citation

Frodermann V, Chau TA, Sayedyahossein S, Toth JM, Heinrichs DE, Madrenas J. A modulatory interleukin-10 response to staphylococcal peptidoglycan prevents Th1/Th17 adaptive immunity to Staphylococcus aureus. J Infect Dis. 2011 Jul 15;204(2):253-62. doi: 10.1093/infdis/jir276. — View Citation

Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O'Sullivan MV, Anderson TL, Roberts SA, Gao W, Christiansen KJ, Coombs GW, Johnson PD, Howden BP. Antibiotic choice may not explain poorer outcomes in patients with Staphylococcus aureus bacteremia and high vancomycin minimum inhibitory concentrations. J Infect Dis. 2011 Aug 1;204(3):340-7. doi: 10.1093/infdis/jir270. — View Citation

Moise PA, Amodio-Groton M, Rashid M, Lamp KC, Hoffman-Roberts HL, Sakoulas G, Yoon MJ, Schweitzer S, Rastogi A. Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant ß-lactams in patients with Staphylococcus aureus bacteremia and mild to moderate renal impairment. Antimicrob Agents Chemother. 2013 Mar;57(3):1192-200. doi: 10.1128/AAC.02192-12. Epub 2012 Dec 17. — View Citation

Rooijakkers SH, Ruyken M, van Roon J, van Kessel KP, van Strijp JA, van Wamel WJ. Early expression of SCIN and CHIPS drives instant immune evasion by Staphylococcus aureus. Cell Microbiol. 2006 Aug;8(8):1282-93. — View Citation

Rose W, Berti AD, Hayney MS, Henriquez K, Ranzoni A, Cooper MA, Shukla SK, Proctor RA, Nizet V, Sakoulas G. Associaction of IL-10 concentrations with bacterial bloodstream inoculum and mortality in patients with Staphylococcus aureus bacteremia. 2014. Abstr. International Symposium Staphylococci & Staphylococcal Infections. abstr 207.

Rose WE, Eickhoff JC, Shukla SK, Pantrangi M, Rooijakkers S, Cosgrove SE, Nizet V, Sakoulas G. Elevated serum interleukin-10 at time of hospital admission is predictive of mortality in patients with Staphylococcus aureus bacteremia. J Infect Dis. 2012 Nov 15;206(10):1604-11. doi: 10.1093/infdis/jis552. Epub 2012 Sep 10. — View Citation

Sakoulas G, Moise PA, Casapao AM, Nonejuie P, Olson J, Okumura CY, Rybak MJ, Kullar R, Dhand A, Rose WE, Goff DA, Bressler AM, Lee Y, Pogliano J, Johns S, Kaatz GW, Ebright JR, Nizet V. Antimicrobial salvage therapy for persistent staphylococcal bacteremia using daptomycin plus ceftaroline. Clin Ther. 2014 Oct 1;36(10):1317-33. doi: 10.1016/j.clinthera.2014.05.061. Epub 2014 Jul 10. — View Citation

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 Aug;57(8):4042-5. doi: 10.1128/AAC.02481-12. Epub 2013 May 20. — View Citation

Spika JS, Peterson PK, Wilkinson BJ, Hammerschmidt DE, Verbrugh HA, Verhoef J, Quie PG. Role of peptidoglycan from Staphylococcus aureus in leukopenia, thrombocytopenia, and complement activation associated with bacteremia. J Infect Dis. 1982 Aug;146(2):227-34. — View Citation

van Hal SJ, Jensen SO, Vaska VL, Espedido BA, Paterson DL, Gosbell IB. Predictors of mortality in Staphylococcus aureus Bacteremia. Clin Microbiol Rev. 2012 Apr;25(2):362-86. doi: 10.1128/CMR.05022-11. Review. — View Citation

Wang FD, Chen YY, Chen TL, Liu CY. Risk factors and mortality in patients with nosocomial Staphylococcus aureus bacteremia. Am J Infect Control. 2008 Mar;36(2):118-22. doi: 10.1016/j.ajic.2007.02.005. — View Citation

Werth BJ, Sakoulas G, Rose WE, Pogliano J, Tewhey R, Rybak MJ. Ceftaroline increases membrane binding and enhances the activity of daptomycin against daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus in a pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2013 Jan;57(1):66-73. doi: 10.1128/AAC.01586-12. Epub 2012 Oct 15. Erratum in: Antimicrob Agents Chemother. 2013 Mar;57(3):1565. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to bacteremia clearance	To determine whether or not early aggressive antibiotic therapy are correlated to shorter time to bacteremia clearance compared to standard therapy	1-4 weeks
Secondary	Comparison of IL-10 levels between standard and aggressive therapy treatments	To determine whether or not patients who have high IL-10 levels treated with aggressive antibiotic therapy have better outcomes compared with standard therapy.	About 2 months from blood draw to the batch results

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