Polymyxin B Monotherapy vs Combination Therapy in Critically Ill Patients With Multi-drug Resistant Pathogens

Critical Illness Clinical Trial

— MUSEUM  

Official title:

Polymyxin B Monotherapy Versus Polymyxin B-Carbapenem Combination Therapy in Critically Ill Patients With Multi-drug Resistant Gram-negative Infection: A Prospective, Parallel-Group, Double-Blind, Randomized Controlled Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03159078
• Other study ID #: B1210116
• Status: Recruiting
• Phase: Phase 3
• Start date: May 25, 2017
• Est. completion date: December 1, 2019

Study information

• Verified date: February 2019
• Source: University of Puerto Rico
• Contact: Juan M Maldonado Lozada, Pharm D
• Phone: 7875570612
• Email: juan.maldonado12[@]upr.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety and efficacy of polymyxin B as monotherapy versus a combined polymyxin B-carbapenem therapy against multidrug-resistant (MDR) gram negative infections. The investigators intend to evaluate if this synergistic drug regimen correlates with improved outcomes against gram-negative infections in critically ill patients including: better clinical resolution, reduced length of stay at hospital, reduced length of stay at the intensive care unit, and less recurrence of infection.

Description:

The "MUSEUM" trial is a single-center, prospective, parallel-group, double-blind, randomized, controlled study design. The trial will be conducted at the Intensive Care Unit of the Puerto Rico Trauma Hospital located in San Juan, Puerto Rico. Patients with clinical and microbiological evidence of an Multi-drug resistant infection related to Hospital-acquired pneumonia (HAP), Ventilator-associated pneumonia (VAP), Complicated Urinary tract infection (cUTI) or Bloodstream infection (BSI) will be considered candidates for the study. The pathogen should be resistant to all antibiotics except to polymyxin B. With a predicted survival rate of 67% (hazard ratio of 0.33), a significance of α = 0.05, power of 80%, and assuming a dropout rate of 15%, the estimated sample size is n = 40 patients (20 per group). In terms of safety, the most clinically relevant adverse effects are nephrotoxicity and neurotoxicity, which will be evaluated and adjudicated. The recurrence of infection will be defined as a new superinfection by the same or other species than the initial infection that is multidrug-resistant. Length of stay at the Hospital will be measured from the day of admission until the day of discharge. Length of stay in the ICU will be measured from the day of admission until the day of discharge from the unit. To our knowledge, this will be the first prospective, double blind, randomized, controlled clinical trial in representation of the critically ill trauma patients infected with Multi-drug resistant pathogens.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 1, 2019
• Est. primary completion date: December 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• 21 years or older admitted to the Intensive Care Unit of the Puerto Rico Trauma Hospital ° Consent form signed,

• Clinical and microbiological evidence of a MDR infection related to HAP, VAP, cUTI or BSI.

• The pathogen should be resistant to almost all antibiotics, AND/OR intermediate resistant to some of the antibiotics, AND/OR susceptible only to a class of antibiotic (i.e. aminoglycosides which are NOT recommended as monotherapy), AND/OR the clinician decision is to start the patient on polymyxin B due to severity of the infection.

• Patient with a diagnosis of MDR infection, who have not received antibiotics at all; OR if received would be < 72 hours with polymyxin B or imipenem at/or after the diagnosis of MDR AND/OR at the time of randomization

• Have a life expectancy of > 24 hours according to the attending physician's criteria.

Exclusion Criteria:

• Pregnant woman

• Prisoners

• Severe hepatic failure (defined by serum conjugated bilirubin > 3 mg/dL)

• End-stage renal disease requiring hemodialysis

• Hypersensitivity to any study drug

• Septic shock at the moment of randomization

• Died within 48 hours of starting the study

Related Conditions & MeSH terms

• Critical Illness
• Infection
• Resistant Infection
• Trauma

Intervention

Drug:
• Polymyxin B
Comparison of Poly B monotherapy vs Polymyxin B plus carbapenem in MDR infections

Locations

Country	Name	City	State
Puerto Rico	Trauma Hospital	San Juan

Sponsors (1)

Lead Sponsor	Collaborator
University of Puerto Rico

Country where clinical trial is conducted

Puerto Rico, 

References & Publications (21)

Anthony KB, Fishman NO, Linkin DR, Gasink LB, Edelstein PH, Lautenbach E. Clinical and microbiological outcomes of serious infections with multidrug-resistant gram-negative organisms treated with tigecycline. Clin Infect Dis. 2008 Feb 15;46(4):567-70. doi — View Citation

Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowerin — View Citation

Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, Bassetti M, Malacarne P, Petrosillo N, Galdieri N, Mocavero P, Corcione A, Viscoli C, Zarrilli R, Gallo C, Utili R. Colistin and rifampicin compared with colistin alone for t — View Citation

Falagas ME, Rafailidis PI, Kasiakou SK, Hatzopoulou P, Michalopoulos A. Effectiveness and nephrotoxicity of colistin monotherapy vs. colistin-meropenem combination therapy for multidrug-resistant Gram-negative bacterial infections. Clin Microbiol Infect. — View Citation

Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, Rice JC, Saint S, Schaeffer AJ, Tambayh PA, Tenke P, Nicolle LE; Infectious Diseases Society of America. Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adu — View Citation

Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of Adults Wit — View Citation

Kassamali Z, Jain R, Danziger LH. An update on the arsenal for multidrug-resistant Acinetobacter infections: polymyxin antibiotics. Int J Infect Dis. 2015 Jan;30:125-32. doi: 10.1016/j.ijid.2014.10.014. Epub 2014 Nov 5. Review. — View Citation

Kellum JA, Lameire N; KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013 Feb 4;17(1):204. doi: 10.1186/cc11454. Review. — View Citation

Landman D, Georgescu C, Martin DA, Quale J. Polymyxins revisited. Clin Microbiol Rev. 2008 Jul;21(3):449-65. doi: 10.1128/CMR.00006-08. Review. — View Citation

Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. Multidrug-resistant, extensively drug-resi — View Citation

Maragakis LL, Perl TM. Acinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options. Clin Infect Dis. 2008 Apr 15;46(8):1254-63. doi: 10.1086/529198. Review. — View Citation

Michel DJ, Knodel LC. Comparison of three algorithms used to evaluate adverse drug reactions. Am J Hosp Pharm. 1986 Jul;43(7):1709-14. — View Citation

Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, Polsky B, Adams-Haduch JM, Doi Y. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Ch — View Citation

Rigatto MH, Vieira FJ, Antochevis LC, Behle TF, Lopes NT, Zavascki AP. Polymyxin B in Combination with Antimicrobials Lacking In Vitro Activity versus Polymyxin B in Monotherapy in Critically Ill Patients with Acinetobacter baumannii or Pseudomonas aerugi — View Citation

Sandri AM, Landersdorfer CB, Jacob J, Boniatti MM, Dalarosa MG, Falci DR, Behle TF, Bordinhão RC, Wang J, Forrest A, Nation RL, Li J, Zavascki AP. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selectio — View Citation

Seifert H. The clinical importance of microbiological findings in the diagnosis and management of bloodstream infections. Clin Infect Dis. 2009 May 15;48 Suppl 4:S238-45. doi: 10.1086/598188. — View Citation

Siddiqui NU, Qamar FN, Jurair H, Haque A. Multi-drug resistant gram negative infections and use of intravenous polymyxin B in critically ill children of developing country: retrospective cohort study. BMC Infect Dis. 2014 Nov 28;14:626. doi: 10.1186/s1287 — View Citation

Sobieszczyk ME, Furuya EY, Hay CM, Pancholi P, Della-Latta P, Hammer SM, Kubin CJ. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. J Antimicrob Chemother. 2004 Aug;54(2):566-9. Epub — View Citation

Struelens MJ. The epidemiology of antimicrobial resistance in hospital acquired infections: problems and possible solutions. BMJ. 1998 Sep 5;317(7159):652-4. Review. — View Citation

Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, Losito AR, Tedeschi S, Cauda R, Bassetti M. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenem — View Citation

Zavascki AP, Bulitta JB, Landersdorfer CB. Combination therapy for carbapenem-resistant Gram-negative bacteria. Expert Rev Anti Infect Ther. 2013 Dec;11(12):1333-53. doi: 10.1586/14787210.2013.845523. Epub 2013 Nov 6. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Resolution of the evidence of clinical infection	Resolution of infection will be subjective to clinical criteria of the physician, AND patient has to be afebrile (temperature < 38°C), or normothermic (temperature 36-37.5°C), AND have white blood cell count within normal limits (> 4,000 and < 10,000 cells/mm3).	7-14 days, according to site of infection
Secondary	30-day mortality	Thirty-day (30-day) mortality will be measured from the day of hospital admission until discharge.	30 days
Secondary	Recurrence of infection	The recurrence of infection will be defined as a new superinfection by the same or other species than the initial infection that is multidrug-resistant.	30 days
Secondary	Length of stay at Hospital	Will be measured from the day of hospital admission until discharge.	30 days
Secondary	Length of stay at ICU.	Will be measured from the day of ICU admission until transfer or discharge.	30 days

External Links

•   Antibiotic resistance threats in the United States
•   Gram-negative Bacteria Infections in Healthcare Settings
•   Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem
•   Performance standards for antimicrobial susceptibility testing: twenty-six informational supplement.
•   Polymyxin B for Injection
•   Primaxin I.V. (Imipenem and Cilastatin for IV Injection).
•   Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli
•   Type of Healthcare-Associated Infections