Evaluating a Novel Individualised Treatment Strategy for Carbapenem-Resistant Gram-Negative Bacteria Infections

NCT04202861 | Unknown DMC

• 1 other identifier: 2018/2880
• Study Type: interventional
• Target: 594
• Locations: 1 country
• Sites: 1

Brief Summary

Carbapenem-resistant (CR) Gram negative bacteria (GNB) - which are resistant to carbapenems (a last-line potent antibiotic with a high therapeutic index) - are also resistant to all other beta-lactam antibiotics. Most CRGNB are also extensively-drug resistant (XDR) (resistant to all classes of antibiotics except polymyxins and/or tigecycline) or pan-drug resistant (PDR) (resistant to all antibiotics), resulting in a dearth of effective options against these life-threatening infections. Against CRGNB, standard therapy includes monotherapy (using polymyxins or tigecycline) or unguided antibiotics combination (polymyxins + carbapenem). Unfortunately, CRGNB can develop resistance after antibiotic monotherapy, resulting in the further development of pan-drug resistance. Unguided antibiotic combinations, selected anecdotally based on past experience, are also unlikely to be useful in our local setting, as effective antimicrobial combinations are bacterial-strain specific due to large variation in molecular mechanisms of resistance.Hence, the investigators propose to evaluate the efficacy of a novel treatment strategy using in vitro antibiotic combination testing (iACT) to guide antibiotic combinations in the management of patients with CRGNB infections in a randomised controlled trial (RCT).

Conditions

Antibiotic Therapy

Outcome Measures

Primary Outcomes (1)

• 30-day all cause mortality rate post therapy initiation after randomization

  We define this as all cause mortality as death of any cause. We aim to compare the difference in 30-day all cause mortality rates post therapy initiation between both arms

  30 days

Secondary Outcomes (2)

• 30-day infection-related mortality post therapy initiation after randomization

  30 days

• Microbiological clearance

  Day 7 post randomisation

Study Arms (2)

in vitro antibiotic combination testing (iACT)

EXPERIMENTAL

For the intervention arm, CRGNB isolates from the index culture should be transported to the Pharmacy Research Lab in Singapore General Hospital as soon as possible to begin iACT. For external sites, a licensed medical courier will be engaged. Once testing is complete, the iACT results will be sent to the physicians and the ID specialist managing the patient. Several antibiotic combinations can usually be used to treat the infection; a subset of results will be published in the iACT report. Participants enrolled into the intervention arm -should ideally be kept on an iACT combination for the required treatment period. However during the treatment period, the treating doctor-in-charge and/or the consulting infectious disease doctor may exercise their discretion in continuing iACT antibiotic combination therapy or modifying the combinations based on their best clinical judgement, according to the clinical conditions and reactions of the patient to the treatment

Diagnostic Test: In vitro antibiotic combination testing (iACT)

Control

NO INTERVENTION

The standard arm will receive standard therapy of either antibiotic monotherapy or unguided combination therapy, a choice based on treating physicians' best clinical judgment. iACT will only be performed on CRGNB isolates from the standard arm at least 30 days after enrolment for collection of microbiological, proteomic and molecular data. Antibiotic combinations found from delayed iACT will be made known to the Infectious Diseases physician caring for the participant.

Interventions

In vitro antibiotic combination testing (iACT) DIAGNOSTIC_TEST

CRGNB isolates from the index culture will be transported to the Pharmacy Research Lab,SGH for iACT testing. iACT results will be sent to the physicians and ID specialist managing the patient once completed. A subset of results will be published in the iACT report. Participants enrolled into the intervention arm -should ideally be kept on an iACT combination for the required treatment period. However during the treatment period, the treating doctor-in-charge and or the consulting infectious disease doctor may wish to continuing iACT antibiotic combination therapy or modifying the combinations based on their best clinical judgement for the patient.

Also known as: Intervention Arm

in vitro antibiotic combination testing (iACT)

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Inpatient at the time of enrolment.
• Age ≥16 years.
• An ongoing infection as defined by the published Centers for Disease Control and Prevention (CDC) /National Healthcare Safety Network (NHSN) or Infectious Diseases Society of America (IDSA) guidelines; Section 16.1-16.6 Appendix specifies the most common examples expected in this study.
• Positive culture of CRGNB isolates from relevant clinical sites (i.e. samples that are not obtained for surveillance purposes, such as rectal swabs)
• No more than 5 calendar days has elapsed since the first positive culture collection.

You may not qualify if:

• Unable to provide consent AND have no legal representative (LR).
• Subjects on palliative care or with less than 24 hours of life expectancy (as discussed with their primary physicians).
• Colonisation only, which is defined as positive isolation of CRGNB isolated at screening sites (e.g., rectal swabs) only
• Prior recruitment into this study.

Sponsors & Collaborators

• Singapore General Hospital: lead
• National Medical Research Council (NMRC), Singapore: collaborator

Study Sites (1)

Andrea Lay Hoon KWA (SGH)

Singapore, 169608, Singapore

RECRUITING

Related Publications (34)

• Cai Y, Chua NG, Lim TP, Teo JQ, Lee W, Kurup A, Koh TH, Tan TT, Kwa AL. From Bench-Top to Bedside: A Prospective In Vitro Antibiotic Combination Testing (iACT) Service to Guide the Selection of Rationally Optimized Antimicrobial Combinations against Extensively Drug Resistant (XDR) Gram Negative Bacteria (GNB). PLoS One. 2016 Jul 21;11(7):e0158740. doi: 10.1371/journal.pone.0158740. eCollection 2016.

  PMID: 27441603 BACKGROUND

• Cai Y, Lim TP, Teo J, Sasikala S, Lee W, Hong Y, Chan EC, Tan TY, Tan TT, Koh TH, Hsu LY, Kwa AL. In Vitro Activity of Polymyxin B in Combination with Various Antibiotics against Extensively Drug-Resistant Enterobacter cloacae with Decreased Susceptibility to Polymyxin B. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5238-46. doi: 10.1128/AAC.00270-16. Print 2016 Sep.

  PMID: 27324776 BACKGROUND

• Cai B, Cai Y, Liew YX, Chua NG, Teo JQ, Lim TP, Kurup A, Ee PL, Tan TT, Lee W, Kwa AL. Clinical Efficacy of Polymyxin Monotherapy versus Nonvalidated Polymyxin Combination Therapy versus Validated Polymyxin Combination Therapy in Extensively Drug-Resistant Gram-Negative Bacillus Infections. Antimicrob Agents Chemother. 2016 Jun 20;60(7):4013-22. doi: 10.1128/AAC.03064-15. Print 2016 Jul.

  PMID: 27090177 BACKGROUND

• Lim TP, Tan TY, Lee W, Sasikala S, Tan TT, Hsu LY, Kwa AL. In-vitro activity of polymyxin B, rifampicin, tigecycline alone and in combination against carbapenem-resistant Acinetobacter baumannii in Singapore. PLoS One. 2011 Apr 21;6(4):e18485. doi: 10.1371/journal.pone.0018485.

  PMID: 21533030 BACKGROUND

• Lim TP, Lee W, Tan TY, Sasikala S, Teo J, Hsu LY, Tan TT, Syahidah N, Kwa AL. Effective antibiotics in combination against extreme drug-resistant Pseudomonas aeruginosa with decreased susceptibility to polymyxin B. PLoS One. 2011;6(12):e28177. doi: 10.1371/journal.pone.0028177. Epub 2011 Dec 5.

  PMID: 22162759 BACKGROUND

• Lim TP, Cai Y, Hong Y, Chan EC, Suranthran S, Teo JQ, Lee WH, Tan TY, Hsu LY, Koh TH, Tan TT, Kwa AL. In vitro pharmacodynamics of various antibiotics in combination against extensively drug-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015 May;59(5):2515-24. doi: 10.1128/AAC.03639-14. Epub 2015 Feb 17.

  PMID: 25691628 BACKGROUND

• Hsu LY, Apisarnthanarak A, Khan E, Suwantarat N, Ghafur A, Tambyah PA. Carbapenem-Resistant Acinetobacter baumannii and Enterobacteriaceae in South and Southeast Asia. Clin Microbiol Rev. 2017 Jan;30(1):1-22. doi: 10.1128/CMR.masthead.30-1. Epub 2016 Oct 19.

  PMID: 27795305 BACKGROUND

• Patel G, Huprikar S, Factor SH, Jenkins SG, Calfee DP. Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies. Infect Control Hosp Epidemiol. 2008 Dec;29(12):1099-106. doi: 10.1086/592412.

  PMID: 18973455 BACKGROUND

• Perez F, Endimiani A, Ray AJ, Decker BK, Wallace CJ, Hujer KM, Ecker DJ, Adams MD, Toltzis P, Dul MJ, Windau A, Bajaksouzian S, Jacobs MR, Salata RA, Bonomo RA. Carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae across a hospital system: impact of post-acute care facilities on dissemination. J Antimicrob Chemother. 2010 Aug;65(8):1807-18. doi: 10.1093/jac/dkq191. Epub 2010 May 31.

  PMID: 20513702 BACKGROUND

• Perez F, Van Duin D. Carbapenem-resistant Enterobacteriaceae: a menace to our most vulnerable patients. Cleve Clin J Med. 2013 Apr;80(4):225-33. doi: 10.3949/ccjm.80a.12182.

  PMID: 23547093 BACKGROUND

• Cai Y, Lee W, Kwa AL. Polymyxin B versus colistin: an update. Expert Rev Anti Infect Ther. 2015;13(12):1481-97. doi: 10.1586/14787210.2015.1093933. Epub 2015 Oct 21.

  PMID: 26488563 BACKGROUND

• Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan KE, Liolios L. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006 Sep;50(9):2946-50. doi: 10.1128/AAC.00103-06.

  PMID: 16940086 BACKGROUND

• Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenem-resistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob Agents Chemother. 2014;58(2):654-63. doi: 10.1128/AAC.01222-13. Epub 2013 Sep 30.

  PMID: 24080646 BACKGROUND

• 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 Chemother. 2012 Apr;56(4):2108-13. doi: 10.1128/AAC.06268-11. Epub 2012 Jan 17.

  PMID: 22252816 BACKGROUND

• 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: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322-8. doi: 10.1128/AAC.02166-13. Epub 2014 Feb 10.

  PMID: 24514083 BACKGROUND

• 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 aeruginosa Infections. Antimicrob Agents Chemother. 2015 Oct;59(10):6575-80. doi: 10.1128/AAC.00494-15. Epub 2015 Aug 10.

  PMID: 26259799 BACKGROUND

• Petrosillo N, Giannella M, Antonelli M, Antonini M, Barsic B, Belancic L, Inkaya A C, De Pascale G, Grilli E, Tumbarello M, Akova M. Clinical experience of colistin-glycopeptide combination in critically ill patients infected with Gram-negative bacteria. Antimicrob Agents Chemother. 2014;58(2):851-8. doi: 10.1128/AAC.00871-13. Epub 2013 Nov 25.

  PMID: 24277037 BACKGROUND

• Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother. 2014 Sep;58(9):5598-601. doi: 10.1128/AAC.02435-13. Epub 2014 Jun 30.

  PMID: 24982065 BACKGROUND

• Chen Z, Chen Y, Fang Y, Wang X, Chen Y, Qi Q, Huang F, Xiao X. Meta-analysis of colistin for the treatment of Acinetobacter baumannii infection. Sci Rep. 2015 Nov 24;5:17091. doi: 10.1038/srep17091.

  PMID: 26597507 BACKGROUND

• Pogue JM, Kaye KS. Is there really no benefit to combination therapy with colistin? Expert Rev Anti Infect Ther. 2013 Sep;11(9):881-4. doi: 10.1586/14787210.2013.827881.

  PMID: 24053270 BACKGROUND

• Cheng A, Chuang YC, Sun HY, Sheng WH, Yang CJ, Liao CH, Hsueh PR, Yang JL, Shen NJ, Wang JT, Hung CC, Chen YC, Chang SC. Excess Mortality Associated With Colistin-Tigecycline Compared With Colistin-Carbapenem Combination Therapy for Extensively Drug-Resistant Acinetobacter baumannii Bacteremia: A Multicenter Prospective Observational Study. Crit Care Med. 2015 Jun;43(6):1194-204. doi: 10.1097/CCM.0000000000000933.

  PMID: 25793437 BACKGROUND

• Teo JQ, Cai Y, Lim TP, Tan TT, Kwa AL. Carbapenem Resistance in Gram-Negative Bacteria: The Not-So-Little Problem in the Little Red Dot. Microorganisms. 2016 Feb 16;4(1):13. doi: 10.3390/microorganisms4010013.

  PMID: 27681907 BACKGROUND

• Teo JWP, La MV, Krishnan P, Ang B, Jureen R, Lin RTP. Enterobacter cloacae producing an uncommon class A carbapenemase, IMI-1, from Singapore. J Med Microbiol. 2013 Jul;62(Pt 7):1086-1088. doi: 10.1099/jmm.0.053363-0. Epub 2013 Apr 4.

  PMID: 23558141 BACKGROUND

• Koh TH, Babini GS, Woodford N, Sng LH, Hall LM, Livermore DM. Carbapenem-hydrolysing IMP-1 beta-lactamase in Klebsiella pneumoniae from Singapore. Lancet. 1999 Jun 19;353(9170):2162. doi: 10.1016/s0140-6736(05)75604-x. No abstract available.

  PMID: 10382730 BACKGROUND

• Koh TH, Sng LH, Babini GS, Woodford N, Livermore DM, Hall LM. Carbapenem-resistant Klebsiella pnuemoniae in Singapore producing IMP-1 beta-lactamase and lacking an outer membrane protein. Antimicrob Agents Chemother. 2001 Jun;45(6):1939-40. doi: 10.1128/AAC.45.6.1939-1940.2001. No abstract available.

  PMID: 11407332 BACKGROUND

• Koh TH, Cao D, Shan QY, Bacon A, Hsu LY, Ooi EE. Acquired carbapenemases in Enterobactericeae in Singapore, 1996-2012. Pathology. 2013 Oct;45(6):600-3. doi: 10.1097/PAT.0b013e3283650b1e.

  PMID: 24018814 BACKGROUND

• Balm MN, La MV, Krishnan P, Jureen R, Lin RT, Teo JW. Emergence of Klebsiella pneumoniae co-producing NDM-type and OXA-181 carbapenemases. Clin Microbiol Infect. 2013 Sep;19(9):E421-3. doi: 10.1111/1469-0691.12247. Epub 2013 May 13.

  PMID: 23668475 BACKGROUND

• Balm MN, Ngan G, Jureen R, Lin RT, Teo J. Molecular characterization of newly emerged blaKPC-2-producing Klebsiella pneumoniae in Singapore. J Clin Microbiol. 2012 Feb;50(2):475-6. doi: 10.1128/JCM.05914-11. Epub 2011 Nov 23.

  PMID: 22116160 BACKGROUND

• Teo J, Ngan G, Balm M, Jureen R, Krishnan P, Lin R. Molecular characterization of NDM-1 producing Enterobacteriaceae isolates in Singapore hospitals. Western Pac Surveill Response J. 2012 Mar 29;3(1):19-24. doi: 10.5365/WPSAR.2011.2.4.010. Print 2012 Jan.

  PMID: 23908903 BACKGROUND

• Teo JQ, Ong RT, Xia E, Koh TH, Khor CC, Lee SJ, Lim TP, Kwa AL. mcr-1 in Multidrug-Resistant blaKPC-2-Producing Clinical Enterobacteriaceae Isolates in Singapore. Antimicrob Agents Chemother. 2016 Sep 23;60(10):6435-7. doi: 10.1128/AAC.00804-16. Print 2016 Oct. No abstract available.

  PMID: 27503652 BACKGROUND

• Hawkey PM. Multidrug-resistant Gram-negative bacteria: a product of globalization. J Hosp Infect. 2015 Apr;89(4):241-7. doi: 10.1016/j.jhin.2015.01.008. Epub 2015 Feb 4.

  PMID: 25737092 BACKGROUND

• Hong JH, Clancy CJ, Cheng S, Shields RK, Chen L, Doi Y, Zhao Y, Perlin DS, Kreiswirth BN, Nguyen MH. Characterization of porin expression in Klebsiella pneumoniae Carbapenemase (KPC)-producing K. pneumoniae identifies isolates most susceptible to the combination of colistin and carbapenems. Antimicrob Agents Chemother. 2013 May;57(5):2147-53. doi: 10.1128/AAC.02411-12. Epub 2013 Mar 4.

  PMID: 23459476 BACKGROUND

• Shields RK, Nguyen MH, Potoski BA, Press EG, Chen L, Kreiswirth BN, Clarke LG, Eschenauer GA, Clancy CJ. Doripenem MICs and ompK36 porin genotypes of sequence type 258, KPC-producing Klebsiella pneumoniae may predict responses to carbapenem-colistin combination therapy among patients with bacteremia. Antimicrob Agents Chemother. 2015 Mar;59(3):1797-801. doi: 10.1128/AAC.03894-14. Epub 2014 Dec 22.

  PMID: 25534733 BACKGROUND

• Clancy CJ, Chen L, Hong JH, Cheng S, Hao B, Shields RK, Farrell AN, Doi Y, Zhao Y, Perlin DS, Kreiswirth BN, Nguyen MH. Mutations of the ompK36 porin gene and promoter impact responses of sequence type 258, KPC-2-producing Klebsiella pneumoniae strains to doripenem and doripenem-colistin. Antimicrob Agents Chemother. 2013 Nov;57(11):5258-65. doi: 10.1128/AAC.01069-13. Epub 2013 Aug 12.

  PMID: 23939888 BACKGROUND

Study Officials

• Andrea LH Kwa, PharmD

  Singapore General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrea LH Kwa, PharmD

CONTACT

65 6326 6959; andrea.kwa.l.h@sgh.com.sg

Anne-Marie Govindasamy, BSc

CONTACT

65 6576 2797; anne.marie.g@sgh.com.sg

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The investigators plan to conduct a randomised controlled trial to evaluate a new treatment strategy for CRGNB infections, termed guided antibiotic combination therapy, using the most effective (synergistic and bactericidal) antibiotic combination indicated by iACT. It is an investigator-initiated, two-site, two-arm, open-label, RCT. The randomisation will be stratified for the 2 hospitals. At each site, treatments will be randomly assigned to study subjects in a 1:1 ratio using a computer-generated, permuted-block randomisation schedule with a random block size known only to the study biostatistician. Randomisation of participants can be done through a web portal, or through backup randomisation envelopes if internet service is disrupted.

Study Record Dates

• First Submitted: April 14, 2019
• First Posted: December 18, 2019
• Study Start: July 8, 2019
• Primary Completion: September 30, 2022
• Study Completion: March 31, 2023
• Last Updated: October 8, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)