The Multi-Drug Resistant Organism Network

Antimicrobial resistance is an important public health threat.^1,2 Higher rates of antimicrobial resistance have several deleterious effects, and antimicrobial resistance is recognized as a global crisis for which urgent interventions are needed. Unfortunately, the prospective enrollment of patients with multidrug-resistant organism infections into interventional studies has been challenging, for several reasons. Patients with multidrug-resistant organism infections often have a high acuity of illness, which translates into a small window during which they may be consented for participation. Chronic illness is also common in this patient population, which means that applying standard exclusion criteria may lead to disqualifying large proportions of at-risk patients. In addition, syndromatic enrollment, which is the industry standard for registrational antibiotic trials (eg, complicated urinary tract infection and complicated intra-abdominal infection trials) is much more straight-forward and time-efficient. In organism-specific trials, there is an unavoidable delay between clinical recognition of the infectious syndrome and confirmation of the bacteriologic diagnosis. This delay is further compounded when antibiotic susceptibility data are required for enrollment as well. To address these issues, we have initiated an international network of study sites focused on the study of multidrug-resistant organism infections.

PATHOGENS OF SPECIFIC INTEREST

The World Health Organization (WHO) recently published their list of priority pathogens for novel antibiotic research and development.³ This list represents the result of a large global panel of experts charged with providing a ranking for multidrug-resistant organisms. Three pathogen classes, notably all gram-negative bacteria, were deemed highest (“critical”) priority: carbapenem-resistant Pseudomonas aeruginosa (CRPa), carbapenem-resistant Acinetobacter baumannii (CRAb), and Enterobacteriaceae resistant to carbapenems (CRE) and/or third-generation cephalosporins. The second (“high”) priority includes gram-positive organisms such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, which are often the cause of health care—associated infections. Also included in the high priority group are gastrointestinal pathogens (fluoroquinolone-resistant Salmonella species and Campylobacter species and clarithromycin-resistant Helicobacter pylori) as well as Neisseria gonorrhoeae resistant to third-generation cephalosporins and/or fluoroquinolones.³

THE ANTIBACTERIAL RESISTANCE LEADERSHIP GROUP

The Antibacterial Resistance Leadership Group (ARLG, arlg.org) under the leadership of Vance Fowler, MD, of Duke University, and Henry Chambers, MD, of the University of California at San Francisco, is funded by the National Institute of Allergy and Infectious Diseases (NIAID), with the mission of developing, designing, and conducting a clinical research agenda to increase knowledge of antibacterial resistance.^4,5 In addition to funding the Multi-Drug Resistant Organism Network and the studies SNAP, CRACKLE, and POP (referenced below), the ARLG has developed and supported more than 40 other studies in the priority areas of gram-positive infections, gram-negative infections, stewardship, and diagnostics.

Other key studies include the following:

• PROVIDE: assessments of optimal vancomycin dosing in patients with bloodstream infection; • PROOF: safety of different dosing regimens of oral Fosfomycin;

• MASTER-GC: multiple diagnostic platforms for extragenital Neisseria gonorrhoeae;

• SCOUT-CAP: efficacy of 5 versus 10 days of antibiotic treatment in pediatric community-acquired pneumonia;

• RADICAL: platforms to distinguish bacterial versus viral causes of acute respiratory infection; and

• ACUMIN: safety of a tetracycline antibiotic in critically ill adults.^6-11

THE MULTI-DRUG RESISTANT ORGANISM NETWORK

Federally supported through the ARLG, the Multi-Drug Resistant Organism Network is a global research network aimed at providing infrastructure for clinical and translational antimicrobial resistance research. In the United States, over 80 hospitals located in 17 states and the District of Columbia participate in the Multi-Drug Resistant Organism Network. Outside of the United States, study sites are actively enrolling patients in South and Central America, China, and the Asia/Pacific region. Currently, the focus of the Multi-Drug Resistant Organism Network is on observational studies that will delineate the global clinical and molecular epidemiology of WHO critical priority pathogens. These data will be used to help design multicenter, prospective, randomized, controlled, interventional therapeutic and diagnostic antimicrobial resistance studies. More important than a network of study sites, the Multi-Drug Resistant Organism Network represents a collaboration between like-minded clinical antimicrobial resistance researchers. This “human capital” of talented infectious disease physicians, microbiologists, and pharmacists is the greatest resource of the Multi-Drug Resistant Organism Network, as these investigators provide insights on which clinical questions to pursue and which methods will be most effective in answering those crucial questions.

SNAP, CRACKLE, POP

The origin of the Multi-Drug Resistant Organism Network is the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE). CRACKLE started in 2011 as a local collaboration between the 3 major health care systems in Cleveland, Ohio.¹² Shortly after, sites were added in Akron, Ohio; Pittsburgh, Pennsylvania; Detroit, Michigan; and Chapel Hill, North Carolina. The motivation behind starting CRACKLE was the increased rate of patients with CRE infections seen in Cleveland hospitals and the associated difficulties in treating these patients. In 60 patients with carbapenem-resistant K pneumoniae (CRKp) evaluated retrospectively in a single-center study at Cleveland Clinic, a 42% 14-day mortality was seen.¹³ With funding from the Clinical and Translational Science Collaborative of Cleveland, hospitalized patients with CRE were prospectively enrolled and their CRE isolates centrally collected and analyzed. Almost 1000 unique patients had been enrolled in CRACKLE-1 when it concluded enrollment in the summer of 2016.

From CRACKLE-1, as well as other studies, it is clear that in CRKp, sequence type (ST) 258 is the predominant ST that can be divided into at least 2 molecularly and clinically distinct clades.^14-18 In addition, a 13% non—mcr-1-mediated colistin resistance rate in CRKp was observed.¹⁹ In the same study, there were limitations with clinically used colistin testing methods. This resulted in a recommendation from the Clinical and Laboratory Standards Institute to avoid the use of e-tests for colistin susceptibility testing in clinical microbiology laboratories, which had been common practice.¹⁹ We also recently published an observational comparison between ceftazidime-avibactam versus colistin in CRE infection, one of the first studies showing a mortality advantage to new gram-negative therapies.²⁰

CRACKLE-2 started enrollment after conclusion of CRACKLE-1 and represents a geographical expansion of a similar prospective, observational approach of hospitalized patients with CRE. Using the infrastructure established for CRACKLE, the Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP), under the leadership of Yohei Doi, MD, PhD, of the University of Pittsburgh, has started to enroll patients with CRAb. To round out the evaluation of critical priority pathogens, the Prospective Observational Pseudomonas (POP) study will start later this year and focus on CRPa.

FUTURE DIRECTIONS

The ultimate goal of the Multi-Drug Resistant Organism Network is to provide an infrastructure of sites in which interventional therapeutic and diagnostic studies can be performed. The observational studies that are currently ongoing will serve 2 purposes. First, they firmly establish the collaboration between sites and the ARLG. Second, these studies provide baseline data on which study design will be based. For instance, the mortality rates typically are lower in a clinical trial than in observational studies. We can predict the extent to which this will occur by using exact patient-level data on which patients are most likely to be included in a specific trial.

The Multi-Drug Resistant Organism Network will form the basis of practice-changing studies in antimicrobial resistance for years to come. This collaborative project is only possible because many people in many hospitals are willing to participate in these often quite time-consuming and complex studies and because of the vision and support of the NIAID.

Dr. van Duin is an associate professor of medicine, in the School of Medicine, and director of the Immunocompromised Host Infectious Diseases Section at the University of North Carolina Institute for Global Health & Infectious Diseases in Chapel Hill, North Carolina.

References:

1. Global Action Plan on Antimicrobial Resistance. World Health Organization website. who.int/antimicrobial-resistance/publications/global-action-plan/en/. Published 2015. Accessed October 11, 2018.
2. Marston HD, Dixon DM, Knisely JM, Palmore TN, Fauci AS. Antimicrobial resistance. JAMA. 2016 Sep 20;316(11):1193-1204. doi: 10.1001/jama.2016.11764.
3. Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018 Mar;18(3):318-327. doi: 10.1016/S1473-3099(17)30753-3.
4. Chambers HF, Bartlett JG, Bonomo RA, et al. Antibacterial resistance leadership group: open for business. Clin Infect Dis. 2014 Jun;58(11):1571-1576. doi: 10.1093/cid/ciu132.
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6. Doi Y, Bonomo RA, Hooper DC, et al. Gram-negative Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group. Clin Infect Dis. 2017 Mar 15;64(suppl_1):S30-S35. doi: 10.1093/cid/ciw829.
7. Doernberg SB, Lodise TP, Thaden JT, et al. Gram-positive bacterial infections: research priorities, accomplishments, and future directions of the antibacterial resistance leadership group. Clin Infect Dis. 2017 Mar 15;64(suppl_1):S24-S29. doi: 10.1093/cid/ciw828.
8. Wenzler E, Bleasdale SC, Sikka M, et al. Phase I study to evaluate the pharmacokinetics, safety, and tolerability of two dosing regimens of oral fosfomycin tromethamine in healthy adult participants. Antimicrob Agents Chemother. 2018 Jul 27;62(8). pii: e00464-18. doi: 10.1128/AAC.00464-18.
9. Patel R, Tsalik EL, Petzold E, et al. MASTERMIND: Bringing microbial diagnostics to the blinic. Clin Infect Dis. 2017 Feb 1;64(3):355-360. doi: 10.1093/cid/ciw788.
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11. Tsalik EL, Petzold E, Kreiswirth BN, et al. Advancing diagnostics to address antibacterial resistance: the diagnostics and devices committee of the antibacterial resistance leadership group. Clin Infect Dis. 2017 Mar 15;64(suppl_1):S41-S47. doi: 10.1093/cid/ciw831.
12. van Duin D, Perez F, Rudin SD, et al. Surveillance of carbapenem-resistant Klebsiella pneumoniae: tracking molecular epidemiology and outcomes through a regional network. Antimicrob Agents Chemother. 2014 Jul;58(7):4035-4041. doi: 10.1128/AAC.02636-14.
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14. van Duin D, Perez F, Rudin SD, et al. Surveillance of carbapenem-resistant Klebsiella pneumoniae: tracking molecular epidemiology and outcomes through a regional network. Antimicrob Agents Chemother. 2014 Jul;58(7):4035-4041. doi: 10.1128/AAC.02636-14.
15. van Duin D, Cober E, Richter SS, et al. Impact of therapy and strain type on outcomes in urinary tract infections caused by carbapenem-resistant Klebsiella pneumoniae. J Antimicrob Chemother. 2015 Apr;70(4):1203-1211. doi: 10.1093/jac/dku495.
16. Chen L, Mathema B, Pitout JD, DeLeo FR, Kreiswirth BN. Epidemic Klebsiella pneumoniae ST258 is a hybrid strain. MBio. 2014 Jun 24;5(3):e01355-14. doi: 10.1128/mBio.01355-14..
17. Deleo FR, Chen L, Porcella SF, et al. Molecular dissection of the evolution of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae. Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4988-4993. doi: 10.1073/pnas.1321364111.
18. Pollett S, Miller S, Hindler J, Uslan D, Carvalho M, Humphries RM. Phenotypic and molecular characteristics of carbapenem-resistant Enterobacteriaceae in a health care system in Los Angeles, California, from 2011 to 2013. J Clin Microbiol. 2014 Nov;52(11):4003-4009. doi: 10.1128/JCM.01397-14.
19. Rojas LJ, Salim M, Cober E, et al. Colistin resistance in carbapenem-resistant Klebsiella pneumoniae: laboratory detection and impact on mortality. Clin Infect Dis. 2017 Mar 15;64(6):711-718. doi: 10.1093/cid/ciw805.
20. van Duin D, Lok JJ, Earley M, et al. Colistin vs. Ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis. 2018 Jan 6;66(2):163-171. doi: 10.1093/cid/cix783.