In the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), trimethoprim-sulfamethoxazole (TMP-SMX) had a limited role in the treatment of less severe carbapenem-resistant Enterobacteriaceae (CRE) infections, especially urinary tract infections. Of tested CRE, only 29% were susceptible to TMPSMX. Development of resistance further limits the use of TMPSMX in CRE infections

Bonomo R.A.

Boshe A.

Cober E.

Doi Y.

Domitrovic T.N.

Evans S.

Fowler V.G., Jr.

Henderson H.I.

Hujer A.M.

Hujer K.M.

Kalayjian R.C.

Kaye K.S.

Luterbach C.L.

Richter S.S.

Rudin S.D.

Salata R.A.

Van Duin D.

Watkins R.R.

Carolina Digital Repository

B R I E F  R E P O R TOpen Forum Infectious DiseasesBRIEF REPORT • ofid • 1The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant EnterobacteriaceaeCourtney L. Luterbach,1 Ashley Boshe,1 Heather I. Henderson,1 Eric Cober,2  Sandra S. Richter,3 Robert A. Salata,4 Robert C. Kalayjian,5 Richard R. Watkins,6,7 Andrea M. Hujer,4,8 Kristine M. Hujer,4,8 Susan D. Rudin,4,8 T. Nicholas Domitrovic,4,8 Yohei Doi,9 Keith S. Kaye,10 Scott Evans,11 Vance G. Fowler Jr.,12,13  Robert A. Bonomo,4,8,14,15,16 and David van Duin1,17,1Institute for Global Health and Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina; 2Department of Infectious Diseases and 3Department of Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio; 4Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; 5Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio; 6Department of Internal Medicine, Northeast Ohio Medical University, Rootstown, Ohio; 7Division of Infectious Diseases, Akron General Medical Center, Akron, Ohio; 8Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio; 9Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 10Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan; 11The Biostatistics Center, The George Washington University, Rockville, Maryland; 12Division of Infectious Diseases and 13Duke Clinical Research Institute, Duke University, Durham, North Carolina; 14Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio; 15Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio; 16CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, Ohio; 17Division of Infectious Diseases, University of North Carolina, Chapel Hill, North CarolinaIn the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), tri-methoprim-sulfamethoxazole (TMP-SMX) had a limited role in the treatment of less severe carbapenem-resistant Enterobacteriaceae (CRE) infections, especially urinary tract infections. Of tested CRE, only 29% were susceptible to TMP-SMX. Development of resistance further limits the use of TMP-SMX in CRE infections.Keywords. antimicrobial resistance; carbapenem-resistant Enterobacteriaceae; Klebsiella pneumonia; trimethoprim-sulfa-methoxazole; urinary tract infection.The increase in carbapenem-resistant Enterobacteriaceae (CRE) infections is of great concern. CRE cause a broad range of infec-tions in humans, including urinary tract, bloodstream, wound, and respiratory infections. Patients in hospitals, nursing homes, and other health care settings are at an increased risk of develop-ing CRE infections due to weakened immune defenses, dysbio-sis, and increased levels of exposure to antimicrobials and other patients harboring multidrug-resistant Gram-negative organ-isms [1]. In the first years of the CRE epidemic, treatment options were severely limited and included polymyxins, tigecycline, and aminoglycosides. Recently, ceftazidime-avibactam, meropen-em-vaborbactam, and plazomicin have been added as possible treatment choices with superior outcomes and improved toler-ability [2, 3]. Other agents are in the development pipeline [2]. However, limited ability of laboratories to provide susceptibility testing, high costs, and reports of treatment-emergent resistance have hindered widespread use of new antibiotics [4].Therefore, resistance rates and use of trimethoprim-sulfa-methoxazole (TMP-SMX) as a low-cost alternative treatment were evaluated in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE) [5].METHODSThe CRACKLE-1 study has been previously described [5]. Briefly, it is a multicenter, prospective observational study of hospitalized patients with CRE involving 18 hospitals located in the Great Lakes region and North Carolina. The 2012 criteria from the Centers for Disease Control and Prevention (CDC) were used to define CRE [5]. A nested cohort was created to include unique patients at the time of their first infection caused by CRE and tested for susceptibility to TMP-SMX during the study period from December 24, 2011, until June 30, 2016. For available strains, detection of carbapenemase genes and repet-itive extragenic palindromic (rep)–polymerase chain reaction (PCR) strain typing was performed as previously described [5]. TMP-SMX in vitro resistance was determined in participating clinical microbiology laboratories and defined per Clinical and Laboratory Standards Institute guidelines as a minimum inhib-itory concentration ≥4/76 µg/mL. Pitt Bacteremia score (PBS) and Charlson comorbidity score (CMS) were calculated as pre-viously described [5]. Antibiotics given within 7 days of the first positive CRE culture were evaluated. Antibiotics of interest were TMP-SMX, polymyxins, aminoglycosides, tigecycline, carbap-enems, fosfomycin, and ceftazidime-avibactam. Statistical anal-yses were performed using R, version 3.5.0 (R Foundation for Statistical Computing) [6]. Received 1 November 2018; editorial decision 10 December 2018; accepted 13 December 2018; Prior presentation. Preliminary results from this study were presented at ASM Microbe; June 1–5, 2017; New Orleans, LA.Correspondence: D. van Duin, MD, PhD, Division of Infectious Diseases, CB 7030, University of North Carolina, 130 Mason Farm Road, Chapel Hill, NC 27599 (david_vanduin@med.unc.edu).Open Forum Infectious Diseases®© The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comDOI: 10.1093/ofid/ofy351applyparastyle “fig//caption/p[1]” parastyle “FigCapt”2 • ofid • BRIEF REPORTRESULTSDuring the study period, 476 unique patients were infected with a CRE tested for susceptibility to TMP-SMX. Of these CRE, 138 (29%) were susceptible to TMP-SMX (Table 1). The baseline characteristics of patients with CRE infection caused by a TMP-SMX-susceptible isolate were similar to those of patients with TMP-SMX-resistant CRE. Similarly, no differences were seen between the 2 groups in chronic comor-bidities, acute illness, or infection types. Common infection types included urinary tract infection (UTI; 32%), bacteremia (24%), and pneumonia (22%). TMP-SMX-susceptible isolates were more likely to be non–Klebsiella pneumoniae CRE species. Overall, 255/276 (92%) of tested CRE were positive for at least 1 carbapenemase gene, which predominantly were blaKPC-2 (45%) and blaKPC-3 (45%).In the group of patients with a TMP-SMX-susceptible iso-late, 110/138 (80%) received at least 1 antibiotic of interest within 7  days of first positive culture. TMP-SMX was part of the treatment regimen in 22/110 (20%) patients and was used as monotherapy treatment in 12/110 (11%) patients. Other commonly used antibiotics in this group included car-bapenems (45%), tigecycline (41%), aminoglycosides (36%), and colistin (21%). Among patients who received TMP-SMX monotherapy, 7 (58%) had UTIs, 3 (25%) had bacteremia, and 2 (17%) had other CRE infections; 11 (92%) were infected with CRKp, and 1 (8%) had an Enterobacter species. As com-pared with patients who received other therapy (n = 88), those treated with TMP-SMX monotherapy (n  =  12) or a TMP-SMX-containing combination regimen (n  =  10) had similar comorbid conditions (median Charlson score [interquartile range {IQR}], 3 [1–5] vs 2 [2–5] and 2.5 [1–6]; P =  .80) but were substantially less acutely ill (median Pitt bacteremia score [IQR], 4 [2–4] vs 2 [0–3] and 2 [2–3]; P = .01). For TMP-SMX-susceptible CRE infections, all-cause 30-day in-hospital mortality in patients treated with TMP-SMX monotherapy or a TMP-SMX-containing combination regimen was similar to patients who did not receive TMP-SMX: 1/12 (8%), 0/10 (0%), and 17/88 (19%; P = .214).We evaluated subsequent resistance development in those patients who presented with initially susceptible TMP-SMX CRE and who later presented with another positive CRE cul-ture. Resistance was observed in 3/4 patients (75%) treated with TMP-SMX who had a subsequent CRE culture at a later date. These 4 patients all received TMP-SMX monotherapy. None of the 10 patients who received TMP-SMX as part of combi-nation therapy had subsequent CRE cultures. In 1 of 3 of these patients, the TMP-SMX-resistant isolate represented a different strain. In the other 2 patients, strain type by rep-PCR and car-bapenemase type were identical in the TMP-SMX-susceptible index strain and the subsequent TMP-SMX-resistant strain. In comparison, subsequent TMP-SMX resistance was observed in 13/29 patients (45%) who were treated with other antibiotics (P = .335). Paired strains were available for 3/13 (23%) in this group, of which all were identical by rep-PCR and carbapene-mase type.DISCUSSIONIn this study, we investigated the use of TMP-SMX in the treat-ment of CRE infections in hospitalized patients. TMP-SMX has demonstrated activity against multiple Enterobacteriaceae spe-cies and in some cases may be one of the few remaining treat-ment options for bacteria resistant to other antibiotic classes. However, increasing global levels of antibiotic resistance to Table 1. Characteristics of Patients Infected With Carbapenem-Resistant Enterobacteriaceae Compared by Susceptibility to Trimethoprim- SulfamethoxazoleAll TMP-SMX Resistant TMP-SMX Susceptible PaNo. 476 338 (71) 138 (29)Female sex 244 (51) 173 (51) 71 (51) 1.0Age, median (IQR), y 65 (53–76) 65 (54–75) 64 (50–76) .840Charlson score, median (IQR) 3 (1–5) 3 (2–5) 3 (1–5) .273Pitt bacteremia score, median (IQR) 3 (1–4) 3 (1–4) 3 (2–4) .605Length of stay, median (IQR), d 13 (7–28) 13 (7–30) 13 (6–24) .75930-d hospital mortality 81 (17) 62 (18) 19 (14) .282Klebsiella pneumoniae 464 (97) 335 (99) 129 (93) <.01Carbapenemase present/testedb 255/276 (92) 176/193 (91) 79/83 (95) .326Infection type .695Bacteremia 116 (24) 84 (25) 32 (23)Pneumonia 105 (22) 76 (22) 29 (21)Urinary tract 152 (32) 105 (31) 47 (34)Wound 65 (14) 49 (15) 16 (12)Other 38 (8) 24 (7) 14 (10)Abbreviations: IQR, interquartile range; TMX-SMP, trimethoprim-sulfamethoxazole.aCompared by Fisher exact test for proportions, Pearson’s chi-squared test for distributions, and median test for medians. bMost common carbapenemase genes detected were blaKPC-2 (45%) and blaKPC-3 (45%). BRIEF REPORT • ofid • 3TMP-SMX has limited the broad use of this antibiotic. Overall, we found that more than two-thirds of tested CRE isolates were already resistant to TMP-SMX. Carbapenem-resistant K. pneu-moniae (CRKp) makes up the majority of collected isolates in the CRACKLE-1 data set. In vitro susceptibility rates of CRKp to TMP-SMX reported in the literature are highly variable and dependent on region of the world, varying between 31% and 82% [7–9].In our cohort, TMP-SMX was infrequently used, even in those patients with TMP-SMX-susceptible isolates. A  case series from Rome describes 14 patients with KPC-producing CRKp infections treated with TMP-SMX, of whom 10 received monotherapy [10]. In that report, clinical cure was achieved in 13/14 cases, and 1/14 patients died within 30 days. However, no controls were provided.In 3 of 4 patients who received TMP-SMX treatment during their initial CRE infection, subsequent CRE isolates were found to be resistant to TMP-SMX. Treatment-emergent resistance is an important issue for all antibiotics used in the treatment of CRE, including ceftazidime-avibactam and tigecycline [4, 11].This study has a number of limitations. CRACKLE is an observational study; therefore, patients were not randomly assigned to different antibiotic treatments. Given the small sample size, we did not adjust for confounding by indication. We explicitly do not aim to provide comparative hypothesis testing analysis of TMP-SMX vs alternative treatments for CRE infections. However, we aim to provide guidance for clinicians by describing the experience with TMP-SMX as a therapeutic option in difficult-to-treat CRE infections.In summary, TMP-SMX resistance rates in CRE were high at baseline and increased after treatment. TMP-SMX was an infrequent treatment choice but may be used in highly selected, clinically stable patients with TMP-SMX-susceptible CRE in the urinary tract.AcknowledgmentsDisclaimer. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs.Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under award numbers UM1AI104681 and R21AI114508, by funding to D.V.D.  and F.P.  from the Clinical and Translational Science Collaborative of Cleveland, and by award number UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) com-ponent of the NIH and NIH roadmap for Medical Research. V.G.F.  was supported by the Mid-Career Mentoring Award K24-AI093969 from the NIH. In addition, research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the NIH under award numbers R21AI114508 (D.v.D.  and R.A.B.), R01AI100560 (R.A.B.), R01AI063517 (R.A.B.), and R01AI072219 (R.A.B.). This study was supported in part by funds and/or facilities provided by the Cleveland Department of Veterans Affairs, award number 1I01BX001974 to R.A.B. from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development, and the Geriatric Research Education and Clinical Center VISN 10 (R.A.B.). Further support came from the Research Program Committees of the Cleveland Clinic (D.V.D.) and an unrestricted research grant from the STERIS Corporation (D.V.D.). Y.D. was supported by research awards R01AI104895, R21AI123747, and R21AI135522 from the NIH. K.S.K. was supported by the National Institute of Allergy and Infectious Diseases (Division of Microbiology and Infectious Diseases protocol 10–0065 and R01AI119446-01).Potential conflicts of interest. S.S.R: research support from bio-Merieux, BD Diagnostics, Roche, Hologic, Diasorin. Y.D.: grant support from Accelerate Diagnostics, NIH; advisory board: Tetraphase, Roche, Geom. K.K: consultant, grant investigator, speaker’s bureau, consulting fee, grant recipient, and speaker honorarium from Allergan; grant recipi-ent, consultant for Merck; consultant for Xellia; consultant for Achaogen. R.R.W.: grant support from Allergan. R.A.B.: grant/research support from Achaogen, Allecra, Entasis, Merck, Roche, Shionogi, Wockhardt. V.G.F.: grant/research support from Advanced Liquid Logic, Cubist, Cerexa, MedImmune, Merck, NIH, Novartis, Pfizer, Theravance; paid consultant for Affinium, Baxter, Cerexa, Cubist, Debiopharm, Durata, Merck, Novartis, NovaDigm, The Medicines Company, MedImmune, Pfizer, Theravance, Trius; honoraria from Arpida, Astellas, Cubist, Inhibitex, Merck, Pfizer, Targanta, Theravance, Wyeth, Ortho-McNeil, Novartis, Vertex Pharmaceuticals; memberships in Merck Co-Chair V710 Vaccine. D.v.D.: advisory board for Actavis, Tetraphase, Sanofi-Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi. Research funding from Scynexis and Steris Inc. No conflicts of interest: C.L.L., A.B., H.I.H., E.C., R.A.S., R.C.K., A.M.H., K.M.H., S.D.R., T.N.D., and S.E. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.References1. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbap-enemase-producing bacteria. Lancet Infect Dis 2009; 9:228–36.2. Petty  LA, Henig  O, Patel  TS, et  al. Overview of meropenem-vaborbactam and newer antimicrobial agents for the treatment of carbapenem-resistant Enterobacteriaceae. Infect Drug Resist 2018; 11:1461–72.3. van Duin D, Lok JJ, Earley M, et al; Antibacterial Resistance Leadership Group. Colistin versus ceftazidime-avibactam in the treatment of infections due to car-bapenem-resistant Enterobacteriaceae. Clin Infect Dis 2018; 66:163–71.4. Shields RK, Chen L, Cheng S, et al. 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The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant Enterobacteriaceae

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The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant Enterobacteriaceae

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