Clostridium difficile Infection

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Jul 16, 2015 - Bass EB, Steinberg EP, Luthra R, et al. ... difficile infection by Leffler and Lamont (April 16 issue)1 updates previous .... J. Thomas Lamont, M.D..
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Since publication of their article, the authors report no further potential conflict of interest. 1. Bass EB, Steinberg EP, Luthra R, et al. Do ophthalmologists,

anesthesiologists, and internists agree about preoperative testing in healthy patients undergoing cataract surgery? Arch Ophthalmol 1995;113:1248-56. 2. Brown SR, Brown J. Why do physicians order unnecessary preoperative tests? A qualitative study. Fam Med 2011;43:338-43. 3. American Academy of Ophthalmology. Routine pre-operative laboratory testing for patients scheduled for cataract surgery: clinical statement. January 2014 (http://www.aao.org/ clinical-statement/routine-preoperative-laboratory-testing -patients-s). 4. Apfelbaum JL, Connis RT, Nickinovich DG, et al. Practice advisory for preanesthesia evaluation: an updated report by the

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American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology 2012;116:522-38. 5. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines: developed in collaboration with the American College of Surgeons, American Society of Anesthesiologists, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, and Society of Vascular Medicine Endorsed by the Society of Hospital Medicine. J Nucl Cardiol 2015;22:162-215. DOI: 10.1056/NEJMc1506125

Clostridium difficile Infection To the Editor: The review article on Clostridium difficile infection by Leffler and Lamont (April 16 issue)1 updates previous reviews and will serve as a valuable reference. The authors address the association between acid suppression and the risk factors for C. difficile infection. We would suggest that evidence of the association of the use of proton-pump inhibitors (PPIs) with C. difficile infection is more compelling than posited. In addition to biologic plausibility, a large, prospective, observational study by Loo et al.2 showed a strong association between PPI use and the development of infection due to C. difficile, and this association has been recognized by the Food and Drug Administration.3 Observational studies also have shown that continuous PPI use is common in patients with C. difficile infection (in 40 to 60% of patients) and may be associated with an increased risk of recurrence.4,5 Furthermore, approximately half of PPIs in patients with C. difficile infection are prescribed continuously without an evidence-based indication.5 We recognize the limitations of observational studies. However, it seems reasonable to acknowledge this potential association and discontinue the unnecessary use of PPIs in patients who are at risk for a first or recurrent C. difficile infection. Emily G. McDonald, M.D. Todd C. Lee, M.D., M.P.H. McGill University Health Centre Montreal, QC, Canada [email protected]

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No potential conflict of interest relevant to this letter was reported. 1. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J

Med 2015;372:1539-48.

2. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen

factors for Clostridium difficile infection and colonization. N Engl J Med 2011;365:1693-703. 3. Food and Drug Administration. FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs) February 8, 2012 (http://www.fda.gov/drugs/drugsafety/ ucm290510.htm). 4. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010;170:772-8. 5. McDonald EG, Milligan J, Frenette C, Lee TC. Continuous proton pump inhibitor therapy and the risk of recurrent Clostridium difficile. JAMA 2015;175:784-91. DOI: 10.1056/NEJMc1506004

To the Editor: Leffler and Lamont do not mention the potential therapeutic role of nontoxigenic strains of C. difficile in the prevention of recurrent C. difficile infection. Results of previous studies involving hamsters and small samples of patients1-3 spurred a recent randomized, controlled trial that showed a significantly lower rate of recurrence of C. difficile infection among patients who received the oral nontoxigenic C. difficile strain M3 than among those who received placebo (11% vs. 30%, P = 0.006).4 The mechanism of action is probably due to the competition between nontoxigenic strains of C. difficile and toxigenic strains of C. difficile for the same metabolic or adherence niche in the gastrointestinal tract. This mechanism was shown by the high correlation between fecal colonization

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with nontoxigenic C. difficile strain M3 and the reduced recurrence rate in the aforementioned trial.4 The administration of a nontoxigenic strain of C. difficile to prevent the relapse of C. difficile infection in patients who are at risk for recurrence may be a valuable and safe therapeutic option with an acceptable side-effect profile. Antonio Facciorusso, M.D.

No potential conflict of interest relevant to this letter was reported.

University of Foggia Foggia, Italy [email protected] No potential conflict of interest relevant to this letter was reported.

DOI: 10.1056/NEJMc1506004

1. Borriello SP, Barclay FE. Protection of hamsters against

Clostridium difficile ileocaecitis by prior colonisation with nonpathogenic strains. J Med Microbiol 1985;19:339-50. 2. Seal D, Borriello SP, Barclay F, Welch A, Piper M, Bonnycastle M. Treatment of relapsing Clostridium difficile diarrhoea by administration of a non-toxigenic strain. Eur J Clin Microbiol 1987;6:51-3. 3. Wilson KH, Sheagren JN. Antagonism of toxigenic Clostridium difficile by nontoxigenic C. difficile. J Infect Dis 1983;147:733-6. 4. Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA 2015;313:1719-27. DOI: 10.1056/NEJMc1506004

To the Editor: Leffler and Lamont correctly state that colectomy for fulminant C. difficile colitis carries a poor prognosis (as high as 80% mortality). However, important data have not been provided. The rates of fulminant C. difficile colitis that is refractory to medical therapy are increasing. A recent systematic review involving more than 500 patients with fulminant, refractory C. difficile colitis concluded that colectomy provided a survival advantage over the continuation of medical therapy.1 Newer colon-preserving techniques, one of which2 is outlined by Leffler and Lamont, show promise; however, data are lacking to show a clear patient benefit over colectomy. Early surgical assessment is recommended in patients with complicated C. difficile infection. This assessment has been shown to reduce mortality and is integral to the multidisciplinary management of the disease. Sam K. Sharma, M.B., B.Ch. Kentaro Nakajima, M.D. Parul J. Shukla, M.B., B.S. Weill Cornell Medical College New York, NY [email protected]

1. Stewart DB, Hollenbeak CS, Wilson MZ. Is colectomy for

fulminant Clostridium difficile colitis life saving? A systematic review. Colorectal Dis 2013;15:798-804. 2. Neal MD, Alverdy JC, Hall DE, Simmons RL, Zuckerbraun BS. Diverting loop ileostomy and colonic lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg 2011;254:423-7.

The Authors Reply: As indicated by McDonald and Lee, Facciorusso, and Sharma et al., the epidemiology and therapy of C. difficile infection are complex and evolving. Regarding the interaction between C. difficile infection and acid blockade, primarily with PPIs, we agree that there is biologic plausibility; studies show an association, and this interaction is possibly mediated by PPIdriven change in the intestinal microbiota.1 In our opinion, whether PPI use is a risk factor for C. difficile infection or a marker of C. difficile infection risk remains uncertain.2 Unfortunately, without a randomized, controlled trial of the effect of PPI use on C. difficile infection, a definitive answer to this important question will remain elusive. Facciorusso quite correctly points out that nontoxigenic strains of C. difficile are potentially effective for the prevention of recurrent C. difficile infection. Although this strategy has been acknowledged for a number of decades, manufacturing and regulatory difficulties have prevented major progress in this area. Gerding et al.3 recently reported the results of a positive, welldesigned trial that suggest that this is a promising approach; these results were not available when our article was published. Sharma and colleagues discuss current best practices for the treatment of fulminant C. difficile infection. We are in full agreement that this disease is best managed by a multidisciplinary team that includes intensivists, specialists in C. difficile infection, and surgeons. Although Stewart and colleagues’ review of surgical outcomes in patients with C. difficile infection does suggest a benefit of surgery,4 it is notable that none of the six studies included in the review showed a significant survival advantage, and two studies actually showed a trend toward higher mortality with surgery. Limited data on ileostomy with colonic lavage do not suggest

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worse outcomes than outcomes after colectomy, and the ability to undergo reanastomosis after recovery is a benefit of an intact colon. Although data are lacking on which surgical technique offers the best survival and long-term outcomes, we would argue that this question is secondary to the question of how best to predict which patients will not have a response to antibiotic therapy and would benefit from surgery before becoming critically ill. Recently published results of a study on predicting severe C. difficile infection may help to inform this difficult clinical decision.5 Daniel A. Leffler, M.D. J. Thomas Lamont, M.D. Beth Israel Deaconess Medical Center Boston, MA [email protected]

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Since publication of their article, the authors report no further potential conflict of interest. 1. Seto CT, Jeraldo P, Orenstein R, Chia N, DiBaise JK. Pro-

longed use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility. Microbiome 2014;2:42. 2. Novack L, Kogan S, Gimpelevich L, et al. Acid suppression therapy does not predispose to Clostridium difficile infection: the case of the potential bias. PLoS One 2014;9(10):e110790. 3. Gerding DN, Meyer T, Lee C, et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA 2015;313:1719-27. 4. Stewart DB, Hollenbeak CS, Wilson MZ. Is colectomy for fulminant Clostridium difficile colitis life saving? A systematic review. Colorectal Dis 2013;15:798-804. 5. Na X, Martin AJ, Sethi S, et al. A multi-center prospective derivation and validation of a clinical prediction tool for severe Clostridium difficile infection. PLoS One 2015;10(4):e0123405. DOI: 10.1056/NEJMc1506004

Anti–PD-1–Related Pneumonitis during Cancer Immunotherapy To the Editor: The use of antibodies against programmed cell death 1 (PD-1), which block inhibitory T-cell checkpoints, is a promising new therapy for advanced cancers.1 Recent trials have shown substantial clinical activity of anti–PD-1 antibodies in advanced cancers and led to the approvals of these agents, including pembrolizumab for melanoma and nivolumab for melanoma and squamous-cell lung cancer.2-4 Pneumonitis related to the use of antibodies against PD-1 is an immune-mediated toxic effect that resulted in three drug-related deaths in a phase 1 trial.1 Clinical identification and management of pneumonitis are contingent on radiographic assessment. We report three cases of pneumonitis associated with the use of anti–PD-1 antibodies in patients with melanoma. A 70-year-old man (Patient 1) received nivo­ lumab and ipilimumab sequentially. A 38-yearold woman (Patient 2) and a 58-year-old man (Patient 3) were treated with nivolumab alone; Patient 2 had previously received ipilimumab before starting the nivolumab trial. The onset of pneumonitis occurred 7.4 to 24.3 months after the initiation of therapy (Table S1 in the Supple­ mentary Appendix, available with the full text of this letter at NEJM.org). Computed tomographic

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(CT) imaging of pneumonitis at the time of diagnosis showed a spectrum of findings that are typically seen in interstitial pneumonias.5 These conditions were morphologically classified as acute interstitial pneumonia–acute respiratory distress syndrome (ARDS) in Patients 1 and 2 and as nonspecific interstitial pneumonia in Patient 3 (Table S2 in the Supplementary Appendix). In Patients 1 and 2 with ARDS-pattern pneumonitis, diffuse ground-glass opacities, reticular opacities, consolidation, and traction bronchiectasis involved all lobes, with decreased lung volumes and effusions (Fig. 1A, 1B, and 1C). In Patient 1, the symptoms rapidly progressed during the 2 weeks before the diagnosis (Fig. 1A and 1B). The two patients were admitted to the intensive care unit and received intravenous antibiotic agents, glucocorticoids, and infliximab. Patient 1 required intubation, and his condition improved over the course of 10 weeks. Patient 2 died 4 weeks after the diagnosis of pneumonitis. Patient 3 had ground-glass opacities and reticular opacities in the peripheral and lower lungs, indicative of nonspecific interstitial pneumonia (Fig. 1D). He discontinued nivolumab for 8 weeks and received oral glucocorticoids as an outpatient, and the pneumonitis resolved after

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