Acknowledgments I thank Dr. Garry Cutter for his expert advice on statistics. Potential conflicts of interest. A.T.: no conflicts. Ashutosh Tamhane Department of Medicine, University of Alabama at Birmingham, Birmingham References 1. Mazurek GH, Weis SE, Moonan PK, et al. Prospective comparison of the tuberculin skin test and 2 whole-blood interferon-g release assays in persons with suspected tuberculosis. Clin Infect Dis 2007; 45:837–45. 2. Hawass NED. Comparing the sensitivities and specificities of two diagnostic procedures performed on the same group of patients. Brit J Radiol 1997; 70:360–6. 3. Altman DG, Gore SM, Gardner MJ, Pocock SJ. Statistical guidelines for contributors to medical journals. In: Altman DG, Machin D, Bryant TN, Gardner MJ, eds. Statistics with confidence. 2nd ed. Bristol, UK: BMJ Books, 2003:171–90. Reprints or correspondence: Dr. Ashutosh Tamhane, Dept. of Medicine, University of Alabama at Birmingham, 845 19th St. South, BBRB 206B, Birmingham, AL 35294 (artamhane @yahoo.com). Clinical Infectious Diseases 2008; 46:474–5 2008 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2008/4603-0021$15.00 DOI: 10.1086/524893 Reply to Tamhane To the Editor—We appreciate other researchers’ interest in refining the statistical approaches for evaluating new tests for Mycobacterium tuberculosis infection, which for the most part are not yet standardized. We concur with Dr. Tamhane’s [1] position regarding the use of McNenar’s test for correlated proportions to compare the sensitivity of the QuantiFERON-TB Gold In-Tube assay (Cellestis) with the sensitivity of the tuberculin skin test. McNemar’s test could also be used to statistically compare the specificities of 2 tests in a cohort of people without infection. However, we do not know whether the subjects without tuberculosis included in our study [2] were infected with M. tuberculosis. Although the subjects did not receive diagnoses of tuberculosis, the majority of these subjects had substantial risk of being infected with M. tuberculosis. IFN-g release assays are promising alternatives to the tuberculin skin test. We strongly encourage efforts to develop and implement tests such as these. Many questions remain to be answered, especially with regard to the predictive value of IFNg release assays. Larger studies with longterm follow-up are needed to determine the value of IFN-g release assays in predicting the risk of active tuberculous disease. Acknowledgments Potential conflicts of interest. All authors: no conflicts. Gerald H. Mazurek,1,2 Nong Shang,1 and Philip A. LoBue1 1 Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, and 2Pulmonary and Critical Care Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia References 1. Tamhane A. Matched-sample analysis: sensitivity, specificity, and P values. Clin Infect Dis 2008; 46:474–5. 2. Mazurek GH, Weis SE, Moonan PK, et al. Prospective comparison of the tuberculin skin test and 2 whole-blood interferon-g release assays in persons with suspected tuberculosis. Clin Infect Dis 2007; 45:837–45. Reprints or correspondence: Dr. Gerald Mazurek, Centers for Disease Control and Prevention, Mail Stop E10, 1600 Clifton Rd., Atlanta, GA 30333 ([email protected]). Clinical Infectious Diseases 2008; 46:475 This article is in the public domain, and no copyright is claimed. 1058-4838/2008/4603-0022 DOI: 10.1086/524894 Traveler’s Diarrhea Chemoprophylaxis: An Alternative Recommendation To the Editor—The article by Hill et al. [1] effectively details guidelines proposed by the Infectious Diseases Society of America for the treatment and prevention of illnesses in travelers to foreign countries. However, the discussion of traveler’s diarrhea chemoprophylaxis deserves further comment. The investigators recommend fluoroquinolones as standard preventative therapy for traveler’s diarrhea. Unfortunately, the authors neglect to discuss the correlation of fluoroquinolone administration with recent epidemic outbreaks of Clostridium difficile–associated diarrhea (CDAD) in North America. In addition, the authors only briefly refer to postinfectious irritable bowel syndrome (IBS) as a potential consequence of traveler’s diarrhea and do not give proper emphasis to the importance of preventing this postinfectious sequela. Several clinical studies have reported increased incidence, severity, and frequency of CDAD in North America [2–6]. Epidemic outbreaks of CDAD are associated with a predominant strain of C. difficile (North American PFGE type 1/ribotype 027) that produces levels of toxins A and B that are 16–23 times higher than the levels of toxins A and B in control strains [6]. Such C. difficile isolates were uncommon prior to 2000, and their widespread emergence is thought to be a result of in- CORRESPONDENCE • CID 2008:46 (1 February) • 475 Downloaded from http://cid.oxfordjournals.org/ by guest on October 6, 2014 between the 2 comparisons. Concerns about the small sample size have been expressed by Mazurek et al. [1], as well, in their comments on precision. Nevertheless, eliminating indeterminate results would be at odds with true comparative performance. Therefore, in such situations, a researcher could perform sensitivity analyses according to intention-to-treat analysis principles. When the statistical significance is set at .05, P values of .06 are not statistically significant. Furthermore, when analyses with and without the indeterminate values are used, the P values should be adjusted. However, as suggested by Altman et al. [3], a P value of .05 is a convenient cutoff point, and P values of .04 and .06, which are not greatly different, should lead to similar interpretations rather than to radically different ones. This also underlines the importance of planned experiments, adequate power for important clinical differences, and decisions based on clinical findings rather than purely on statistical findings. sociated with fluoroquinolone administration (e.g., CDAD) and the importance of preventing postinfectious sequelae (e.g., postinfectious IBS). Reprints or correspondence: Dr. Bradley Connor, The New York Center for Travel and Tropical Medicine, 50 E. 69th St., New York, NY 10021 ([email protected]). Clinical Infectious Diseases 2008; 46:475–6 2008 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2008/4603-0023$15.00 DOI: 10.1086/526347 Acknowledgments Financial support. Salix. Potential conflicts of interest. B.A.C. has been a consultant and served on the speakers’ bureaus for Salix, GlaxoSmithKline, Acambis, and Sanofi. Bradley Connor The New York Center for Travel and Tropical Medicine, New York, New York References 1. Hill DR, Ericsson CD, Pearson RD, et al. The practice of travel medicine: guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1499–539. 2. Pe´pin J, Valiquette L, Alary M-E, et al. Clostridium difficile–associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004; 171: 466–72. 3. Pe´pin J, Alary M-E, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005; 40:1591–7. 4. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile–associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442–9. 5. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene–variant strain of Clostridium difficile. N Engl J Med 2005; 353: 2433–41. 6. Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366:1079–84. 7. Neal KR, Barker L, Spiller RC. Prognosis in post-infective irritable bowel syndrome: a six year follow up study. Gut 2002; 51:410–3. 8. Gwee KA, Graham JC, McKendrick MW, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996; 347:150–3. 9. Okhuysen PC, Jiang ZD, Carlin L, Forbes C, DuPont HL. Post-diarrhea chronic intestinal symptoms and irritable bowel syndrome in North American travelers to Mexico. Am J Gastroenterol 2004; 99:1774–8. 10. DuPont HL, Jiang Z-D, Okhuysen PC, et al. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med 2005; 142:805–12. 476 • CID 2008:46 (1 February) • CORRESPONDENCE Reply to Connor To the Editor—Dr. Connor [1] raises important issues about the use of antibiotics to treat traveler’s diarrhea (TD). He highlights the association of fluoroquinolones with the increasing problem of Clostridium difficile–associated diarrhea and its associated morbidity and mortality. He then proposes an alternative approach to the prevention of TD by prescribing prophylactic rifaximin for travelers, with the goal of decreasing the risk of TD and preventing a potential long-term sequela of TD, postinfectious irritable bowel syndrome. Dr. Connor’s letter [1] may be read to imply that the Infectious Diseases Society of America guidelines [2] recommend widespread use of antibiotic prophylaxis with a fluoroquinolone to prevent TD. The guidelines clearly do not endorse this approach. They state that, based on currently available data, antibiotic prophylaxis with any antimicrobial against TD is not recommended for most travelers and should only be prescribed after a careful risk-benefit assessment for an individual traveler [2]. Instead, the guidelines endorse targeted short-course treatment of travelers with TD using antibiotics with demonstrated efficacy for the treatment of a subgroup of individuals. Dr. Connor [1] also raises the specific concern of whether fluoroquinolones—as opposed to rifaximin—should be used for treatment because of the association of fluoroquinolones in certain contexts with C. difficile–associated diarrhea. The Infectious Diseases Society of America guidelines are in agreement that inappropriate use of all antibiotics should be avoided to reduce the risk of C. difficile–associated diarrhea and other adverse events. The literature regarding the treatment of TD Downloaded from http://cid.oxfordjournals.org/ by guest on October 6, 2014 creasing antibiotic resistance to the fluoroquinolone antibiotics [4, 5]. Because fluoroquinolone administration is a primary risk factor for acquiring CDAD, control of antibiotic prescribing is a crucial preventative measure for precluding the spread of this serious illness. Thus, the association of quinolone antibiotics with the increasing incidence and severity of CDAD should serve as rationale for their exclusion from guidelines for traveler’s diarrhea chemoprophylaxis, except perhaps in rare circumstances—a position contrary to the recommendations of Hill et al [1]. An additional point of concern regarding the article by Hill et al. [1] is the lack of discussion on the critical role that traveler’s diarrhea prophylaxis may play in preventing the serious potential sequelae of postinfectious IBS. Postinfectious IBS is characterized by the onset of IBS symptoms following an episode of acute gastroenteritis (e.g., traveler’s diarrhea) in the presence of previously normal bowel function [7]. Given the accumulating evidence validating its pathophysiology, postinfectious IBS is an emerging topic of clinical importance in gastroenterology. Based on clinical studies, the incidence of postinfectious IBS is substantial, with 7%–30% of individuals receiving a diagnosis of postinfectious IBS after an enteric infection [7–9]. In addition, the impact of postinfectious IBS on quality of life can last for several months or years. Because traveler’s diarrhea is a primary risk factor for developing postinfectious IBS, antibiotic chemoprophylaxis may provide an opportunity to prevent this potentially serious illness. In this regard, the nonabsorbed antibiotic rifaximin has demonstrated clinical efficacy in preventing traveler’s diarrhea in US students traveling to Mexico and may provide a safer option for traveler’s diarrhea chemoprevention [10]. The travel medicine guidelines proposed by Hill et al. [1] are valuable; however, additional factors influencing traveler’s diarrhea chemoprevention should be emphasized, including the serious risks as-