between the 2 comparisons. Concerns

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 (gym6@cdc.gov).
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
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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 (bconnor@pol.net).
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
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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-