Correspondence
Clostridium difficile
N Engl J Med 2009; 360:636-638February 5, 2009
- Article
To the Editor:
I would add two comments to Kelly and LaMont's review of the management of Clostridium difficile infection (Oct. 30 issue).1 First, in the diagnosis of C. difficile infection, it is important to note that the positive predictive value of commercially available assays for the detection of C. difficile toxin is unacceptably low, and a two-stage testing strategy for C. difficile with an initial sensitive rapid screening test and confirmation of positive samples by a reference method has recently been recommended.2 Second, the benefit of anion-exchange resins such as cholestyramine in the treatment of recurrent C. difficile–associated diarrhea was first recognized in the early 1980s and should not be forgotten as a management option.3
3 ReferencesRichard C.G. Pollok, Ph.D.
St. George's University of London, London SW17 0QT, United Kingdom1
Kelly CP ,LaMont JT . Clostridium difficile -- more difficult than ever. N Engl J Med 2008;359:1932-1940
Full Text | Medline2
Planche T ,Aghaizu A ,Holiman R , et al. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis 2008;8:777-784
CrossRef | Web of Science | Medline3
Viscidi RP ,Bartlett JG . Antibiotic-associated pseudomembranous colitis in children. Pediatrics 1981;67:381-386
Web of Science | Medline
To the Editor:
In commenting on the rising incidence of C. difficile infection, Kelly and LaMont make no mention of the association between the use of proton-pump inhibitors and the risk of C. difficile–associated disease. Proton-pump inhibitors are among the most widely prescribed medications in the world. The inhibition of gastric acid removes the normal defense mechanism against ingested bacteria and spores.1 Gastric acid suppression by proton-pump inhibitors is associated with an increased risk of enteric infection, especially with campylobacter, salmonella,2 and C. difficile.1,3-5 The use of proton-pump inhibitors could be an important factor in the increasing incidence of C. difficile infection.
5 ReferencesSammy A. Baierlein, M.D.
Ligusterstrasse 20, 95488 Eckersdorf, Germany
sammybaierlein@web.de Anja Wistop, M.D.
Klinikum Kulmbach, 95326 Kulmbach, Germany1
Yearsley KA ,Gilby LJ ,Ramadas AV ,Kubiak EM ,Fone DL ,Allison MC . Proton pump inhibitor therapy is a risk factor for Clostridium difficile-associated diarrhoea. Aliment Pharmacol Ther 2006;24:613-619
CrossRef | Web of Science | Medline2
Garcia Rodriguez LA ,Ruigomez A ,Panes J . Use of acid-suppressing drugs and the risk of bacterial gastroenteritis. Clin Gastroenterol Hepatol 2007;5:1418-1423
CrossRef | Web of Science | Medline3
Aseeri M ,Schroeder T ,Kramer J ,Zackula R . Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol 2008;103:2308-2313
CrossRef | Web of Science | Medline4
Cunningham R ,Dial S . Is over-use of proton pump inhibitors fuelling the current epidemic of Clostridium difficile-associated diarrhoea? J Hosp Infect 2008;70:1-6
CrossRef | Web of Science | Medline5
Dial S ,Alrasadi K ,Manoukian C ,Huang A ,Menzies D . Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171:33-38
CrossRef | Web of Science | Medline
To the Editor:
Kelly and LaMont, in their review of C. difficile infection, conclude that the avoidance of improper antibiotic use is the mainstay of primary prevention. However, there are other strategies and other important points about primary prevention. The long-term use of proton-pump inhibitors impairs normal gastric acidity and its defensive functions, thereby doubling the risk of C. difficile colitis.1,2 The Centers for Disease Control and Prevention has issued other specific guidelines for primary prevention of C. difficile infection. One must recognize that alcohol solutions are ineffective in killing C. difficile spores and that correct hygiene can be achieved only with the use of soap and water, not with alcohol-based sanitizers.3 Proper hygiene for health care personnel and equipment may be as important as proper antibiotic use in preventing this infection.4,5
5 ReferencesEmanuel Della-Torre, M.D.
Lorenzo Dagna, M.D.
Nicoletta Saporiti, M.D.
Università Vita-Salute San Raffaele, I-20132 Milan, Italy1
Kahrilas PJ . Gastroesophageal reflux disease. N Engl J Med 2008;359:1700-1707
Full Text | Web of Science | Medline2
Dial S ,Delaney JA ,Barkun AN ,Suissa S . Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005;294:2989-2995
CrossRef | Web of Science | Medline3
Boyce JM ,Pittet D . Guideline for Hand Hygiene in Health-Care Settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR Recomm Rep 2002;51:1-45
Medline4
McDonald LC ,Killgore GE ,Thompson A , et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005;353:2433-2441
Full Text | Web of Science | Medline5
Johnson S ,Gerding DN ,Olson MM , et al. Prospective, controlled study of vinyl glove use to interrupt Clostridium difficile nosocomial transmission. Am J Med 1990;88:137-140
CrossRef | Web of Science | Medline
To the Editor:
Kelly and LaMont provide a description of illness caused by C. difficile across an age spectrum from youth to old age. Absent from this spectrum are neonates, the population from which this organism was first isolated.1 C. difficile and its toxin are present in about 50% of healthy newborn infants, and the organisms are virtually normal flora in the neonatal intensive care unit (ICU).2 Despite this ubiquity, as well as the virulence of C. difficile infection in older populations, the frequent use of antibiotics in neonatal ICUs, and the well-known vulnerability of newborn infants — and premature infants, in particular — to bacterial infections, C. difficile has not convincingly been associated with any common illnesses in this patient population. The explanation for this paradox remains obscure.
2 ReferencesDavid M. Coulter, M.D.
University of Utah School of Medicine, Salt Lake City, UT 84158
david.coulter@hsc. utah. edu 1
Hall IC ,O'Toole E . Intestinal flora in new-born infants: with a description of a new pathogenic anaerobe, Bacillus difficilis. Am J Dis Child 1935;49:390-402
Web of Science2
Remington JS, Klein JO, Wilson CB, Baker CJ, eds. Infectious diseases of the fetus and newborn infant. 6th ed. Philadelphia: Elsevier Saunders, 2006:631-2.
Author/Editor Response
The primary limitation of the commonly used enzyme immunoassays for the detection of C. difficile toxin in stool is their poor sensitivity and inadequate negative predictive value; specificities and positive predictive values are generally high. The two-stage strategy referenced by Pollok may address this limitation but requires two tests using different assay methods to confirm a positive result. It is hoped and expected that newer diagnostic methods such as a polymerase-chain-reaction assay or tissue-culture cytotoxicity testing adapted for easy use in general clinical microbiology laboratories will soon provide more accurate and convenient testing alternatives.
Cholestyramine and colestipol were not listed as preferred treatment options for two reasons: they have been shown to have poor efficacy in the primary treatment of C. difficile infection, and they are cumbersome to use in recurrent C. difficile infection because of their binding to vancomycin.1
A link between the use of proton-pump inhibitors and an increased risk of C. difficile infection, as noted by Baierlein and Wistop, has been reported in several epidemiologic studies. However, these studies have not demonstrated a cause-and-effect connection; an indirect association through confounding variables remains a real possibility. Unlike infection with other enteric pathogens, C. difficile infection may result from ingestion of acid-resistant spores negating the effect of proton-pump-inhibitors. However, infection through acid-sensitive vegetative forms cannot be ruled out.2
In the vast majority of patients with C. difficile infection, the infection develops during or after antimicrobial therapy, which remains the single most important risk factor for this disease. Thus, prudent use of antimicrobial agents is central in preventing C. difficile infection. It remains to be shown whether avoidance of proton-pump inhibitors can provide protection against C. difficile infection.
In response to Della-Torre and colleagues: neither alcohol solutions nor soap and water kill C. difficile spores, but hand hygiene with the use of soap and running water may be more likely to physically remove spores from the hands and is therefore preferred in high-risk situations.
In response to Coulter: newborn children do not have an established colonic microflora and are therefore susceptible to colonization by C. difficile. It is not clear, however, why colitis does not develop in neonates harboring toxigenic C. difficile. Passive immunity from maternal antibodies is a possibility, but since many women are themselves susceptible to C. difficile infection, it seems unlikely that maternal antibodies would be so broadly protective. An alternative hypothesis, based on studies in animals, is that a toxin receptor or other intestinal factors that are necessary for pathogenesis may not be expressed in neonates.3
3 ReferencesCiarán P. Kelly, M.D.
J. Thomas LaMont, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 022151
Zimmerman MJ ,Bak A ,Sutherland LR . Treatment of Clostridium difficile infection. Aliment Pharmacol Ther 1997;11:1003-1012
CrossRef | Web of Science | Medline2
Jump RL ,Pultz MJ ,Donskey CJ . Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob Agents Chemother 2007;51:2883-2887
CrossRef | Web of Science | Medline3
Eglow R ,Pothoulakis C ,Itzkowitz S , et al. Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor. J Clin Invest 1992;90:822-829
CrossRef | Web of Science | Medline
