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Lactulose Is Associated With Decreased Risk of Clostridium difficile Infection in Decompensated Cirrhosis

2017; Elsevier BV; Volume: 15; Issue: 6 Linguagem: Inglês

10.1016/j.cgh.2017.01.012

1542-7714

Anant Agarwalla, Andrew T. Weber, Sonya Davey, Keith Hamilton, David S. Goldberg, Andrew D. Rhim, Yu‐Xiao Yang,

Helicobacter pylori-related gastroenterology studies

Clostridium difficile infection (CDI) is the leading cause of nosocomial infectious diarrhea in developed countries.1Kelly C.P. LaMont J.T. Clostridium difficile: more difficult than ever.N Engl J Med. 2008; 359: 1932-1940Crossref PubMed Scopus (1101) Google Scholar The composition of human gut microbiome is associated with the development of CDI. This theory is bolstered by the increase in CDI risk after antibiotic exposure and the success of fecal microbiota transplant in treating refractory CDI.2Drekonja D. Reich J. Gezahegn S. et al.Fecal microbiota transplantation for Clostridium difficile infection: a systematic review.Ann Intern Med. 2015; 162: 630-638Crossref PubMed Scopus (268) Google Scholar Use of non-digestible oligosaccharides (eg, lactulose, oligofructose) as prebiotics may be a safe and effective approach to restoring or strengthening colonization resistance against CDI by selectively promoting the growth of a host's indigenous microbiota.3Kondepundi K.K. Ambalam P. Nilsson I. et al.Prebiotic-non-digestible oligosaccharides preference of probiotic bifidobacteria and antimicrobial activity against Clostridium difficile.Anaerobe. 2012; 18: 489-497Crossref PubMed Scopus (70) Google Scholar, 4Ito Y. Moriwaki H. Muto Y. et al.Effect of lactulose on short-chain fatty acids and lactate production and on the growth of faecal flora, with special reference to Clostridium difficile.J Med Microbiol. 1997; 46: 80-84Crossref PubMed Scopus (52) Google Scholar Lactulose has been shown to alter the colonic microenvironment in ways that inhibit C difficile growth.3Kondepundi K.K. Ambalam P. Nilsson I. et al.Prebiotic-non-digestible oligosaccharides preference of probiotic bifidobacteria and antimicrobial activity against Clostridium difficile.Anaerobe. 2012; 18: 489-497Crossref PubMed Scopus (70) Google Scholar We sought to determine whether lactulose use was associated with a decreased risk of CDI. We conducted a matched nested case-control study among end-stage liver disease (ESLD) patients admitted to an academic health system between 2005 and 2013. Patients were identified by the presence of ESLD on discharge diagnosis codes.5Goldberg D. Lewis J. Halpern S. et al.Validation of three coding algorithms to identify patients with end-stage liver disease in an administrative database.Pharmacoepidemiol Drug Saf. 2012; 21: 765-769Crossref PubMed Scopus (101) Google Scholar Admissions were excluded if the patient was hospitalized for less than 24 hours, had incomplete medical records, had undergone prior liver transplantation, or had a history of CDI. Cases were identified by incident diagnosis of CDI during admission on the basis of stool toxin or polymerase chain reaction testing for toxigenic genes. For each case, controls were selected by using incidence density sampling matching on age, sex, admission date, and duration of hospital stay. The exposure of interest was at least 10 g/day of lactulose for more than 48 hours. Conditional logistic regression was used to calculate the odds ratio (OR) for CDI risk associated with lactulose use. We examined the following potential confounders: Model for End Stage Liver Disease score, intensive care unit stay, race, type of hepatic decompensation, use of rifaximin, metronidazole, or other antibiotics grouped by class. Variables were included in the multivariate model if their inclusion changed the crude OR for CDI risk by more than 5%. The study included 112 eligible cases matched with 928 controls. The 2 groups differed in history of hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and use of rifaximin, metronidazole, and cephalosporins (Table 1).Table 1Patient CharacteristicsControls (n = 928)Cases (n = 112)P valueaP values were calculated by using Student t test or Pearson χ2 test. P values for age and sex are noted as not applicable because these were matching variables.Age, mean (SD), y57.9 (7.7)58.7 (9.6)N/AMale sex, n (%)595 (64.1)73 (65.1)N/ARace, n (%).96 White585 (63.9)70 (62.5) Black275 (30.0)35 (31.2) Other55 (6.0)7 (6.25)Decompensations,bDecompensations during index admission; patient may have had other decompensations in the past. n (%).65 Ascites511 (55.1)63 (56.3).81 Varices with bleeding46 (5.0)9 (8.0).17 Varices with no bleeding196 (21.1)26 (23.2).62 Hepatorenal syndrome132 (14.2)10 (8.9).12 SBP15 (1.6)8 (7.1)<.001 HE208 (22.4)16 (14.3).05Model for End Stage Liver Disease1816.08Intensive care unit stay, n (%)318 (34.3)42 (37.5).50Antibiotic use, n (%)cOther antibiotics include clindamycin, colistimethate, polymyxin B, and tigecycline.534 (57.5)65 (58.0).92 Rifaximin238 (25.6)12 (11.0)<.001 Metronidazole142 (15.3)6 (5.3)<.01 Aminoglycosides30 (3.2)7 (6.3).10 Carbapenem/monobactams22 (2.4)5 (4.5).19 Cephalosporin210 (22.6)42 (37.5)<.001 Fluoroquinolone234 (25.2)24 (21.4).38 Penicillins202 (21.8)32 (28.6).10 Other20 (2.2)3 (2.7).72a P values were calculated by using Student t test or Pearson χ2 test. P values for age and sex are noted as not applicable because these were matching variables.b Decompensations during index admission; patient may have had other decompensations in the past.c Other antibiotics include clindamycin, colistimethate, polymyxin B, and tigecycline. Open table in a new tab The prevalence of lactulose use was significantly lower among cases than controls (crude OR, 0.48; 95% confidence interval [CI], 0.31–0.74; P < .001). A diagnosis of HE as well as exposure to rifaximin, metronidazole, and cephalosporins significantly changed the crude OR by >5%. HE was automatically excluded from the regression model because it was highly correlated with rifaximin use. The adjusted OR accounting for these variables was 0.60 (95% CI, 0.37–0.97; P = .04). In secondary analyses, the effect estimates were unchanged when excluding patients who received rifaximin (adjusted OR, 0.52; 95% CI, 0.31–0.89; P = .02) or had SBP (OR, 0.60; 95% CI, 0.36–1.01; P = .053). There was no difference in the frequency of CDI testing between the lactulose users (23%) vs non-users (19%), P = .3. Lactulose use was associated with a reduced risk of CDI among hospitalized ESLD patients. This association was independent of comorbidities or concurrent antibiotics. This is consistent with a prior report that oligofructose reduces the risk of relapsing CDI.6Lewis S. Burmeister S. Brazier J. Effect of the prebiotic oligofructose on relapse of Clostridium difficile-associated diarrhea: a randomized controlled study.Clin Gastroenterol Hepatol. 2005; 3: 442-448Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar There are several important limitations to this study. Several strategies were used to minimize confounding. The cases and controls were matched on key characteristics. The primary association remained significant even after accounting for measured confounders in a multivariable model. Secondary analyses, restricted among those without SBP or rifaximin, also yielded similar results to our primary analysis. Nevertheless, we cannot completely exclude residual confounding. We found that lactulose users were actually tested more frequently for CDI, making differential testing an unlikely explanation for our results. Finally, although prior studies have demonstrated a similar effect of lactulose on geriatric inpatients,7Shah S. Lewis A. Leopold D. et al.Gastric acid suppression does not promote clostridial diarrhoea in the elderly.Q J Med. 2000; 93: 175-181Crossref Scopus (71) Google Scholar the generalizability of our finding in non-cirrhotic patients is unclear. In conclusion, lactulose use among hospitalized ESLD patients was associated with a significantly lower risk of CDI. These results will need confirmation in other patient populations and in a prospective setting, but they lend further support to the importance of the gut microbiome in CDI pathogenesis and the role of prebiotics such as lactulose in CDI prevention.