Predictors of Death after Clostridium difficile Infection: A Report on 128 Strain-Typed Cases from a Teaching Hospital in the United Kingdom

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1 BRIEF REPORT Predictors of Death after Clostridium difficile Infection: A Report on 128 Strain-Typed Cases from a Teaching Hospital in the United Kingdom Vhairi Wilson, 1 Liz Cheek, 2 Giovanni Satta, 1 Karen Walker-Bone, 3 Marc Cubbon, 1 Diane Citron, 4 Dale N. Gerding, 5,6 and Martin J. Llewelyn 1,3 1 Department of Microbiology and Infection, Brighton and Sussex University Hospitals National Health Service Trust, and 2 School of Computing, Mathematical and Information Sciences, University of Brighton, Brighton, and 3 Brighton and Sussex Medical School, Falmer, United Kingdom; 4 RM Alden Laboratory, Culver City, California; and 5 Hines VA Hospital, Hines, and 6 Loyola University Chicago Stritch School of Medicine, Maywood, Illinois We assessed the relationship between strain type, clinical factors, and outcome in 128 patients with Clostridium difficile infection. Strain type was not associated with any outcome measure. On multivariate analysis, ischemic heart disease and hypoalbuminemia predicted death. Metronidazole treatment in severe disease was associated with a higher rate of treatment failure and death. The severity of Clostridium difficile infection (CDI) appears to have increased as new strains in particular, restriction endonuclease (REA) type BI/ribotype 027 (North American pulsefield type 1) have emerged [1, 2]. However, much of the evidence that BI/027 strains are more virulent comes from settings where BI/027 strains have emerged rapidly. Recent reports from settings where BI/027 strains are endemic have failed to demonstrate an association with severe disease, but the mortality rates in these studies were relatively low [3, 4]. We conducted a prospective cohort study of CDI cases to establish the relative importance of CDI strain type, compared with clinical and management factors, in CDI outcome. Methods. Brighton and Sussex University Hospitals NHS Trust is an 820-bed teaching hospital where the CDI rate in 2006 was 29 cases per 10,000 bed-days [5]. Received 7 January 2010; accepted 12 March 2010; electronically published 7 May Reprints or correspondence: Dr Martin Llewelyn, Brighton and Sussex Medical School, Medical Research Building, University of Sussex, Falmer, BN1 9PS, United Kingdom (m.j. llewelyn@bsms.ac.uk). Clinical Infectious Diseases 2010; 50(12):e77 e by the Infectious Diseases Society of America. All rights reserved /2010/ E2$15.00 DOI: / A prospective study of new CDI cases was conducted from 1 June 2007 through 30 June Anonymized clinical data were gathered on the first working day after diagnosis and again at day 30. Throughout the study, patients were treated by the attending clinical team guided by the hospital s CDI treatment policy, which recommends first-line therapy with metronidazole for mild disease and with oral vancomycin for severe disease, as defined below. A case was defined as a patient for whom a stool specimen tested positive for toxins A or B (using the Premier toxin A and B ELISA [Meridian Bioscience]) and who had passed 3 liquid stools in the 24-h period before assessment. Only patients who were new cases were included in the study. Stool samples were frozen at 80 C and subsequently cultured for C. difficile. Isolates underwent REA typing, and ribotypes were inferred from REA types [6]. Informed consent was obtained from the patient or, in the event of mental incapacity, from their next of kin. Severe disease was defined as (1) the presence of ileus or toxic megacolon or (2) the presence of 2 of the 7 following possible markers of severity: fever (temperature, 138 C); 15 stools passed per 24 h; bloody diarrhea; abdominal pain, distension, tenderness, or ascites; cardiovascular compromise or dehydration requiring intravenous fluids; white blood cell count on the day of assessment, 115 or! cells/l; and albumin level on the day of assessment,!25 g/l. The primary outcome was all-cause 30-day mortality rate. Secondary outcomes were recurrence (ie, additional diarrhea after resolution that required another course of treatment 30 days after completion of treatment); CDI-related mortality, which was determined from the patient s clinical progress and death certificate data; and early treatment failure (ie, change of first choice treatment drug, dose, or route of administration during the first CDI episode). Univariate logistic regression was performed for each variable, with all-cause 30-day mortality as the binary dependent variable. A multivariate model was developed including independent variables with P values!.1. A parsimonious model was also obtained using forward step-wise inclusion of variables and a P value of.05 at entry. Analyses were performed with SPSS software, version 15.0 (SPSS Inc). Results. C. difficile could not be cultured for 9 of 137 cases; these 9 cases were excluded. Fifty-one isolates (39.9%) were REA group DH (ribotype 106), 34 (26.5%) were REA group BI (ribotype 027), and 43 (33.6%) comprised other groups, BRIEF REPORT CID 2010:50 (15 June) e77

2 most commonly G (ribotype 002; 7 cases [5.5%]), J (ribotype 001; 6 cases [4.7%]), and N (ribotype 015; 4 cases [3.1%]). Forty-six patients (35.9%) died 30 days after diagnosis. In 22 cases (17.2%), death was related to CDI. Of 14 patients who were not treated, 4 died before day 30 (3 deaths were unrelated to CDI, and 1 was CDI related). Early treatment failure occurred in 57 (50.0%) of 114 patients who received specific treatment for CDI. Twenty-two patients (19.6%) experienced 1 recurrence. Table 1 shows the characteristics of patients by 30-day survival and the univariate odds ratios (ORs) for death. There was no excess mortality associated with BI/027 cases (OR, 1.14; 95% confidence interval [CI], ), nor was there any association between BI/027 cases and severe disease (OR, 1.30; 95% CI, ), relapse (OR, 1.56; 95% CI, ), early treatment failure (OR, 1.39; 95% CI, ), or attributable mortality (OR, 1.05; 95% CI, ). In the multivariate model, only ischemic heart disease remained a statistically significant independent predictor of death 30 days after diagnosis (OR, 4.08; 95% CI, ; P p Table 1. Characteristics of 128 Patients with Clostridium difficile Infection, by Survival at 30 Days, and Univariate Odds Ratios (ORs) for Death Characteristic No. (%) of patients Patients who survived (n p 82) Patients who died (n p 46) OR (95% CI) BI/027 strain 21 (25.6) 13 (28.3) 1.14 ( ).75 Age 175 years 57 (69.5) 34 (73.9) 2.08 ( ).11 Male sex 35 (42.7) 20 (43.5) 1.03 ( ).93 Hospital contact 56 (73.7) 27 (64.3) 0.64 ( ).29 Nursing home contact 79 (96.3) 45 (97.8) 1.71 ( ).63 Community onset 27 (32.9) 12 (26.1) 0.72 ( ).42 Comorbidity Ischemic heart disease 25 (30.9) 24 (52.2) 2.44 ( ).03 Renal failure 23 (28.1) 18 (39.1) 1.65 ( ).20 Cancer 18 (22.2) 13 (28.9) 1.42 ( ).41 Cerebrovascular disease 21 (25.9) 11 (23.9) 0.90 ( ).80 COPD 13 (16.1) 13 (28.3) 2.06 ( ).11 Immunocompromise 13 (15.8) 8 (17.4) 1.12 ( ).81 Diabetes 15 (18.3) 4 (8.7) 0.43 ( ).13 At least 2 comorbidities 42 (51.2) 33 (71.7) 2.42 ( ).02 Marker of severity.01). The parsimonious model included only ischemic heart disease and albumin level 25 g/l as predictors (OR for ischemic heart disease, 3.88 [95% CI, ; P p.003] OR for albumin level, 3.13 [95% CI, ; P p.014]). Albumin level and C-reactive protein level were closely linked, and inclusion of C-reactive protein level in the model did not have a notable impact on results. The interaction of strain type (BI/027 or other) yielded P values!.1 for community-onset CDI (OR, 0.38; 95% CI, ), renal impairment (OR, 2.72; 95% CI, ), presence of 2 comorbidities (OR, 1.39; 95% CI, ), and passing of 5 stools per day (OR, 0.27; 95% CI, ). None of the interaction terms were included in the final model, which again included only ischemic heart disease and albumin level 25 g/l as independent predictors of death. Metronidazole treatment was not significantly associated with all-cause mortality. However, among 78 patients with severe disease who received specific treatment, metronidazole was associated with a higher risk of death (OR, 3.56; 95% CI, 1.07 White blood cell count cells/l 24 (30.0) 15 (33.3) 1.17 ( ).70 Albumin level!25 g/l 20 (28.2) 19 (46.3) 2.20 ( ).05 Urea level 10 mmol/l 28 (35.0) 24 (52.2) 2.03 ( ).06 Creatinine level 100 mmol/l 36 (46.2) 27 (58.7) 1.66 ( ).18 CRP level 100 mg/l 28 (37.8) 28 (63.6) 2.88 ( ).01 Five or more stools passed in first 24 h after onset 22 (26.8) 14 (30.4) 1.19 ( ).66 Severe disease a 52 (63.4) 33 (71.7) 1.46 ( ).34 First-line treatment with metronidazole 47 (57.3) 34 (73.9) 2.11 ( ).06 P NOTE. CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein. a Severe disease is defined in Methods. e78 CID 2010:50 (15 June) BRIEF REPORT

3 Table 2. Characteristics of 128 Patients, According to Clostridium difficile Strain C. difficile strain Characteristic BI/027 (n p 34) DH/106 (n p 51) Other (n p 43) Age, median years (IQR) 82.5 (74 89) 85 (78 92) b 80 (67 87) b.03 Male sex 19 (55.9) 17 (33.3) 19 (44.2).12 Hospital contact, proportion (%) 23/33 (69.7) 31/47 (70.0) 29/38 (76.3).58 Nursing home contact 18 (52.9) 25 (49.0) 27 (62.8).40 Community onset 9 (26) 14 (27.5) 16 (37.2).50 Comorbidity Ischemic heart disease 16 (47.1) 16 (31.4) 17 (39.5).34 Renal failure 14 (41.2) 14 (27.5) 13 (30.2).39 Cancer 6 (17.6) 16 (31.4) 9 (20.9).29 Cerebrovascular disease, proportion (%) 9/34 (26.5) 11/50 (21.6) 12/43 (27.9).79 COPD 6 (17.6) 12 (23.5) 8 (18.6).76 Immunocompromise 5 (14.7) 13 (25.5) 3 (7.0).05 Diabetes 10 (29.4) 2 (3.9) 7 (16.3).01 At least 2 comorbidities 20 (58.5) 29 (56.9) 26 (60.5).94 Severity White blood cell count, cells 10 9 /L Mean SD Proportion (%) with 15 cells 10 9 /L 11/32 (34.4) 19/50 (38.0) 9/43 (20.9).19 Albumin level, g/l Mean SD Proportion (%) with!25 g/l 13/30 (43.3) 12/44 (27.3) 14/38 (36.8).35 Urea level, mmol/l Median (IQR) 10.6 ( ) 7.8 ( ) 7.6 ( ).15 Proportion (%) with 10 mmol/l 18/32 (56.3) 19/51 (37.3) 15/43 (34.9).13 Creatinine level, mmol/l Median (IQR) 136 ( ) c 82 (53 137) 76 ( )!.01 Proportion (%) with 100 mmol/l 23/32 (71.9) 22/51 (43.1) 18/41 (43.9).02 CRP level, mg/l Median (IQR) 87.5 ( ) ( ) c 81.5 ( ).02 Proportion (%) 100 mg/l 10/30 (33.3) 30/48 (62.5) 16/40 (40.0).02 Five or more stools passed in the first 24 h after onset 12 (35.3) 14 (27.5) 10 (23.3).50 Five or more stools passed at any time during infection 15 (44.1) 30 (58.8) 21 (48.8).38 Severe disease 24 (70.6) 34 (66.7) 27 (62.8).77 First-line metronidazole treatment 23 (67.6%) 33 (64.7%) 25 (58.1%).67 Outcome Early treatment failure, proportion (%) 10/31 (32.3) 15/47 (31.9) 7/35 (20.0).42 Recurrence, proportion (%) 8/34 (23.5) 10/48 (20.8%) 5/43 (11.6).35 Death at 30 days 13 (38.2) 19 (37.3) 14 (32.6).85 Attributable death 6 (17.6) 11 (21.6) 5 (11.6).44 P a NOTE. COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein. a One-way analysis of variance was used to compare means, the Kruskal-Wallis test was used to compare medians, and the x 2 test was used to compare proportions. b Strains significantly different using multiple comparisons with Bonferroni adjustment. c Strain significantly different from the other 2 using multiple comparisons with Bonferroni adjustment.

4 11.90; P p.03) and was associated with a higher rate of early treatment failure, compared with oral vancomycin (OR, 5.13; 95% CI, ; P p.002). Furthermore, of the 22 patients (17.2%) for whom death was related to CDI, 20 received specific treatment: 17 received metronidazole alone, 2 received a combination of metronidazole and vancomycin, and 1 received vancomycin alone (OR for CDI-related mortality for metronidazole versus vancomycin, 9.20; 95% CI, ; P p.01). The high mortality in our cohort and the lack of an association between BI/027 strains and adverse outcome could be explained if DH/106 were also behaving as a virulent strain type. We analyzed the relationship between strain type (BI/027, DH/106, and others) and comorbidity, severity, and outcome (Table 2). Patients with DH/106 CDI were older and more immunocompromised, whereas those with BI/027 CDI were more frequently diabetic; however, overall, comorbid disease was not related to strain type. Patients with BI/027 CDI had a higher creatinine level at presentation, whereas those with DH/ 106 CDI had a higher C-reactive protein level at presentation; however, overall, the severity of disease was not related to strain type. No differences in any outcome measure were found in a comparison of strain types. Discussion. In the past decade, the incidence of CDI has increased throughout North America and Europe. Equally concerning have been reports of increasing severity of CDI [1, 2]. These changes have been associated with the emergence of hypervirulent BI/027 strains [7]. The distribution of strain types among the cases in our study (DH/106, 40%; BI/027, 26%) and the almost complete disappearance of J/001 strains are typical of English hospitals at the present time [8]. The mortality rate among the patients in our study is typical of studies in which outbreaks of BI/027 CDI have been reported. However, we did not find any statistically significant relationships between strain type and death, severity of presentation, early treatment failure, or relapse, either on univariate analysis or in a logistic regression analysis to detect interaction between strain type and underlying disease. In contrast, the major determinants of death among our patients were comorbid disease in particular, ischemic heart disease and severity of illness at presentation manifested as hypoalbuminemia and renal impairment. No validated system yet exists for assessing severity of CDI at presentation, and our predetermined scoring system was based on the UK Department of Health guidelines. However, our findings are in keeping with recent reports that deterioration in renal function and hypoalbminemia are markers of poor prognosis [9, 10]. Several recent reports have indicated that metronidazole may be associated with slower response to treatment and lower cure rates than oral vancomycin for CDI [11, 12]. One major finding of our study is that the inferiority of metronidazole in severe CDI translates into a higher overall mortality rate. In the past year, 2 studies have indicated that BI/027 strains may not be associated with worse outcome in settings where BI/027 strains are endemic [3, 4]. The failure of these studies to demonstrate an impact of strain type on disease may be simply a result of small study size but may represent true differences in the behavior of BI/027 strains in settings where it is epidemic versus not epidemic. The differing ability of antibiotics to induce toxin production by BI/027 strains is one potential explanation for this. DH/106 strains of C. difficile are common in the United Kingdom but infrequently seen elsewhere. It is possible that we did not find BI/027 cases to be more severe because DH/106 strains are also hypervirulent. It is intriguing, then, that the patients with DH/106 CDI in our study had a more marked C-reactive protein response at diagnosis. Our numbers are small, though, and another study performed in an English hospital similar to our own demonstrated a trend toward higher mortality among 44 patients with BI/027 CDI, compared with 33 who had DH/106 CDI. DH/106 strains are typically quinolone resistant and have toxinotype 0 (nonbinary toxin producing) [13]. Our study is small, was conducted in a single health care center, and cannot exclude the possibility that BI/027 strains are associated with worse outcome. However, the detailed clinical data we have gathered has allowed us to place the role of strain-type in the context of patient and management factors. Multicenter studies with more participants are needed to validate our findings. Efforts to improve outcome of CDI should focus on assessment of risk, disease severity, and optimization of treatment for all patients with CDI rather than focus on hypervirulent BI/027 strains. Acknowledgments Financial support. The costs of C. difficile culture and typing of isolates in this study were met by grants from Optimer Pharmaceuticals (to D.C. and D.N.G.) and the US Department of Veterans Affairs Research Service (through a grant to D.N.G.). Potential conflicts of interest. D.N.G. holds patents for the treatment and prevention of CDI licensed to ViroPharma Incorporated; serves as a consultant for Cepheid, BD GeneOhm, Merck, GOJO Industries, Optimer Pharmaceuticals, Schering-Plough, Cubist, Actelion, and Medicines Company, Dr. Reddy s, TheraDoc, and ViroPharma; and holds research grants from Cepheid, MassBiologics, Merck, GOJO Industries, Optimer Pharmaceuticals, and ViroPharma. D.M.C. is on the speakers bureau for Cubist. All other authors: no conflicts. References 1. 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