Anaerobe 30 (2014) 65e69

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Clinical microbiology

Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China Haihui Huang a, Shi Wu a, Renjie Chen b, Shaohua Xu a, Hong Fang c, Andrej Weintraub c, Carl Erik Nord c, * a b c

Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China Department of Health Statistics and Social Medicine, School of Public Health, Fudan University, Shanghai, China Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden

a r t i c l e i n f o

a b s t r a c t

Article history: Received 12 March 2014 Received in revised form 26 August 2014 Accepted 29 August 2014 Available online 8 September 2014

Clostridium difficile infection (CDI) is an increasing concern in China. However, the risk factors of CDI are rarely reported in the Chinese population. A prospective observational study was therefore conducted among patients with hospital-acquired C. difficile diarrhoea and the risk factors of CDI in a retrospective case-control study. The CDI patients were compared with the non-CDI diarrhoeal patients and those without diarrhoea, respectively. The recurrent CDI patients were compared with the corresponding nonrecurrent CDI patients and those without diarrhoea, respectively. Overall, of the 240 patients with hospital-acquired diarrhoea 90 (37.5%) were diagnosed as CDI, and 12 (13.3%) of the 90 CDI patients experienced recurrence. Multivariate analysis indicated that renal disease, malignancy, hypoalbuminemia, prior antibiotic treatment, chemotherapy, nasogastric tube use, length of stay >14 days and intra-abdominal surgery, defined daily dose of antimicrobial agents 19, prior use of more than three antimicrobial agents, and use of carbapenems were independent risk factors for the first episode of CDI. Use of laxatives, the first- and second-generation narrow-spectrum cephalosporins or metronidazole was identified as protective factors. It is necessary to make testing of C. difficile available as a routine practice and control these risk factors in Chinese hospitals to avoid CDI outbreaks. © 2014 Elsevier Ltd. All rights reserved.

Keywords: Clostridium difficile infection Risk factor Diarrhoea Case-control study Shanghai, China

1. Introduction During the last 10 years, the incidence and severity of Clostridium difficile infection (CDI) have increased dramatically in Europe and North America [1,2]. C. difficile has become the leading cause of health-care-associated diarrhoea and one of the most important healthcare-associated infections [3]. This is primarily due to the emergence of the epidemic C. difficile NAP1/027 clone [4], although its prevalence has declined in many parts of Europe [5]. Since 2007, CDI has also attracted more attention in China. However, from the results of some small studies, it seems that the CDI profile in China is different from that in USA, Canada and Europe. In China, CDI outbreak is rarely reported, fewer patients have critically severe CDI and the CDI outcomes are better than in USA, Canada and Europe. The prevalent strain of C. difficile ribotype 027 is rarely reported in China, while another clone of C. difficile ribotype 017 is prevalent in some hospitals in China [6,7].

* Corresponding author. Tel.: þ46 8 585 87838; fax: þ46 8 585 87933. E-mail address: [email protected] (C.E. Nord). http://dx.doi.org/10.1016/j.anaerobe.2014.08.015 1075-9964/© 2014 Elsevier Ltd. All rights reserved.

The most consistently reported risk factors for CDIs are advanced age, underlying disease severity, length of stay, and antibiotic exposure, particularly use of clindamycin, cephalosporins and fluoroquinolones [3]. The risk factors for CDIs in hospitalized patients are still not clear in China, even though they are crucial for formulating the appropriate measures to control the CDIs in China. Therefore, we conducted a prospective study among specific inpatient population in a university hospital from September 2008 through April 2009 to determine the relative prevalence of CDI, and a retrospective case-control study to assess the associated risk factors of CDI. 2. Materials and methods 2.1. Study setting and population This study was conducted in a 1216-bed University Hospital (Huashan Hospital) in Shanghai, China, during 8 months. Nine inpatient wards were included (General Intensive Care Unit (ICU), Neurological ICU, General Surgery, Haematology, Nephrology, Cardiovascular and 3 Geriatrics), a total of 273 beds. Patients were

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H. Huang et al. / Anaerobe 30 (2014) 65e69

included if they: (1) were 18 years or older on admission; (2) had acute hospital-acquired diarrhoea. Exclusion criteria included history of chronic diarrhoea or human immunodeficiency virus infection. One coordinator visited the wards daily to ensure that the patients met the criteria at follow-up. The study was approved by the Institutional Review Board of Huashan Hospital.

1:1) and the patients with first episode of CDI as cases compared with the concurrent hospitalized patients in the same ward without diarrhoea as controls (control group 2, case/control ratio 1:2) The cases and corresponding controls were matched in terms of time and place of hospitalization to reduce the confounding factors.

2.2. Definitions

2.5. Collection of clinical and demographic data

A case of CDI was defined as presence of diarrhoea (3 loose stools/day) or toxic megacolon with a positive toxin-producing C. difficile in stool by culture, or endoscopic or histopathologic evidence of pseudomembranous colitis. Severe diarrhoea was defined as bloody diarrhoea and/or diarrhoea with hypovolaemia or hypoalbuminemia (albumin level 38  C) and leucocytosis (WBC >12  109 cells/L), and/or pseudomembranous colitis [8]. A recurrent case of CDI is characterized by a positive specimen within 2e8 weeks since the last positive result. An incident case of CDI is characterized by a positive specimen result 8 or more weeks after a previous positive result or by the absence of a previous positive result. A toxin-positive test result within 2 weeks of the previous positive result is considered a confirmation of the initial positive result [9].

The following data were collected using a standardized questionnaire specifically designed for this study: administrative data (age, gender, ward, community versus hospital acquisition, comorbidity); known predisposing risk factors in the 3 months preceding the onset of diarrhoea (antimicrobial treatment, chemotherapy, nasogastric intubation, surgery), biological parameters (hypoalbuminemia, WBC count, serum creatinine), and clinical course (severity, clinical and laboratory finding, treatment, complication and outcome). The exposure to antimicrobial agents and proton-pump inhibitors (PPIs) was standardized according to the World Health Organization Defined Daily Dose (DDD) system and the number of days of therapy (DOTs) [17].

2.3. Microbiological methods

Categorical variables were expressed as percentages. The measurement data were presented as the median and interquartile range (IQR). Predictors of CDI were investigated using logistic regression analysis. Only the first episode of CDI for an individual patient was included in the analysis. The variables identified as statistically significant (P < 0.01) in univariate analysis were included in the multivariate analysis. Odds ratio and 95% confidence interval were used to quantify the strength of these associations. Statistical analyses were performed with SAS statistical package version 9.1 (SAS Institute, Cary, NC, USA).

Stool specimens were preserved at 70  C immediately after collection and then sent to the Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska University Hospital Stockholm, Sweden. All samples were investigated for the presence of C. difficile, Clostridium perfringens, Bacteroides fragilis, Shigella, Salmonella, Yersinia, Campylobacter, and Escherichia coli by standard methods [10]. C. difficile toxin A and B were detected by conventional PCR. The presence of toxin B was confirmed by the cytotoxicity neutralization assay. The toxigenic C. difficile isolates were typed by PCR ribotyping [11]. C. perfringens enterotoxin was detected by PCR amplification of cpe gene [12]. B. fragilis was isolated and counted as described by Nord et al. [13]. The lower limit of detection was 102 colony-forming units (CFU)/g faeces. The B. fragilis toxin (bft) gene was detected by PCR [14]. In order to detect the five different diarrhoeagenic E. coli pathotypes [enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), enterohaemorrhagic E. coli (EHEC) and enteroinvasive E. coli (EIEC)], a mixture of eight primer pairs was used in a multiplex PCR [15]. Predominant growth of Staphylococcus aureus (90% of the total bacterial growth) on fresh blood agar plates was considered significant [16]. Production of enterotoxins A, B, C, D and E and toxic shock syndrome toxin by Staphylococcus was detected by enzymelinked immunosorbent assay (Tecra International Pty. Ltd., Frenchs Forest, NSW, Australia) and reverse passive latex agglutination (Oxoid, Basingstoke, United Kingdom), respectively. Methicillin resistance was detected by cefoxitin disk diffusion and confirmed by the presence of mecA gene. Toxigenic S. aureus isolates were typed by PFGE. 2.4. Control patients A retrospective cohort study was conducted among the hospitalized patients at Huashan Hospital. Two sets of case/control groups were compared for analysis of the risk factors of CDI. Specifically, the patients with first episode of CDI as cases compared with the diarrhoeal patients whose faecal sample was negative for toxigenic C. difficile as controls (control group 1, case/control ratio

2.6. Statistical analysis

3. Results 3.1. Bacterial pathogens During the study period, 260 consecutive stool specimens were collected from 240 eligible patients. After the duplicate specimens were excluded (without symptom resolution) between 2 weeks, 252 stool specimens from 240 patients were enrolled in this study. Overall, 240 of the 7724 inpatients were identified with hospital-acquired diarrhoea. One hundred and two episodes of CDI were identified in 90 patients. The incidence of CDI per patients was presented by wards (Table 1). According to the cases per 100,000 patient-days, the incidence of CDI was the highest in general ICU, followed by neurological ICU and nephrology ward. The mean age of the 90 patients with CDI was 61.7 ± 19.8 [51.0e78.0] years. Recurrence of CDI was reported in 12 patients with a mean age of 61.4 ± 18.4 [56.0e71.0] years. Of the 90 isolates from the first episode of CDI, 017 (35.6%) was the most common ribotype, followed by 001 (15.6%) and H (12.2%). Ribotype 027 was not identified and one strain of ribotype 078 was identified. Of the 12 strains isolated from recurrent diarrhoea, 6 showed the same ribotype as that from the first episodes. In addition to C. difficile, 20 strains of enterotoxin D-producing S. aureus and one strain each of ETEC and EPEC were isolated from the patients. Nine cases of S. aureus infections were mixed with CDI. PFGE typing showed that these S. aureus strains belonged to nine different types. Enterotoxin-producing C. perfringens or B. fragilis strains were not identified. The common pathogens of community-acquired diarrhoea such as Salmonella species were not isolated.

H. Huang et al. / Anaerobe 30 (2014) 65e69

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Table 1 Incidence of Clostridium difficile infection in the selected wards. Ward

No. of bed

Hospital-acquired diarrhoea

CDI case

No. of admissions

No. of CDI per 1000 admissions

No. of patient-days

No. of CDI per 100,000 patient-days

Geriatrics Nephrology Haematology General Surgery Cardiovascular Neurological ICU General ICU Total

100 26 28 33 31 30 25 273

41 29 21 84 6 13 46 240

16 20 4 23 1 10 16 90

757 829 505 1807 1134 2101 591 7724

21.1 24.1 7.9 12.7 0.9 4.8 27.1 11.7

25,760 7497 7438 13,399 8022 3200 4722 70,038

62.1 266.8 53.8 171.7 12.5 312.5 338.8 128.5

CDI, Clostridium difficile infection; ICU, intensive care unit.

3.2. Risk factors Univariate analysis indicated that a number of factors were significantly associated with the first episodes of CDI (Table 2). After adjustment, renal disease (OR, 3.37; 95% CI, 1.55 e 7.31; P ¼ 0.002), hypoalbuminemia (OR, 2.45; 95% CI, 1.39 e 4.34; P ¼ 0.002) and serum creatinine >195 mmol/L (OR, 2.41; 95% CI, 1.13 e 5.15; P ¼ 0.023) were independently associated with the development of CDI when compared with the patients with non-CDI diarrhoea. However, when compared with the patients without diarrhoea, malignancy (OR, 3.64; 95% CI, 1.92 e 6.91; P < 0.001), prior

antibiotic treatment (OR, 3.58; 95% CI, 1.53 e 8.38; P ¼ 0.003), chemotherapy (OR, 3.62; 95% CI, 1.52 e 8.61; P ¼ 0.004), nasogastric tube use (OR, 3.32; 95% CI, 1.53 e 7.20; P ¼ 0.002), length of stay >14 days (OR, 3.29; 95% CI, 1.59 e 6.80; P ¼ 0.001) and intra-abdominal surgery (OR, 2.76; 95% CI, 1.49 e 5.10; P ¼ 0.001) were included as the independent risk factors while serum creatinine >195 mmol/L (OR, 1.57; 95% CI, 0.80 e 3.08; P ¼ 0.19) was excluded. Laxative use (OR, 0.28; 95% CI, 0.12 e 0.66; P ¼ 0.004) was a protective factor. After controlling for age, sex, hypoalbuminemia, prior antibiotic treatment, chemotherapy, nasogastric tube use, length of stay and intra-abdominal surgery, DDDs of antimicrobial agents 19 (OR,

Table 2 Univariate analysis of the potential predictors for development of Clostridium difficile infection. Variable

CDI n (%)

Age (years) 65 to 7 days Chemotherapy 17 (18.9) Nasogastric tube 35 (38.9) Mechanical ventilation 12 (13.3) Dialysis 9 (10.0) Antiperistaltic agents 1 (1.1) Laxative 8 (8.9) Parenteral nutrition 15 (16.7) Previous hospitalization 24 (26.7) Length of stay > 14 days 56 (62.2) Intra-abdominal surgery 28 (31.1) Biological markers at CDI diagnosis Blood WBC > 10  109/L 24 (26.7) Hypoalbuminemia 25e35 g/L 45 (50.0) 195 mmol/L 32 (35.6)

Control 1a n (%)

Control 2b n (%)

Or 1c (95% CI)

Or 2d (95% CI)

59 (39.3) 11 (7.3) 92 (61.3)

61 (33.9) 14 (7.8) 106 (58.9)

0.89 (0.51,1.57) 1.86 (0.76, 4.54) 1.14 (0.66, 1.97)

1.14 (0.65, 1.97) 1.91 (0.82, 4.45) 1.26 (0.75, 2.14)

28 (18.7) 2 (1.3) 0 59 (39.3) 15 (10.0) 17 (11.3) 12 (8.0)

38 (21.1) 2 (1.1) 0 27 (15.0) 35 (19.4) 8 (4.4) 31 (17.2)

1.07 NA NA 0.77 1.17 0.61 3.72

0.93 NA NA 2.83 0.58 1.81 1.56

127 (84.7) 106 (70.7)

119 (66.1) 90 (50.0)

18 (12.0) 55 (36.7) 17 (11.3) 7 (4.7) 0 21 (14.0) 32 (21.3) 40 (26.7) 62 (41.3) 64 (42.7)

19 (10.6) 24 (13.3) 8 (4.4) 16 (8.9) 0 41 (22.8) 11 (6.1) 42 (23.3) 68 (37.8) 27 (15.0)

1.47 1.07 1.72 1.71 1.09 1.20 2.51 NA 0.60 0.73 1.02 1.84 0.60

48 (32.0) 46 (30.7) 5 (3.3) 36 (24.0)

CDI, Clostridium difficile infection; CI, confidence interval; PPI, proton-pump inhibitor. a Patients with diarrhoea but CDI negative. b Patients without diarrhoea. c CDI patients vs. control 1. d CDI patients vs. control 2. e Hemotological malignancy is excluded. f P < 0.1 in univariate analysis. g P < 0.05 in multivariate analysis.

(0.55, 2.07)

(0.45, (0.52, (0.25, (1.74,

1.33) 2.64) 1.53) 7.96)g

(0.64, (0.60, (0.92, (0.83, (0.64, (0.54, (0.92,

6.37) 1.93) 3.21) 3.51) 1.88) 2.65) 6.87)

(0.25, (0.37, (0.55, (0.89, (0.35,

1.41) 1.45) 1.87) 3.83) 1.05)

4.56 2.71 1.65 1.97 4.13 3.31 1.14 NA 0.33 3.11 1.61 3.32 2.60

(0.50, 1.75)

(1.56, (0.28, (0.64, (0.84,

5.16)f,g 1.20) 5.17) 2.88)g

(2.14, (1.56, (0.87, (0.97, (2.26, (1.30, (0.48,

9.70) 4.70) 3.14) 4.02)g 7.56)g 8.42) 2.69)

(0.15, (1.37, (0.86, (1.65, (1.42,

0.75)g 7.10) 3.01) 6.70)g 4.77)g

0.88 (0.48, 1.61) 47 (26.1) 4 (2.2) 40 (22.2)

2.50 (1.43, 4.36)g 3.06 (0.88, 10.63) 2.43 (1.14, 5.16)g

3.15 (1.82, 5.44)g 4.93 (1.32, 18.4)g 1.54 (0.79, 3.01)

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H. Huang et al. / Anaerobe 30 (2014) 65e69

3.07; 95% CI, 1.12 e 8.42; P ¼ 0.029), use of more than three antimicrobial agents (OR, 2.86; 95% CI, 1.07 e 7.66; P ¼ 0.037), use of carbapenems (OR, 4.06; 95% CI, 1.84 e 9.00; P < 0.001) were also independent risk factors. However, use of first or second generation of narrow-spectrum cephalosporins (OR, 0.44; 95% CI, 0.21 e 0.93; P ¼ 0.031) or metronidazole (OR, 0.25; 95% CI, 0.08 e 0.75; P ¼ 0.014) were identified as protective factors. 3.3. Outcomes Of the 90 CDI patients, only two had severe infections. The symptoms of diarrhoea resolved after changing or discontinuing the antimicrobial agents in 53 patients. Thirty-seven patients received treatment with metronidazole, berberine (10 a-6,60 -dimethoxy-2,20 -dimethyltubocuraran-70,120 -diol) and/or vancomycin. At the end of this study, 76 patients were cured. Twelve patients experienced recurrence but were cured after re-treatment. The outcome was unknown for one of the patients. Another patient failed to vancomycin and metronidazole combination therapy and finally died. This patient was at the advanced stage of myelodysplastic syndrome complicated with severe CDI.

implemented as soon as possible to avoid the CDI outbreaks like in USA, Canada and Europe. First of all, testing of C. difficile should be made available as a routine practice in the clinical laboratory. Based on our results in a Chinese hospital, to reduce CDI risk, efforts should be made to minimize the frequency and duration of antimicrobial therapy and the number of antimicrobial agents prescribed. Invasive procedures should be spared when appropriate, especially those involving the gastrointestinal tract. Shorter length of hospital stay may be also useful for reducing the risk of CDI. Fundings This work was supported by a grant from National Natural Science Foundation of China (No. 30973594 and 81101292) and Shanghai Pujiang Programme (10PJ1401800). Conflict of interest The authors declare no conflicts of interest.

4. Discussion

References

C. difficile is one of the most common pathogens causing hospital-acquired diarrhoea. In the present study, 240 of the 7724 inpatients had hospital-acquired diarrhoea. The diarrhoea was confirmed as CDI in 90 patients, much higher than the previously reported prevalence [18]. This is mainly due to the fact that only nine wards were selected in this study. CDI was more prevalent in the ICU and geriatric wards. Severe infection was found in only two patients. The majority (98.7%, 88/90) of the CDI patients were cured. Ribotype 017 (A-Bþ) was the most common genotype and ribotype 027 was not found. Yan et al. [19] also reported that one fourth of the C. difficile isolates were ST-37 (ribotype 017). CDI is not uncommon in Chinese hospitals, but CDI outbreaks, severe cases and recurrence rate are relatively lower, and the outcomes of CDI are better in China than in the USA, Canada and Europe [1,5,20]. This may be due to the fact that the 027 strain is not prevalent in China. The two most prominent risk factors for CDI are exposure to antibiotics, especially broad-spectrum antibiotics and exposure to the organism. Other known risk factors include older age, gastrointestinal surgery, nasogastric tube feeding, hypoalbuminemia, reduced gastric acid and concurrent diseases, including inflammatory bowel disease [8,21,22]. Antibiotic exposure is considered to be the most important factor predisposing patients to CDI. Historically, third-generation cephalosporins and clindamycin have been implicated as risk factors of CDI. In the past 10 years, increasing use of newer fluoroquinolones, particularly moxifloxacin, may have promoted several outbreaks of CDI caused by ribotype 027 [3,4,8,16]. However, only carbapenem use was found as independent risk factor of CDI in this study. As in other reports [17], use of metronidazole can significantly reduce the risk of CDI. In our study population, none of the patients received clindamycin. Fluoroquinolone antibiotics were used by only one fourth of the patients. This may contribute to the situation of no ribotype 027 prevalence and fewer patients with severe CDI in Huashan Hospital. In conclusion, C. difficile as a major pathogen of hospitalacquired diarrhoea is common in China. The risk factors of CDI in hospitalized Chinese patients are similar to those reported in other countries. Therefore, we propose that C. difficile should be considered as one of the most important pathogens of nosocomial infections in China. Appropriate and effective measures should be

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Risk factors of Clostridium difficile infections among patients in a university hospital in Shanghai, China.

Clostridium difficile infection (CDI) is an increasing concern in China. However, the risk factors of CDI are rarely reported in the Chinese populatio...
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