- Email: [email protected]
Clostridium difficile infection in a geriatric ward
Arch. Gerontol. Geriatr., 13 (1991) 255-262
255
© 1991 Elsevier Science Publishers B.V. All rights reserved 0167-4943/91/$03.50 AGG00415
Clostridium difficile infection in a geriatric ward I n g r i d M o n s i e u r a, T o n y M e t s a, S a b i n e L a u w e r s b, Veerle De Bock a and Michel Delm6e c Division of Geriatrics, b Department of Microbiology, Academic Hospital, Free University of Brussels (V.U.B.), Brussels, and c Microbiology Unit, University of Louvain, Brussels, Belgium (Received 10 October 1990; revised version received 25 April 1991; accepted 14 June 1991)
Summary In a prospective, longitudinal study we searched for the presence of Clostridium difficile in the stools of 100 consecutively hospitalized elderly patients (mean age: 82; SD: 9.5 years). C. difficile was found on admission in 6 patients, 3 of whom were asymptomatic carriers. Ten patients acquired C. difficile during hospitalization. Four different types of C. difficile were isolated. The various types were clustered in time, indicating that the infection was acquired from the environment. Aged; Clostridium difficile; Clostridium difficile-associated infection
diarrhea; Elderly; Geriatrics; Nosocomial
Introduction
Clostridium difficile was isolated for the first time in 1935 from the faeces of children (Hall and O'Toole, 1935). It was only in 1978, however, that its etiological role in pseudomembranous colitis was recognized (Bartlett et al., 1978). Since then C. difficile has been associated with outbreaks of less severe colitis and with diarrhea in hospitalized patients receiving antimicrobial therapy. For several clusters of cases or large outbreaks in hospitals direct infection from the environment has been suggested (Mulligan et al., 1979; Fekety et al., 1981; Greenfield et al., 1981; Delm6e et al., 1986a; Heard et al., 1986; McFarland et al., 1989). Geriatric patients seem to be more susceptible to C. difficile infection and up to 30% of the patients in chronic care facilities have been found to be carriers (Bender et al., 1986). Most studies are cross-sections of populations, set up at the moment of an outbreak of symptomatic C. difficile infection. Only limited information is available about the dynamics of C. difficile infection in geriatric hospitalized patients. Therefore we undertook a prospective, longitudinal study in order to Correspondence to: Dr. T. Mets, Geriatrics, A.Z.-V.U.B., Laarbeeklaan 101, B-1090 Brussels, Belgium.
256 determine the prevalence of the carrier state and the acquisition rate of C. difficile in geriatric ward hospitalized patients.
Patients and Methods
Patients One hundred patients, consecutively admitted to the geriatric ward (having 13 rooms and 29 beds) of the Academic Hospital, Free University Brussels (V.U.B.), during a period of three months were enrolled in the study. Consent was obtained from the patients or from their relatives. Within 48 hours a rectal swab was taken for culture of C. difficile. The first available stools were obtained for cytotoxicity testing. Culture and cytotoxicity testing were repeated weekly until discharge of the patients. For each patient medical history, demographic data, diagnosis, medication, room location and frequency of stools were noted. If C. difficile was detected or diarrhea occurred, enteric precautions were taken to limit the spread (Kuijper, 1986). Vancomycin treatment was started for symptomatic patients having C. difficile in the stools.
Definitions Diarrhea: loose stools, more than once a day for at least 48 hours. C. difficile-associated diarrhea: diarrhea not attributable to any other cause, which occurred at the same time as a positive culture a n d / o r cytotoxin test for C.
difficile. Antibiotic associated diarrhea: diarrhea occurring after ingestion of antibiotics and without demonstration of C. difficile. Asymptomatic carrier: patient who had a positive culture on admission, without diarrhea and no recent hospitalization.
Laboratory techniques Rectal swabs were transported in an anaerobe culture medium (PortACul universal transport medium; Becton Dickinson). Within 4 hours rectal swab specimens were inoculated on a selective C. difficile agar (oxoid CM 601) and anaerobically incubated for 48 hours, at 35°C (George et al., 1979). Characteristic colonies were submitted to an oxygen tolerance test. Thereafter the microorganisms were further identified by microscopical examination of Gram-stained smears, the presence of paracresol odour and by analysis of fermentation products by gas-liquid chromatography (Sutter et al., 1985). The cytotoxic effect of C. difficile was tested by inoculation of a faecal-filtered suspension on a monolayer of cultured LLC-MK2 cells (Lashner et al., 1986). Rounding of at least 20% of the ceils after 24-48 hours and a complete neutralisation of the effect by C. difficile antitoxin (Wellcome) were considered as a positive cytotoxin test. Further characterization of isolated C. difficile was obtained by in vitro testing for cytotoxicity, sorbitol testing and typing by means of a slide
257
agglutination technique and by polyacrylamide gel electrophoresis analysis (Delm6e et al., 1985, 1986b).
Statistical analysis Differences between means were analysed with Student's t-test. Differences between groups were evaluated by the Chi-squared test or by Fisher's exact probability test for small groups.
Results
In a three-months' period, 100 patients consecutively hospitalized on the geriatric ward were studied. There were 74 women and 26 men. The mean age was 82 (SD 9.5) years. The mean length of stay on the ward was 22 days. Thirty-nine patients were severely ill and 9 patients died during the study period. Neurological disease was the most frequent reason for admission (25 patients), followed by respiratory pathology (18 patients) and cardiovascular problems (17 patients). In the period preceding hospitalization, 13 patients used antibiotics. During their hospital stay 52 patients received antibiotics. Of the 341 rectal swabs taken during the study 25 were positive for C. difficile. Twenty-four of the isolates could be typed. Of the 234 collected faeces specimens 4 yielded a positive cytotoxin test. In 16 of the 100 patients C. difficile could be cultured or the toxin demonstrated at some time during their hospitalization (see Fig. 1). In six patients C. difficile was demonstrated upon admission. Three of these patients were asymptomatic carriers; one of them had used antibiotics. The other 3 patients had C. difficile-associated diarrhea which had recently developed; all three came from a surgical ward, where they had received antibiotics and two of them had undergone an intervention. 100 PATIENTS
84 NEGATIVE 6 POSITIVE AT ADMISSION
I 3 ASYMPTOMATIC (A2, A14*, H)
10 POSITIVE AFTER ADMISSION
1
I
3 SYMPTOMATIC (A14, A14) (1 positive cytotoxicity) test, culture negative)
6 ASYMPTOMATIC (A2, A14, H, K, K) (1 strain was not typed)
Subsequently C. difficile type K was isolated in this patient
Fig. 1. Isolation of Clostridium difficile.
I 4 SYMPTOMATIC (A14 °, K, K, K)
258 TABLE I
Comparison between patients with and without presence of ('. d!/ficile
C. difficile Number of patients Mean age (years) Number of patients using antibiotics Mean length of stay (days) Number of patients with severe illness Mortality
Difference
Positive
Negative
16 84 ( S D 7.5)
84 81 ( S D 6.0)
NS
12 33 ( S D 15)
40 21 ( S D 12)
p <. 11.02 p < II.0(ll
31 8
NS NS
8 2
Ten patients acquired C. difficile on the geriatric ward (four of them in the second, four in the third, one in the sixth and one in the eighth week of hospitalization). Four of them had C. difficile associated diarrhea; all four had received antibiotics. The other six patients, of whom four had received antibiotics, were asymptomatic. Only for four patients the stool specimens yielded a positive cytotoxin test. All four patients had C. difficile associated diarrhea. None of the patients had symptoms suggestive for pseudomembranous colitis; no colonoscopic examinations were performed. Additional features for the 16 patients in whom C. difficile could be demonstrated are given in Table 1 and are compared with those of the other patients. In the C. difficile positive group, five types of antibiotics were used (penicillins, cephalosporins, co-trimoxazole, quinolones, nitrofurantoin); there was no antibiotic which was more often associated with the presence of C. difficile. No patient presented arguments for immunodepression: there was no leukopenia or use of corticosteroids in the C. difficile-positive group; of the seven patients presenting a malignancy, only one had a C. difficile infection. Typing of the different C. difficile strains by the agglutination serogrouping technique yielded three different types: A, H and K. Within group A there were two subtypes, identified by polyacrylamide gel electrophoresis: A2 and A14 (see Table II). The distribution of the various types is shown in Fig. 1. For 2 patients, 2 different types were subsequently found. T A B L E 11
Isolation and typing of C. di[~'icile strains Number of positive cultures
Agglutination sero grouping
2 6 2 14
A A H K
Sorbitol
Toxin production
Page profile
Period of isolation (weeks)
+ + +
+
weakly + + +
A2 AI4 H K
1 3 2-9 13-14 3, 9 14
259 As shown in Table II, the isolation of the various types of C. difficile was clustered in time. Four of the 9 patients who acquired C. difficile on the ward and for whom complete typing of the strain was performed, stayed in rooms where previously C. difficile had been found in a patient. All four of these patients acquired a type of C. difficile which was recently isolated in another patient in that room.
Discussion The aim of the study was to determine the prevalence of C. difficile carriers in a geriatric population and to study the acquisition rate in a hospital environment within this population. In contrast with most other studies on C. difficile, we did a longitudinal, prospective study, set up at a moment when no dramatic cases of C. difficile-associated diarrhea were present (Kim et al., 1983; Delm6e et al., 1986a). Until now only a few studies were done in elderly people. Bender et al. (1986) report a prevalence of C. difficile of 30% in a chronic care facility in the U.S.A. They suggest that C. difficile may be endemic in patients on long stay wards. These findings are in contrast with those of Campbell et al. (1988), who failed to detect C. difficile in a geriatric hospital in England. We found a prevalence of C. difficile of 16%. We found the microorganism on admission in six patients, three of whom were asymptomatic carriers. The prevalence of asymptomatic carriers of 3% in the geriatric population described here is comparable with the prevalence of 3% found in healthy adults (Viscidi et al., 1981). The acquisition rate of C. difficile was 10%. This figure is much lower than the 21% reported by McFarland et al. (1989). The higher incidence in that study can be explained by the higher frequency of collecting rectal swabs (every three days) and by the many surgical patients who were enrolled. In the study of McFarland et al. as well as in our study enteric precautions were taken for all patients with diarrhea. The patients in the study of McFarland et al. stayed on a general medical ward and were younger (mean age 66 years for patients who had a nosocomial acquisition of C. difficile ). As suggested previously, it is necessary to type the different strains for epidemiological studies (Delm6e et al., 1985). The three asymptomatic carriers on admission, harboured three different types of C. difficile. This finding is expected in patients coming from a different environment without epidemiological connections. In the patients who acquired C. difficile during their hospitalization four different types of C. difficile were demonstrated. Although the yield of rectal swab cultures and of stool cultures for the recovery of C. difficile is equivalent, the detection methods are not 100% sensitive (McFarland et al., 1987). Therefore, the possibility that some patients carried the microorganism already on admission cannot be excluded. The diversity of the acquired types of C. difficile might suggest an endogenous origin. However, it is well known that the microorganism is present in the hospital environment and can be transmitted by the hands of health care
260
workers (Mulligan et al., 1979; McFarland et al., 1989). Four patients in our study acquired a type of C. difficile, previously isolated from a patient staying in the same room. Moreover, the types of C. difficile were clustered in time, indicating infection from the environment or cross-infection. It is probable that repeatedly new types of C. difficile were introduced in the ward. In two of the patients different types of C. difficile were subsequently recovered, indicating that recurrent infection is possible. This finding has also been reported by others (Johnson et al., 1989). It was previously suggested that there is a relationship between serogroup and virulence or pathogenicity (Delm6e et al., 1985). Recent reports confirm this relationship (Johnson et al., 1990). In our study only patients having the A14 or K type were symptomatic. However, four patients harbouring one of these types were asymptomatic. Only in four patients the cytotoxin test was positive and all four were symptomatic. It has been suggested that the cytotoxin test is more reliable for the diagnosis of C. difficile associated disease than culture (Nash et al., 1982). As shown by our study, the cytotoxin test does not identify all patients with C. dlfficile associated diarrhea (Boriello and Honour, 1983). None of the patients had symptoms suggestive of pseudomembranous colitis. Only 6 of the 52 patients who received antibiotics (11%) developed a C. difficile-associated diarrhea. This figure is much lower than the 20-30% mentioned by Viscidi et al. (1981) in adults. As also described by others, a relationship existed between C. difficile-associated diarrhea and the use of antibiotics; several types of antibiotics had been used (Aronsson et al., 1982). We have no good explanation why the length of the hospital stay was associated with the occurrence of C. difficile. For most of the patients the C. difficile infection remained subclinical and could not have influenced the duration of hospitalization. On the other hand, patients acquiring C. difficile did not present more severe illness; besides, for eight of the patients the infection took place early (either in the second or third week) in the hospitalization. No association was found with antacida intake (Gerding et al., 1986), the diagnosis of cerebrovascular accident (Nakamura et al., 1982) or the severity of the underlying disease. We conclude that the prevalence of C. difficile carriers among our elderly population is rather low. However, in hospitalized geriatric patients the acquisition rate is high. The distribution of the types indicates that C. difficile is acquired from the environment or as a cross-infection. Probably new strains are regularly introduced in the ward. The pathogenicity of the various strains seems to be variable.
References Aronsson, B., M611by, R. and Nord, C.E. (1982): CTostridium difficile and antibiotic associated diarrhea in Sweden. Scand. J. Infect. Dis. 35 (Suppl.), 53-58. Bartlett, J.G., Chang, W.TI, Gurwith~ M., Gorbach, S.L. and Onderdonck, A.B. (1978): Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N, Engl. J. Med., 298, 531-534. Bender, B.S., Laughon, B.E., Gaydos, C., Forman, M.S., Bennett, R., Greenough, W.B., Sears, S.D. and Bartlett J.G. (1986): Is Clostridium difficile endemic in chronic-care facilities? Lancet, i. 11-13.
261 Borriello, S.P. and Honour, P. (1983): Concomitance of cytotoxigenic and non-cytotoxigenic Clostridium difficile in stool specimens. J. Clin. Microbiol. 18, 1006-1007. Campbell, R.R., Beere, D., Wilcock, G.K. and Brown, E.M. (1988): CIostridium difficile in acute and longstay elderly patients. Age Ageing, 17, 333-336. Delm~e, M., Homel, M. and Wauters, G. (1985): Serogrouping of Clostridiurn difficile strains by slide agglutination. J. Clin. Microbiol., 21,323-327. Delm6e, M, Bulliard, G. and Simon, G. (1986a): Application of a technique for serogrouping Clostridium difficile in an outbreak of antibiotic-associated diarrhea. J. Infect., 13, 5-9. Delm~e, M., Laroche, Y., Avesani, V. and Cornelis, E. (1986b): Comparison of serogrouping and polyacrylamide gel electrophoresis for typing Clostridium difficile. J. Clin. Microbiol., 24: 991-994. Fekety, R., Kim, K.H., Brown, D, Batts, D.H., Cudmore, M. and Silva, J. (1981): Epidemiology of antibiotic associated colitis: isolation of Clostridium difficile from the hospital environment. Am. J. Med., 70, 906-908. George, W.L., Sutter, V.L., Citron, D. and Finegold, S.M. (1979): Selective and differential medium for isolation of Clostridiurn difficile. J. Clin. Microbiol., 9, 214-219. Gerding, D.N., Olson, M.M., Peterson, L.R., Teaslay, D.G., Gebhard, R.L., Schwartz, M.L. and Lee, J.T. (1986): Clostridium difficile-associated diarrhea and colitis in adults. A prospective case-controlled epidemiologic study. Arch. Intern. Med., 146, 95-100. Greenfield, C., Szawathowski, M., Noone, P., Burroughs, A., Bass, N. and Pounder, R. (1981): Is pseudomembranous colitis infectious? Lancet, i, 371-372. Hall, I.C. and O'Toole, E. (1935): Intestinal flora in new-born infants. Am. J. Dis. Child., 49, 390-402. Heard, S.R.,, O'Farrell, S., Holland, D., Crook, S., Barnett, M.J. and Tabaqchali, S. (1986): The epidemiology of Clostridiurn difficile with use of a typing scheme: nosocomial acquisition and cross-infection among immunocompromised patients. J. Infect. Dis., 153, 159-162. Johnson, S., Adelmann, A., Clabots, C.R., Peterson, L.R. and Gerding, D.N. (1989): Recurrences of Clostridium difficile diarrhea not caused by the original infecting organism. J. Infect. Dis., 159, 340-343. Johnson, S., Clabots, C.R., Linn, F.V., Olson, M.M., Peterson, L.R. and Gerding, D.N. (1990): Nosocomial Clostridium difficile colonisation and disease. Lancet, 336, 97-100. Kim, K., Dupont, H.L. and Pickering, L.K. (1983): Outbreaks of diarrhea associated with Clostridiurn difficile and its toxin in day-care centers: evidence of person-to-person spread. J. Pediatr., 102, 376-382. Kuijper, E.J. (1986): Is pseudomembranous colitis contagious ? Ned. Tijdschr. Geneesk., 130, 1805-1807. Lashner, B.A., Todorczuk, J., Sahm, D.F. and Hanauer, M.D. (1986): Clostridiurn difficile culture-positive toxin-negative diarrhea. Am. J. Gastroenterol., 81,940-943. McFarland, L.V., Coyle, M.B., Kremer, W.H. and Stamm, W.E. (1987): Rectal swab cultures for Clostridium difficile surveillance studies. J. Clin. Microbiol., 25, 2241-2242. McFarland, L.V., Mulligan, M.E., Kwok, R.Y.Y. and Stamm, W.E. (1989): Nosocomial acquisition of Clostridiurn difficile infection. N. Engl. J. Med., 320, 204-210. Mulligan, M.E., Rolfe, R.D., Finegold, S.M. and George, W.L. (1979): Contamination of a hospital environment by Clostridium difficile. Curr. Microbiol., 3, 173-175. Nakamura, S., Mikawa, M., Tanabe, N., Yamakawa, K., Nishida, S. (1982): Effect of clindamycin on cytotoxin production of Clostridium difficile. Microbiol. Immunol., 26, 985-992. Nash, J.Q., Chattopadhyay, B., Honeycombe, J. and Tabaqchali, S. (1982): Clostridium difficile and cytotoxin in routine faecal specimens. J. Clin. Path., 35, 561-565. Sutter, V.L., Citron, D.M., Edelstein, M.A.C. and Finegold, S.M. (1985): Anaerobic Bacteriology Manual, 4th edn. Star Publishing comp., Belmont, CA. Viscidi, R., Willey, S. and Bartlett, J.G. (1981): Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations. Gastroenterology, 81, 5-9.
255
© 1991 Elsevier Science Publishers B.V. All rights reserved 0167-4943/91/$03.50 AGG00415
Clostridium difficile infection in a geriatric ward I n g r i d M o n s i e u r a, T o n y M e t s a, S a b i n e L a u w e r s b, Veerle De Bock a and Michel Delm6e c Division of Geriatrics, b Department of Microbiology, Academic Hospital, Free University of Brussels (V.U.B.), Brussels, and c Microbiology Unit, University of Louvain, Brussels, Belgium (Received 10 October 1990; revised version received 25 April 1991; accepted 14 June 1991)
Summary In a prospective, longitudinal study we searched for the presence of Clostridium difficile in the stools of 100 consecutively hospitalized elderly patients (mean age: 82; SD: 9.5 years). C. difficile was found on admission in 6 patients, 3 of whom were asymptomatic carriers. Ten patients acquired C. difficile during hospitalization. Four different types of C. difficile were isolated. The various types were clustered in time, indicating that the infection was acquired from the environment. Aged; Clostridium difficile; Clostridium difficile-associated infection
diarrhea; Elderly; Geriatrics; Nosocomial
Introduction
Clostridium difficile was isolated for the first time in 1935 from the faeces of children (Hall and O'Toole, 1935). It was only in 1978, however, that its etiological role in pseudomembranous colitis was recognized (Bartlett et al., 1978). Since then C. difficile has been associated with outbreaks of less severe colitis and with diarrhea in hospitalized patients receiving antimicrobial therapy. For several clusters of cases or large outbreaks in hospitals direct infection from the environment has been suggested (Mulligan et al., 1979; Fekety et al., 1981; Greenfield et al., 1981; Delm6e et al., 1986a; Heard et al., 1986; McFarland et al., 1989). Geriatric patients seem to be more susceptible to C. difficile infection and up to 30% of the patients in chronic care facilities have been found to be carriers (Bender et al., 1986). Most studies are cross-sections of populations, set up at the moment of an outbreak of symptomatic C. difficile infection. Only limited information is available about the dynamics of C. difficile infection in geriatric hospitalized patients. Therefore we undertook a prospective, longitudinal study in order to Correspondence to: Dr. T. Mets, Geriatrics, A.Z.-V.U.B., Laarbeeklaan 101, B-1090 Brussels, Belgium.
256 determine the prevalence of the carrier state and the acquisition rate of C. difficile in geriatric ward hospitalized patients.
Patients and Methods
Patients One hundred patients, consecutively admitted to the geriatric ward (having 13 rooms and 29 beds) of the Academic Hospital, Free University Brussels (V.U.B.), during a period of three months were enrolled in the study. Consent was obtained from the patients or from their relatives. Within 48 hours a rectal swab was taken for culture of C. difficile. The first available stools were obtained for cytotoxicity testing. Culture and cytotoxicity testing were repeated weekly until discharge of the patients. For each patient medical history, demographic data, diagnosis, medication, room location and frequency of stools were noted. If C. difficile was detected or diarrhea occurred, enteric precautions were taken to limit the spread (Kuijper, 1986). Vancomycin treatment was started for symptomatic patients having C. difficile in the stools.
Definitions Diarrhea: loose stools, more than once a day for at least 48 hours. C. difficile-associated diarrhea: diarrhea not attributable to any other cause, which occurred at the same time as a positive culture a n d / o r cytotoxin test for C.
difficile. Antibiotic associated diarrhea: diarrhea occurring after ingestion of antibiotics and without demonstration of C. difficile. Asymptomatic carrier: patient who had a positive culture on admission, without diarrhea and no recent hospitalization.
Laboratory techniques Rectal swabs were transported in an anaerobe culture medium (PortACul universal transport medium; Becton Dickinson). Within 4 hours rectal swab specimens were inoculated on a selective C. difficile agar (oxoid CM 601) and anaerobically incubated for 48 hours, at 35°C (George et al., 1979). Characteristic colonies were submitted to an oxygen tolerance test. Thereafter the microorganisms were further identified by microscopical examination of Gram-stained smears, the presence of paracresol odour and by analysis of fermentation products by gas-liquid chromatography (Sutter et al., 1985). The cytotoxic effect of C. difficile was tested by inoculation of a faecal-filtered suspension on a monolayer of cultured LLC-MK2 cells (Lashner et al., 1986). Rounding of at least 20% of the ceils after 24-48 hours and a complete neutralisation of the effect by C. difficile antitoxin (Wellcome) were considered as a positive cytotoxin test. Further characterization of isolated C. difficile was obtained by in vitro testing for cytotoxicity, sorbitol testing and typing by means of a slide
257
agglutination technique and by polyacrylamide gel electrophoresis analysis (Delm6e et al., 1985, 1986b).
Statistical analysis Differences between means were analysed with Student's t-test. Differences between groups were evaluated by the Chi-squared test or by Fisher's exact probability test for small groups.
Results
In a three-months' period, 100 patients consecutively hospitalized on the geriatric ward were studied. There were 74 women and 26 men. The mean age was 82 (SD 9.5) years. The mean length of stay on the ward was 22 days. Thirty-nine patients were severely ill and 9 patients died during the study period. Neurological disease was the most frequent reason for admission (25 patients), followed by respiratory pathology (18 patients) and cardiovascular problems (17 patients). In the period preceding hospitalization, 13 patients used antibiotics. During their hospital stay 52 patients received antibiotics. Of the 341 rectal swabs taken during the study 25 were positive for C. difficile. Twenty-four of the isolates could be typed. Of the 234 collected faeces specimens 4 yielded a positive cytotoxin test. In 16 of the 100 patients C. difficile could be cultured or the toxin demonstrated at some time during their hospitalization (see Fig. 1). In six patients C. difficile was demonstrated upon admission. Three of these patients were asymptomatic carriers; one of them had used antibiotics. The other 3 patients had C. difficile-associated diarrhea which had recently developed; all three came from a surgical ward, where they had received antibiotics and two of them had undergone an intervention. 100 PATIENTS
84 NEGATIVE 6 POSITIVE AT ADMISSION
I 3 ASYMPTOMATIC (A2, A14*, H)
10 POSITIVE AFTER ADMISSION
1
I
3 SYMPTOMATIC (A14, A14) (1 positive cytotoxicity) test, culture negative)
6 ASYMPTOMATIC (A2, A14, H, K, K) (1 strain was not typed)
Subsequently C. difficile type K was isolated in this patient
Fig. 1. Isolation of Clostridium difficile.
I 4 SYMPTOMATIC (A14 °, K, K, K)
258 TABLE I
Comparison between patients with and without presence of ('. d!/ficile
C. difficile Number of patients Mean age (years) Number of patients using antibiotics Mean length of stay (days) Number of patients with severe illness Mortality
Difference
Positive
Negative
16 84 ( S D 7.5)
84 81 ( S D 6.0)
NS
12 33 ( S D 15)
40 21 ( S D 12)
p <. 11.02 p < II.0(ll
31 8
NS NS
8 2
Ten patients acquired C. difficile on the geriatric ward (four of them in the second, four in the third, one in the sixth and one in the eighth week of hospitalization). Four of them had C. difficile associated diarrhea; all four had received antibiotics. The other six patients, of whom four had received antibiotics, were asymptomatic. Only for four patients the stool specimens yielded a positive cytotoxin test. All four patients had C. difficile associated diarrhea. None of the patients had symptoms suggestive for pseudomembranous colitis; no colonoscopic examinations were performed. Additional features for the 16 patients in whom C. difficile could be demonstrated are given in Table 1 and are compared with those of the other patients. In the C. difficile positive group, five types of antibiotics were used (penicillins, cephalosporins, co-trimoxazole, quinolones, nitrofurantoin); there was no antibiotic which was more often associated with the presence of C. difficile. No patient presented arguments for immunodepression: there was no leukopenia or use of corticosteroids in the C. difficile-positive group; of the seven patients presenting a malignancy, only one had a C. difficile infection. Typing of the different C. difficile strains by the agglutination serogrouping technique yielded three different types: A, H and K. Within group A there were two subtypes, identified by polyacrylamide gel electrophoresis: A2 and A14 (see Table II). The distribution of the various types is shown in Fig. 1. For 2 patients, 2 different types were subsequently found. T A B L E 11
Isolation and typing of C. di[~'icile strains Number of positive cultures
Agglutination sero grouping
2 6 2 14
A A H K
Sorbitol
Toxin production
Page profile
Period of isolation (weeks)
+ + +
+
weakly + + +
A2 AI4 H K
1 3 2-9 13-14 3, 9 14
259 As shown in Table II, the isolation of the various types of C. difficile was clustered in time. Four of the 9 patients who acquired C. difficile on the ward and for whom complete typing of the strain was performed, stayed in rooms where previously C. difficile had been found in a patient. All four of these patients acquired a type of C. difficile which was recently isolated in another patient in that room.
Discussion The aim of the study was to determine the prevalence of C. difficile carriers in a geriatric population and to study the acquisition rate in a hospital environment within this population. In contrast with most other studies on C. difficile, we did a longitudinal, prospective study, set up at a moment when no dramatic cases of C. difficile-associated diarrhea were present (Kim et al., 1983; Delm6e et al., 1986a). Until now only a few studies were done in elderly people. Bender et al. (1986) report a prevalence of C. difficile of 30% in a chronic care facility in the U.S.A. They suggest that C. difficile may be endemic in patients on long stay wards. These findings are in contrast with those of Campbell et al. (1988), who failed to detect C. difficile in a geriatric hospital in England. We found a prevalence of C. difficile of 16%. We found the microorganism on admission in six patients, three of whom were asymptomatic carriers. The prevalence of asymptomatic carriers of 3% in the geriatric population described here is comparable with the prevalence of 3% found in healthy adults (Viscidi et al., 1981). The acquisition rate of C. difficile was 10%. This figure is much lower than the 21% reported by McFarland et al. (1989). The higher incidence in that study can be explained by the higher frequency of collecting rectal swabs (every three days) and by the many surgical patients who were enrolled. In the study of McFarland et al. as well as in our study enteric precautions were taken for all patients with diarrhea. The patients in the study of McFarland et al. stayed on a general medical ward and were younger (mean age 66 years for patients who had a nosocomial acquisition of C. difficile ). As suggested previously, it is necessary to type the different strains for epidemiological studies (Delm6e et al., 1985). The three asymptomatic carriers on admission, harboured three different types of C. difficile. This finding is expected in patients coming from a different environment without epidemiological connections. In the patients who acquired C. difficile during their hospitalization four different types of C. difficile were demonstrated. Although the yield of rectal swab cultures and of stool cultures for the recovery of C. difficile is equivalent, the detection methods are not 100% sensitive (McFarland et al., 1987). Therefore, the possibility that some patients carried the microorganism already on admission cannot be excluded. The diversity of the acquired types of C. difficile might suggest an endogenous origin. However, it is well known that the microorganism is present in the hospital environment and can be transmitted by the hands of health care
260
workers (Mulligan et al., 1979; McFarland et al., 1989). Four patients in our study acquired a type of C. difficile, previously isolated from a patient staying in the same room. Moreover, the types of C. difficile were clustered in time, indicating infection from the environment or cross-infection. It is probable that repeatedly new types of C. difficile were introduced in the ward. In two of the patients different types of C. difficile were subsequently recovered, indicating that recurrent infection is possible. This finding has also been reported by others (Johnson et al., 1989). It was previously suggested that there is a relationship between serogroup and virulence or pathogenicity (Delm6e et al., 1985). Recent reports confirm this relationship (Johnson et al., 1990). In our study only patients having the A14 or K type were symptomatic. However, four patients harbouring one of these types were asymptomatic. Only in four patients the cytotoxin test was positive and all four were symptomatic. It has been suggested that the cytotoxin test is more reliable for the diagnosis of C. difficile associated disease than culture (Nash et al., 1982). As shown by our study, the cytotoxin test does not identify all patients with C. dlfficile associated diarrhea (Boriello and Honour, 1983). None of the patients had symptoms suggestive of pseudomembranous colitis. Only 6 of the 52 patients who received antibiotics (11%) developed a C. difficile-associated diarrhea. This figure is much lower than the 20-30% mentioned by Viscidi et al. (1981) in adults. As also described by others, a relationship existed between C. difficile-associated diarrhea and the use of antibiotics; several types of antibiotics had been used (Aronsson et al., 1982). We have no good explanation why the length of the hospital stay was associated with the occurrence of C. difficile. For most of the patients the C. difficile infection remained subclinical and could not have influenced the duration of hospitalization. On the other hand, patients acquiring C. difficile did not present more severe illness; besides, for eight of the patients the infection took place early (either in the second or third week) in the hospitalization. No association was found with antacida intake (Gerding et al., 1986), the diagnosis of cerebrovascular accident (Nakamura et al., 1982) or the severity of the underlying disease. We conclude that the prevalence of C. difficile carriers among our elderly population is rather low. However, in hospitalized geriatric patients the acquisition rate is high. The distribution of the types indicates that C. difficile is acquired from the environment or as a cross-infection. Probably new strains are regularly introduced in the ward. The pathogenicity of the various strains seems to be variable.
References Aronsson, B., M611by, R. and Nord, C.E. (1982): CTostridium difficile and antibiotic associated diarrhea in Sweden. Scand. J. Infect. Dis. 35 (Suppl.), 53-58. Bartlett, J.G., Chang, W.TI, Gurwith~ M., Gorbach, S.L. and Onderdonck, A.B. (1978): Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N, Engl. J. Med., 298, 531-534. Bender, B.S., Laughon, B.E., Gaydos, C., Forman, M.S., Bennett, R., Greenough, W.B., Sears, S.D. and Bartlett J.G. (1986): Is Clostridium difficile endemic in chronic-care facilities? Lancet, i. 11-13.
261 Borriello, S.P. and Honour, P. (1983): Concomitance of cytotoxigenic and non-cytotoxigenic Clostridium difficile in stool specimens. J. Clin. Microbiol. 18, 1006-1007. Campbell, R.R., Beere, D., Wilcock, G.K. and Brown, E.M. (1988): CIostridium difficile in acute and longstay elderly patients. Age Ageing, 17, 333-336. Delm~e, M., Homel, M. and Wauters, G. (1985): Serogrouping of Clostridiurn difficile strains by slide agglutination. J. Clin. Microbiol., 21,323-327. Delm6e, M, Bulliard, G. and Simon, G. (1986a): Application of a technique for serogrouping Clostridium difficile in an outbreak of antibiotic-associated diarrhea. J. Infect., 13, 5-9. Delm~e, M., Laroche, Y., Avesani, V. and Cornelis, E. (1986b): Comparison of serogrouping and polyacrylamide gel electrophoresis for typing Clostridium difficile. J. Clin. Microbiol., 24: 991-994. Fekety, R., Kim, K.H., Brown, D, Batts, D.H., Cudmore, M. and Silva, J. (1981): Epidemiology of antibiotic associated colitis: isolation of Clostridium difficile from the hospital environment. Am. J. Med., 70, 906-908. George, W.L., Sutter, V.L., Citron, D. and Finegold, S.M. (1979): Selective and differential medium for isolation of Clostridiurn difficile. J. Clin. Microbiol., 9, 214-219. Gerding, D.N., Olson, M.M., Peterson, L.R., Teaslay, D.G., Gebhard, R.L., Schwartz, M.L. and Lee, J.T. (1986): Clostridium difficile-associated diarrhea and colitis in adults. A prospective case-controlled epidemiologic study. Arch. Intern. Med., 146, 95-100. Greenfield, C., Szawathowski, M., Noone, P., Burroughs, A., Bass, N. and Pounder, R. (1981): Is pseudomembranous colitis infectious? Lancet, i, 371-372. Hall, I.C. and O'Toole, E. (1935): Intestinal flora in new-born infants. Am. J. Dis. Child., 49, 390-402. Heard, S.R.,, O'Farrell, S., Holland, D., Crook, S., Barnett, M.J. and Tabaqchali, S. (1986): The epidemiology of Clostridiurn difficile with use of a typing scheme: nosocomial acquisition and cross-infection among immunocompromised patients. J. Infect. Dis., 153, 159-162. Johnson, S., Adelmann, A., Clabots, C.R., Peterson, L.R. and Gerding, D.N. (1989): Recurrences of Clostridium difficile diarrhea not caused by the original infecting organism. J. Infect. Dis., 159, 340-343. Johnson, S., Clabots, C.R., Linn, F.V., Olson, M.M., Peterson, L.R. and Gerding, D.N. (1990): Nosocomial Clostridium difficile colonisation and disease. Lancet, 336, 97-100. Kim, K., Dupont, H.L. and Pickering, L.K. (1983): Outbreaks of diarrhea associated with Clostridiurn difficile and its toxin in day-care centers: evidence of person-to-person spread. J. Pediatr., 102, 376-382. Kuijper, E.J. (1986): Is pseudomembranous colitis contagious ? Ned. Tijdschr. Geneesk., 130, 1805-1807. Lashner, B.A., Todorczuk, J., Sahm, D.F. and Hanauer, M.D. (1986): Clostridiurn difficile culture-positive toxin-negative diarrhea. Am. J. Gastroenterol., 81,940-943. McFarland, L.V., Coyle, M.B., Kremer, W.H. and Stamm, W.E. (1987): Rectal swab cultures for Clostridium difficile surveillance studies. J. Clin. Microbiol., 25, 2241-2242. McFarland, L.V., Mulligan, M.E., Kwok, R.Y.Y. and Stamm, W.E. (1989): Nosocomial acquisition of Clostridiurn difficile infection. N. Engl. J. Med., 320, 204-210. Mulligan, M.E., Rolfe, R.D., Finegold, S.M. and George, W.L. (1979): Contamination of a hospital environment by Clostridium difficile. Curr. Microbiol., 3, 173-175. Nakamura, S., Mikawa, M., Tanabe, N., Yamakawa, K., Nishida, S. (1982): Effect of clindamycin on cytotoxin production of Clostridium difficile. Microbiol. Immunol., 26, 985-992. Nash, J.Q., Chattopadhyay, B., Honeycombe, J. and Tabaqchali, S. (1982): Clostridium difficile and cytotoxin in routine faecal specimens. J. Clin. Path., 35, 561-565. Sutter, V.L., Citron, D.M., Edelstein, M.A.C. and Finegold, S.M. (1985): Anaerobic Bacteriology Manual, 4th edn. Star Publishing comp., Belmont, CA. Viscidi, R., Willey, S. and Bartlett, J.G. (1981): Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations. Gastroenterology, 81, 5-9.