The disease caused by Clostridium difficile in geriatric patients

Summary

Background:
The disease caused by the bacterium Clostridium difficile / Clostridium Difficile associated disease/diarrhoea (CDAD) is becoming a serious problem especially in geriatric patients, who are now relatively often treated by broad-spectrum antibiotics.

The goal of our study was to evaluate the occurrence of the risk factors and to evaluate as a complex the relationships and coherence which lead to the CDAD disease in the definite group of seniors treated by us.

Patients and methods:
The retrospective study evaluated a group of 67 ill with diagnosed CDAD, who were hospitalized at the clinic of internal medicine, geriatrics and practical medicine, Faculty of Medicine and Faculty Hospital in Brno from January 2007 till October 2010. There were included 46 women (68.7%) and 21 men (31.3%) who were of the average age of 78.8 ±10.3 years (56 till 96 years). The decisive moment in the diagnosis of CDAD was the discovery of enterotoxines A and B in the faeces of patients.

Outcomes:
The mean time of hospitalization of the patients suffering from CDAD was significantly higher (p=0.01) in comparison with the others (24.63 ± 16.34 vs. 11.5 ± 10.7 days). Polymorbidity was also high in these patients. On average, each patient was ill with 11.3 diseases. The most frequent diseases were: high blood pressure (76.1% of the patients), ischemic heart disease 68.7% and the third most often diagnosis was the cerebrovascular disease 50.7%. We found out that only 13 patients (19.4%) did not take the antibiotics at all, further 54 patients (80.6%) used one or more antibiotics. From the file of 67 patients 12 of them died (17.9%), the section was done in 7 of them, and colitis pseudomembranosa was proved in 3 of them. In 8 of the cases relapse of the colitis was proved.

The conclusion:
The infection of the clostridium is a very serious disease which increases the morbidity and mortality in geriatric patients. Besides the demands on the diagnostics and therapy, it influences also the duration of the hospitalization.

The key words:
Clostridium difficile, colitis pseudomembranosa, Enzyme Linked Fluorescent Assay, the geriatric patient, ribotype 027/NAP1/B1

Introduction

The infection of the clostridium difficile (CDAD) is quite common and well described nosological entity. The diseases connected with the positivity of CDAD fluctuate from the light diarrhoea to the serious colitis pseudomembranosa. CDAD is sensitive grampositive sporulating microbe producing the toxin. Its colonies appear commonly in the spaces like bathrooms, sinks and floors in the hospitals and institutions of the long term care (1, 2). The infection can persist in the rooms where the infected patients were for 40 days (3). The elevated risk of the development of CDAD colitis is mainly in the patients who used broad-spectrum antibiotics, mainly those anti anaerobic microbes, like cephalosporines, clindamycin, ampicillin/amoxicillin, fluorochinolones etc. (4, 5). The disease occurs usually 3-9 days after using the antibiotics, but sometimes after many weeks. The most important inducing factor is the intestinal disorders of microflora caused by antibiotics. This condition is fulfilled in more that 90% of the patients. The pre-existing presence of CDAD or more common the exposure to environmentally present CDAD leads to colonisation of the intestine and consequential superinfection of the clostridium toxins. Diseased in immunosuppression, newborns and sucklings, people with intestinal inflammation and ischemia, patients after surgery of intestine and frail seniors belong to the especially risky group in which the risk of the development of the secondary toxic colitis with the possibility of the ischemia and perforation can be very high (6, 7) CDAD produces 2 types of toxins A and B which can lead to critical form of colitis pseudomembranosa (PME). If PME develops, the lethality can reach 45% in the risk groups of diseased. The hospitalized patients have the intestine colonised by CDAD in 10 to 25 % of cases. When diarrhoea occurs in short time after the dismissal, nosocomial infection of CDAD should always be thought about.

Methodology

The goal of our study was to evaluate the occurrence of the risk factors which lead to the CDAD disease. It dealt with retrospectively processed findings in 67 patients with the clostridium infection hospitalized at the clinic of internal, geriatric and internal medicine in Faculty Hospital in Brno from January 2007 till October 2010. Our workplace admits internally diseased patients without selection from the area of Brno, which counts about 100 000 people. The proof of toxin A/B in the faeces by the means of diagnostic test on the principal of imunochromatography (X/pect Remel) was used in the file of patients positive for clostridium difficile in order to make the diagnosis of CDAD in the first 2 years of the period and in the last year by establishing toxin A/B on the principal of ELFA – Enzyme Linked Fluorescent Assay. The toxin A/B was positive in the faeces of 66 patients (in 1 case was proved by section)

ELISA techniques detect clostridium toxins with the 63-94% sensitivity and 75-100% specificity. When the first sample is negative for CDAD, it is necessary to do repeated proof of the faeces. (8)

The alternative method to prove clostridium infection is the endoscopic examination of the colon, where it is possible to establish diagnosis on the base of the image of the colitis pseudomembranosa with the typical whitish islands of slough on the mucosa. In the case of this diagnosis, this examination is not commonly performed because there is a big threat of the perforation of the fragile colon. Endoscopy was performed in 6 cases in our file. Ultrasonography of the intestine has also its place in the diagnostic algorithm. In some severe cases thickening of the wall of the colon and free fluid present in the abdominal cavity can be seen here. The examination was done in 11 cases with the proof of the inflammatory thickening of the wall of the colon. In the consequence with the foundation of the new highly virulent ribotype O27/NAP1/B1, the incidence and mortality grow.

The results were statistically worked out on the level of 95% confidence level. (t-test, Fischer-test)

The results

in our retrospective study we included altogether 67 patients with confirmed clostridium infection hospitalized on the Clinic of internal, geriatric and practical medicine in FN Brno from January 2007 till October 2010. (see graph no.1) We have found out that the occurrence of the disease has had a rising trend in these years. In 2007 we did not intercept any patients with CDAD positivity, in the following year 12 patients were positive, in 2009 31 patients were positive, and till October 2010 21 patients. There were 46 women (68.7%) and 21 men (31.3%) (65% vs. 35% p=0.001) in the file, the average age of diseased was 78.8 ± 10.3 years, the interval 51 till 96 years. In our study group the portion of diseased over 74 years old is statistically significant p=0.021, see graph no.2. The average period of hospitalisation of the diseased was prolonged to 24.63 ± 16.34 days in the comparison to average period of hospitalisation in the others 11.49 ± 10.75 days (p=0.01).

Polymorbidity of patients was also high, on average each of them had 11.3 diseases, the minimum was 6 diagnoses, and maximum was 21 diagnoses in a patient. The most numerous in our file was the arterial hypertension in 51 patients (76.1%), ischemic heart disease in 46 patients (68.7%), AS universalis in 52 patients (77.6%), cerebrovascular disease in 34 patients (50.7%), 17 diabetics (25.4%), 11 patients with malignity (16.4%), 7 patients with the intestinal disease (10.4%) and 8 patients with autoimmune disease (11.9%).

55% of patients had normal weight, 36% of patients were overweight (BMI 25-30), 9% of patients had obesity (BMI over 30). 19% of patients were in the zone of underweight (BMI under 20). Malnutrition is a significant factor. We evaluated the value of albumin and its average was 31.87 g/L, whereas the minimum value was 15.2 g/L and the maximum 43.7 g/L. There were 62.5% of patients in the sample with the albumin level under 35g/L, which is statistically significant proportion p= 0.025.

The analysis of the clinical picture showed the set of facts that follow. Development of temperature was in 52.1% (p=0.4425) of the diseased, 29.2% (p=0.998) of them mentioned abdominal ache. Diarrhoea did not develop only in 1 patient; otherwise it occurred in all of the other patients. What was interesting was that the diagnosis in this patient was established by section, where the pathologist determined colitis pseudomembranosa as the cause of death. In the count of 11 patients (16.4%) diarrhoea occurred before hospitalisation, in 55 patients (82.1%) diarrhoea developed after use of antibiotic therapy. On average diarrhoea developed after 7.5 ± 7.5 days of use of the antibiotics.

Ileus developed in the case of 2 patients, colitis pseudomembranosa developed in 4 patients. We did not register any case of toxic magacolon. Leucocytosis is an independent risk factor connected with elevated risk of complications (3), in our file it occurred in 42 patients, the average value was 17.22 ± 10.5x10⁹ /l (the maximum value was 59x10⁹/l).

Among the risk factors of the disease the use of antibiotics in anamnesis was the most often. We found out that only 13 patients had not used any antibiotics and other 54 patients (80.6%) used 1 or more antibiotics. One antibiotic was used by 30 patients (44.8%), 2 antibiotics were used by 26 patients (38.8%), 3 antibiotics were used by 6 (9%) and 4 antibiotics were used by 2 of them (3%). These indicators show significantly that the probability of the occurrence of the clostridium infection is not elevated by the number of used antibiotics, but only by use of any antibiotics (minimum 1 ATB p<0.001 used), see graph no.3. From the list of the antibiotics used the following occurred most often: chinolons in 25 patients (37.3%), penicillins with beta-lactamase inhibitors in 24 patients (35.8%), cephalosporines in 11 patients (16.4%), trimoxazole in 7 patients (10.4%), aminoglycosides in 5 patients (7.5%).

Delirious states occurred in 7 patients (10.5%), dementia was present in 20 patients (29.9%) and depression in 11 patients (16.4%)

We were interested also in the mobility of the patients –21 people (31.3%) were completely immobile, 27 diseased were able to move with help (40.3%). 15 patients (22.4%) were capable of independent walk. As many as 16 patients (23.9%) had decubital ulcer and 19 patients (28.4%) had repeated falls in anamnesis.

Furthermore we evaluated the representation of each of the used treatments. In 7 patients with the light form of the disease the diet regime was enough. Only Metronidazol was used in 76% of the patients, Vancomycine in 2%, and combined therapy was used in 10 % patients. 12 % were without antibiotics. 12 patient from the file of 67 patients died (17.9%) and section was done in 7 of them. In 3 cases colitis pseudomembranosa was confirmed. Relapse occurred in altogether 10 patients (14.9%) The occurrence of the relapse is not statistically significant p= 0.999.

The discussion

Hall and O'Toole (9) discovered in the 1935 Clostridium difficile like a part of the normal microflora in newborns. This pathogen occurs in about 3-5% healthy adult population, whereas the occurrence is more often in children, geriatric patients and less mobile people. Hospitalised individuals have the colon CDAD colonized in 10-25% of the cases. When it begins shortly after the dismissal from the hospital, it is necessary to think about the possibility about the nosocomial CDAD infection.

Since 2003 highly virulent strain of Clostridium difficile, which caused extensive fatal colitis in the North America and Europe, occurs. This strain is characterised on the base of PCR ribotypisation like ribotype O27/NAP1/B1. (4, 10, 11). The transfer of the Clostridium difficile happens through faecal oral route. The vegetative form of the bacterium produces two toxins (toxin A and B).

Diarrhoea, fever, and the abdominal ache belong among the main symptoms of the clostridium infection. We recognized these as the dominant symptoms. The state can be complicated by subileus and ileus, development of colitis pseudomembranosa and, in the worst cases, by toxic megacolon with the possible perforation of the colon and peritonitis which usually ends by death. Many cases, especially in geriatric patients, proceed atypically. Diarrhoea does not have to be profuse. With small portions of faeces it can easily be interpreted as incontinence, mainly in badly cooperating patients. What is dominating is meteorism, vaguely abdominal pain and deteriorating of the state, and in some serious cases leucocytosis occurs, too (4, 13), as it was in our file. PME typically begins 7 to 10 days after the beginning of the antibiotic therapy, although the occurrence of the symptoms can vary from days to weeks.

Speaking of therapy, in CDAD it is fundamental to isolate the patient and make epidemiological precautions. In a mild disease it is usually enough to remove the cause – that is to terminate the antibiotic therapy and keep the regime. In the rather serious and very serious diseases it is necessary to put the targeted on antibiotic therapy (metronidazole, vankomycin) (12). In 10 to 20% of cases, relapse comes after the ending of the antibiotic therapy (in our file 14.9%). It correlates with the retrospective study Cadena (14) in the file of 129 patients, where 29% had relapse. Cadena (14) recognized the use of fluorochinolon as the highest risk factor of the relapse of colitis (71%), indispensable is also the number of the patients with ictus (29%). The clostridium infection is the fatal complication of the antibiotic therapy in the hospital. Its' incidence is of a rising trend. The study was performed during 2003-2005 in the Canadian province Quebec, which included 30 hospitals. They proved 4-5 times rising CDAD incidence (156.3 cases per 100 000) in comparison to 1991, when the incidence was 35.6 cases per 100 000. Mortality rose nearly 5 times, from 4.5% in the 1991 to 22% in 2004 (4). Issa (15) similarly found the doubling of the occurrence of CDAD in the USA in inflammatory colitis, morbus Crohn and colitis ulcerosa.

Marya (16) also confirms the growing incidence. He evaluated the occurrence of the clostridium infections since 2000-2005 according to the national register in the United States in a retrospective study. The number of the diseased with the diagnosed CDAD rose from 134.361 in 2000 to 291.303 in 2005. The highest growth of incidence was in the group of patient older than 85 years. The rising incidence of the disease is showed also in our work. The part of the diseased at the age higher than 74 is also statistically significant p=0.001 in our sample, whereas women are more struck (68.7% vs. 31.3%)

There are not many works which deal with the sample of the “oldest old”. Cober (17) studied the risk factors in the patients older than 80. The number of leucocytes and ischemic heart disease were found as the independent factors of therapeutic failure.

Besides the antibiotic therapy in anamnesis Raveh (18) also proved the use of diuretics and the high age of the patients as the significant risk factors. As far as the risk factors are concerned in our sample, the anticipated influence of using the antibiotics in anamnesis was proved as the risk for CDAD, as described above. They lead to the elimination of the normal intestinal microflora which is made by anaerobic microorganisms. Even if the antibiotics are stopped, more often the restitution of the microflora comes only after 3 months. Only 13 patients (19.4%) did not use any antibiotics, further 54 patients (80.6%) used one or more antibiotics. It was confirmed that the probability of the occurrence of the clostridium infection is not elevated by the number of the antibiotics, but only by their use (used minimum one antibiotic p=0.001). From the used antibiotics the following were most often: chinolons, penicillins combined with beta-lactamase inhibitors, cephalosporines, trimoxazol. According to other authors (10, 12, 19), clindamycine, cephalosporines and fluorochinolons were the most risky ones.

On the other hand we did not find, unlike other authors, higher occurrence of CDAD in the patients with the disease of colon, autoimmune disease or in the patients cured by cytostatics, which was also caused by a small sample of patients. Furthermore, another important risk factor was malnutrition of the patients, 62.5% of them had the value of albumin under 35g/L which is statistically significant p=0.025.

In the therapy of diarrhoea by CDAD (21) it is important to end the antibiotic therapy and initiate the supporting remedies (enough liquid, including infusions, correction of electrolyte disturbances). In a quarter of the diseased with diarrhoea these precautions are sufficient. Further step of the therapy is to apply metronidazole 250mg/day, or 125-250mg of vankomycine/day. In our work metronidazol was confirmed as the most used antibiotics in the therapy of CDAD. The consequences of the clostridium infection CDAD include, besides higher morbidity and mortality, also a longer period of hospitalisation, higher expenses per the patient and higher number of the re-hospitalisations for the relapse (22, 23, 24). Similarly to Johnson (25), we proved the tight relationship between the period of the hospitalisation and the occurrence of CDAD.

Hygienic precautions are an inevitable part of lowering the incidence of CDAD. Kuijper (26) found out that 30-60% of places in hospitals are contaminated by spores of C.difficile. It is necessary to obey the rules of the barrier nursing with the focus on the feacal-oral transfer of the infection. This concerns mainly the right technique of washing and the disinfection of the hands. Mortality of our sample made 17.9% which is a comparable value to Vaishavi (27) who described the mortality in weakened geriatric patients even in 25%. Significant differences between mortality of younger and geriatric patients was also confirmed by Zilberberg (28, 29) on the sample of 278 critically diseased. He enunciates in his work that 30-days mortality in geriatric diseased is by 68% higher than in younger groups.

The conclusion

The serious problems in senior population with CDAD present relapses, malnutrition, dehydration, uremia and circulatory shock, which can, at the older age, lead also to higher mortality. In the end is necessary to stress the importance of being cautious when prescribing antibiotics to patients with the clostridium infection in anamnesis and, generally, to very old and frail seniors (30, 31), because significantly higher is not only the risk of relapse with all complications, but also mortality.

Abbreviations:

• CDAD - Clostridium difficile - Clostridium difficile associated disease/diarrhoea
• EIA - Enzyme Linked Fluorescent Assay
• PME – Pseudomembranous enterokolitis
• MMSE – Mini mental test examination
• ADL – Activities of daily living

Contact:
MUDr. Katarína Bielaková
Klinika interní, geriatrie a praktického lékařství, LF MU a FN Brno
Jihlavská 20, 625 00 Brno
Tel: 532 23 2398 ,
e-mail: bielakovak@seznam.cz