Clostridium Difficile Infection in Medical ICUs of a Teaching Hospital in Iran

INTRODUCTION

Clostridium difficile infection (CDI) is a major cause of infectious diarrhea in hospitals (1). CDI has been associated with an increase in morbidity, hospital length of stay, medical expenses and mortality (2). Intensive care unit (ICU) patients are at higher risk for CDI (3).

The incidence rate of CDI has increased worldwide. However, several studies have explained that the incidence of clostridium difficile infection in ICU patients has not risen recently (4-6). On the other hand, in developing countries, data on the epidemiology of CDI in ICU are scarce (7). In addition, the rate of CDI in intensive care patients is different among world regions (21, 8, 9). Moreover, variable seasonal incidence rates were reported in the literature (1).

Multiple risk factors have identified for CDI. Aside from inpatient hospitalizations, antibiotic therapy and old age, other factors like presence of a nasogastric tube, acquired hospital pneumonia, immunosuppressed states, diabetes mellitus, history of kidney transplantation and prolonged mechanical ventilation may increase the risk for CDI in critically ill patients (10-12).

Different mortality rates due to CDI in the intensive care units have been reported by several studies (6, 13, 14). Infection control, antibiotic stewardship measures and severity of underlying disorders may have a role in this regard (6). There is limited information about the incidence, risk factors and mortality rate due to CDI in critically ill patients in IRAN (15, 16). Majority of studies have focused on the antibiotic susceptibility, molecular epidemiology and diversity of ribotypes (16, 17). This prospective study aimed to estimate the incidence of CDI, comparing mortality rate and presumptive risk factors for CDI between case and control group in the general ICUs of a teaching hospital.

MATERIALS AND METHODS

This single centre prospective study was conducted at three medical ICUs of Baharloo Hospital with 35 ICU beds from July 2017 to February 2019. This public teaching hospital located at the south district of Tehran, IRAN. Adult patients, at least 18 years old, diagnosed with diarrhea after 72 hours of ICU admission were eligible to enter in this study. Patients were excluded if had a prior colectomy, chronic renal failure, inflammatory bowel disease, hepatic failure or if diarrhea onset occurring less than 72 h following ICU admission (1). Patients using laxatives concurrently were excluded as well. Diarrhea was clinically defined as three or more loose stools per day. Stool culture and glutamate dehydrogenase (GDH) in combination with enzymatic Immunoassay were tested for all stool samples (6, 9, 18). Patients with diarrhea, based on whether they had positive or negative stool results for clostridium difficile were divided into case and control groups. The incidence rate of CDI was calculated as CDI cases per 10,000 patient- days (12). Relevant data including demographic characteristics, cause of admission, length of stay, laboratory findings, potential risk factors, duration of endotracheal intubation and nasogastric feeding period prior to the onset of diarrhea were collected. The incidence rate of CDI during the study period, Acute Physiological and Chronic Health Evaluation II (APACHE II) score and mortality rate were calculated.

Statistical analysis was performed using SPSS 16 edition (SPSS Inc., Chicago, IL). Variables with a normal distribution were demonstrated with mean ± SD and compared using Student’s t-test. Variables with a non-normal distribution were explained with median and interquartile range (IQR). To compare categorical variables, the χ2 test or Fisher’s test was performed. A two-tailed P value of less than 0.05 was considered statistically significant. We performed a multivariate logistic regression analysis including all potential risk factors for CDI to estimate the correlation between CD+ and mortality. Data were adjusted for age, sex, antibiotic use, diabetes mellitus and duration of nasogastric-feeding.

RESULTS

During the study period, July 2017 and February 2019, 114 patients developed ICU-onset diarrhea. Regarding exclusion criteria, 13 patients were excluded, therefore 101 patients entered in this study.

47 patients (46.53%) had positive stool results for CDI, using stool culture and glutamate dehydrogenase (GDH) in combination with enzymatic immunoassay.  54 patients (53.46%) experienced negative stool results for CDI. The overall incidence of ICU- onset CDI was 22.38 cases per 10,000 patient – days in our teaching medical ICUs. All variables for ICU patients with or without CDI have summarised in Table 1.

25 of 47 (53.2%) diarrheic patients with CD+ were female. In the control group, 31 of 54 (57.4%) were female. The mean age of CD+ group was 68.74± 16.94 years and for CD- group was 68.44±19.26 years. The mean APACHE II score at ICU admission was 15.38±4.46 and 16.82±6.04 in case and control groups, respectively. Differences in sex, age and APACHE II score were not statistically significant between two groups. The hospital and ICU length of stay were statistically different between CD+ and CD- patients. Median days (IQR) of ICU length of stay were 40(51) and 30.50(44) for CDI+ and control patients, respectively (P value< 0.05). There was a significant difference in proton pump inhibitors (PPIs) usage between case and control groups. No significant difference was found in overall mortality between case and control patient population. The most common cause of ICU admission was cerebrovascular accident (19.8%) followed by cardiovascular diseases (14.9%). Table 2

Duration of endotracheal intubation and nasogastric-feeding prior to the onset of diarrhea in CDI positive patients were significantly more than control group. Whereas the rate of endotracheal intubation was significantly different between groups, the rate of nasogastric tube insertion was not statistically significant between case-patients and controls

.

Table 3

Laboratory results in the first day of diarrhea were summarized in Table 4. The leukocytosis and folate serum level were significantly higher in the CD+ than CD- group. By adjusting age, sex, antibiotic usage, diabetes mellitus and duration of nasogastric-feeding, no correlation between CDI and mortality was found. Table 5

DISCUSSION

CDI incidence rate is different between ICUs, ranging from 8.7 to 53.9 cases per10, 000 patient-days in medical or surgical ICUs to 7.9 to 8.3 cases per 10, 000 patient-days in neurosurgical, burn, or cardiothoracic ICUs (21, 2, 19). Data on CDI in critically ill patients, in IRAN, are scarce and most of the studies have focused on CD molecular typing, antimicrobial susceptibility, ribotype and molecular epidemiology (17, 20). One study done on burn patients in IRAN revealed that the prevalence of hospital-acquired diarrhea in burn centre was 120 per 10,000 admissions (21). The incidence of CDI in our medical ICUs was 22.38 cases per 10, 000 patient-days during the study period. Furthermore, seasonal patterns of CDI have also reported in a study in Taiwan (1). On the other hand, one study at Greek university showed that the incidence of CDI in ICU was as low as 1.3% (6). This discrepancy may be related to differences in the patient population, type and location of ICUs, underlying illness, comorbidities, local infection control guidelines and antibiotic exposure in different ICUs among different countries.

Similar to most studies, we realized that the hospital and ICU length of stay in the CDI+ patients were longer than the control group (13, 22). However, G. Samonis et al. demonstrated that no significant differences occurred among study groups for the duration of hospitalization in a 7-year retrospective study. They argued that an increase in the length of stay was not a sequel of CDI but a reflexing of the severity of other diseases among study groups (23).

Traditionally, recognized risk factors are elderly patients, antimicrobial therapy and inpatient hospitalizations (2). In our study, contrary to these researches, significant differences between CDI+ and control group regarding age, antibiotic therapy and APACHE II score were not detected. Several possible explanations for such results are because sicker and older patients with considerable underlying diseases were referred to our hospital. Therefore, both the case and control groups were more exposed to antibiotics. Inconsistent with our findings, Matthaiou DK. and Gutierrez-Pizarraya et al. revealed that there were no significant differences in age, antibiotic usage and APACHE II when comparing patients with and without CDI (6, 24).

Other potential and somewhat controversial risk factors including the presence of a nasogastric tube (NGT), chronic renal failure, corticosteroid therapy, hospital-acquired pneumonia and mechanical ventilation were discussed in several studies (5, 6, 12, 24-26). The present study could not appear any significant differences in terms of corticosteroid consumption and the rate of nasogastric tube insertion between case and control groups. However, the duration of NG feeding in CDI+ was significantly longer than control group. Therefore, the NG feeding duration may increase the possibility of acquisition of CDI in ICU patients. There are several convincing explanations in this regard. Firstly, NGT insertion and manipulation of the feeding tube by ICU staff lead to transfer C. difficile from the hands of personnel. Second, lack of dietary fibre and contamination of formula may play a role in the growth of C. difficile. These drawbacks may result in intestinal flora imbalances, thereby promoting the occurrence of CDI (27).

We found that duration of endotracheal intubation prior to the onset of diarrhea in CDI+ group was significantly higher than control group. Respiratory assistance by mechanical ventilation and nosocomial infections like ventilator-acquired pneumonia (VAP) may result in prescribing broad-spectrum antibiotics in these patients. Therefore, changes in gastrointestinal normal flora may occur, and CDI develops in endotracheal intubated patients. A research conducted by Chunhui Li et al. reported that treatment of hospital-acquired pneumonia could lead to subsequent clostridium difficile infection (12). However, in our study, the duration of endotracheal intubation seems important but data about VAP and other nosocomial infections are unclear. Further studies are warranted to delineate this finding.

The increase of gastric PH by proton pump inhibitors (PPIs) administration may cause alteration of intestinal flora and impair leukocyte function. Therefore, bacterial overgrowth occurs in patients who admitted in intensive care unit (28). Inconsistent with our results, Buendgens L et al. showed that gastric acid suppression treatment increases the prevalence of CDI in medical ICUs (29, 30). However, prescription of H2 blocker was not significantly different among ICU groups in those studies. Contrary to the present study, Faleck DM et al. revealed that PPIs did not increase the risk for CDI acquisition in ICU patients (31).

Upon comparing laboratory findings, there was a significant difference in serum folate level between case and control groups. There is no obvious explanation for this result. Several studies have performed on zinc level in mice to describe susceptibility to CDI. They have explained that dietary zinc changes microbiota profiling and decreases resistance to CDI (32). Further studies are warranted to manifest the relation of serum folate level to CDI in human.

Matthaiou DK  et al. have reported that CDI mortality has a wide range, up to more than 50%, among different studies (6). On the contrary, Dodek PM and et al. concluded that the acquisition of C. difficile infection in ICU did not increase the risk of the hospital or ICU mortality (13). Although a high rate of mortality, 57.4% in CDI+ group, was reported in our ICU setting, there was no statistically significant difference between study groups. A logistic regression model showed no correlation between CD positive cases and mortality. In other words, high rate mortality in our ICU setting may be related to patient comorbidities, chronic underlying diseases, the severity of illness of ICU patients or other unknown factors. Therefore, mortality rate directly attributable to CDI was not calculable. Further multicentre studies investigating the mortality rate of CDI in ICU are needed. Our study comes with several limitations. A single-center study cannot represent the whole situation in IRAN. The small sample size is another important limitation in this study. Potential confounding factors, such as patient comorbidities and other nosocomial infections may have caused an estimation bias with mortality results.

In conclusion, this prospective study revealed that the incidence of ICU- onset CDI was 22.38 cases per10, 000 patient-days. In addition, a high mortality rate in our medical ICUs was determined. Antibiotic administration and age were not identified as risk factors for developing CDI in ICU patients, whereas PPIs, duration of endotracheal intubation and NG feeding were associated with increased risk for CDI in ICU patient population. Recognizing the causal relationship between duration of endotracheal intubation and NG feeding with CDI might be essential for the protocol of CDI treatment. Further studies with larger sample size are warranted to explore these findings. Moreover, we encountered with higher serum folate level in CDI+ patients. The finding that requires further investigation.

References

1. Lee JC, Hung YP, Lin HJ, Tsai PJ, Ko WC. Clostridium difficile Infections in Medical Intensive Care Units of a Medical Center in Southern Taiwan: Variable Seasonality and Disease Severity. PLoS One. 2016;11(8):e0160760.
2. Balsells E, Shi T, Leese C, Lyell I, Burrows J, Wiuff C, et al. Global burden of Clostridium difficile infections: a systematic review and meta-analysis. J Glob Health. 2019;9(1):010407.
3. Karanika S, Paudel S, Zervou FN, Grigoras C, Zacharioudakis IM, Mylonakis E. Prevalence and Clinical Outcomes of Clostridium difficile Infection in the Intensive Care Unit: A Systematic Review and Meta-Analysis. Open Forum Infect Dis. 2016;3(1):ofv186.
4. Gerding DN, Muto CA, Owens RC, Jr. Measures to control and prevent Clostridium difficile infection. Clin Infect Dis 2008;46 Suppl 1(Supplement_1): S43–S49.
5. Bouza E, Rodriguez-Creixems M, Alcala L, Marin M, De Egea V, Braojos F, et al. Is Clostridium difficile infection an increasingly common severe disease in adult intensive care units? A 10-year experience. J Crit Care. 2015;30(3):543-9.
6. Matthaiou DK, Delga D, Daganou M, Koutsoukou A, Karabela N, Mandragos KE, et al. Characteristics, risk factors and outcomes of Clostridium difficile infections in Greek Intensive Care Units. Intensive and Critical Care Nursing. 2019.
7. Jalali M, Khorvash F, Warriner K, Weese JS. Clostridium difficile infection in an Iranian hospital. BMC Res Notes. 2012;5.
8. Alvarez-Lerma F, Palomar M, Villasboa A, Amador J, Almirall J, Posada MP, et al. Epidemiological study of Clostridium difficile infection in critical patients admitted to the Intensive Care Unit. Med Intensiva. 2014;38(9):558-66.
9. Salva S, Duran N, Rodriguez V, Nieto L, Serra J, Rello J, et al. Clostridium difficile in the ICU: study of the incidence, recurrence, clinical characteristics and complications in a university hospital. Med Intensiva. 2014;38(3):140-5.
10. Tirath A, Tadros S, Coffin SL, Kintziger KW, Waller JL, Baer SL, et al. Clostridium difficile infection in dialysis patients. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2017;65(2):353-7.
11. Chiang SR, Lai CC, Ho CH, Chen CM, Chao CM, Wang JJ, et al. Prolonged Mechanical Ventilation Assistance Interacts Synergistically with Carbapenem for Clostridium difficile Infection in Critically Ill Patients. J Clin Med. 2018;7(8).
12. Li C, Duan J, Liu S, Meng X, Fu C, Zeng C, et al. Assessing the risk and disease burden of Clostridium difficile infection among patients with hospital-acquired pneumonia at a University Hospital in Central China. Infection. 2017;45(5):621-8.
13. Dodek PM, Norena M, Ayas NT, Romney M, Wong H. Length of stay and mortality due to Clostridium difficile infection acquired in the intensive care unit. J Crit Care. 2013;28(4):335-40.
14. Gasperino J, Garala M, Cohen HW, Kvetan V, Currie B. Investigation of critical care unit utilization and mortality in patients infected with Clostridium difficile. J Crit Care. 2010;25(2):282-6.
15. Borren NZ, Ghadermarzi S, Hutfless S, Ananthakrishnan AN. The emergence of Clostridium difficile infection in Asia: A systematic review and meta-analysis of incidence and impact. PLOS ONE. 2017;12(5):e0176797.
16. Jalali M, Khorvash F, Warriner K, Weese JS. Clostridium difficile infection in an Iranian hospital. BMC Research Notes. 2012;5(1):159.
17. Shoaei P, Shojaei H, Khorvash F, Hosseini SM, Ataei B, Tavakoli H, et al. Molecular epidemiology of Clostridium difficile infection in Iranian hospitals. Antimicrobial Resistance & Infection Control. 2019;8(1):12.
18. Yoo IY, Song DJ, Huh HJ, Lee NY. Simultaneous Detection of Clostridioides difficile Glutamate Dehydrogenase and Toxin A/B: Comparison of the C. DIFF QUIK CHEK COMPLETE and RIDASCREEN Assays. Ann Lab Med. 2019;39(2):214-7.
19. Wang X, Cai L, Yu R, Huang W, Zong Z. ICU-Onset Clostridium difficile infection in a university hospital in China: a prospective cohort study. PLoS One. 2014;9(11):e111735.
20. Goudarzi M, Goudarzi H, Alebouyeh M, Azimi Rad M, Shayegan Mehr FS, Zali MR. Antimicrobial susceptibility of clostridium difficile clinical isolates in Iran. Iran Red Crescent Med J. 2013;15.
21. Alinejad F, Barati M, Satarzadeh Tabrisi M, Saberi M. Hospital acquired diarrhea in a burn center of Tehran. Iran J Microbiol. 2015;7(6):310-4.
22. Magee G, Strauss ME, Thomas SM, Brown H, Baumer D, Broderick KC. Impact of Clostridium difficile-associated diarrhea on acute care length of stay, hospital costs, and readmission: A multicenter retrospective study of inpatients, 2009-2011. Am J Infect Control. 2015;43(11):1148-53.
23. Samonis G, Vardakas KZ, Tansarli GS, Dimopoulou D, Papadimitriou G, Kofteridis DP, et al. Clostridium difficile in Crete, Greece: epidemiology, microbiology and clinical disease. Epidemiol Infect. 2016;144(1):161-70.
24. Gutierrez-Pizarraya A, Martin-Villen L, Alcala-Hernandez L, Marin Arriaza M, Balandin-Moreno B, Aragon-Gonzalez C, et al. Epidemiology and risk factors for Clostridium difficile infection in critically ill patients in Spain: The PROCRID study. Enferm Infecc Microbiol Clin. 2018;36(4):218-21.
25. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-55.
26. Hong SJ, Feuerstadt P, Brandt LJ. MELD is the only predictor of short-term mortality in cirrhotic patients with C. difficile infection. Dig Liver Dis. 2019;51(2):275-80.
27. Wijarnpreecha K, Sornprom S, Thongprayoon C, Phatharacharukul P, Cheungpasitporn W, Nakkala K. The risk of Clostridium difficile associated diarrhea in nasogastric tube insertion: A systematic review and meta-analysis. Dig Liver Dis. 2016;48(5):468-72.
28. Ofori E, Ramai D, Dhawan M, Mustafa F, Gasperino J, Reddy M. Community-acquired Clostridium difficile: epidemiology, ribotype, risk factors, hospital and intensive care unit outcomes, and current and emerging therapies. J Hosp Infect. 2018;99(4):436-42.
29. Buendgens L, Bruensing J, Matthes M, Duckers H, Luedde T, Trautwein C, et al. Administration of proton pump inhibitors in critically ill medical patients is associated with increased risk of developing Clostridium difficile-associated diarrhea. J Crit Care. 2014;29(4):696 e11-5.
30. Jasiak NM, Alaniz C, Rao K, Veltman K, Nagel JL. Recurrent Clostridium difficile infection in intensive care unit patients. Am J Infect Control. 2016;44(1):36-40.
31. Faleck DM, Salmasian H, Furuya EY, Larson EL, Abrams JA, Freedberg DE. Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit. The American journal of gastroenterology. 2016;111(11):1641-8.
32. Zackular JP, Moore JL, Jordan AT, Juttukonda LJ, Noto MJ, Nicholson MR, et al. Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection. Nat Med. 2016;22(11):1330-4.

INTRODUCTION

Clostridium difficile infection (CDI) is a major cause of infectious diarrhea in hospitals (1). CDI has been associated with an increase in morbidity, hospital length of stay, medical expenses and mortality (2). Intensive care unit (ICU) patients are at higher risk for CDI (3).

The incidence rate of CDI has increased worldwide. However, several studies have explained that the incidence of clostridium difficile infection in ICU patients has not risen recently (4-6). On the other hand, in developing countries, data on the epidemiology of CDI in ICU are scarce (7). In addition, the rate of CDI in intensive care patients is different among world regions (21, 8, 9). Moreover, variable seasonal incidence rates were reported in the literature (1).

Multiple risk factors have identified for CDI. Aside from inpatient hospitalizations, antibiotic therapy and old age, other factors like presence of a nasogastric tube, acquired hospital pneumonia, immunosuppressed states, diabetes mellitus, history of kidney transplantation and prolonged mechanical ventilation may increase the risk for CDI in critically ill patients (10-12).

Different mortality rates due to CDI in the intensive care units have been reported by several studies (6, 13, 14). Infection control, antibiotic stewardship measures and severity of underlying disorders may have a role in this regard (6). There is limited information about the incidence, risk factors and mortality rate due to CDI in critically ill patients in IRAN (15, 16). Majority of studies have focused on the antibiotic susceptibility, molecular epidemiology and diversity of ribotypes (16, 17). This prospective study aimed to estimate the incidence of CDI, comparing mortality rate and presumptive risk factors for CDI between case and control group in the general ICUs of a teaching hospital.

MATERIALS AND METHODS

This single centre prospective study was conducted at three medical ICUs of Baharloo Hospital with 35 ICU beds from July 2017 to February 2019. This public teaching hospital located at the south district of Tehran, IRAN. Adult patients, at least 18 years old, diagnosed with diarrhea after 72 hours of ICU admission were eligible to enter in this study. Patients were excluded if had a prior colectomy, chronic renal failure, inflammatory bowel disease, hepatic failure or if diarrhea onset occurring less than 72 h following ICU admission (1). Patients using laxatives concurrently were excluded as well. Diarrhea was clinically defined as three or more loose stools per day. Stool culture and glutamate dehydrogenase (GDH) in combination with enzymatic Immunoassay were tested for all stool samples (6, 9, 18). Patients with diarrhea, based on whether they had positive or negative stool results for clostridium difficile were divided into case and control groups. The incidence rate of CDI was calculated as CDI cases per 10,000 patient- days (12). Relevant data including demographic characteristics, cause of admission, length of stay, laboratory findings, potential risk factors, duration of endotracheal intubation and nasogastric feeding period prior to the onset of diarrhea were collected. The incidence rate of CDI during the study period, Acute Physiological and Chronic Health Evaluation II (APACHE II) score and mortality rate were calculated.

Statistical analysis was performed using SPSS 16 edition (SPSS Inc., Chicago, IL). Variables with a normal distribution were demonstrated with mean ± SD and compared using Student’s t-test. Variables with a non-normal distribution were explained with median and interquartile range (IQR). To compare categorical variables, the χ2 test or Fisher’s test was performed. A two-tailed P value of less than 0.05 was considered statistically significant. We performed a multivariate logistic regression analysis including all potential risk factors for CDI to estimate the correlation between CD+ and mortality. Data were adjusted for age, sex, antibiotic use, diabetes mellitus and duration of nasogastric-feeding.

RESULTS

During the study period, July 2017 and February 2019, 114 patients developed ICU-onset diarrhea. Regarding exclusion criteria, 13 patients were excluded, therefore 101 patients entered in this study.

47 patients (46.53%) had positive stool results for CDI, using stool culture and glutamate dehydrogenase (GDH) in combination with enzymatic immunoassay.  54 patients (53.46%) experienced negative stool results for CDI. The overall incidence of ICU- onset CDI was 22.38 cases per 10,000 patient – days in our teaching medical ICUs. All variables for ICU patients with or without CDI have summarised in Table 1.

25 of 47 (53.2%) diarrheic patients with CD+ were female. In the control group, 31 of 54 (57.4%) were female. The mean age of CD+ group was 68.74± 16.94 years and for CD- group was 68.44±19.26 years. The mean APACHE II score at ICU admission was 15.38±4.46 and 16.82±6.04 in case and control groups, respectively. Differences in sex, age and APACHE II score were not statistically significant between two groups. The hospital and ICU length of stay were statistically different between CD+ and CD- patients. Median days (IQR) of ICU length of stay were 40(51) and 30.50(44) for CDI+ and control patients, respectively (P value< 0.05). There was a significant difference in proton pump inhibitors (PPIs) usage between case and control groups. No significant difference was found in overall mortality between case and control patient population. The most common cause of ICU admission was cerebrovascular accident (19.8%) followed by cardiovascular diseases (14.9%). Table 2

Duration of endotracheal intubation and nasogastric-feeding prior to the onset of diarrhea in CDI positive patients were significantly more than control group. Whereas the rate of endotracheal intubation was significantly different between groups, the rate of nasogastric tube insertion was not statistically significant between case-patients and controls

.

Table 3

Laboratory results in the first day of diarrhea were summarized in Table 4. The leukocytosis and folate serum level were significantly higher in the CD+ than CD- group. By adjusting age, sex, antibiotic usage, diabetes mellitus and duration of nasogastric-feeding, no correlation between CDI and mortality was found. Table 5

DISCUSSION

CDI incidence rate is different between ICUs, ranging from 8.7 to 53.9 cases per10, 000 patient-days in medical or surgical ICUs to 7.9 to 8.3 cases per 10, 000 patient-days in neurosurgical, burn, or cardiothoracic ICUs (21, 2, 19). Data on CDI in critically ill patients, in IRAN, are scarce and most of the studies have focused on CD molecular typing, antimicrobial susceptibility, ribotype and molecular epidemiology (17, 20). One study done on burn patients in IRAN revealed that the prevalence of hospital-acquired diarrhea in burn centre was 120 per 10,000 admissions (21). The incidence of CDI in our medical ICUs was 22.38 cases per 10, 000 patient-days during the study period. Furthermore, seasonal patterns of CDI have also reported in a study in Taiwan (1). On the other hand, one study at Greek university showed that the incidence of CDI in ICU was as low as 1.3% (6). This discrepancy may be related to differences in the patient population, type and location of ICUs, underlying illness, comorbidities, local infection control guidelines and antibiotic exposure in different ICUs among different countries.

Similar to most studies, we realized that the hospital and ICU length of stay in the CDI+ patients were longer than the control group (13, 22). However, G. Samonis et al. demonstrated that no significant differences occurred among study groups for the duration of hospitalization in a 7-year retrospective study. They argued that an increase in the length of stay was not a sequel of CDI but a reflexing of the severity of other diseases among study groups (23).

Traditionally, recognized risk factors are elderly patients, antimicrobial therapy and inpatient hospitalizations (2). In our study, contrary to these researches, significant differences between CDI+ and control group regarding age, antibiotic therapy and APACHE II score were not detected. Several possible explanations for such results are because sicker and older patients with considerable underlying diseases were referred to our hospital. Therefore, both the case and control groups were more exposed to antibiotics. Inconsistent with our findings, Matthaiou DK. and Gutierrez-Pizarraya et al. revealed that there were no significant differences in age, antibiotic usage and APACHE II when comparing patients with and without CDI (6, 24).

Other potential and somewhat controversial risk factors including the presence of a nasogastric tube (NGT), chronic renal failure, corticosteroid therapy, hospital-acquired pneumonia and mechanical ventilation were discussed in several studies (5, 6, 12, 24-26). The present study could not appear any significant differences in terms of corticosteroid consumption and the rate of nasogastric tube insertion between case and control groups. However, the duration of NG feeding in CDI+ was significantly longer than control group. Therefore, the NG feeding duration may increase the possibility of acquisition of CDI in ICU patients. There are several convincing explanations in this regard. Firstly, NGT insertion and manipulation of the feeding tube by ICU staff lead to transfer C. difficile from the hands of personnel. Second, lack of dietary fibre and contamination of formula may play a role in the growth of C. difficile. These drawbacks may result in intestinal flora imbalances, thereby promoting the occurrence of CDI (27).

We found that duration of endotracheal intubation prior to the onset of diarrhea in CDI+ group was significantly higher than control group. Respiratory assistance by mechanical ventilation and nosocomial infections like ventilator-acquired pneumonia (VAP) may result in prescribing broad-spectrum antibiotics in these patients. Therefore, changes in gastrointestinal normal flora may occur, and CDI develops in endotracheal intubated patients. A research conducted by Chunhui Li et al. reported that treatment of hospital-acquired pneumonia could lead to subsequent clostridium difficile infection (12). However, in our study, the duration of endotracheal intubation seems important but data about VAP and other nosocomial infections are unclear. Further studies are warranted to delineate this finding.

The increase of gastric PH by proton pump inhibitors (PPIs) administration may cause alteration of intestinal flora and impair leukocyte function. Therefore, bacterial overgrowth occurs in patients who admitted in intensive care unit (28). Inconsistent with our results, Buendgens L et al. showed that gastric acid suppression treatment increases the prevalence of CDI in medical ICUs (29, 30). However, prescription of H2 blocker was not significantly different among ICU groups in those studies. Contrary to the present study, Faleck DM et al. revealed that PPIs did not increase the risk for CDI acquisition in ICU patients (31).

Upon comparing laboratory findings, there was a significant difference in serum folate level between case and control groups. There is no obvious explanation for this result. Several studies have performed on zinc level in mice to describe susceptibility to CDI. They have explained that dietary zinc changes microbiota profiling and decreases resistance to CDI (32). Further studies are warranted to manifest the relation of serum folate level to CDI in human.

Matthaiou DK  et al. have reported that CDI mortality has a wide range, up to more than 50%, among different studies (6). On the contrary, Dodek PM and et al. concluded that the acquisition of C. difficile infection in ICU did not increase the risk of the hospital or ICU mortality (13). Although a high rate of mortality, 57.4% in CDI+ group, was reported in our ICU setting, there was no statistically significant difference between study groups. A logistic regression model showed no correlation between CD positive cases and mortality. In other words, high rate mortality in our ICU setting may be related to patient comorbidities, chronic underlying diseases, the severity of illness of ICU patients or other unknown factors. Therefore, mortality rate directly attributable to CDI was not calculable. Further multicentre studies investigating the mortality rate of CDI in ICU are needed. Our study comes with several limitations. A single-center study cannot represent the whole situation in IRAN. The small sample size is another important limitation in this study. Potential confounding factors, such as patient comorbidities and other nosocomial infections may have caused an estimation bias with mortality results.

In conclusion, this prospective study revealed that the incidence of ICU- onset CDI was 22.38 cases per10, 000 patient-days. In addition, a high mortality rate in our medical ICUs was determined. Antibiotic administration and age were not identified as risk factors for developing CDI in ICU patients, whereas PPIs, duration of endotracheal intubation and NG feeding were associated with increased risk for CDI in ICU patient population. Recognizing the causal relationship between duration of endotracheal intubation and NG feeding with CDI might be essential for the protocol of CDI treatment. Further studies with larger sample size are warranted to explore these findings. Moreover, we encountered with higher serum folate level in CDI+ patients. The finding that requires further investigation.

References

1. Lee JC, Hung YP, Lin HJ, Tsai PJ, Ko WC. Clostridium difficile Infections in Medical Intensive Care Units of a Medical Center in Southern Taiwan: Variable Seasonality and Disease Severity. PLoS One. 2016;11(8):e0160760.
2. Balsells E, Shi T, Leese C, Lyell I, Burrows J, Wiuff C, et al. Global burden of Clostridium difficile infections: a systematic review and meta-analysis. J Glob Health. 2019;9(1):010407.
3. Karanika S, Paudel S, Zervou FN, Grigoras C, Zacharioudakis IM, Mylonakis E. Prevalence and Clinical Outcomes of Clostridium difficile Infection in the Intensive Care Unit: A Systematic Review and Meta-Analysis. Open Forum Infect Dis. 2016;3(1):ofv186.
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