A review of mortality due to Clostridium difficile infection

doi:10.1016/j.jinf.2010.03.025

Journal of Infection

Volume 61, Issue 1, July 2010, Pages 1-8

https://doi.org/10.1016/j.jinf.2010.03.025 Get rights and content

Summary

In this review we examine published literature to ascertain mortality in relation to Clostridium difficile infection (CDI) and the factors associated with mortality. In the 27 studies that had sufficient data, there were 10975 cases of CDI with great heterogeneity in the methods for reporting mortality. We calculated the overall associated mortality to be at least 5.99% within 3 months of diagnosis. The most important finding is that higher mortality is associated with advanced age, being 13.5% in patients over 80 years. Studies performed after 2000 had a significantly higher mortality than those before this date. We propose minimum standards for reporting mortality in future studies.

Introduction

Clostridium difficile is the most common cause of hospital acquired infectious diarrhoea in the developed world and has re-emerged in recent years with apparent greater morbidity and mortality. The re-emergence of C. difficile is believed to be partly due to the appearance of a more virulent strain and due to an ageing population. Reported mortality rates from C. difficile infection (CDI) in the United States increased from 5.7 per million in 1999 to 23.7 per million in 2004; the median age of death was 82 years.¹ In the UK the Department of Health (DH) has instituted mandatory surveillance of CDI and of deaths due to this. This revealed a preponderance of elderly patients, with 81% of reported C. difficile cases in England being over the age of 65 and 30% over 85. The number of death certificates mentioning CDI in the UK also rose from 1804 cases in 2003 to 8324 cases in 2007. The age specific mortality rose from 0.2/1 000 000 population in the <45 years age group to 2055/1 000 000 in the population over 84 years of age.2, 3

It has been difficult to determine the true attributable mortality for CDI in the absence of severe features such as pseudomembranous colitis (PMC) as these patients are frequently frail and elderly with multiple co-morbidities. In this review, we examine the published literature on mortality due to CDI.

Section snippets

Methods

We searched Pubmed, Embase and Google Scholar for C. difficile mortality for the period January 1980–March 2010, including ‘related articles’ and the papers cited therein. Studies were limited to those published in English. We used the search terms (C. difficile OR pseudomembranous colitis) AND (mortality OR death OR outbreak*). Only studies that included data on attributable mortality or where attributable mortality could be calculated from the data provided were included. One person (JAK)

Results

Ninety nine studies were identified and the abstracts obtained. Twenty seven studies met the study criteria and were included (Table 1). Results are ordered according to the start date of the study. Of the 27 studies we included, there were six prospective descriptive studies, ten retrospective descriptive studies, ten case control studies and one report of an outbreak situation. C. difficile testing methodology included multiple methods in eight studies, enzyme immunoassay in eight studies,

Discussion

There is much heterogeneity among published studies in terms of definitions, patient groups, type and quality of study, information collected and information available. Only seven of the 27 included studies were prospective descriptive studies while only seven of the ten case control studies provided a time frame. Many studies lacked any demographic information.

This is reflected by attributable mortality rates ranging from 0% at a long-term care facility in the USA¹⁹ to 44% at a care of the

Conflicts of interest

None.

Authors' contributions

JAK conceived the idea and reviewed all titles and abstracts for potentially eligible articles. Studies were reviewed by JAK & DAE, all three authors contributed to the analysis of data and writing of manuscript.

Acknowledgements

Dr Margaret Gillham, Papworth Hospital NHS Trust, for review of manuscript.

References (49)

A. Gulihar et al.
Clostridium difficile in hip fracture patients: prevention, treatment and associated mortality
Injury
(2009)
M. Warny et al.
Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe
Lancet
(2005)
C. Kenneally et al.
Analysis of 30-day mortality for clostridium difficile-associated disease in the ICU setting
Chest
(2007)
U. Changela et al.
Risk factors and mortality associated with Clostridium difficile-associated diarrhoea at a VA hospital
Int J Antimicrob Agents
(2004)
L. Kyne et al.
Simultaneous outbreaks of two strains of toxigenic Clostridium difficile in a general hospital
J Hosp Infect
(1998)
T.D. Cartmill et al.
Management and control of a large outbreak of diarrhoea due to Clostridium difficile
J Hosp Infect
(1994)
B.A. Jobe et al.
Clostridium difficile colitis: an increasing hospital-acquired illness
Am J Surg
(1995)
M. Salazar et al.
Clostridium difficile-related death rates in Texas 1999–2005
J Infect
(2009)
J. Bishara et al.
Mortality of patients with antibiotic-associated diarrhoea: the impact of Clostridium difficile
J Hosp Infect
(2008)
J.F. Hall et al.
Outcome of colectomy for Clostridium difficile colitis: a plea for early surgical management
Am J Surg
(2008)

C.W. Ang et al.

The acquisition and outcome of ICU-acquired Clostridium difficile infection in a single centre in the UK

J Infect

(2008)

K.W. Garey et al.

Meta-analysis to assess risk factors for recurrent Clostridium difficile infection

J Hosp Infect

(2008)

S.P. Stone et al.

The ORION statement: guidelines for transparent reporting of outbreak reports and intervention studies of nosocomial infection

Lancet Infect Dis

(2007)

M.D. Redelings et al.

Increase in Clostridium difficile-related mortality rates, United States, 1999–2004

Emerg Infect Dis

(2007)

H. Creagh

Number of deaths due to C difficile rose by 72% in a year

BMJ

(2008)

Anonymous

Deaths involving C. difficile: England & Wales 2003–2007

Health Stat Q

(2008)

M. Arvand et al.

Clostridium difficile ribotypes 001, 017, and 027 are associated with lethal C. difficile infection in Hesse, Germany

Euro Surveill

(2009)

C. Hardt et al.

Univariate and multivariate analysis of risk factors for severe Clostridium difficile-associated diarrhoea: importance of co-morbidity and serum C-reactive protein

World J Gastroenterol

(2008)

D. Gravel et al.

Health care-associated clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial infection surveillance program study

Clin Infect Dis

(2009)

E.R. Dubberke et al.

Attributable outcomes of endemic Clostridium difficile-associated disease in nonsurgical patients

Emerg Infect Dis

(2008)

V.G. Loo et al.

A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality

N Engl J Med

(2005)

P.M. Polgreen et al.

An outbreak of severe Clostridium difficile-associated disease possibly related to inappropriate antimicrobial therapy for community-acquired pneumonia

Infect Control Hosp Epidemiol

(2007)

D.M. Musher et al.

Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole

Clin Infect Dis

(2005)

D.M. Musher et al.

The long-term outcome of treatment of Clostridium difficile colitis

Clin Infect Dis

(2007)

Cited by (116)

Clostridium difficile colitis portends poor outcomes in lower extremity orthopaedic trauma surgery
2022, Injury
Clostridium difficile is the most common cause of healthcare-associated infectious diarrhea and colitis, and carries the potential for high morbidity, particularly in frail patient populations. The purpose of this study was to utilize a large nationally representative database in order to report 1.) the incidence of CDC in patients with operative lower extremity fractures, 2.) risk factors for the development of CDC, 3.) the association of CDC with length of stay (LOS), readmission, and 30-day mortality rates.
The ACS-NSQIP (2015–2019) was queried for patients who underwent surgical fixation of lower extremity fractures. A backward elimination multivariate regression model was used to identify risk factors for CDC. Chi squared and multivariate regression that controlled for preoperative variables and comorbidities were used to compare outcomes in patients with and without CDC.
95,532 patients were included, 681 (0.71%) of whom developed CDC. Risk factors for CDC were advanced age, ASA class ≥ 3, smoking, dialysis, anemia, hypoalbuminemia, preoperative SIRS, preoperative wound infections, preoperative sepsis, and the use of spinal anesthesia or MAC/IV sedation. Patients with CDC had significantly increased 30-day mortality rates (10.6% vs 4.4%; OR 1.80, 95% CI 1.41–2.31), readmission (34.2% vs 7.5%; OR 5.13, 95% CI 4.36–6.05, and length of stay (7.5 days vs 5.3 days) compared to patients without CDC.
The incidence of CDC in lower extremity orthopedic trauma patients was 0.71%. An occurrence of CDC was associated with approximately a 2.5 times increase in 30-day mortality, five times the readmission rate, and a longer hospital stay compared to patients without CDC. Mitigating the spread of c. diff through improved antibiotic stewardship and prompt treatment of CDC is paramount to decreasing the burden this infection imposes on orthopedic trauma patients and the healthcare system.
Clostridioides (Clostridium) difficile in children with diarrhoea in Vietnam
2022, Anaerobe
Clostridioides (Clostridium) difficile commonly causes hospital-acquired infection which can range from mild diarrhoea to life-threatening toxic megacolon and even death. Reports on C. difficile infection (CDI) in Vietnam are limited, so this study was designed to evaluate the prevalence, molecular epidemiology and antimicrobial susceptibility of C. difficile isolated from children with diarrhoea in Vietnam. Infants are often colonised with C. difficile and it was hypothesised that those colonising strains would represent strains of C. difficile circulating in the hospital/region at the time, however, this was not an attempt to determine if C. difficile was the cause of the diarrhoea.
Diarrhoeal stool samples collected at two children's hospitals in northern Vietnam from October 1, 2020 to February 28, 2021 were transported to Perth, Western Australia, for culture of C. difficile and further investigations on isolates; PCR ribotyping, toxin gene profiling and antimicrobial susceptibility testing.
From these hospitals, 370 diarrhoeal stool samples were collected, most from children aged 1–15 months (71.9%; 266/370). The overall prevalence of C. difficile in stool samples from children aged ≤16 years was 37.8% (140/370) and the highest prevalence was in the 2–12 months age group (52.9%; 74/140). In total, 151 isolates of C. difficile were recovered; the proportion of toxigenic isolates was 16.6% (25/151). Of the 25 toxigenic C. difficile isolates, the toxin gene profiles A⁺B⁺CDT⁻ and A⁻B⁺CDT⁻ comprised 72% and 28%, respectively. The four most prevalent C. difficile ribotypes (RTs) were QX 011 (25/151), RT 010 (25/151), QX 107 (12/151) and RT 012 (11/151). All isolates were susceptible to vancomycin, metronidazole and fidaxomicin, while there was significant resistance to clindamycin (90.1%), and some to moxifloxacin (6.6%) and rifaximin (3.3%).
The prevalence of C. difficile in children with diarrhoea was high (37.8%) although the proportion of toxigenic strains was comparatively low. The clinical significance of any isolate needs to be determined.
Assessing risk factors, mortality, and healthcare utilization associated with Clostridioides difficile infection in four Latin American countries
2021, Brazilian Journal of Infectious Diseases
Citation Excerpt :
Concurrently with the observed increase in CDI incidence rates, CDI associated mortality has risen in the past two decades.4,14 Based predominantly on Western data sets, mortality from CDI is estimated at 6.0% and is highest in older individuals.14 As available investigations of the epidemiology of CDI have focused on resource-rich settings, comparatively less is known about the burden in other regions.15
Clostridioides difficile infection (CDI) is the most common cause of healthcare-associated infections in Western countries. Risk factors, mortality, and healthcare utilization for CDI in Latin America are poorly understood. This study assessed risk factors and burden associated with nosocomial CDI in four Latin American countries.
This retrospective, case-control study used databases and medical records from 8 hospitals in Argentina, Brazil, Chile, and Mexico to identify nosocomial CDI cases from 2014 − 2017. Cases were patients aged ≥18 years with diarrhea and a positive CDI test ≥72 h after hospital admission. Two controls (without diarrhea; length of hospital stay [LOS] ≥3 days; admitted ±14 days from case patient; shared same ward) were matched to each case. CDI-associated risk factors were assessed by univariate and multivariable analyses. CDI burden (LOS, in-hospital mortality) was compared between cases and controls.
The study included 481 cases and 962 controls. Mean age and sex were similar between cases and controls, but mean Charlson comorbidity index (4.3 vs 3.6; p < 0.001) and recent hospital admission (35.3% vs 18.8%; p < 0.001) were higher among cases. By multivariable analyses, CDI risk was associated with prior hospital admission within 3 months (odds ratio [OR], 2.08; 95% CI: 1.45, 2.97), recent antibiotic use (ie, carbapenem; OR, 2.85; 95% CI: 1.75, 4.64), acid suppressive therapy use (OR, 1.71; 95% CI: 1.14, 2.58), and medical conditions (ie, renal disease; OR, 1.48; 95% CI: 1.19, 1.85). In-hospital mortality rate (18.7% vs 6.9%; p < 0.001) and mean overall LOS (33.5 vs 18.8 days; p < 0.001) were higher and longer, respectively, in cases versus controls.
Antibiotic exposure, preexisting medical conditions, and recent hospital admission were major risk factors for CDI in Argentina, Brazil, Chile, and Mexico. CDI was associated with increased in-hospital risk of death and longer LOS. These findings are consistent with published literature in Western countries.
Recommendations and guidelines for the treatment of Clostridioides difficile infection in Taiwan
2020, Journal of Microbiology, Immunology and Infection
Clostridioides difficile infection (CDI) is a major enteric disease associated with antibiotic use and a leading cause of hospital-acquired infections worldwide. This is the first guideline for treatment of CDI in Taiwan, aiming to optimize medical care for patients with CDI. The target audience of this document includes all healthcare personnel who are involved in the medical care of patients with CDI. The 2018 Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group was formed, comprising of infectious disease specialists from 13 medical centers in Taiwan, to review the evidence and draft recommendations using the grading of recommendations assessment, development, and evaluation (GRADE) methodology. A nationwide expert panel reviewed the recommendations during a consensus meeting in March 2019. The recommendation is endorsed by the Infectious Diseases Society of Taiwan (IDST). This guideline describes the epidemiology and risk factors of CDI, and provides recommendations for treatment of CDI in both adults and children. Recommendations for treatment of the first episode of CDI, first recurrence, second and subsequent recurrences of CDI, severe CDI, fulminant CDI, and pediatric CDI are provided.
Designed ankyrin repeat protein (DARPin) neutralizers of TcdB from Clostridium difficile ribotype 027
2019, mSphere
We report the engineering and characterization of designed ankyrin proteins as potent neutralizers of TcdB toxin secreted by a hypervirulent ribotype 027 strain of Clostridium difficile. We further show that although TcdB toxins from both ribotype 027 and VPI 10461 interact efficiently with TcdB receptors CSPG4 and Pvrl3, TcdB₀₂₇ lacks significant ability to bind the only known physiologically relevant TcdB receptor, Frizzled 1/2/7.
Clostridium difficile infection (CDI) is a leading cause of hospital-acquired diarrhea. In recent decades, the emergence of the “hypervirulent” BI/NAP1/027 strains of C. difficile significantly increased the morbidity and mortality of CDI. The pathogenesis of CDI is primarily mediated by the action of two toxins, TcdA and TcdB, with TcdB being the major virulent factor in humans. In this report, we describe the engineering of a panel of designed ankyrin repeat proteins (DARPins) that potently neutralize TcdB from the BI/NAP1/027 strains (e.g., TcdB_UK1). The most effective DARPin, D16, inhibits TcdB_UK1 with a 50% effective concentration (EC₅₀) of 0.5 nM, which is >66-fold lower than that of the FDA-approved anti-TcdB antibody bezlotoxumab (EC₅₀, ∼33 nM). Competitive enzyme-linked immunosorbent assays (ELISAs) showed that D16 blocks interactions between TcdB and its receptor, chondroitin sulfate proteoglycan 4 (CSPG4). The dimeric DARPin U3D16, which pairs D16 with DARPin U3, a disrupter of the interaction of TcdB with Frizzled 1/2/7 receptor, exhibits 10-fold-to-20-fold-enhanced neutralization potency against TcdB from C. difficile strains VPI 10463 (laboratory strain) and M68 (CF/NAP9/017) but identical activity against TcdB_UK1 relative to D16. Subsequent ELISAs revealed that TcdB_UK1 did not significantly interact with Frizzled 1/2/7. Computation modeling revealed 4 key differences at the Frizzled 1/2/7 binding interface which are likely responsible for the significantly reduced binding affinity.
IMPORTANCE We report the engineering and characterization of designed ankyrin proteins as potent neutralizers of TcdB toxin secreted by a hypervirulent ribotype 027 strain of Clostridium difficile. We further show that although TcdB toxins from both ribotype 027 and VPI 10461 interact efficiently with TcdB receptors CSPG4 and Pvrl3, TcdB₀₂₇ lacks significant ability to bind the only known physiologically relevant TcdB receptor, Frizzled 1/2/7.
Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial
2018, The Lancet Infectious Diseases
Citation Excerpt :
Clostridium difficile is the leading cause of infectious health-care-associated diarrhoea in developed countries.1 C difficile infection is particularly serious in older individuals, in whom it is associated with severe infection and complications, including recurrence and death.2–4 Prevention of recurrence of C difficile infection has been identified as a key unmet need.5
Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin.
In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1–5, then once daily on alternate days on days 7–25) or vancomycin (125 mg oral capsules, four times daily on days 1–10), stratified by baseline C difficile infection severity, cancer presence, age (≥75 years vs <75 years), and number of previous C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967.
Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1·0–20·7], p=0·030; odds ratio 1·62 [95% CI 1·04–2·54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug.
Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection.
Astellas Pharma, Inc.

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ReviewA review of mortality due to Clostridium difficile infection

Summary

Introduction

Section snippets

Methods

Results

Discussion

Conflicts of interest

Authors' contributions

Acknowledgements

Injury

Lancet

Chest

Int J Antimicrob Agents

J Hosp Infect

J Hosp Infect

Am J Surg

J Infect

J Hosp Infect

Am J Surg

J Infect

J Hosp Infect

Lancet Infect Dis

Increase in Clostridium difficile-related mortality rates, United States, 1999–2004

Emerg Infect Dis

Number of deaths due to C difficile rose by 72% in a year

BMJ

Deaths involving C. difficile: England & Wales 2003–2007

Health Stat Q

Clostridium difficile ribotypes 001, 017, and 027 are associated with lethal C. difficile infection in Hesse, Germany

Euro Surveill

Univariate and multivariate analysis of risk factors for severe Clostridium difficile-associated diarrhoea: importance of co-morbidity and serum C-reactive protein

World J Gastroenterol

Health care-associated clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial infection surveillance program study

Clin Infect Dis

Attributable outcomes of endemic Clostridium difficile-associated disease in nonsurgical patients

Emerg Infect Dis

A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality

N Engl J Med

An outbreak of severe Clostridium difficile-associated disease possibly related to inappropriate antimicrobial therapy for community-acquired pneumonia

Infect Control Hosp Epidemiol

Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole

Clin Infect Dis

The long-term outcome of treatment of Clostridium difficile colitis

Clin Infect Dis

Review
A review of mortality due to Clostridium difficile infection