Research Article
Risk Factors for Clostridium Difficile Colitis in Patients Undergoing Treatment for Gynecologic Cancer
Blake EA1*, Sheeder J1, Carrubba A1, Okland T3, Doo D1 and Guntupalli S2
1Department of Obstetrics and Gynecology, University of Colorado, USA
2Department of Obstetrics and Gynecology, University of Colorado School of Medicine, USA
*Corresponding author: Erin Blake, Department of Obstetrics and Gynecology, University of Colorado 12631 East 17th Avenue, Room 4007, B198-6 Aurora, CO 80045, Denver, CO, USA
Published: 30 Jan, 2017
Cite this article as: Blake EA, Sheeder J, Carrubba A,
Okland T, Doo D, Guntupalli S. Risk
Factors for Clostridium Difficile Colitis
in Patients Undergoing Treatment for
Gynecologic Cancer. Clin Oncol. 2017;
2: 1190.
Abstract
Objectives: Clostridium Difficile Associated Diarrhea (CDAD) is a common potentially dangerous
complication of treatment for gynecologic cancers and is an important metric for quality of hospital
care. We evaluated risk factors associated with CDAD in gynecologic oncology patients.
Design: Retrospective chart review
Setting: Inpatient gynecologic oncology ward
Patients: Women with histological confirmation of a gynecologic malignancy admitted for >24
hours were abstracted at a tertiary referral center over four years. Both surgical and medical
admissions included.
Methods: Details regarding health status and treatments were abstracted. Diagnosis of CDAD was
made witha positive PCR result. Standard statistical tests were used.
Results: A total of 728 women were included. Fifteen patients had positive PCR proven CDAD
(2.01%). In bivariate analysis, cephalosporin exposure (OR 0.21, 95% CI 0.06-0.74) and surgical
admission (OR 0.28, 95% CI 0.09- 0.87) were associated with decreased risk of CDAD. Platinum
based chemotherapy use (OR 3.61, 95% CI 1.29-10.13), radiation therapy (OR 6.82, 95% CI 1.81-
25.7), and early stage (OR 3.59, 95% CI 1.26-10.21) were associated with increased risk of CDAD. In
logistic regression analysis, chemotherapy use (aOR 5.7, 95% CI 1.91-17.10) and early stage disease
(aOR 5.7, 95% CI 1.22-11.05), were found to be independent predictors of CDAD. Cephalosporin
use was independently found to be associated with decreased risk of CDAD (aOR 0.20, 95% CI
0.05-0.75).
Conclusions: Platinum based chemotherapies and early stage disease are significant risk factors
for the development of CDAD in gynecologic oncology patients. Attention to these risk factors is
warranted to prevent the dangerous sequelae of infection with this organism.
Introduction
Clostridium Difficile Associated Diarrhea (CDAD) is an increasingly common organism
diagnosed in hospital in patient populations and is viewed as an important metric for the quality
of hospital care. C. difficile is a gram-positive, anaerobic bacillus that forms notably resilient
spores with the primary route of transmission via the fecal-oral route. While most carriers of C.
difficile are asymptomatic, colonization with this microbe can result in CDAD, characterized by
pseudomembranous plaques lining the colon and profuse, foul smelling diarrhea. C. difficile spores
are resistant to many of the hand sanitizers used frequently in hospital settings and susceptible only
to thorough hand washing with bactericidal agents.
As of 2007, C. difficile was the leading national cause of gastroenteritis-associated deaths [1].
A recent national study showed that in 2011, approximately half a million new cases of C. difficile
were diagnosed, and this organism was associated with almost 30,000 deaths [2]. C. difficile is now
the most common hospital acquired infection in the United States [3]. Furthermore, this organism
poses a considerable economic burden; increased costs associated with acute care facilities alone in
the United States are upwards of 4 billion dollars annually [3,4].
Known factors that increase risk of C. difficile infection include age greater than 65, female
gender, and white race [2]. Other documented characteristics that increase risk of C. difficile infection
include prolonged hospital stay, immunocompromised status, and exposure to broad spectrum antibiotics, cytotoxic drugs, and proton pump inhibitors [5]. The additional morbidity imposed by C. difficile infection is potentially
devastating, especially when imposed on patients that are at a baseline
compromised health status. One of the most severe complications
of C. difficile infection is toxic megacolon requiring colectomy. A
recent study found that the number of colectomies due to C difficile
colitis is increasing nationally, and the mortality associated with these
procedures is 30% [6].
Gynecologic oncology patients are at especially high risk for
infection with C. difficile due to the presence of many of these known
risk factors. However, while there is no shortage of literature on C.
difficile infection in various hospital populations, there is little data
specific to women diagnosed with gynecologic malignancies. The
purpose of this study was to identify aspects of care that increase risk
for developing C. difficile cololitis in order to enable us to modify our
standards of care to reduce risk in our gynecologic oncology inpatient
population.
Table 1
Table 1
Risk factors for development of Clostridium Difficile Associated Diarrhea (CDAD) in gynecologic cancer patients.
Methods
Institutional review board approval was obtained through
the Colorado Multiple Institutional Review Board (COMIRB).
A retrospective chart review of all inpatient admissions to the
gynecologic oncology service in a single institution from September
2011 through March 2015 was conducted. Both medical and surgical
admissions were included. Exclusion criteria included absence of
biopsy proven malignancy, admission for less than 24 hours, and lack
of laboratory confirmation of C. difficile infection. A team of medically
trained researchers conducted a detailed review of individual charts.
Specific definitions for each variable collected were distributed to
each research assistant prior to initiation of data collection. Data
was abstracted for elements of care including patient demographic,
admission, disease and treatment information.
Basic demographic information and details regarding patients’
overall state of health were collected for each individual patient. Age, body mass index, histologic diagnosis, and disease stage and status were noted. Medical comorbidities were also examined in detail. Comorbidities were collected based on the patient’s diagnoses as
per admission problem list at time of admission. If a comorbidity,
such as anemia, had previously existed but resolved during dates of
admission, it was not listed as positive in the patient’s data for that
particular admission. Other variables relevant to patient disease and
health outcomes, such as albumin level, were also extracted.
Elements of treatment and care during inpatient admissions
were also collected. Variables extracted were duration of admission,
surgical versus medical admission, and chief complaint or reason for
admission. Aspects of treatment during course of care noted were
inpatient administration of proton pump inhibitors, total parenteral
nutrition and corticosteroids, use of nasogastric tube, and recent
exposure to chemotherapy or radiation therapy. Antimicrobial
therapy was recorded according to drug class. Diagnosis of C.
Difficile toxin presence was documented only if there was a
laboratory confirmed positive polymerase chain reaction result in
the institution’s electronic medical record system and associated
symptoms of diarrhea.
The primary outcome was to examine the elements of treatment,
health and disease status, and inpatient admission that independently
predicted infection with C. difficile in gynecologic oncology patients.
Statistical analysis was performed with IBM SPSS statistics version
21. Statistical significance was estimated with chi-square tests for
dichotomous and categorical variables and Student’s t-tests were used
to compare continuous variables. Multivariable analyses were used to
determine factors that were independently associated with positive
C. difficile infection. Variables significant in bivariate analyses were
included in the multivariable model. For all tests, a p value of <.05 was
considered statistically significant.
Table 2
Table 2
Medication exposure as a risk factor for Clostridium Difficile Associated
Diarrhea (CDAD) in gynecologic cancer patients.
Results
A total of 728 women fit inclusion criteria and were included in the analysis (mean age 60, range 21-87). Demographic data are
shown in (Table 1). A total of 15 patients had positive PCR proven
C. difficile infection (2.01%). In terms of demographic and clinical
characteristics, neither age nor BMI were associated with increased
risk of diagnosis with CDAD.
Cancer diagnoses included cervical (11.0%), uterine/endometrial
(32.1%), ovarian/fallopian tube/primary peritoneal (53.3%), and
vulvar/vaginal (3.5%).
Early stage disease was significantly associated with increased risk
of CDAD (p <0.005; OR 3.60, CI 1.26-10.2). Exposure to treatments
for malignancy including chemotherapeutics and radiation was
analyzed. Notably, platinum agents (p<0.01; OR 3.61, 95% CI 1.29-
10.13) were associated with increased risk of CDAD. Neither taxanes
nor bevacizumab were associated with increased risk of CDAD.
Pelvic radiation within a month of admission was also associated with
increased risk of developing CDAD (p <0.02; OR 6.82, 95% CI1.81-
25.7).
Exposure to different classes of medication was also analyzed.
Neither use of PPI or corticosteroid exposure was associated with
increased risk of hospital acquired CDAD. Multiple different classes
of antibiotics were examined independently. Cephalosporins were
the most commonly represented antibiotics, and they were associated
with decreased risk of CDAD (p <0.01; OR 0.21, 95% CI 0.06-
0.74). Penicillins, fluoroquinolones, carbanepenems, vancomycin,
clindamycin, sulfonamides, and nitrofurantoin were not statistically
associated with increased risk of CDAD.
Multiple medical comorbidities were extracted, and none of
the comorbidities examined were associated with increased risk
of CDAD. Gastroesophageal reflux disease was not associated with
CDAD at a statistically significant level (p = 0.058; OR 3.08, CI
1.04-9.09) although 66.7% of patients positive for CDAD in our
study did carry this diagnosis. Other gastrointestinal comorbidities
including Crohn’s disease or presence of a colostomy were also not
statistically associated with CDAD. Cardiovascular comorbidities
such as hypertension and hyperlipidemia were not associated with
increased risk for CDAD. Diabetes mellitus, chronic kidney disease,
and hepatic disease were not found to be statistically associated with
CDAD. Neutropenia was also not found to be a statistically significant
risk factor for acquisition of CDAD.
Other aspects of inpatient hospital admission thought to
potentially have an impact on risk of acquiring CDAD were also
analyzed. Neither hospital admission number nor length of stay was
associated with increased risk of CDAD. Surgical admission did show
a protective association towards CDAD (p = 0.032; OR 0.28, 95% CI
0.09-0.87). Neither use of total parenteral nutrition nor nasogastric
tube showed increased association with CDAD.
Following logistic regression analysis, platinum agents (p = 0.02;
aOR5.7, 95% CI 1.91-17.10), early stage disease (p <0.01; aOR 5.7,
95% CI 1.22-11.05), and cephalosporins (p = 0.02; aOR 0.20, 95% CI
0.05-0.75) all retained their significant associations.
Discussion
The purpose of this study was to examine factors independently
associated with inpatient diagnosis of C. difficile infection, and
information was abstracted regarding both intrinsic and modifiable
factors. The aim of our study was to identify components of care
that put our patients at increased risk for this potentially devastating condition in order to enable us to modify our standards of care to reduce risk in our gynecologic oncology inpatient population.
Many modifiable risk factors have been identified in patient
populations outside of gynecologic oncology. Administration of
several classes of medications has been specifically associated with
higher rates of C. difficile infection. Antibiotic and PPI exposure are
frequently cited as a risk factor for acquisition of C. difficile infection
[7-10]. Notably, our study found antibiotic exposure to have either
a protective or insignificant effect, depending on class. Although
the majority of patients with CDAD had been prescribed PPIs while
inpatients, there was not a statistically significant association between
these agents and CDAD amongst our population. Anti-neoplastics
have also been shown to increase risk for CDAD [9,11]. Exposure
to chemotherapeutics is a common risk factor amongst gynecologic
patients. Carboplatin and paclitaxel, the two most common agents
used in gynecologic oncology, have been associated with especially
morbid presentations of CDAD [12]. The findings in our study were
consistent with those of many others in that platinum agents were
significantly associated with a higher risk of CDAD. While platinum
agents will remain as an integral component of the care we provide
our gynecologic cancer patients, this finding serves to reinforce a high
index of suspicion for CDAD in women who present with diarrhea
after receiving chemotherapy. Our study also found that radiation
within the past month is associated with increased risk of CDAD. This
association has not previously been demonstrated amongst cancer
patients receiving radiation with the exception of occasional case
reports [13] and those with head and neck malignancies [14]. A wellknown
potential side effect of pelvic radiation is diarrhea or radiation
proctitis; however, findings of our study indicate that there should
also be a high index of suspicion for CDAD in patients who have
recently been treated with radiation. Other than early stage disease,
our study found that most intrinsic risk factors, such as medical
comorbidities, were not associated with increased risk of CDAD.
Investigation into both intrinsic and iatrogenic factors leading
to increased risk of acquiring C. difficile infection during inpatient
admission is relevant because this hospital acquired infection is
becoming increasingly prevalent in hospitals across the country.
Inpatient populations are at unacceptably high risk for colonization
with the organism. Studies have shown that bacterial spores which are
acquired via fecal-oral transmission can be detected in greater than
50% of patients hospitalized for 4 weeks in an inpatient facility [15].
The national estimated incidence of asymptomatic colonization of C.
difficile is 2%; however, the estimated rate of colonization in patients
with exposure to health care facilities is much higher at approximately
25% [16]. The 2% infection rate documented amongst the patients
followed in our study was much lower than the national average
for healthcare associated C. difficile colonization; however, only
symptomatic patients were screened for the microbe. Additionally,
many C. difficile infections are diagnosed in an outpatient community
setting, even if the infection was initially acquired during an inpatient
admission. One of the weaknesses of this study is that we did not
capture the patients presenting with CDAD outside of the inpatient
admission [2,17].
This study was designed as a retrospective review of a specific
population at a single institution, which enabled us to analyze
treatment course and outcomes with a rare degree of detail. Some
of the benefits of performing a study at a single institution include
consistency amongst the physician providers as well as a presumed
baseline equivalent risk of colonization with C. difficile, an important consideration when the primary outcome is related to an infectious
agent. However the design of this study did result in an overall
statistical under-powering due to the rare nature of our primary
outcome. The overall rate of colonization amongst patients tested was
much lower than anticipated based on national statistics. While this is
a testament to infection control at the institution studied, the results
might not be generalizable to populations with a higher incidence of
infection or exposure to a more virulent strain of C. difficile.
Overall, this study lends important insight into factors that might
affect risk of acquiring CDAD in gynecologic oncology inpatient
populations. Providers are encouraged to continue to carefully
consider the risks and benefits of pharmacologics used during
admissions. Patients who are noted to be at especially high risk of
contracting CDAD include those that have been exposed to platinum
agents and radiation and those with early stage disease. Awareness
of increased risk amongst certain populations can enable preemptive
measures to avoid infection, such as emphasizing hand washing with
soap and water prior to any interaction with these patients.
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