International Journal of Multidisciplinary and Current

Educational Research (IJMCER)

ISSN: 2581-7027 ||Volume|| 5 ||Issue|| 2 ||Pages 75-82 ||2023||

The Role of Antibiotics in the Development of

Pseudomembranous Colitis Caused by the Bacterium Clostridium
Difficile

Nedim Pervan1, Mufida Aljičević2*, Rusmir Baljić3, Velma Rebić2, Sabina

Mahmutović Vranić2
1,
Medical School, Sarajevo, Bosnia and Herzegovina
2,
Department of Microbiology, Faculty of Medicine, University of Sarajevo, Bosnia and Herzegovina
3,
Clinic for Infection Diseases Clinical Centre University of Sarajevo, Bosnia and Herzegovina

ABSTRACT: The most common pathogen responsible for the development of pseudomembranous colitis is
the bacterium Clostridium difficile. The gut microbiota has a protective role because it prevents the adhesion of
pathogens to receptors on host cells. Materials and Methods: In this retrospective study, data from medical
histories of the patient with confirmed Clostridium difficile infection, was hospitalized at the Clinic for Infection
Diseases in the Clinical Centre of Sarajevo University.

RESULTS: Of all patients, 81.2% used antibiotics before the onset of symptoms. The largest number of
antibiotics used were group β lactam antibiotics (46.9%), while from the group of other antibiotics, quinolones
were used the most (45.5%). The largest number of patients experienced the first attack (89.1%). Metronidazole
was the most common drug of choice for Clostridium difficile infection (81.3%). The combination of
metronidazole and vancomycin was received in 15.6% of cases, and in 3.1% of cases.

CONCLUSIONS: Our study showed that pseudomembranous colitis developed in a small percentage in
patients who had not used antibiotics at all before the onset of symptoms. In patients undergoing antibiotic
therapy, the risk of developing C. difficile pseudomembranous colitis was slightly higher with β-lactam
antibiotics than with other antibiotics.

KEYWORDS: antibiotics, pseudomembranous colitis, Clostridium difficile

I. INTRODUCTION
Pseudomembranous colitis (PMC) is a manifestation of severe colon disease usually associated with
Clostridium difficile (C. difficile) infection, but there may be other etiological factors for the disease. The
development of the disease is favored by a prolonged hospital stay, older age (over 65 years), and severe
primary illness (comorbidities). Before using broad-spectrum antibiotics, PMC usually occurred in ischemic
disease, obstruction, sepsis, uremia, and heavy metal poisoning [1, 2]. The entire gastrointestinal tract (GIT) is
inhabited by microorganisms, predominantly bacteria. The majority of bacteria are found in the cecum and
transversal colon, where the bacterial population range from around 1012 to 1014/ml. Intestinal microflora plays a
major role in the host defense, stimulates the production of IgA, and modulates local T-lymphocytes [3, 4], so
that intestines, together with microbiota, form 70% of the human immune system [5].

C. difficile is a gram-positive, sporogenic, anaerobic bacterium. Almost 50% of newborns carry this bacterium
asymptomatically during the first year of life, and only 3% of children older than two years and adults [4]. It is
very easily transmitted in a hospital environment and found in 20-30% of hospitalized patients, and about one-
third of them become ill [5]. C. difficile becomes pathogenic in situations of intestinal flora imbalance
(dysbiosis), which usually occurs with the application of antibiotic therapy [6]. When broad-spectrum antibiotics
are administered orally, they destroy the physiological flora of the intestine and inevitably lead to the
development of intestinal infection. This is the reason that C. difficile endospores translate into vegetative forms,
followed by uncontrolled growth of bacteria. C. difficile is generally a non-invasive bacterium because it does
not enter the bloodstream from the colon. It remains in the lumen of the intestine where it produces toxins that
cause the development of antibiotic-associated diarrhea [4, 6]. C. difficile also causes infectious diarrhea in the
population, often without the use of antibiotics. Pathogenic strains of C. difficile have a so-called locus of
pathogenicity, which contains genes encoding two toxins: the tcdA gene (C. difficile toxin A) and the tcdB gene
(C. difficile toxin B).

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Toxin A breaks down the compounds that hold the cells of the lining of the colon together, which triggers
inflammation and allows for fluid loss. Toxin B directly kills colon cells and stimulates the formation of lesions
that fuse into the characteristic pseudomembrane [5].Severe forms of diarrhea, often associated with intense
inflammation and the formation of lesions in the colon, often develop in hospitalized patients taking
antimicrobial drugs. It can be said that pseudomembranous colitis is a by-product of modern medicine because,
before the use of antibiotics took on wide proportions, this disease occurred very rarely [4]. If bacteria resistant
to applied antibiotics are present in the gut, they will multiply uncontrollably, which can result in severe
enterocolitis (eg antibiotic-associated diarrhea caused by C. difficile) [7].

The clinical presentation of Clostridium difficile infection (CDI) may vary from an asymptomatic carrier to a
fulminant form of the disease with toxic megacolon [8]. CDI symptoms may occur during antibiotic use or one
month later, but usually, they occur within 3-9 days after antibiotic therapy [9]. All antibiotics present a risk of
post-antimicrobial diarrhea/CDI. However, fluoroquinolones, clindamycin, and penicillins have the highest risk
potency for post-antimicrobial CDI. Additional risk factors are age above 65, impaired immune system,
comorbidities, previous infection with C. difficile, etc. [10]. An asymptomatic carrier represents a reservoir of
infection that can contaminate the hospital or other environment. C. difficile is in the etiology of about 20% of
cases of post-microbial diarrhea which represents the mild form of the disease and is characterized by more than
3 loose stools in 24h without general symptoms [11]. The infectious Diseases Society of America /IDSA/ and
the Society for Healthcare Epidemiology of America /SHEA/ in 2017, issued new recommendations for the
treatment for CDI in adults and children. The first step in treatment management is to assess the severity of the
disease, and according to that to give a proper antibiotic treatment [12].Metronidazole is recommended only for
mild/moderate first episode or when vancomycin or fidaxomicin is not available. Its use should be avoided
especially in the elderly or people with developed CDI in irritable bowel disease. Vancomycin 500 mg 4 x 1 per
os as well as metronidazole intravenously is recommended for patients with fulminant CDI form. Metronidazole
is not recommended in relapses. If the patient previously used metronidazole, vancomycin per os is given. If the
patient has previously used vancomycin, it should be used again but in a prolonged tapered regime, or
fidaxomicin could be given instead. If the patient has more than one relapse, it could be treated with
vancomycin, fidaxomicin, or fecal transplantation [12, 13].

II. MATERIALS AND METHODS

The study is retrospective, involving patients who were hospitalized at the Clinic for Infectious Diseases of the
Clinical Center of the University of Sarajevo (KCUS) in a ten-year period (from 2011/01/01 to 2019/12/31). The
study included only those patients with confirmed C. difficile infection. In the microbiological laboratory, all
stool samples were tested with the C. difficile GDH Ag Rapid test, and then only positive samples were further
tested with the Serazym Clostridium difficile toxin A+B test. Data obtained from medical records included the
age and sex of the patient, the duration of hospitalization, information as to whether it was the first episode of
the disease or recurrence, used antibiotic therapy prior to the onset of symptoms, and manner of use (orally or
parenterally), treatment duration before the onset of symptoms, whether the therapy was administered in a clinic
or in an outpatient setting, which therapy was prescribed at the clinic, the duration of therapy, and the outcome
per patient. The results are presented in tables and graphs through an absolute and relative number of cases,
arithmetic mean with standard deviation and value range, or median and interquartile ranges. The non-
parametric chi-square test, the Ficher exact test, the Mann-Whitney test, and the Kruskal-Wallis test were used
to test the differences between the observed groups.

III. RESULTS
The study included a total of 64 patients with a proven presence of C. difficile by Ag (GDH) and EIA (tox A and
B) tests. In the ten-year period, the largest number of registered cases was recorded in 2012, 20 or 31.3% of
them, followed by 2016, 15 or 23.4% of them, while the smallest number was recorded in 2011. where were
only 2 or 3.1% (Graph 1).

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Graph 1. Distribution of registered patients from 2011 to 2019.

Patients were divided into three groups depending on the antibiotics they used, namely the group that used β
lactam antibiotics, the group that used other antibiotics, and those that did not use antibiotics at all before the
symptoms began. The comparison of average age by observation groups shows that on average the oldest
patients were using β lactams before the onset of symptoms with an average age of 73.6 ± 13.3 years (range 24-
91 years), followed by patients using other antibiotics with an average age of 72.3 ± 13.8 years (range 35-92
years), and youngest patients who did not use antibiotics with an average age of 69.3 ± 13.9 years (range 42-87
years) with H = 1.253, p=0.534; p>0.05.Out of the total number of subjects, 64.1% (41 subjects) were males and
35.9% (23 subjects) were females. The analysis of sexual distribution by observation groups shows that men
were more represented in all three groups, without statistically significant differences between groups p> 0.05
(Table 1).

Out of the total number of patients, 18.8% did not use any antibiotics prior to the onset of symptoms. Out of the
total number of patients, the most used antibiotic group was β lactam antibiotics (46.9%) and the group of other
antibiotics (34.3%). In the group of other antibiotics, the most frequent were quinolone antibiotics (45.5%), and
sulphonamides (18.2%), (Table 2).

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The groups were compared according to whether they had the first episode or whether it was a recurrence. The
first episodes were slightly less prevalent in the group of patients using β lactams (93.3%) than those using other
antibiotics. Although recurrence is slightly higher (6.7%) in the group of β lactam antibiotics compared to other
antibiotics (4.5%) (Table 3)

Patients from both groups were treated in an ambulance (outpatient basis) or hospital. Out of the total number of
treated patients, 60% of them using β lactam antibiotics were treated in hospital conditions, while 81.8% using
other antibiotics were treated in an ambulance. Out of the total number of patients, the most commonly used
antibiotic in both groups was metronidazole, in 81.3% of cases, and no statistically significant difference was
seen (p > 0.05). In the group of patients using β lactam antibiotics, there was the need to use combined therapy
in 20% of the cases, as opposed to the group receiving other antibiotics (9.1%). The need for therapy did not
have 9.1% of the cases from the group of other antibiotics (Table 4).

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A comparison of the average duration of hospital stay by observation groups shows that the longer duration of
hospitalization was noted in patients using β lactam antibiotics with an average duration of 20.4±6.7 days (range
8-35 days) and shorter for patients using other antibiotics with an average duration of hospitalization of
19.8±10.3 days (range 1-50 days). According to the median, the comparison of hospital stay, and the observed
groups, shows that the longer hospital stay had patients using β lactam antibiotics with a median duration of
M=21 days (interquartile range 16-23 days), compared to patients using other antibiotics with a median duration
of 17.5 days (interquartile range 13-26 days). The Mann-Whitney analysis shows that there is no significant
difference between the observed groups with Z=-0.826, p=0.409; p > 0.05 (Graf 2).

Graph 2. Duration of hospital stay compared by groups

Out of the total number of patients, the fatal outcome was more frequent when β lactam antibiotics were used in
3 or 10% of the cases compared to the group where other antibiotics were used, with a fatal outcome occurred in
1 or 4.5% of the cases. The statistical analysis shows that there is no significant difference from the fatal
outcome between groups (p> 0.05) (Table 5).

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IV. DISCUSSION
The study involved a total of 64 patients with the presence of C. difficile, 41 men and 23 women, aged from 24
to 92. The largest number of registered cases was recorded in 2012, 20 (31.3%), and in 2011, only 2 (3.1%). The
median age of patients is 76.5 (67.5-80.8). In a study by Pechal et al., the median age of the respondents was 74
(59–83) years and CDI was the most common in the elderly (> 65 years)[14]. In our study, the relationship
between male and female patients was 64.1%: 35.9% in favor of the male sex, in contrast to the study by
Stevens et al. where the authors state that the difference in race and sex was not observed [15]. In a study
published in 2015 by Natarajan et al., the authors noted that CDI rates in short-term monitoring were 5 times
higher in women with non-toxic C. difficile strain compared to women without C. difficile. The HR (hazard
ratio)=5.13 (95% CI:1.47-17.83) and the comparative HR for men was HR=0.44 (95% CI:0.04-4.43). Long-term
monitoring, however, produced a similar result for both men and women [16]. Antibiotics are known to be one
of the major risk factors for CDI (4), as confirmed in this study, in which 81.2% of patients previously used
antibiotics prior to CDI symptoms. Only 18.8% of them did not use antibiotics before the onset of symptoms,
including recurrent cases. The most abundant group of used antibiotics was from the β lactam antibiotic group,
46.9%. According to the WHO report on the control of antibiotic consumption in the world from 2016-2018, the
most commonly used oral form of antibiotic was amoxicillin, and the most commonly used parenteral antibiotic
was ceftriaxone, both from the group of β lactam antibiotics. Other antibiotics account for 34.3%, of which
45.5% were quinolone antibiotics and 18.2% sulphonamides. These findings are not surprising, because the
most frequently prescribed antibiotics really are β lactams [17]. Deshpanade et al. in a meta-analytical study
[18], investigating the effect of antibiotics on the emergence of community-associated CDI (CA-CDI). The
results showed that the greatest risk for developing CA-CDI has clindamycin, fluoroquinolones, and then
cephalosporins, where tetracyclines do not increase the risk for CDI [18]. It is also known that the duration of
therapy increases the risk of CDI. Since quinolones are the most common in the group of other antibiotics
(45.5%), data may suggest that there may be a link between the use of antibiotics, that have an increased risk of
developing CDI, and shortening the time of therapy needed to show symptoms of the disease. Although
different factors play a role here, above all C. difficile strains, comorbidities, immune system function, other
treatments in use, age, and the underlying disease that needed the use of antibiotics in the first place.

According to the IDSA/SHEA guideline from 2017, metronidazole is no longer the first choice when it comes to
treating CDI. Metronidazole is recommended only for mild/moderate first episodes or when vancomycin or
fidaxomicin are not available [12]. According to the results obtained in our study, out of the total number of
patients, metronidazole was used in 81.3% of the cases, in combination with vancomycin, in 15.6% of the cases,
and vancomycin alone was not used. It is concluded that the therapeutic protocol at the clinic does not match
with the IDSA/SHEA guideline from 2017. However, these are relatively new directions, and the data were
collected from the period 2011-2019, so it is understandable there is a discrepancy in therapeutic management.
The IDSA/SHEA guideline recommendations from 2010 indicate that metronidazole is the first choice for the
first mild or moderate CDI episode and the first recurrent episode, and vancomycin for the first severe CDI
episode. From this, it is concluded that the therapeutic protocol at the Infectious clinic of the Clinical center of
the University of Sarajevo was in correlation with the IDSA/SHEA guideline recommendations from 2010 [19].
Out of the total number of patients, only 3.1% did not require therapeutic treatment because they had an

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asymptomatic CDI form. It is interesting that in the group of patients using β lactam antibiotics, there was a
need for combined therapy in 20% of the cases, as opposed to the group receiving other antibiotics (9.1%).
By comparing disease outcomes by groups, our study shows that death was more common in the case of using β
lactam antibiotics (10%) compared to the group in which other antibiotics were used (4.5%). It is interesting to
mention that a recent study from 2020 by Goldstein et al [20] showed that there is a link between the use of
penicillin and the increase in mortality caused by sepsis in elderly people in the USA, as well as a link between
the use of cephalosporin and the sepsis mortality rate in the age group from 18-49, while no link was found for
those over 50 years of age. This study may partially support the result of mortality was higher in the group that
used β lactam antibiotics, but it definitely needs to be taken with a reserve because antibiotics are not the only
factor that determines the mortality outcome. Many other factors, such as age, comorbidities, drug utilization,
main illness, and the state of the immune system have a greater impact on the outcome of the disease.

V. CONCLUSION
Our study showed that pseudomembranous colitis developed in a small percentage of patients who did not use
antibiotics at all before the onset of symptoms. Patients undergoing antibiotic therapy had a slightly higher risk
of developing C. difficile pseudomembranous colitis with β-lactam antibiotics compared with some other
antibiotics.
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