Introduction
Clostridioides difficile is an anaerobic bacterium responsible for most of the diarrheal cases in Europe and
North America.[1 ] This toxigenic bacterium is estimated to have a 30-day mortality rate of 5.8% and
an annual infection rate exceeding half a million.[1 ]
[2 ] The incidence as well as severity of C. difficile infection (CDI) have significantly increased in the past two decades, making it the
most common nosocomial infection.[1 ]
[2 ] The most common cause of its infection is using antibiotics such as cephalosporins,
clindamycin, penicillin, etc.[1 ]
[3 ] Apart from this, chronic kidney disease, chronic liver illness, malnutrition, previous
infection with C. difficile , and use of proton-pump inhibitors are some of the etiological factors.[1 ]
[3 ]
[4 ]
Antibiotic-associated CDI typically presents as acute watery diarrhea in more than
20% of patients.[1 ]
[3 ] In advanced cases, complications such as fulminant colitis, sepsis, and toxic megacolon
may occur, often with the formation of pseudomembranes in the intestine.[1 ] In rare instances, protein-losing enteropathy and reactive arthritis have been reported
as complications.[1 ] Laboratory diagnostic methods include cytotoxic assay, enzyme-linked immunoassay
(EIA), nucleic acid amplification test (NAAT), and toxigenic culture specific to C. difficile toxigenic strains. However, in some cases, despite negative test results for the
bacterium, patients exhibit clinical symptoms resembling CDI.[1 ] Such patients need advanced investigations such as computed tomography (CT), colonoscopy,
and magnetic resonance imaging to confirm the presence of active C. difficile colitis.
In the present case, we report a similar patient with postoperative septic shock with
negative laboratory investigations for C. difficile but pseudomembranous colitis on colonoscopy. Though such cases are uncommon, they
highlight the complexity of antibiotic-associated diarrhea (AAD), especially in elderly
patients with multiple comorbidities. The screening investigations should be supplemented
by a thorough clinical examination, with CDI considered as a differential diagnosis.
Case Report
An 88-year-old female was transferred to a tertiary care facility on May 11, 2024,
from an outside hospital for further management following a postoperative septic shock.
She had undergone left distal femur plating under spinal anesthesia on May 9, 2024,
after a fall at her home 2 weeks earlier, which resulted in a left distal femur periprosthetic
fracture. In the immediate postoperative period, she developed high-grade fever, hypotension
requiring vasopressor support, sweating, and dizziness. After transferring to the
intensive care unit (ICU), her laboratory parameters showed mild anemia, normal white
blood cell count with a neutrophilic predominance, elevated inflammatory markers,
and mild electrolyte imbalance. Low procalcitonin indicated an absence of severe systemic
bacterial infection ([Table 1 ]). Mildly elevated cardiac markers suggested myocardial stress likely secondary to
hypotension rather than acute coronary syndrome, given normal serial cardiac enzymes
and no fresh electrocardiogram (ECG) changes.
Table 1
Investigations table
15/05
16/05
17/05
18/05
19/05
20/05
21/05
22/05
23/05
24/05
25/05
27/05
Hemoglobin (g/dL)
9.7
10.6
9.1
8.6
8.7
8.6
8.4
7.8
10.3
10.6
11
11
Leukocytes count (×103 )
6.92
12.9
5.93
10
13
14
91
0
8
8
9
9
CRP
8.9
203
240
249
139
85.5
136
162
84.7
54.8
17.9
PCT
1.65
0.49
0.176
0.173
Sodium
134
135
133
131
135
133
131
136
138
136
132
133
Potassium
3.74
5.07
3.96
4.74
3.87
4.39
3.41
3.77
4.10
4.12
3.93
3.88
Creatinine
0.58
0.87
0.62
0.51
0.46
0.51
0.50
C. difficile testing
GE PCR panel negative
C. difficile toxin (real-time RT-PCR CB-NAAT) - not detected
C. difficile toxin (real-time RT-PCR CB-NAAT) - not detected
EGD scopy and colonoscopy
Abbreviations: CB-NAAT, cartridge-based nucleic acid amplification test; CRP, C-reactive
protein; EGD, esophagogastroduodenoscopy; PCT, procalcitonin; RT-PCR, reverse transcription
polymerase chain reaction.
She had background of ischemic heart disease (status post-percutaneous transluminal
coronary angioplasty in 2016) with an ejection fraction (EF) of 40%, hypothyroidism,
trigeminal neuralgia, bilateral total knee replacement, and cataract excision. Initial
investigations showed a right bundle branch block and new anteroseptal T-wave inversion
in anterior leads on ECG, though serial cardiac enzymes were normal. A two-dimensional
echocardiogram indicated no change with an EF of 40% and no right ventricular dysfunction.
Laboratory results revealed a drop in hemoglobin, leukocytosis, and elevated inflammatory
markers. She was started on intravenous meropenem and teicoplanin and received one
unit of packed cell volume along with intravenous iron supplementation (ferric carboxymaltose).
She was shifted back to ward on hospital day 4.
On hospital day 5, the patient developed severe hypotension (blood pressure [BP]:
70/40 mm Hg), altered sensorium, and abdominal discomfort. She was resuscitated with
500 mL of crystalloid, improving her BP to 100/60 mm Hg, but she remained drowsy and
complained of persistent abdominal discomfort. She was subsequently transferred back
to the ICU for close monitoring and intravenous fluid management. Despite initial
stability, she experienced recurrent episodes of hypotension and severe lower abdominal
pain. Examination revealed hard, impacted stools, prompting manual evacuation, enema,
and administration of laxatives.
Further laboratory workup showed mild abnormalities. Imaging studies, including chest
X-ray and abdominal ultrasound, were unremarkable except for gaseous dilated bowel
loops. A CT scan of the abdomen and pelvis revealed fecal-loaded colonic loops with
a maximum diameter of 5.2 cm in the sigmoid colon and mild circumferential wall thickening
in the descending colon ([Fig. 1A ]).
Fig. 1 (A ) A computed tomography (CT) scan revealing thickened colon wall. (B ) Colonoscopy showing extensive pseudomembranous colitis in the rectum and sigmoid
colon.
The patient developed frequent watery, foul-smelling diarrhea, with up to 15 episodes
per day. A gastroenteritis polymerase chain reaction (PCR) panel (hospital day 7)
and C. difficile toxin assay (hospital day 8) were negative ([Table 1 ]). However, because of the high clinical suspicion of colitis, endoscopic evaluation
was performed. Esophagogastroduodenoscopy revealed a hiatus hernia and mottled erythematous
mucosa in the gastric body and antrum. A colonoscopy on hospital day 12 showed extensive
pseudomembranous colitis in the rectum and sigmoid colon with mucosal friability and
erythema ([Fig. 1B ]). A rectal biopsy confirmed pseudomembranous colitis. On histopathology of the rectum,
multiple greyish, friable tissue bits aggregated to 0.7 cm gross and intact to ulcerated
rectal mucosa were observed on microscopy ([Fig. 2 ]). The later was covered with acute inflammatory exudate. However, the lamina propria
showed moderately increased inflammatory infiltrate.
Fig. 2 A histopathology of the rectum showing acute inflammatory exudate.(A ) Crypt abscesses and acute inflammatory infilterates.(B ) Dense neutrophilic infilteration of lamina propria.
The patient was managed in isolation with contact precautions and barrier nursing.
Tablet vancomycin (250 mg four times a day), vancomycin retention enema, and injection
metronidazole (500 mg three times a day) were initiated. She showed clinical improvement
with reduced stool frequency and consistency, improved oral intake, and was gradually
mobilized. She was shifted out of ICU. However, on hospital day 22, she became drowsy
and was shifted back to the ICU. The evaluation showed hypoventilation secondary to
drowsiness (SpO2 92–93% on room air) and a urine routine revealing 50 to 55 pus cells/hpf. Urine culture
grew multidrug-resistant Klebsiella sensitive only to a combination of ceftazidime-avibactam and aztreonam. Hence, started
on these medications. Despite initial improvement, she developed increased stool frequency,
necessitating discontinuation of these antibiotics after 7 days.
Vancomycin was continued for 4 weeks, while metronidazole was given for 10 days. Repeat
endoscopy (on June 10, 2024) was done, which showed remarkable improvement and she
was shifted back to ward ([Fig. 3 ]). Patient's condition stabilized, with a reduced frequency of diarrhea and improved
oral intake, and she was discharged on hospital day 42.
Fig. 3 Repeat colonoscopy showing improvement in large intestine.
On periodic follow-up after her discharge, patient has been doing very well clinically
with improved oral intake.
Discussion
The current case presented the diagnostic and therapeutic challenges of management
of pseudomembranous colitis in an elderly patient following distal femur plating.
It underscored early recognition, diagnostic diligence, and judicious antibiotic use
in postoperative sepsis and AAD. Differential diagnosis could be AAD; noninfectious
osmotic diarrhea due to cathartic agents like laxative, milk, and magnesium salts;
chronic underlying condition—inflammatory bowel disease (IBD) and irritable bowel
syndrome; and infectious diarrhea caused by Salmonella/Shigella/Vibrio/amoeba. Each
condition may present with diarrhea, abdominal discomfort, and systemic signs of infection
or inflammation, making it crucial to evaluate the likelihood of each based on clinical
findings, diagnostic tests, and patient history.
The patient was on broad-spectrum antibiotics, which makes AAD a potential diagnosis.
However, her symptoms worsened with abdominal pain, fever, and a marked increase in
stool frequency, suggesting something more severe than AAD.[5 ]
C. difficile -associated diarrhea is a common cause of AAD, especially in elderly or immunocompromised
patients exposed to broad-spectrum antibiotics.[6 ] CDI typically manifests with watery, foul-smelling diarrhea, abdominal cramping,
fever, and leukocytosis.[6 ] In severe cases, it leads to pseudomembranous colitis, which was confirmed in this
patient through endoscopy and rectal biopsy. Osmotic diarrhea due to cathartic agents
(laxatives, milk, magnesium salts) occurs when substances in the intestine cause excess
water retention. Cathartic agents, including laxatives (given for impacted stools
in this case), milk, or magnesium salts, can lead to diarrhea by drawing water into
the gut lumen. The patient was treated with enemas, manual evacuation, and laxatives,
which could have temporarily contributed to her diarrhea.[7 ] The improvement of her symptoms after targeted antibiotic therapy (vancomycin and
metronidazole) further supports an infectious origin rather than osmotic diarrhea.
CDI is a significant cause of nosocomial diarrhea, particularly in patients with recent
antibiotic exposure, hospitalization, or advanced age. The pathogenesis of CDI involves
disruption of normal gut flora, colonization by C. difficile , and subsequent production of exotoxins—primarily toxins A and B. These toxins inactivate
Rho GTPases, leading to cytoskeletal disassembly, apoptosis of colonic epithelial
cells, and formation of pseudomembranes, a hallmark of severe colitis.[8 ]
[9 ]
Diagnosis of CDI should be considered in patients with unexplained, new-onset diarrhea
(≥ 3 unformed stools in 24 hours) and risk factors such as antibiotic use.[10 ] Only liquid stool should be submitted for testing, as formed stools from asymptomatic
individuals may reflect colonization rather than active infection and do not require
treatment.[10 ] A key limitation in diagnosis is that C. difficile toxins degrade rapidly at room temperature and may become undetectable within 2 hours.
Therefore, stool samples should be tested promptly or stored at 4°C if delays are
expected.[10 ]
Laboratory diagnosis begins with either a single or multistep algorithm. Glutamate
dehydrogenase (GDH) is a highly sensitive enzyme produced by both toxigenic and non-toxigenic
strains of C. difficile , making it a useful screening tool with high negative predictive value. However,
its lack of specificity necessitates further confirmatory testing.[11 ]
The most widely used confirmatory test is the EIA for toxins A and B. Though rapid
and widely available, EIAs have variable sensitivity (75–85%) and excellent specificity
(95–100%). Due to their limited sensitivity, EIAs alone may yield false-negative results,
particularly in low-toxin producing strains.[12 ]
[13 ]
To improve diagnostic accuracy, a two-step or three-step algorithm is recommended.
The initial GDH screening is followed by toxin testing, and in cases of discordant
results (e.g., GDH positive but toxin negative), a NAAT such as PCR is employed. NAAT
detects the toxin genes (TcdA, TcdB) with high sensitivity (80–100%) and specificity
(87–99%). However, since NAAT identifies the presence of genes rather than active
toxin production, it cannot distinguish between colonization and infection, potentially
leading to overdiagnosis.[14 ]
Stool culture, though considered a gold standard due to its high sensitivity, is time-consuming,
labor-intensive, and lacks clinical practicality. Similarly, the cell culture cytotoxicity
neutralization assay allows for direct detection of functional toxin activity and
is highly specific but is also resource-intensive and not routinely available in most
clinical settings.[10 ]
In complex cases—especially where noninfectious etiologies such as IBD are suspected,
or in the presence of atypical symptoms—further evaluation with colonoscopy may be
warranted. Colonoscopy is typically reserved for patients with persistent or severe
symptoms despite negative stool tests or when toxic megacolon or pseudomembranous
colitis is suspected. Endoscopic findings may reveal pseudomembranes, confirming the
diagnosis.[10 ]
In summary, timely diagnosis of CDI relies on a rational sequence of testing—starting
with GDH and toxin EIAs and, if needed, confirmed by NAAT. Test results should always
be interpreted in conjunction with clinical findings to guide appropriate management
and avoid overtreatment of asymptomatic carriers
In our institute, GDH testing is not available; hence, NAAT for C. difficile was performed directly. Despite testing the patient with a comprehensive gastroenteritis
PCR panel once and C. difficile -specific NAAT twice, all results were negative. Given the persistence of symptoms
and high clinical suspicion, we proceeded with colonoscopy, which provided crucial
diagnostic insights and guided further management.
In cases of AAD being unresponsive to initial management, a low threshold for endoscopic
evaluation should be maintained, as early diagnosis and targeted therapy can significantly
improve patient outcomes. Though a rarely reported case, it also reinforced the need
for strict antibiotic stewardship and infection control measures in high-risk populations.