Colitis, antibiotic-associated A04.7

The causative agent of antibiotic-associated colitis was first described as C. difficile by Bartlett et al. in 1977 (Bartlett 1977).

Antibiotic-associated colitis (AAC) is a gastrointestinal complication following the administration of antibiotics - regardless of the dosage form (Braun 2022) (Akanbi 2017).

Uncomplicated course:

The most common course of AAC is uncomplicated. After discontinuation of the antibiotic, the diarrhea resolves on its own (Braun 2022).

Severe course of CDI:

A severe course is when at least one of the following criteria applies:

• Leukocytosis > 15 x 10^9 / L
• Fever > 38.5° C
• Increase in serum creatinine to > 50 % of the initial value (Manthey 2023)

Complicated (fulminant) CDI:

This is characterized by at least one of the following criteria<.

• Septic shock
• Hypotension with a systolic pressure of < 100 mm Hg
• Ileus
• Lactate in serum ≥ 20 mg / dl
• Perforation
• Fulminant disease dynamics
• Toxic megacolon (Manthey 2023)

The incidence of antibiotic-associated colitis has increased significantly worldwide since the 1990s (Loeschke 1999). C. difficile infection (CDI) is now the most common pathogen-related cause of nosocomial diarrhea (Manthey 2023).

Approx. 1/3 d. F. in the outpatient sector and 2/3 in the inpatient hospital sector, old people's homes and nursing homes (Herold 2023).

AAC is the most common complication of antibiotic therapy with an incidence of between 5 - 35 % (Storr 2021).

However, C. difficile is part of the normal intestinal flora in approx. 80 % of all infants and 1 - 3 % of all adults; only hypervirulent strains such as NAP1 / BI / 027 cause severe courses of the disease (Herold 2023).

Antibiotic-associated colitis can occur up to 3 months after antibiotic treatment. Risk factors are also:

• Age > 65 years
• Severe underlying diseases
• Immunosuppression
• Chronic inflammatory bowel disease (CED)
• Taking proton pump inhibitors (by inhibiting gastric acid production)
• Abdominal surgical interventions (Herold 2023)
• C. difficile infection (CDI) in the last 12 months
• Condition after organ or stem cell transplantation
• Chronic internal comorbidities
• Hospitalization or hospitalization within the last 3 months
• Accommodation in community facilities of the healthcare system (Manthey 2023)

The choice of antibiotic plays a major role in the occurrence of community-acquired AAC (Manthey 2023). Antibiotics with anaerobic activity and high biliary excretion are particularly affected (Fuessle 2002). Two meta-analyses have shown that these include the following antibiotics in particular:

• 1. clindamycin (odds ratio 16.8 - 20.4)
• 2. fluoroquinolones(QR 5.5 - 5.7)
• 3. cephalosporins (QR 4.5 - 5.7)
• 4. penicillin derivatives (QR 2.7 - 3.3)
• 5. macrolides (QR 2.5 - 2.7)
• 6. cotrimoxazole (QR 1.8)

(Manthey 2023)

The disease is mainly caused by toxins of the anaerobic, spore-forming rod Clostridioides difficile, formerly known as Clostridium difficile. Clostridioides difficile is the most common pathogen causing nosocomial diarrhea (Herold 2023). However, cases have also been described where AAC was caused by Klebsiella oxytoca. This usually results in hemorrhagic diarrhea and is referred to as AAHC, i.e. antibiotic-associated hemorrhagic colitis (Akanbi 2017).

The administration of antibiotics leads to a change in the physiological intestinal flora in which C. difficile can colonize. The organism secretes an enterotoxin and a cytotoxin, which are usually referred to as toxin A and toxin B respectively (Bush 2023). The two toxins are clinically indistinguishable (Braun 2022).

The toxins lead to increased fluid secretion predominantly in the colon and the pseudomembranes typical of the disease develop. These are discrete white plaques that can confluent in severe cases (Bush 2023).

On the other hand, there are also asymptomatic carriers of toxin-producing strains. On the other hand, not all strains of C. difficile produce toxins (Bush 2023).

The clinical picture is characterized by sudden changes in stool consistency and frequency (Manthey 2023).

The diarrhea can be light, with semi-solid stools or liquid with blood admixtures. There may be abdominal pain. Nausea and vomiting are rare (Bush 2023).

Signs of exsiccosis may include:

• hypotension
• Tachycardia
• Standing skin folds
• Renal dysfunction up to oliguria
• Impaired consciousness
• Rhabdomyolysis (Manthey 2023).

If AAC is suspected, a mushy, liquid stool sample should be examined microbiologically at an early stage. A diagnosis from formed stool is not indicated (Manthey 2023).

The severity of the disease can be assessed with the following imaging parameters:

Transabdominal sonography

Particular attention should be paid to dilated intestinal loops, lymph node enlargement, free fluid and intestinal peristalsis (Manthey 2023).

Abdominal computed tomography

Particular attention should be paid to signs of perforation, peritonitis and extraintestinal metastases (Manthey 2023).

In Germany, the immunological detection of glutamate dehydrogenase (GDH) in stool is generally used as a sensitive screening test (Manthey 2023). However, all C. difficile strains - even non-toxic ones - produce glutamate dehydrogenase (GDH) antigen (Bush 2023).

Alternatively, the toxin gene can also be detected using a nucleic acid amplification test, the so-called NAT (Manthey 2023), although this is more expensive.

Direct immunological detection of toxins A and B is required to detect the toxins themselves. This confirms the diagnosis (Manthey 2023).

In the presence of a positive GDH but negative toxin detection, clarification can be obtained by toxigenic culture (Manthey 2023).

In order to assess the severity of the disease, the following laboratory parameters should also be determined:

• Blood count including differential blood count
• C-reactive protein
• Retention values
• electrolytes
• Acid-base balance
• Procalcitonin
• In case of fever: blood cultures (Manthey 2023)

Reproduction is exclusively anaerobic. Cultivation is therefore difficult. Spore formation results in increased resistance to environmental influences (Herold 2023).

The most important differential diagnoses for IBD are:

• Diverticulitis
• Diverticular-associated colitis
• Irritable bowel syndrome
• celiac disease
• NSAID enteritis and colitis
• Chlamydia-associated proctitis
• Autoimmune enteropathy
• Infectious enteritis
• Ischemic colitis (Wiestler 2020)

• Gangrenous colon
• Colonic perforation (Farooq 2015)
• Megacolon (Manthey 2023)

Immediate discontinuation of both antibiotics - where medically justifiable - and any antimicrobial agents remains the cornerstone of treatment (Dinleyici 2019).

As pseudomembranous colitis is an infectious disease, patients should be isolated immediately (Braun 2022).

Motility inhibitors and proton pump inhibitors should be avoided immediately (Manthey 2023).

If the clinical picture is mild in patients without other risk factors, the spontaneous course after discontinuation of antibiotics can be awaited under close clinical observation. In all other cases, specific therapy should be started immediately. According to the guideline, the suggested primary therapy is:

- Fidaxomicin 2 x 200 mg / day p.o. for 10 days (preferred first-line therapy)

or

- Vancomycin 4 x 125 mg / day p.o. for 10 days (Manthey 2023)

If the clinical picture is mild and there are no other risk factors, treatment with metronidazole 3 x 400 mg / day p.o. can be considered. Metronidazole, together with vancomycin, was the gold standard of therapy for decades. However, several studies have now shown that metronidazole has a significantly reduced treatment response compared to vancomycin (Manthey 2023).

Adequate fluid and electrolyte replacement is also important (Manthey 2023).

Fecal microbiome transfer:

Another form of treatment is fecal microbiota transplantation (Dinleyici 2019).

Fecal microbiome transfer has proven to be more effective than drug therapies. Internationally, this is recommended from the second recurrence onwards. In Germany, however, this is difficult to implement for medical law reasons (Lange 2022).

The additional administration of probiotics (in particular Saccharomyces boulardii) has proven effective in treatment (Dinleyici 2019).

The mortality rate of CDI is still very high at 20 % (Manthey 2023).

The course of ribotypes 014 and 020 is predominantly relatively mild. Ribotype 027 and the toxin-producing ribotypes 017 and 078 generally have a relatively dangerous course (Herold 2023).

The 30-day mortality rate of a nosocomial Clostridioides difficile infection (CDI) is between 3 - 30 %, depending on additional risk factors (Herold 2023).

Recurrences occur in around 20 % of patients after initial treatment with metronidazole or vancomycin. Treatment with fidaxomicin was able to reduce the recurrence rate by approx. 50 % (Manthey 2023).

The use of probiotics, such as Saccharomyces boulardii in particular, is an effective preventative measure (Dinleyici 2019).

CDI becomes notifiable in the event of a severe course, which is defined as:

• Need for inpatient treatment of community-acquired CDI
• Need for surgical intervention in the context of a CDI, e.g. megacolon, colectomy, refractory colitis, perforation
• Need for treatment in an intensive care unit due to CDI itself or its complications
• Death as a direct cause of death from CDI within 30 days of diagnosis or CDI as a condition contributing to death (Manthey 2023).

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