Common Antibiotics for Diverticulitis Have Higher C difficile Risks

David A. Johnson, MD


February 25, 2021

This transcript has been edited for clarity.

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.

Diverticulitis has been the subject of a number of recent guidelines [1,2,3] and evidence-based best practice recommendations from the American Gastroenterological Association. There's a consensus that antibiotics should be reserved for patients who really need them, and their routine use in uncomplicated diverticulitis is no longer recommended.

Antibiotics should be considered for patients considered high risk, meaning those who are immunocompromised; have increased C-reactive protein values (> 140 mg/L) or white blood cell count (> 15,000); have evidence on a CT scan of long segment involvement (≥ 6.5 cm); have pericolonic diverticular-related fluid collection, abscess, or perforation; or who have had symptoms for more than 5 days and are not responding to conservative treatment.

Outside of such patients with a clear need, the recommendation is to put a hold on antibiotics, as the evidence tells us that we're really overutilizing them.

But what antibiotics should we use in cases where they're necessary? A number of studies have suggested that a variety of antibiotic therapies, including quinolones, aminoglycosides, cephalosporins, and penicillin-derivatives, are quite comparable. These studies have looked at a variety of outcomes related to treatment, but none of them have really evaluated adverse events.

A Much Needed Analysis

Thankfully, a very meaningful and impactful study from investigators at the University of North Carolina has just been published, which evaluates the harms of antibiotics.

They looked at two data sources. The first was the IBM MarketScan Commercial Claims and Encounters Database, which features private insurance–related longitudinal data for patients over approximately two decades. In the second, they compiled a 20% random sample of Medicare claims from a database consisting of Parts A (hospital), B (medical), and D (prescription drug).

The investigators did a brilliant job of stratifying for risks and adjusting for potential biases with these two cohorts. The median age was 52 years old in the MarketScan cohort and 73 years old in the Medicare cohort. Given that Medicare includes patients aged 65 years and older, this provided an older, more complicated population.

The study's primary outcomes included 1-year risks for inpatient admission for diverticulitis, urgent surgery, and Clostridioides difficile infection.

Some studies have suggested that fluoroquinolones are the most common cause of C difficile infection. In this study, the investigators compared the use of amoxicillin-clavulanate with the standard fluoroquinolones — which are typically ciprofloxacin and perhaps less commonly levofloxacin — plus metronidazole to cover anaerobes.

Interestingly, the rate of use of fluoroquinolones with metronidazole was about eight times greater than amoxicillin-clavulanate. Over the past two decades in particular, that number has increased where the relative prevalence of fluoroquinolones with metronidazole is approximately 90%. When you think about how you've treated diverticulitis, you've probably adopted fluoroquinolones with metronidazole as an almost standard procedure.

Investigators determined that there were no differences in the 1-year risk for hospitalization or need for emergency surgery. Trend analyses suggested that in the Medicare cohort, the fluoroquinolones-with-metronidazole group actually had a higher rate of readmission and lower rate of urgent surgery, but the authors said the analysis was imprecise and therefore lacked statistical difference.

A Troubling Trend for C difficile Infection

There was one exception to this. In the Medicare group, the rate of C difficile infection was significantly higher in the fluoroquinolones-with-metronidazole group compared with the amoxicillin-clavulanate group (1.2% vs 0.6%, respectively). This 0.6% higher risk means that the number needed to harm for C difficile as it relates to this particular approach was 167. Therefore, one patient out of 167 treated with fluoroquinolones with metronidazole would develop C difficile compared with if they had received amoxicillin-clavulanate.

C difficile is one of the leading causes of hospitalization, and of nosocomial infection in particular. It leads to approximately 30,000 related deaths in the United States. Once you develop a C difficile infection, your relative risk for recurrence is about 20%, with that relative risk going up each time recurrence happens. When it comes to the 30-day mortality associated with C difficile, the numbers are generally around 6%-7%. But some studies looking at more complicated patients based on age, comorbid diseases, and repetitive events indicate that these numbers may approach 30%. Therefore, C difficile is a major issue as it relates to potential prevention.

The US Food and Drug Administration recommended that fluoroquinolones be reserved only for cases where there were no other viable antibiotics, given the considerable risks they pose. Many of us may think about fluoroquinolones and tendon rupture, but in fact there's a significant potential association with hypoglycemia, mental status–related complications, and vascular anomalies, including dissection and aneurysm. With metronidazole, you obviously have neuropathy, which is associated with fluoroquinolones alone as well. Amoxicillin-clavulanate is associated with diarrhea and a variety of reactions related to penicillin.

Please keep in mind that this study did not assess drug-related injury, which is something that's possible with all three of the treatments.

Takeaway Lessons

This study tells us that if you reach for the standard treatment of fluoroquinolone with metronidazole, which is eight times more common in this country than amoxicillin-clavulanate, we're taking a potentially significant risk in the Medicare population, particularly as it relates to C difficile. Again, the number needed to harm is 167 patients. Once someone experiences a C difficile infection, it opens up the possibility of repetitive infections.

This study looks at the efficacy difference for the first time and shows it to be essentially balanced between these two antibiotic approaches. But the incidence of harm is dramatically different as it relates to fluoroquinolone with metronidazole in the Medicare population.

Diverticulitis is incredibly common and something we treat all the time. When you have a Medicare patient, or even a patient who has certain complications, you need to start thinking about alternatives. This study really rings a bell that we can do better.

I'm Dr David Johnson. Thanks again for listening. We'll see you next time.

David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.

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