diverticulitis Rx: amoxacillin/clavulanate

 A comparative effectiveness study sponsored by the NIH found that the combination amoxicillin/clavulanate was as effective as, and less onerous than, treatment with metronidazole/fluoroquinolone (see diverticulitis augmentin AIM2021 in dropbox, or doi:10.7326/M20-6315)

 

Details:

-- nationwide population claims-based data in the US for those 18-64yo with private employer-based insurance through the MarketScan database (from 2000-2018) and a 20% sample of Medicare claims for those 65 and older (2006-2015), for immunocompetent patients with acute diverticulitis in the outpatient setting

-- demographics, in brief:

    -- MarketScan: median age 52, major comorbidities: GERD 8%/arthritis 5%/obesity 4%, meds: antihypertensives 36%/statins 23%/NSAIDs 20%/PPIs 16%/SSRIs 12%, 96% without an inpatient admission in the past year. CT scans were done more commonly in the metronidazole/fluoroquinolone group (61% vs 49%)

    -- Medicare: median age 74, 92% white, comorbidities: arthritis 28%/GERD 26%/pulmonary vascular disease 16%/cerebrovascular disease 14%/COPD 12%/heart failure 11%, meds: antihypertensives 76%/statins 52%/PPIs 30%/anticoagulants 20%/antidiabetic drugs 19%/SSRIs 15%, 87% without an inpatient admission in the past year.  CT scans were done more commonly in the metronidazole/fluoroquinolone group (54% vs 40%)

-- MarketScan: 106,361 new users of metronidazole/fluoroquinolone (89%) and 13,160 of amoxicillin/clavulanate (11%)

-- Medicare: 17,639 new users of metronidazole/fluoroquinolone (87%) and 2709 of amoxicillin/clavulanate (13%)

-- covariates assessed include demographics (age at diagnosis, race though only available for Medicare), meds, medical comorbidities, and health care use (including outpatient visits in prior year, in-patient admission and CT imaging).

-- primary outcome: 1 year risk for inpatient admission, urgent surgery, and C. difficile infection; and 3-year risk for elective surgery

 

Results:

MarketScan data:

-- one-year hospitalization risk: risk difference of 0.1 percentage points (-0.3 to 0.6), nonsignificant difference

-- one-year urgent surgery risk: risk difference 0.0 percentage points (-0.1 to 0.1), nonsignificant difference

-- three-year elective surgery: risk difference of 0.2 percentage points (-0.3 to 0.7), nonsignificant difference

-- one year risk of C. difficile infection: risk difference of 0.0 (-0.1 to 0.1), nonsignificant difference

-- 1-yr weighted cumulative burden of diverticulitis-related ED visits: higher with metronidazole/fluoroquinolone (79.7/1000 patients) vs amoxicillin/clavulanate (74.2/1000 patients), though “the difference was imprecise and not statistically significant”. No difference in cumulative burden of outpatient or inpatient visits

 

Medicare data:

-- one-year hospitalization risk: risk difference of 0.1 percentage points (-0.7 to 0.9), nonsignificant difference

-- one-year urgent surgery risk: risk difference -0.2 percentage points (-0.6 to 0.1), nonsignificant difference

-- three-year elective surgery risk: risk difference -0.3 percentage points (-1.1 to 0.4), nonsignificant difference

-- one year risk of C. difficile infection: risk difference of 0.6 percentage points (0.2 to 1.0), was significantly higher for metronidazole/fluoroquinolone vs amoxicillin/clavulanate. The absolute number was 1.2% for metronidazole/fluoroquinolone vs 0.6% amoxicillin/clavulanate (ie, number-needed-to-harm by prescribing metronidazole/fluoroquinolone in those >65yo was 167)

-- 1-yr weighted cumulative burden of diverticulitis-related ED visits: higher with metronidazole/fluoroquinolone (61.8/1000 patients) vs amoxicillin/clavulanate (47.5/1000 patients), though “the difference was imprecise and not statistically significant”. Similarly for the cumulative burden of outpatient or inpatient visits

 

Commentary:

-- acute diverticulitis is common, 209 cases per 100,000 person-years

-- this study found minimal differences in outcomes with either therapy, though the milder antibiotic amoxicillin/clavulanate seems to have been associated with fewer cases of c. diff and a pretty strong trend to decrease in ED visits, and outpatient visits

-- the US FDA has advised that fluoroquinolones be used only in conditions with no alternative treatment options, leading to this study to see if the amoxicillin/clavulanate option was clinically equivalent

    --in particular, potential fluoroquinolone risks include hypoglycemia, adverse psych effects, peripheral neuropathy, aortic dissection, aneurysm, and adverse effects on tendons/muscles/joints/nerves with increased tendon ruptures.  both the fluroquinolones and amoxicillin/clavulanate are associated with drug-induced liver injury (amoxicillin/clavulanate with cholestasis, including jaundice, nausea, itching, and typically 1-6 weeks after starting it but can be weeks after stopping the med; fluoroquinolones with mild transient aminotransferase elevations and rarely with severe liver toxicity)

-- in this study they used propensity match scoring was used to mathematically equalize the cohorts per the coviariates that they assessed (for a blog questioning the validity of propensity scoring, see http://gmodestmedblogs.blogspot.com/2020/03/tramadol-fo-oa-inc-mortalityprobs-with.html )

 

--of some note, the formal name of C diff infection has changed from Clostridium difficile to Clostridioides difficile (which is much more difficile to pronounce). But at least those busy infectious disease renamers (who probably have just too much time on their hands) still allow us mere mortals to use the same abbreviation of C diff both verbally and in written form

 

Limitations:

--data-mining study based on billing claims. Not always so accurate overall, and especially for important potential confounders, such as diet (eg, eating high red meat or low fiber diets tends to decrease intestinal transport and increase intraluminal pressures, predisposing people to diverticulosis). Other associations with increased diverticulitis risk are with smoking, high BMI,  and lack of physical exercise,. None of these are part of the analysis above.

-- as a billing-based study we have no patient-level data on whether the meds were actually taken, just pharmacy billing receipts. Perhaps those on metronidazole/fluoroquinolones had higher adverse events (esp GI) and patients did not take the antibiotics as often (??leading to more ED visits)

-- likely that the adverse effects of the meds are under-reported, especially since this was for outpatient treatment (and, who has time to report the more minor but important adverse effects??: we mostly just alter the therapy without formal reports, and move on to the next patient in the waiting room)

-- there may have been undocumented differences in the treatment regimens chosen by outpatient clinicians: perhaps those patients with more severe cases were on the metronidazole/fluoroquinolone therapy, and this led to more ED visits, etc. Or some other potential confounder as in the first point above... (hard to know without a randomized controlled trial)

    -- eg, only 40-60% of patients had CTs done, raising a couple of issues:

          --they were done more often in the metronidazole/fluoroquinolone group than amoxicillin/clavulanate:  ??does this reflect higher disease severity in the former??

          --?? was the diagnosis of “acute diverticulitis” accurate in the large % of the cohorts without the CT done?? And, again, the amoxicillin/clavulanate group may have had more misdiagnosed diverticulitis in their group (since they had fewer CT scans done), perhaps distorting their results

 so,

--though the risk of any of the measured outcomes was quite low, and the difference was basically non-significant for both the short-term and longer-term outcomes:

    --the metronidazole/fluoroquinolone combo was much more frequently prescribed

    --there was a significant (though small) increase in C difficile infections with the former (and this can be pretty miserable, recurrent, and hard to treat). In this study the increase in C diff was limited to the >65yo group

--so probably does make sense to prescribe amoxicillin/clavulanate to outpatients with likely acute diverticulitis, with close followup

  

--I must admit that my teaching was to use the fluoroquinolone/metronidazole combo for diverticulitis (hit it hard/cover all bases), though I would always cringe prescribing the ciprofloxacin (as would my microbiome). This study makes both of us happier….

for a blog on antibiotic overprescribing, with reference to many other blogs on antibiotic resistance, microbiome changes, not necessarily taking the full 10-day course of antibiotics, some hopeful prescribing changes of late, etc, see http://gmodestmedblogs.blogspot.com/2019/01/antibiotic-overprescribing-2-more.html  

geoff

 

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