penicillin allergy increased MRSA and c diff

​A population-based cohort study found that patients labeled as penicillin allergic had an increased risk of both methicillin-resistant Staphylococcal aureus and Clostridium difficile (seepenicillin allergy inc mrsa c diff bmj2018 in dropbox, or doi: 10.1136/bmj.k2400​).

Details:
-- 11.1 million patients in The Health Improvement Network (THIN), an electronic medical record database of the population-based cohort in the UK of general practices, with information both of drug allergies as well as drug prescriptions
-- 64,141 patients had documented penicillin allergy (of whom 74% really had documented penicillin allergy, 15% intolerance, 11% adverse effects) were compared to 237,258 matched comparators.
-- 86% of allergies were considered to be moderate severity (6% severe or very severe), and 74% were considered to have likely certainty of allergy
-- penicillin-allergic patients were similar to comparators for age, sex, BMI, socioeconomic status, smoking status, and alcohol use.
-- Comorbidities were also similar: diabetes, renal disease, hemodialysis, malignancy, liver disease, HIV, Charlson comorbidity Index, previous antibiotic prescriptions, use of PPIs and systemic steroids, nursing home residency, visits to a GP, and hospital admissions [all of these medical comorbidities were less than 9% of each group; PPIs were in 25%, systemic steroids in 33%]
-- other antibiotic allergies were also more common in those with a stated penicillin allergy
-- follow-up 6.0 years
-- development of methicillin-resistant Staphylococcus aureus (MRSA) and C. difficile (CD) was compared between those with and without documented penicillin allergy

Results:
-- MRSA:
    --442 patients with penicillin allergy vs 923 comparator patients
    -- patients matched for age, sex, entry study time and the multivariate adjusted hazard ratio (includes above comorbidities and number of antibiotic prescriptions): 69% increase of MRSA, HR 1.69 (1.51-1.90)
    -- adjusted risk difference: 49/100,000 person-years
-- CD: 442 patients with penicillin allergy and 1246 comparators
    -- patients matched for age, sex, entry study time and the multivariate adjusted hazard ratio, as above: 26% increase of CD, HR 1.26 (1.12-1.40)
    -- adjusted risk difference: 27/100,000 person-years
-- those with penicillin allergy had:
    -- fewer prescriptions for penicillin, adjusted incident rate ratio 0.30 (0.30-0.31)
    -- four-fold prescriptions for macrolide antibiotics, adjusted IRR 4.15 (4.12-4.17)
    -- two-fold prescriptions for fluoroquinolones, adjusted IRR 2.10 (2.08-2.13)
    -- 26% increased sulfonamide antibiotics, adjusted IRR 1.26 (1.25-1.27)
    -- vancomycin, aminoglycosides, and linezolid were also prescribed more often, but infrequently
-- by antibiotic class that patients received, adjusted risk ratio (ARR):
    -- macrolide antibiotics: 72% increased risk of MRSA, ARR 1.72 (1.54-1.91), and 30% increased risk for CD, ARR 1.30 (1.18-1.43)
    -- clindamycin: threefold risk for MRSA, ARR 2.97 (2.11-4.16), and for CD, ARR 2.76 (2.00-3.81)
    -- fluoroquinolones: twice the risk of MRSA, ARR 2.38 (2.12-2.67), and of CD, ARR 1.72 (1.54-1.93)
-- more than half of the increased MRSA risk and more than one third of the increased CD risk in patients with penicillin allergy was attributable to beta-lactam alternative antibiotics

Commentary:
-- overall, 1/3 of patients report some drug allergy, most commonly to penicillins, documented in 5 to 16% of patients.
-- Studies suggest that about 95% of patients with reported penicillin allergy are in fact penicillin-tolerant.
-- 80% of patients with immediate hypersensitivity to penicillin are no longer allergic 10 years later (many with true penicillin allergy do outgrow the allergy over time)
-- <0.1% of patients with penicillin allergy undergo confirmatory allergy testing. Yet, over 90% can be safely treated with penicillin
-- however, the label of penicillin allergic typically leads to prescribing broader spectrum antibiotics with their attendant effects on development of antibiotic resistance, as found in this study

-- this study does confirm the results of other studies showing that "penicillin allergy" in outpatient care was strongly associated with the development of MRSA, CD, vancomycin-resistant Enterococcus, etc

-- C. difficile infections are particularly onerous: more than one half million infections and 15,000 deaths each year in the US. It is important to emphasize that 1/3 of C. difficile infections are community-acquired (as inthe above study), where overuse of broad-spectrum antibiotics is quite common

-- the presumed mechanisms of action include the increased devastation of the microbiome, particularly by broad-spectrum antibiotics.

-- relevant prior blogs:

    -- antibiotic overprescribing:  http://gmodestmedblogs.blogspot.com/2016/01/antibiotic-overprescribing-and-acute.html and http://gmodestmedblogs.blogspot.com/2015/07/antibiotic-overprescribing.html/ documents that the vast majority of outpatient antibiotic prescriptions are inappropriate; and http://gmodestmedblogs.blogspot.com/search?q=antibiotics+skin+abscess  a study finding that 80+% of people with abscesses get better without antibiotics

    -- penicillin allergy: http://gmodestmedblogs.blogspot.com/2013/09/penicillin-skin-testing_11.html  presents data that in 146 patients with history of IgE-mediated penicillin allergy, who on intradermal testing and (if negative) had test doses of penicillin, only 1 actually had a positive skin test and the remaining 145 did fine with the test dose; http://gmodestmedblogs.blogspot.com/2017/03/penicillin-allergy.html/ a study using a computerized guideline-based management app in inpatients with "penicillin allergy", found an 80% increased odds of getting penicillin or cephalosporin, though this paled in comparison to the almost 6-fold increase in those who actually had a skin test done (a small group, but none were allergic)

    -- and, of course, the microbiome: an array of prior blogs on the effect of antibiotics on the microbiome (see http://gmodestmedblogs.blogspot.com/search?q=microbiome+and+antibiotics​ )

so, this study adds to the pretty substantial argument that

    -- "penicillin allergy" is really common and leads to use of much broader-spectrum, microbiome-toxic antibiotics, creating an array of problems including antibiotic resistance and overgrowth of invasive species

    -- the vast, vast majority of those labeled as "allergic", even if they had IgE-mediated allergy in the past, do just fine with penicillin

    -- it probably does make sense to do pretty routine formal penicillin allergy testing, thereby allowing the use of penicillin in some infections which really do need this drug (eg syphilis), as well as for specific infections which can be treated with penicillin (and in the long-run, this is undoubtedly a cost-effective and socially-responsible strategy)

geoff​

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