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Primary Care Corner with Geoffrey Modest MD: Antibiotics, microbiome changes and colorectal adenoma

21 Apr, 17 | by gmodest

by Dr Geoffrey Modest

There been a few studies over the past suggesting a relationship between the gut microbiome and colorectal cancer, as well as between antibiotic exposure and colorectal cancer. An evaluation of the Nurses’ Health Study recently confirmed prospectively that there was a dose-response curve between women’s prior use of antibiotics and colorectal adenomas (see doi.org/10.1136/ gutjnl-2016-313413).

Details:

— 16,642 women aged at least 60 who had at least one colonoscopy between 2004 and 2010 and had reported their antibiotic use in a 2004 questionnaire, comparing antibiotic users versus nonusers

— mean age 70, family history of cancer in 20%, diabetes in 9%, BMI 25, hormone therapy 20%, regular use of aspirin in 40%, multivitamins in 78%, 20 pack-years of smoking in those who were ever-smokers, 2.3 g of alcohol per day, 6 servings of red meat per week.

Results:

— 1195 cases of adenomas were detected

— women who used antibiotics for more than 2 months between the ages of 20 and 39 had a 36% increased risk of adenomas by multivariate analysis, OR =1.36 (1.03-1.79)

— women who used antibiotics for more than 2 months between the ages of 40 and 59 had a 69% increased risk by multivariate analysis, OR = 1.69 (1.24 – 2.31)

— there was a trend between increasing antibiotic use at age 20-39 (p=0.002) and also at 40-59 (p=0.001), in each case with progressively more adenomas when increasing antibiotic use, from no use to 1-14 days, to 15 days-2 months, to >2 months.

— this association was similar for low risk versus high risk adenomas (high-risk being defined as size > 1 cm, with tubulovillous/villous histology, or > 2 detected lesions), though was slightly stronger for proximal lesions.

— there was no association between antibiotic use in the prior 4 years and risk of adenoma [ie, the microbiota were not influenced by recent antibiotic usage]

— women who used antibiotics for a longer duration were overall similar to those who did not in terms of family history, personal disease/screening history, and lifestyle factors, but were more likely to regularly use menopausal hormonal therapy, aspirin, and undergo colonoscopy for symptoms rather than routine screening.

Commentary:

–the Nurses’ Health Study is an ongoing prospective cohort study of 121,700 US female nurses aged 30 to 55 at enrollment in 1976. The advantage of looking at this cohort is the high quality of data collected (which had accurate data both on an array of lifestyle issues as well as medical problems/medications etc, as well as specifically on prior intermittent antibiotic use many years beforehand), and the long-term follow-up

— the presumed mechanism for a relationship between antibiotics and colorectal adenomas is through the effect of antibiotics on the microbiota. For unclear reasons antibiotics may induce either temporary, quasi-stable states, or alternative stable states. The specific microbiota changes associated with colon cancer include depletion of Bacteroides, Firmicutes (Clostridia), and Proteobacteria (Enterobacteriaceae) and enrichment of Fusobacteria.

— of course, though this was a really good prospective study following lots of items (a rather long questionnaire….), there could well be unaccounted-for differences between the antibiotic users and nonusers which could explain the microbiome differences as well as the increase in adenomas. The noted differences between these groups (eg, using postmenopausal hormones, aspirin, having nonscreening colonoscopies) were accounted for, but were there other issues? were there differences in psychosocial issues between the groups? were those on these meds and getting antibiotics more anxious or stressed out (and there is some evidence that increased cortisol levels, often found with stress, can effect changes in the microbiome)? Were these women on the above meds also taking other unassessed meds that could affect the microbiome and adenoma rate (and perhaps leading to the long-term changes in the microbiome)? As with all observational studies, one cannot attribute causality to an association.

–so, I bring this up mostly because this study has a great database, and long-term follow-up, and reinforces many of the articles brought up before regarding the effects of microbiota changes and human disease. And, it provides us with an even stronger imperative to try to decrease antibiotic use, except when clearly indicated. 

See here for an array of articles on the microbiome, including mechanism by which microbiota changes might lead to a variety of diseases including NAFLD, cancer, diabetes, metabolic syndrome, heart disease….  ​

See here for another array of articles, but dealing with the consequences of overuse of antibiotics in humans and livestock and microbial resistance

Primary Care Corner with Geoffrey Modest MD: Probiotics in c diff

9 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent systematic review with a meta-analysis looked at 19 published studies on the efficacy of probiotics in preventing C. difficile infections (CDI) in inpatients put on antibiotics, finding benefit if given close to the 1st dose of antibiotics (see 10.1053/j.gastro.2017.02.003).

Details:

  • 6261 subjects were involved in these 19 studies
  • The studies were done in the USA, UK, Turkey, Canada, Norway, China, Italy, and Germany. Several different probiotic formulations were used, most with Lactobacillus species. The daily dose of probiotics varied dramatically from 4 to 900 colony forming units, most started the probiotics within the 1st 2 days of beginning the antibiotics, duration of probiotics varied from 14 days to 14 days after completion of the antibiotic course, and the age varied from those greater than 18 up to age 80 (weighted average 68 years). Commonly excluded groups were those who were pregnant, immunocompromised, required intensive care, had pre-existing GI disorders. The hospitals’ baseline incidence of CDI range from 1.5 to 7.4%
  • Overall 4 probiotic species were studied: Lactobacillus, Saccharomyces, Bifidobacterium, and Streptococcus.

Results:

  • The overall incidence of CDI in the probiotic cohort was 1.6% (54/3277); in the control group it was 3.9% (115/2984), with p<0.001.
  • The pooled relative risk of CDI was decreased 58% with probiotics, RR 0.42 (0.30-.57)
  • The number needed to treat was 43 patients to prevent one case of CDI
  • Meta-regression analysis showed that there was a significant decline in probiotic efficacy for each day in delay of starting probiotics after the 1st dose of antibiotic, with an 18% decrease for every day the probiotics were delayed (p=0.04)
    • Probiotics given within the 1st 2 days of starting antibiotics had a 68% risk reduction of CDI, RR 0.32 (0.22-0.48) than starting later, where there was a 30% reduction, RR 0.70 (0.40-1.23)
  • No adverse events attributable to probiotics (in general adverse events tended to be less in the probiotic group)
  • Overall quality of the evidence was high. The magnitude of efficacy was the same when analysis was limited only to the high qualities trials

Commentary:

  • CDI incidence has increased dramatically in the past 10 years, more than doubling and costing $4.8 billion, with attendant morbidity and mortality (more than 29,000 deaths in 2011). The standard treatment has approximately 20% treatment failure and around half of the patients have recurrence, especially those who are older.
  • Certain probiotics seem to colonize the gut well, despite concurrent use of antibiotics: specifically Lactobacillus and Bifidobacterium.
  • To me it is difficult to assess with certainty their conclusions about timing, given the inconsistency of the approach to treatment (huge variability in types and doses of probiotics), as well as the fact that the vast majority of studies treated early, within the first 2 days or so. However, it does make intuitive sense that if we are to protect the gut with probiotics, that should be done early, especially before there is a large overgrowth of C. difficile
  • The best guess of the authors, though not definitive, was at the most efficacious probiotics were: Lactobacillus, and Lactobacillus in combination with either Streptococcus or both Streptococcus and Bifidobacterium
  • A review of the individual studies found that they all found benefit from the probiotics, though for some of the individual studies these did not reach statistical significance.
  • A cost-benefit analysis done in the UK suggested that using a Lactobacillus probiotic in hospitalized patients over 65 on antibiotics would lead to a cost savings of over $500 per patient. Another study in Canada also suggested cost savings.
  • So, though current guidelines, for example from the American College of Gastroenterology, do not recommend the use of probiotics for the primary prevention of CDI, this meta-analysis is pretty convincing that they work with no evident adverse effects. And, I would think, should be strongly considered in outpatients put on broad-spectrum antibiotics (e.g. Ciprofloxacin).

Prior blogs:

http://blogs.bmj.com/ebm/2014/12/03/primary-care-corner-with-geoffrey-modest-md-probiotics-in-irritable-bowel-syndrome/ is a blog on the efficacy of probiotics in irritable bowel syndrome

http://blogs.bmj.com/ebm/category/microbiome/ has a slew of blogs on the microbiome

http://blogs.bmj.com/ebm/category/clostridium-difficile/ has many blogs C. diff

and, http://blogs.bmj.com/ebm/category/antimicrobial-resistance/ has many on antimicrobial resistance

Primary Care Corner with Geoffrey Modest MD: Penicillin Allergy???

8 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A large concern in treating patients with infections is the very high prevalence of “penicillin allergy”, leading to the use of broad-spectrum antibiotics as well as 2nd or 3rd line medications, which are usually more toxic, along with their attendant effects on antimicrobial resistance as well as secondary infections such as C. difficile­­­­. A recent article looked at 2 methodologies to determine the safety of using beta-lactams in these “penicillin allergic” patients (see 10.1016/j.jaci.2017.02.005).

Details:

  • Of 1000 medicine in-patients with a noted penicillin allergy in a single Boston hospital, 625 were admitted with a presumed infection: mean age 66, 60% female, 70% white/16% black, reported penicillin allergy was rash or hives in 60%/angioedema 15%, anaphylaxis 8%
  • Patients were assessed during 3 different time periods: 148 patients in a standard-of-care group (SOC), 278 in a penicillin skin testing group (ST), and 199 in a group using a computerized guideline-based management app (APP) to predict real allergy
  • ST group: excluded patients with penicillin intolerance (such as GI upset), patients taking medications that might interfere with skin testing (such as antihistamines), and also patients with multiple beta-lactam allergies, penicillin anaphylaxis in the last 5 years, or type II-IV hypersensitivity reactions to penicillin
  • APP group: the clinical support basically divided people into low risk (benign delayed maculopapular rash); medium-to high-risk (urticaria, angioedema, anaphylaxis, recent or severe delayed maculopapular rash; and those who should avoid a beta-lactam (history of Stevens-Johnson syndrome, toxic epidermal necrolysis or exfoliative dermatitis; DRESS syndrome or acute interstitial nephritis; or serum sickness-like reaction)
  • Primary outcome was the actual use of penicillin or cephalosporin during the hospitalization

Results:

  • ST group: 179 (64%) were felt to be skin test eligible, but only 43 (24%) actually receive skin testing and none of those were allergic, defined as negative skin test and tolerance of an oral amoxicillin 250 mg test dose. As compared to the SOC group,
    • Nonsignificant 30% increased odds of use of penicillin or cephalosporin overall, adjusted OR 1.3 (0.8-2.0), but a highly-significant 5.7-fold increased use in a per protocol analysis, adjusted OR 5.7 (2.6-12.5), p<0.001 [the per protocol analysis limited the analysis to those few who actually got the skin test]
    • Of the ST per protocol patients, there was increased odds of penicillin or cephalosporin prescriptions for discharge treatment, with OR 2.5 (1.04-6.2)
  • APP group: 292 unique website views (averaging 26 seconds only), 112 users (38%) completed clinical decision support. Patients in the low or moderate-to-high risk groups as above were given test doses of beta-lactam antibiotics with an initial dose of 1/10 of an IV dose or 1/4 of an oral dose. The 2nddose was administered 30 minutes later, comprising the remainder of the therapeutic dose. Nurses assessed patients every 30 minutes for the duration of the challenge. As compared to the SOC group,
    • Significant 80% increased odds of use of penicillin or cephalosporin, adjusted OR 1.8 (1.1-2.9), p=0.03

Commentary:

  • Penicillin allergy is remarkably common, up to 15% of all inpatients are recorded as having a penicillin allergy, and 5-25% of inpatients who are treated for infections. Three quarters of patients with an alleged penicillin allergy would otherwise use a beta-lactam antibiotic in other studies, but in the SOC group only half of them received one.
  • Not using a beta-lactam antibiotic when that would otherwise be indicated leads to more treatment failures, adverse events, and antibiotic resistant organisms such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.
  • There were few patients who actually had skin testing, mostly because of difficulty in coordinating the testing for those felt to be eligible, which the authors note would have been different if they hired an on-site clinician for that purpose (some patients also refused skin testing).
  • Another concern about skin testing is that fewer than 15% of US hospitals have the appropriate reagent on formulary. The per protocol analysis of the ST arm may be open to bias (vs the intention-to-treat analysis looking at the overall group), however the low numbers of patients getting skin testing clearly biased the results to negative.
  • However, it is quite remarkable how much effect the pretty simple computerized guideline and decision support provided. It should, however, be pointed out that this was not a clean randomized-controlled trial, so there are potential inherent biases (including the possibility that there were different sensibilities and approaches to treating infections, perhaps related to the different time periods above, or proclivities of the ID departments, ward attendings, residents, etc.)
  • These results parallel those in a prior blog regarding skin testing. See http://blogs.bmj.com/ebm/2013/09/12/primary-care-corner-with-geoffrey-modest-md-most-with-pcn-allergy-will-test-negative-for-it-and-can-be-given-pcn-safely/which found that of 146 patients with history suggestive of IgE-mediated penicillin allergy (but excluding those with history of anaphylaxis), only one patient had a positive skin test, and the remaining 145 did fine with oral penicillin. Of note, as opposed to the prior blog, those with Type I (IgE- mediated) hypersensitivity reactions were excluded from the above study.
  • Why is “penicillin allergy” so rampant?? as a singular anecdote, 25 years ago one of my children had otitis media in the middle of the night when he was less than a year old, and as a really tired parent I decided to watch him instead of getting antibiotic treatment (he wasn’t really very sick appearing, and at that point in Europe most otitis media was not being treated with antibiotics), he remained relatively stable for the next day or 2, then developed a maculopapular rash. If he had been given a beta-lactam antibiotic, he would have been labeled as penicillin allergic perhaps for the rest of his life. I do realize that there are negatives to treating family members, however my tiredness won out….
  • So, what does this all mean? The combination of the current and prior blog strongly suggest that true penicillin allergy is really quite unusual (the number quoted is <5% of those with listed penicillin allergy). And the ability to use beta-lactams for common outpatient (and inpatient) infections is really useful, especially as we are trying so hard to protect our microbiome and decrease resistance. [And, by the way, adverse reactions, need for hospitalization, costs…]. It would be really great to have a large study looking at the computer-assisted app to see the real incidence of bad allergic reactions to beta-lactams in each of the low and moderate-to-high risk groups, with an eye to using beta-lactams, perhaps initially in a monitored setting (depending on the actual incidence of severe reactions in these cohorts in subsequent studies).

Primary Care Corner with Geoffrey Modest MD: Fluoroquinolone Warning

16 Dec, 16 | by EBM

By Dr. Geoffrey Modest

There was another FDA warning recently, this time regarding systemic fluoroquinolones (ciprofloxacin, levofloxacin, etc.), leading to a boxed warning, the FDA’s strongest warning (see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm500665.htm for the summary, and http://www.fda.gov/Drugs/DrugSafety/ucm511530.htm for the full report).

Details:

  • Fluoroquinolones are associated with disabling and potentially permanent adverse effects on tendons (tendinitis, tendon rupture), muscles (muscle weakness or pain), joints (joint pain or swelling), peripheral nerves (peripheral neuropathy), and the central nervous system (anxiety, depression, hallucinations, suicidal thoughts, psychosis, confusion). Other adverse effects include worsening of myasthenia gravis, skin rash, sunburn (photosensitivity/phototoxicity), irregular heartbeat (including prolonged QT interval), severe diarrhea (they are the leading cause of Clostridium difficile-associated diarrhea). Multiple problems can occur in the same patient. The peripheral neuropathy may be irreversible.
  • Therefore, fluoroquinolones should only be used in patients where no other treatment options are available for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections. Also for serious bacterial infections where the benefits outweigh the risks.
  • The prior warnings for tendinitis, tendon rupture, and worsening of myasthenia gravis has been extended by the above problems.
  • Side effects may occur within hours to weeks after starting the fluoroquinolone and continue an average of 14 months to as long as nine years after stopping the medicines. (Though, as noted, some may be irreversible)
  • The majority (74%) of reported cases were in patients 30 to 59 year-olds, some with severe resulting disabilities. Most of the adverse reactions involve the musculoskeletal system, peripheral nervous system, and central nervous system. Long-term pain was most commonly reported symptoms, 97% of all cases reporting pain associated with musculoskeletal adverse effects
  • And one should stop treatment at the first sign of an adverse reaction

Commentary:

  • Although many of the musculoskeletal and central nervous system effects have been known for many years, the above update includes many other conditions. And some of the newly included conditions (e.g. peripheral neuropathy) can last forever.
  • My sense locally is that fluoroquinolones are still being used quite frequently for uncomplicated urinary tract infections and other relatively minor infections. Hopefully the above warning will further discourage their potentially unnecessary usages.
  • I’m also very concerned about antibiotic resistance overall, as many of you know. Please see http://blogs.bmj.com/ebm/category/id-microbial-resistance/ for many blogs highlighting in rather scary detail the increasing antibiotic resistance in general, both in the US and worldwide. And I am also concerned about the effect of broad-spectrum antibiotics in particular and fundamental changes in the gut microbiome which can lead to many known, and probably many more unknown, health complications (see many blogs in http://blogs.bmj.com/ebm/category/microbiome/ )

Primary Care Corner with Geoffrey Modest MD: FDA Warnings Fluoroquinolones, Aripiprazole, Olanzapine

31 May, 16 | by EBM

By Dr. Geoffrey Modest

The FDA has sent out several Drug Safety warnings in the past few weeks.

  1. Fluoroquinolones
  • Given the widespread reports of adverse effects of fluoroquinolones, the FDA issued a report in 2013 requiring a label change (see http://www.fda.gov/Drugs/DrugSafety/ucm365050.htm ). Specifically, they noted an association with disabling peripheral neuropathy (with the onset of peripheral neuropathy often within a few days of starting the fluoroquinolone, and ongoing symptoms for more than a year in some patients, long after stopping the med).
  • There already were labels warning about risks of tendinitis, tendon rupture, CNS effects, exacerbations of myasthenia gravis, QTc prolongation/torsades, phototoxicity, and hypersensitivity (and I did send one patient to the ICU with anaphylaxis from ciprofloxacin around 15 years ago)
  • The actual warning from 5/12/16 states that the FDA “is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options”. See http://www.fda.gov/downloads/Drugs/DrugSafety/UCM500591.pdf .
  1. Aripiprazole
  • The FDA just issued a safety alert for aripiprazole (goes by trade name Abilify). See http://www.fda.gov/downloads/Drugs/DrugSafety/UCM498825.pdf. This medication has FDA approved indications for treating schizophrenia, bipolar disorder, Tourette’s disorder, and irritability associated with autistic disorder. It is also used (and apparently advertised widely on TV) in combination with antidepressants to treat depression. The FDA is warning that it might be associated with compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex. And these urges desist on stopping the drug or with dose reduction. But 4 cases had a return to this behavior with rechallenge. They do note that these impulse-control problems are rare (184 case reports since 2002, though there are apparently 1.6 million patients on the drug), with pathological gambling being the most common. The recommendation is just that we and patients be alert to this possibility. And we should closely monitor patients at higher risk for impulse-control problems, including personal/family history of obsessive-compulsive disorder, impulse-control disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors. But in most cases there was no prior history of compulsive behaviors overall, and none had a history of pathological gambling, compulsive sexual behavior, binge eating, or compulsive shopping prior to taking aripiprazole.
  • On reading about aripiprazole it is quite remarkable the array/diversity of actions it has: (per com) — “Aripiprazole exhibits high affinity for dopamine D2and D3, serotonin 5-HT1A and 5-HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors, and moderate affinity for the serotonin reuptake site. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.]” It is certainly true that many CNS-active drugs have multiple effects on multiple neurotransmitters, leading to many of their attendant adverse effects, though aripiprazole outdoes seem to outdo some of the others.
  1. Olanzapine
  • The FDA issued a drug safety communication about olanzapine and DRESS syndrome (see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm500123.htm ).
  • DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) often starts as a rash that spreads to all parts of the body, and includes 3 or more of: rash, eosinophilia, fever, lymphadenopathy, and systemic complications (hepatitis, myocarditis, pericarditis, nephritis, pancreatitis, pneumonitis), and often occurs after a long latency of 2-8 weeks after drug exposure. there is a 10% mortality rate
  • 23 cases of DRESS have been reported since 1996. One patient has died.

 

So, as with all FDA reports, these cases likely significantly underestimate the true incidence of problems, since in a busy clinical session, it is difficult/time-consuming to report the adverse events. But it is important for us as clinicians to know about these potential issues. The most important one for us is the fluoroquinolone advisory. As many blogs and articles have articulated: many too many antibiotics are being used for non-bacterial infections (bronchitis, sinusitis…), and there has been a very unfortunate shift to using more broad-spectrum and resistance-producing antibiotics (more azithromycin for strep, etc., than narrower antibiotics like penicillin). And I think many of us do still use ciprofloxacin for uncomplicated urinary tract infections.

See http://blogs.bmj.com/ebm/2015/08/03/primary-care-corner-with-geoffrey-modest-md-antibiotic-overprescribing-2/ for studies on antibiotic overprescribing and their consequences

Primary Care Corner with Geoffrey Modest MD: Oral Fluconazole in Pregnancy and Spontaneous Abortion: FDA Safety Alert

11 May, 16 | by EBM

By Dr. Geoffrey Modest

The FDA just posted a drug safety alert on the use of fluconazole in pregnancy (see http://www.fda.gov/downloads/Drugs/DrugSafety/UCM497705.pdf ), based on a recent JAMA article (see Molgaar-Nielsen D. JAMA2016; 315: 58). Details of the JAMA study:

  • A Danish nationwide registry-based cohort study from 1997-2013, of 1,405,663 pregnancies, looking at the association between oral fluconazole use to treat vaginal candidiasis during pregnancy and spontaneous abortion, and comparing that to use of topical azole antifungals
  • Demographics: 26% were <age 25, 31% age 25-29, 27% 30-34, 13% 35-39; pretty even distribution of household income by quintiles, and pretty equal level of education

Results:

  • 86% had cumulative dose of fluconazole of 150-300mg, first dose at median 69 days of gestation
  • Of 3315 women exposed to oral fluconazole from 7-23 weeks gestation:
    • 147 had a spontaneous abortion, a 48% increase over pregnancies matched on propensity score (a statistical technique used in analysis of observational data which attempts to match cases and controls by accounting for likely covariates/confounders that could affect the results, in this case including maternal age, calendar year, gestational age), with HR 1.48 (1.23-1.77)
  • Of 5382 women exposed to fluconazole from week 7 to birth:
    • 21 had stillbirth, a nonsignificant HR of 1.32 (0.82-2.14) [but pretty small number of events]
  • Use of topical azoles vs fluconazole:
    • 130 of 2823 women given fluconazole vs 118 of 2823 on topical azoles had a spontaneous abortion, a 62% increase associated with fluconazole use, with HR 1.62 (1.26-2.07)
    • 20 of 4301 women given fluconazole vs 22 of 4301 on topical azoles had a stillbirth, a nonsignificant HR 1.18 (0.64-2.16)
  • Further analysis of the spontaneous abortions (all numbers statistically significant):
    • 32% increase within 2 weeks of taking fluconazole; 65% increase after 2 weeks
    • 32% increase in gestational week 7-10 (the vast majority of fluconazole scripts were during this time period), though 90% in gestational weeks 11-22.
    • No statistical difference between lower cumulative dose of fluconazole (150-300mg) vs higher dose (350-5600mg), though small numbers of women at those higher doses

So,

  • The CDC had previously recommended using topical antifungals when treating pregnant women, even if needed for longer periods of time than usual. However, the FDA previously suggested that there did not seem to be an increased risk of problems when women were exposed to a single 150mg dose of fluconazole. But given the above Danish study, theyposted a safety alert suggesting “cautious prescribing of oral fluconazole in pregnancy” while they are completing their review.
  • Vaginal yeast infections are really common in pregnancy: about 10% of pregnant women get them.
  • Although the 48% increase in spontaneous abortions seems large, I am told by statistician types that this level of increase in a retrospective study, even with attempts at propensity matching, may not be found to be significant in a prospective randomized trial. For example, were the women with very severe vaginal candidiasis more likely to get the perhaps bigger gun (oral fluconazole), but in fact it really was the extensive candidiasis that caused the spontaneous abortion? Or potentially T-cell dysfunction which led to the candidiasis and the spontaneous abortion???
  • BUT, a few issues to support the FDA alert:
    • I really doubt there will ever be a formal RCT, since the event rate is small, the number of women needed to be involved would be huge, these are drugs off-patent so drug companies would have little/no interest in paying the rather large cost of a study, and there are more pressing studies for the NIH to fund
    • The study did suggest that the associationfound with fluconazole is not found with the topical azoles
    • And, probably in general, and especially in pregnancy, it probably is better to give topical/local than systemic meds that go right into the blood stream, and then into the fetus
  • So, I think this probably should be a game-changer: to be safe, we should go with the topical azoles in pregnant women with yeast infections…
  • And, as with all of these remarkable huge registry studies done in many western European countries, we in the US stand out again for not having a coherent health care system with systematic registries looking at meds, outcomes, etc. And we do not have universal accessible health care which would allow a registry to get reasonable data from the overall population….

Primary Care Corner with Geoffrey Modest MD: TMP/SMX For Uncomplicated Skin Abscesses

10 Mar, 16 | by EBM

By Dr. Geoffrey Modest

NEJM just a published a study looking at trimethoprim-sulfamethoxazole (TMP/SMX) vs placebo in patients with uncomplicated skin abscesses (see N Engl J Med 2016;374:823).

Details:

  • Study done in 5 US ERs, assessing TMP/SMX at dose of 320mg/1600mg (i.e., two DS tablets) twice daily (n=630) for 7 days vs placebo (n=617). Patients had to have the abscess for at least 1 week, and it had to be at least 2cm in diameter, including the induration.
  • Mean age 35; 58% male; 4.0 days of symptoms; 18% with fever; 11% diabetic; 4% with chronic skin conditions; site: 13% head/neck, 21% trunk/abdomen/back, 21% groin/buttocks, 23% arms/hands, 21% legs/feet; mean abscess size 2.5 cm x 2.0 cm x 5cm deep; erythema 7.0×5.0cm; wound culture: 45% MRSA, 16% methicillin-sensitive S. aureus, 12% coagulase-negative staph, 5% strep)
  • Main outcome was clinical cure 7-14 days after the end of the treatment period

Results:

  • Of those who took at least 1 dose of med, 64.7% were 100% adherent, and an additional 17.2% took 76-99% of the meds.
  • ​Modified intention-to-treat population (took at least one dose of med): clinical cure in 80.5% on TMP/SMX vs 73.6% on placebo (difference 6.9 percentage points (2.1-11.7, p=0.005)
  • Per-protocol population (took at least 75% of doses during first 5 days and had in-person test-of-cure): clinical cure in 92.9% on TMP/SMXvs 85.7% on placebo (difference 7.2 percentage points (3.2-11.2, p<0.001)
  • 7-14 days after treatment period, TMP/SMX also associated with lower rates of:
    • Subsequent surgical drainage (3.4% vs 8.6%, difference of -5.2 percentage points (-8.2 to -2.2)
    • ​Skin infections at new sites (3.1% vs 10.3%, difference of -7.2 percentage points (-10.4 to -4.1)
    • Infections in household members (1.7% vs 4.1%, difference of -2.4 percentage points (-4.6 to -0.2)
    • No difference in invasive infections (0.4% in each group)
  • Extended follow-up at 42-56 days: an invasive infection occurred in 1 patient in the TMP/SMX arm, “unrelated to the original abscess”
  • Adverse events: overall similar rates, most considered mild. Most common were GI (42.7% vs 36.1%); no cases of c. diff-diarrhea.

So, this study raises a few issues:

  • Historically, the primary treatment for cutaneous abscesses had been incision and drainage (I&D). Smaller studies have shown no benefit of antibiotics. The concern here is that >80% of abscesses are cured with I&D alone (as in the current study), so there needs to be a pretty large study to show efficacy of antibiotics in the remaining patients. Also, there is some question in the literature as to whether the situation now is different in the era of MRSA, that antibiotics may play a greater role in treatment of abscesses. To show this, there would need to be an even larger study to see if MRSA needs different treatment. But, from a primary care perspective, we do not know the organism at the time of presentation and need to treat empirically anyway, and this study is therefore applicable/useful.
  • Of course, TMP/SMX is not benign: it can be associated with c. diff infections, renal/electrolyte problems, hepatotoxicity, drug interactions, and other life-threatening reactions (g. Stevens-Johnson syndrome in about 3/100K people, or erythema multiforme). Overall, adverse reactions are on the order of 5%, though higher in those with HIV, esp if more severely immunocompromised. And there is the development of resistant organisms and microbiome changes (though, interestingly, a VA study did not find significant increases in antibiotic resistance in the post- vs pre- MRSA period, after which much more TMP/SMX has been prescribed — see Antimicrob Agents Chemother. 2012; 56 (11): 5655)
  • Still not so clear what the correct dose should be: there are data that a single DS pill bid achieves adequate serum levels for MRSA, and that is what I have been prescribing (the guidelines I’ve seen recommend 1-2 tabs bid, g. NEJM 2014; 370: 1039), though the current study was extra cautious and used the 2 tablet bid regimen
  • So, this study does raise the issue of routinely using TMP/SMX for abscesses in people with uncomplicated skin infections. As with many clinical issues, the right path for an individual patient is not so clear. The positives of treating are the higher cure rate by 7%, but also the pretty significant 5% decrease in need for subsequent surgical drainage and the 7% decrease in skin infections in new sites. The negatives are the immediate adverse effects of TMP/SMX, about 5% but including some rare fatal reactions, the potential for drug resistance (though not so much in above cited study) and perhaps longish term microbiomeMy bias is that I would lean more strongly to using antibiotics in a few instances:  in immunocompromised person (including diabetes)​, in some sites more than others (e.g., face/neck and groin area — anecdotally, I did have a patient many years ago with a groin abscess, and put on anti-staph antibiotics, but developed a fatal case of necrotizing fasciitis, so I do treat groin infections much more aggressively/broadly, covering anaerobes as well), and in a really mean looking, large (?not sure how to quantitate) abscess, especially if large surrounding area of cellulitis/induration or systemic symptoms (fevers, etc.). I think the conclusion is that there needs to be a discussion with the patient and a collaborative decision, reviewing risks/benefits.

For prior blog on using bleach baths for recurrent infections, see http://blogs.bmj.com/ebm/2014/04/02/primary-care-corner-with-geoffrey-modest-md-bleach-baths-to-decrease-recurrent-skin-infections/

the recommendations are for 1/4 cup of bleach in 1/4 bathtub (13 gallons of water), though will add the caveat, per Dr. Richard Bird, that it is not uncommon for people to add a lot more bleach or into only small amounts of water, and that they can get an associated cough or precipitate asthma (toxic reaction to the bleach/chlorine). Also can get rashes.​

Primary Care Corner with Geoffrey Modest MD: Antibiotics and Eosinophilia/Hypersensitivity Reactions

8 Jan, 16 | by EBM

By Dr. Geoffrey Modest

Another blog on the potential broader issues with antibiotics… in general, the major issues are those related to antibiotic resistance (see http://blogs.bmj.com/ebm/category/antimicrobial-resistance/ for blogs) and ecological changes in the microbiome (see http://blogs.bmj.com/ebm/category/microbiome/ for blogs). Another issue was highlighted in a recent study of those on longer-term antibiotics and eosinophilia/hypersensitivity reactions (see doi:10.1016/j.jaci.2015.04.005​).

Details:

  • 824 patients (60% male, median age 60) on long-term, initially in-hospital antibiotics (median therapy duration of 41 days), followed prospectively. All received at least 2 weeks of antibiotics after discharge. Study from 2012-2013. 63% were on only one antibiotic.
  • Most were treated for orthopedic infections (n=464) or bacteremia (n=161), most had gram positive organisms (n=641) and the most common antibiotics were cephalosporins (46%), vancomycin (40%) and penicillins (27%).

Results:

  • 210 (25% had eosinophilia, defined as absolute eos count (AEC)>500 (range: 500-8610).
  • Median time to developing eosinophilia was 15 days ([BUT: the labs were supposed to be drawn weekly, so hard to get very specific data on timing)].
  • More eosinophilia in those on vancomycin, penicillin, rifampin, and linezolid. No increased risk with fluoroquinolones or cephalosporins. metronidazole was associated with decreased eosinophilia.
  • Patients more likely to have eosinophilia were older (64 vs 59), and discharged to skilled nursing facility vs home (51% vs 39%) [i.e., likely sicker].
  • 64 of the 210 patients with eosinophilia (30%) had hypersensitivity reactions (HSR) including rash (n=32, 15%), renal injury (n=31, 15%) and liver injury (n=13, 7%). Less commonly in those without eosinophilia: rash occurred in 6%, renal injury in 10% and liver injury in 7%.
  • So, those with eosinophilia were significantly more likely to have a rash [HR=4.16 (2.53-6.83), p<0.001] and renal injury[HR=2.13 (1.36-3.33), p<0.001], though liver injury did not reach significance [HR=1.75 (0.92-3.33), p=0.09].
  • ​Those with eosinophilia who developed HSRs had eosinophilia earlier in the course of therapy (11 vs 17 days, with caveat noted above about accuracy of this timing), and had higher peak AEC (median 857 vs 699).
  • Possible DRESS syndrome (drug rash with eosinophilia and systemic symptoms) occurred in 7 (0.8%) of the 824 patients (3% of those who developed eosinophilia), of whom 4 (57%) were getting vancomycin, 3 on penicillins, 2 on metronidazole and 1 each on gentamicin, ceftriaxone and cefepime. 2 of the 7 with DRESS syndrome died.

So, a few points:

  • 60% of inpatients get antibiotics, and antibiotics are the most common cause of HSRs.
  • Though this study looked at sick inpatients with serious infections, there are a few issues of concern for us in primary care:
    • ​They found that the time to develop eosinophilia was about 15 days after starting antibiotics, but they have no consistent daily CBCs to see if that really is true (ie, could be much less time).
    • But even if one needs several weeks of antibiotics, this also happens in the outpatient setting (acne, chronic Lyme disease, refractory prostatitis….).
    • They looked at patients on high dose antibiotics and mostly parenteral (except for those on linezolid), but I’m not sure there is a significant difference with long-term oral antibiotics.
    • They found a lot more DRESS syndrome than previously described (typically 0.01 to 0.1%, as opposed to the 0.8% above). For a review of the DRESS syndrome, see Am J Med(2011) 124, 588. ​And I had one kid on minocycline for acne who developed DRESS syndrome after 2-3 weeks, leading to a 3 week hospitalization with an ICU stay for his hepatitis, pneumonitis and renal disease, and a pretty prolonged and awful recovery.
    • Unclear why metronidazole was associated with less eosinophilia. They suggest it could be from treating c diff infections, but I think that is less likely, since the main culprit for c diff is the fluorquinolones, and these antibiotics were not associated with eosinophilia in this study, so a little hard for me to reconcile this. Perhaps metronidazole has a direct drug effect on eosinophils??
    • Also, sometimes it was difficult to disentangle the relationship with antibiotics, since in many cases patients were on multiple antibiotics.
    • The significance of asymptomatic eosinophilia is unclear, but an untested hypothesis would be to assess those on more prolonged courses of antibiotics (e.g. >10 days) and in those who develop eosinophilia, to randomly stop/change antibiotics vs continuing, to see if fewer of the serious hypersensitivity reactions occur (which makes intuitive sense, since the more serious HSRs were in those developing more significant eosinophilia and earlier after starting antibiotics. And the presence of eosinophilia was so highly associated with HSRs). Also, some of these patients in the study (and in clinical practice) developed hypereosinophilia (AEC>1500) which itself does induce tissue damage (no data supplied in the study on how often hypereosinophilia occurred or with which antibiotics, though this might be another reason to check AECs).
    • ​Bottom line: this is just another of the many reasons we should  limit antibiotics to the clearest indications, the least time possible, and even consider alternative options more readily (e.g. oral retinoic acid for acne might be safer than antibiotics???, or using bleach baths for recurrent skin infections?? – see http://blogs.bmj.com/ebm/2014/04/02/primary-care-corner-with-geoffrey-modest-md-bleach-baths-to-decrease-recurrent-skin-infections/ for the latter).

See http://blogs.bmj.com/ebm/2015/04/16/primary-care-corner-with-geoffrey-modest-md-antibiotics-for-pneumonia/​, a Danish study finding that less-broad antibiotics (e.g. b-lactams such as amoxicillin or amox/clavulanate) work as well for community-acquired pneumonia as those plus macrolide, or fluoroquinolone

 

Primary Care Corner with Geoffrey Modest MD: Longterm Microbiome Changes with Antibiotics

3 Dec, 15 | by EBM

By Dr. Geoffrey Modest

A small study was done looking at antibiotic exposure and changes in both the salivary and gut microbiomes (see http://mbio.asm.org/content/6/6/e01693-15.full.pdf+html, or  doi:10.1128/mBio.01693-15​). This study involved 2 clinical sites, one in Sweden and one in the UK, randomly assigned to placebo vs different antibiotics, and looking at changes in the microbiomes both before a single antibiotic exposure and for up to one year after.

Details:

  • 30 people in the Swedish site were randomized to placebo, ciprofloxacin, or clindamycin; 44 people in the UK were randomized to placebo, amoxicillin, or minocycline (dosage not stated).
  • For the Swedish site:
    • The fecal microbiome diversity was significantly reduced for up to 4 months in the clindamycin group, and up to 12 months in the ciprofloxacin group.
    • The salivary microbiomes in the same groups showed only a short-term reductions in diversity and only immediately after the clindamycin or ciprofloxacin exposure.
  • For the UK site:
    • ​There was a significant reduction in microbiome diversity in both the fecal and saliva samples only at the 1 week samples after the minocycline exposure, which resolved by the 1 month analysis. Amoxicillin was not associated with any change in the microbiome in saliva or the gut.
  • The changes in the microbiome were largely a reduction in the production of the short-chain fatty acid butyrate in the gut, especially by clindamycin and ciprofloxacin, and butyrate production has the positive effect of inhibiting inflammation, carcinogenesis and oxidative stress in the gut. (Butyrate production was decreased in correspondence to the decreased gut population of many different bacterial species, such as Faecalibacterium, — see the article for the details).
  • Prior to antibiotic exposure they detected antibiotic resistant genes in both the saliva and gut microbiomes, even in this healthy population.

So, it is unclear why the 2 microbiomes behaved differently, with the salivary microbiome being minimally affected and quite resilient and the gut microbiome having prolonged changes of up to a year after a single exposure to antibiotics (ciprofloxacin being the worst of those studied). However, this type of study reinforces the need to minimize antibiotic usage (also reinforced by the presence of antibiotic resistant genes evident in the gut of these healthy volunteers even prior to the antibiotics), and preferentially to use ​antibiotics which have lesser microbiome effects (in this case, penicillins). One wonders if there is a “tipping-point” of repeated broad-spectrum antibiotic administration leading to more permanent changes in the microbiome.

See http://blogs.bmj.com/ebm/category/microbiome/ for an array of prior blogs on the microbiome;  http://blogs.bmj.com/ebm/2015/08/03/primary-care-corner-with-geoffrey-modest-md-antibiotic-overprescribing-2/ about antibiotic overprescribing; and http://blogs.bmj.com/ebm/2015/02/28/primary-care-corner-with-geoffrey-modest-md-pharyngitis-and-fusobacterium/​ which argues that penicillin is the drug-of-choice for pharyngitis, over azithromycin.​

Primary Care Corner with Geoffrey Modest MD: And the Drug Company Shenanigans Continue

30 Sep, 15 | by EBM

By Dr. Geoffrey Modest

I realize that I have blogged lots about drug company malfeasance/shenanigans. But they keep on coming and seem to be getting worse. Here is another from the NY Times on Daraprim (the brand name for pyrimethamine, a 62-year old drug used for parasitic infections, most notably for toxoplasmosis in HIV-infected patients but also occasionally for acute malaria) — see http://nyti.ms/1PgLfRl. [Thanks to Paul Susman for bringing this to my attention].

Issues:

  • Turing pharmaceuticals just acquired the drug and “immediately raised the price to $750 a tablet from $13.50”, though several years ago it was $1/pill. Of note, “Daraprim’s distribution is now tightly controlled, making it harder for generic companies to get the samples they need for the required testing”.
  • Also, cycloserine (used to treat multi-drug resistant TB) was recently acquired by Rodelis Therapeutics, which increased the 30-day supply from $500 to $10,800
  • The frequently-used antibiotic doxycycline went from $20/bottle in Oct 2013 to $1849 in April 2014
  • And, from NPR’s All-Things-Considered (see http://n.pr/1J2qmnE ), naloxone (Narcan, available since 1971), the main drug used to reverse potentially lethal opioid overdoses, is now a national focus in dealing with the opioid crisis (huge increases in the numbers of people trained to use it, large-scale programs to distribute and make free access to the intranasal form for opioid users, police, etc.) Injectable naloxone had been about $1/shot. The intranasal naloxone is made by only one company (Amphastar). NPR comments that in Baltimore, the price of naloxone in February of $20/dose jumped to $40/dose in July (thanks to sarah taylor for this reference).
  • And, speaking of opioids, though this is more an FDA and drug company joint shenanigans, oxycontin was just approved for kids over 11 years old (see http://nyti.ms/1KRRDut for the FDA press release and http://nyti.ms/1N19lT0 for an editorial). However, there are several studies finding that children are at a higher risk of addiction than adults (see blogs in http://bit.ly/1PNzEtg and a USA Today article http://usat.ly/1LdOLxA ). My feeling on this is that there are some small numbers of kids who need chronic opioids for pain control, that fentanyl patches are already available, and that oxycontin has such a long history of abuse/addiction and is already being abused by kids (“1 in 25 high school seniors has abused oxycontin” per the USA Today report, the number of prescription painkillers has quadrupled since 1999, and >44,000 Americans die of drug overdoses every year). So, seems to me that the risks far outweigh the benefits (except for Purdue Pharmaceuticals, which is undoubtedly laughing all the way to the bank….)

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