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ID- antimicrobial Resistance

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: 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: antibiotic-resistant bacteria of concern

2 Mar, 17 | by EBM

By Dr. Geoffrey Modest

The WHO just published a list of 12 bacterial families that they feel pose the greatest threat to human health (see http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/ ). These are considered the “priority pathogens”, which should serve as a focus for research and development of new antibiotics. The most critical group includes multi-drug-resistant bacteria that pose a particular threat in hospitals, nursing homes, and among patients who require devices such as ventilators and blood catheters. These bacteria have become resistant to a large number of antibiotics including carbapenems and third-generation cephalosporins, the best available drugs for treating multidrug resistant bacteria. The 2nd and 3rd tier priorities include increasingly drug-resistant bacteria that can cause more common diseases such as gonorrhea and salmonella. The goal is to spur governments to incentivize basic science and advance research and development, both public and private sector, to invest in new antibiotic discovery. The list does not include tuberculosis, which does have increasing resistance, but is covered by other programs.

Priority 1: critical

  1. Acinetobacter baumanii, carbapenem-resistant
  2. Pseudomonas aeruginosa, carbapenem-resistant
  3. Enterobacteriaceae, carbapenem-resistant, ESBL-producing

Priority 2: high

  1. Enterococcus faecium, vancomycin-resistant
  2. Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant
  3. Helicobacter pylori, clarithromycin-resistant [see http://blogs.bmj.com/ebm/category/gi-h-pylori/​ for multiple blogs on H Pylori resistance and optimal treatment strategies]
  4. Campylobacter spp., fluoroquinolone-resistant
  5. Salmonellae, fluoroquinolone resistant
  6. Neisseria gonorrheae, cephalosporin-resistant, fluoroquinolone-resistant

Priority 3: medium

  1. Streptococcus pneumoniae, penicillin-non-susceptible
  2. Haemophilus influenzae, ampicillin-resistant
  3. Shigella spp., fluoroquinolone-resistant

Commentary:

  • This WHO publication follows others which have warned of scarily increasing bacterial antibiotic-resistance world-wide (e.g., see http://blogs.bmj.com/ebm/2014/07/11/primary-care-corner-with-geoffrey-modest-md-whos-remarkable-scary-report/ )​
  • The focus of this current publication is to spur on research and development of new antibiotics.  BUT, though not mentioned, the elephant in the room is that we need to decrease the future development and spread of antibiotic-resistant bacteria. Some of this is decreasing the unnecessary use of antibiotics for nonbacterial illnesses (see prior blogs, as below, in the file: http://blogs.bmj.com/ebm/category/id-microbial-resistance/). But the largest part of this has to do with industrial use of antibiotics in livestock, where antibiotics are used to increase the weight of animals and prevent infections largely in the setting of huge industrial farms, where there is great opportunity for sharing of pathogens. Although there are different estimates out there on the quantity of antibiotics used, one study by the Union of Concerned Scientists suggested that 24.6 million pounds of antimicrobials are used annually for nontherapeutic purposes in chickens, cattle, and swine vs 3.0 million pounds used for humans (see Landers TF. A review of antibiotic use in food animals: perspective, policy, and potential. Public Health Rep. 2012 Jan-Feb 127(1): 4.).  i.e. 90% goes to animals….
  • An additional issue is that drug companies have been loath to develop new antibiotics. As for-profit organizations, they see much more income from life-long drugs, such as those for lipids, diabetes, etc. (the gift that keeps on giving), vs those prescribed for just a 10-day course. (The apparent exception is for hepatitis c, where the meds are given for several months, these were new meds for a very serious and very common condition, and they were able to jack up the price independent of their actual costs of R&D). And, many of the drug-resistant bugs, at this point, are in areas of the world where there is not lots of money to be made (see http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1​ ) .  From the blog of 7/11/14: “at this point we really need new antibiotics developed. There have been no new class of antibiotics since 1987. Issue is that the $$ is in chronic meds. Even over-charging for antibiotics doesn’t help much if it’s for only a 10 day course. And, will append below a previous blog  which shows that the vast majority of R&D by big pharma is for look-alike drugs and not for important break-throughs (though their arguments supporting the huge costs of drugs hinges on the expense of R&D)”
  • So, bottom line, we do need new antibiotics to deal with the spread of these “superbugs”. But we really do need to intensify internal pressure on clinicians to decrease antibiotic overprescribing and, especially, external pressure on industrial farming to dramatically decrease antibiotic usage.

 

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: STI Infection Therapy WHO Guidelines

25 Sep, 16 | by EBM

By Dr. Geoffrey Modest

Because of growing antibiotic resistance, the World Health Organization (WHO) published updated guidelines for the treatment of sexually-transmitted infections: see http://www.who.int/mediacentre/news/releases/2016/antibiotics-sexual-infections/en/.  See end of this blog for links to other relevant blogs on STIs, antibiotic resistance, etc.

Details:

  • 131 million people are infected with chlamydia, 78 million with gonorrhea and 5.6 million with syphilis
  • All have increasing antibiotic resistance, especially gonorrhea, where some strains do not respond to available antibiotics (see blogs at end). Quinolones are not recommended, as a result.
  • There is a 7-fold increased risk of transmission of HIV in both ulcerative and nonulcerative lesions (also with other STIs, such as HSV-2, chancroid, trichomoniasis)
  • There is increasing evidence of trichamonas being resistant to nitroimidazoles (and there really is no other rx)
  • Syphilis has more resistance to azithromycin
  • Chlamydia has more treatment failures to tetracyclines and macrolides

Gonorrhea (see http://www.who.int/reproductivehealth/publications/rtis/gonorrhoea-treatment-guidelines/en/ ) for details. I will highlight differences with the 2015 MMWR on STIs (see: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm )

  • Genital and anorectal GC infections
    • Typically cause urethritis in men and mucopurulent discharge in women. Can be asymptomatic, esp in women. Pharyngeal and rectal infections are largely asymptomatic
    • Use local resistance data to determine the choice of therapy
    • If local resistance data not available, use dual therapy:
      • Ceftriaxone 250mg IM as a single dose plus azithromycin 1 g as a single dose, or
      • Cefixime 400mg orally as a single dose plus azithromycin 1 g as a single dose [MMWR: only use if ceftriaxone not available, increasing reports of cefixime resistance)]
    • If recent local resistance data are available, can use single therapy based on the local resistance pattern: [MMWR: no single treatment recommended: there are some data suggesting synergy of the dual therapy and perhaps slower development of resistance]
      • Ceftriaxone 250mg IM as a single dose
      • Cefixime 400mg orally as a single dose
      • Spectinomycin 2gm IM as a single dose
    • Oropharyngeal GC infections (MMWR noted treatment failure after single dose therapy and therefore prefer dual therapy. especially for pregnant women):
      • If local resistance data not available, use dual therapy:
        • Ceftriaxone 250mg IM as a single dose plus azithromycin 1 g as a single dose, or
        • Cefixime 400mg orally as a single dose plus azithromycin 1 g as a single dose [MMWR: this one is not recommended]
      • If recent local resistance data are available, can use single therapy based on the local resistance pattern:
        • Ceftriaxone 250mg IM as a single dose
      • Treatment failure:
        • If reinfection suspected, re-treat with above, reinforce sexual abstinence or use of condom, and provide partner Rx
        • Otherwise, contour treatment to GC susceptibility
        • Retreat with one of the following:
          • Ceftriaxone 500mg IM as a single dose plus azithromycin 2 g as a single dose, or
          • Cefixime 800mg orally as a single dose plus azithromycin 2 g as a single dose
          • Gentamicin 240 mg IM as a single dose plus azithromycin 2 gas a single dose
          • Spectinomycin 2g IM as a single dose (if not oropharyngeal GC) plus azithromycin 2 gas a single dose
          • MMWR: treat as dictated by susceptibility testing. Options include: can try gemifloxacin 320 orally plus azithro 2gm, or single doses of gentamicin 240 mg IM plus azithro 2gm; and get test-of-cure 7-14 days later, preferably by culture. No comment on the double dose treatment proposed by WHO noted above (doubling the dose of cephalosporin and azithro). They also place treatment of sex partners as priority right away, not mentioned in WHO until likely reinfection.
        • GC ophthalmia neonatorum, use one of:
          • Ceftriaxone 50 mg/kg (max of 150mg) IM as single dose, or
          • Kanamycin 25 mg/kg (max of 75mg) IM as single dose, or
          • Spectinomycin 25 mg/kg (max of 75mg) IM as single dose
        • Use topical ocular prophylaxis for all neonates to prevent GC and chlamydia eye infections, as determined by cost and local resistance
          • Tetracycline hydrochloride 1% eye ointment
          • Erythromycin 0.5% eye ointment [MMWR: this is recommended med]
          • Povidone iodine 2.5% solution (water-based, not alcohol-based)
          • Silver nitrate 1% solution
          • Chloramphenacol 1% eye ointment
        • MMWR also suggests treatment for adult gonococcal conjunctivitis with ceftriaxone 1 gm IM plus azithro 1 g orally, both in a single dose

Chlamydia (see http://www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/ )

  • Can be asymptomatic in men and women
  • Uncomplicated genital chlamydia [MMWR recommends the same 2 primary treatments, adds levofloxacin 500mg orally once a day for 7 days, and has ofloxacin as 300 mg bid for 7 days. Does not include tetracycline. And again pushes more for treatment of sex partners]
    • Azithromycin 1 g orally as a single dose (most convenient dosing), or
    • Doxycycline 100mg orally twice a day for 7 days (cheapest treatment). These 2 are the major recommendations
    • Tetracycline 500 mg 4 times a day for 7 days, erythromycin 500mg orally twice a day for 7 days, ofloxacin 200-400 mg orally twice a day for 7 days (alternative regimens)
  • Anorectal chlamydia
    • Priority is doxycycline 100mg bid for 7 days, secondary would be azithromycin 1gm orally as a single dose
  • Genital chlamydia in pregnant woman [MMWR also recommends azithro as primary, then options of amoxacillin or a variety of erythromycin-based therapies similar to WHO]
    • Use azithromycin over amoxicillin (500mg orally 3 times a day for 7 days), and that over erythromycin, regimens as above
  • LGV (lymphogranuloma venereum)
    • Doxycycline 100mg bid for 21 days preferred, can do azithromycin 1 g orally weekly for 3 weeks
  • Neonatal chlamydia conjunctivitis (ophthalmia neonatorum) [MMWR prioritizes the erythromycin regimen]
    • Azithromycin20 mg/kg/day orally once a day for 3 days (preferred), or erythromycin 50 mg/kg/day, orally in 4 divided doses for 14 days
  • Neonatal ocular prophylaxis
    • Same as for GC above

Syphilis (see http://www.who.int/reproductivehealth/publications/rtis/syphilis-treatment-guidelines/en/ )

  • Primary syphilis: painless chancre (may be extra-genital, at site of inoculation) after mean incubation of 21 days, and heals spontaneously in 3-10 weeks
  • Secondary syphilis: generalized rash (varies widely, and I have seen a couple of cases looking just like pityriasis rosea), but typically palms and soles, symmetric, non-itchy. In moist areas (anus/labia), can be white-gray raised lesion of condyloma lata, which are teeming with treponemes (i.e., wear gloves…)
  • latent syphilis: positive serology, no clinical signs/symptoms, and divided into early latent (<2yrs) or late latent (>2 years, or if unknown)
  • If untreated, most remain in late latent stage, with 25% developing the late clinical sequelae of tertiary syphilis (can be >30 years after infection). Neurosyphilis can occur at any stage, even within the first few months: acute mental status changes, meningitis, stroke, cranial nerve dysfunction, auditory/ophthalmic/ocular abnormalities. Late neurosyphilis (tabes dorsalis, general paresis) occurs 10 to >30 years after infection
  • MMWR basically agrees with below, though has additional recommendations for kids, treating tertiary and neurosyphilis, as well as coinfection with HIV (not different from non-HIV, though may have more clinical symptoms, such as neurosyphilis.
  • Early syphilis (primary, secondary and early latent)
    • Benzathine penicillin G 2.4 million units IM once (preferred)
    • Procaine penicillin G 1.2 million unit IM for 10-14 days
    • In penicillin-allergic, or above not available: doxycycline 100mg orally bid for 14 days (cheaper and oral), or ceftriaxone 1 g IM daily for 10-14 days, or (last) azithromycin 2 g orally once only (if local susceptibilities support its use)
  • Pregnant women with early syphilis
    • As above with emphasis on penicillin regimens
    • In those penicillin allergic: can use the erythromycin or ceftriaxone or azithromycin, as above. (Can’t use doxycycline in pregnancy, and erythromycin and azithromycin do not cross the placental barrier completely. So if use either of these, should treat the newborn soon after delivery)
  • Late syphilis (infection >2 years, or syphilis of unknown duration without evidence of treponemal infection)
    • Benzathine penicillin G 2.4 million units IM once weekly for 3 injections, and interval between doses cannot exceed 14 days (preferred)
    • Procaine penicillin 1.2 million units IM daily for 20 days
    • If penicillin-allergic: doxycycline 100mg orally bid for 30 days
  • Late syphilis (infection >2 years or syphilis of unknown duration without evidence of treponemal infection), in pregnant women
    • Benzathine penicillin G 2.4 million units IM once weekly for 3 injections, and interval between doses cannot exceed 14 days (preferred)
    • Procaine penicillin 1.2 million units IM daily for 20 days
    • If penicillin-allergic: erythromycin 500mg orally qid for 30 days. And treat the newborn
  • Congenital syphilis
    • Aqueous benzyl penicillin 100,000-150,000 U/kg/day intravenously for 10-15 days (preferred)
    • Procaine penicillin 50,000 U/kg/day IM for 10-15 days
  • Infants who are clinically normal but whose mothers had syphilis which was adequately treated
    • Risk of transmission depends on: maternal titers from non-treponemal tests (e.g. RPR), timing of maternal treatment and stage of maternal infection
    • If decide to treat: benzathine penicillin 50,000U/kg/day as single IM dose

Commentary:

Why is the WHO report important??

  • It highlights the really major issue on increasing antibiotic resistance, and the WHO has really been at the forefront in studying this issue and publicizing pretty dire warnings
  • We are seeing more international patients who may have been treated for an STI and we should know what are the acceptable regimens internationally
  • In the US, I would go by the MMWR recommendations, though I think the suggestions of higher dose meds for treatment failure of gonorrhea make sense, but is supported only by successful reports in individuals who had failed a variety of treatments, and not from formal studies. In someone who is less likely to come back for test-of-cure, based on this I would probably use the higher dose regimen as per WHO. If they are very likely to return, it is reasonable to try the MMWR regimens with close follow-up. I am also still somewhat concerned about the treatment of syphilis in those with HIV, given early reports of failure, and still do use the longer regimen (2-3 shots for early syphilis), as per the relevant blog cited below.

For prior blogs, see http://blogs.bmj.com/ebm/category/sti/ , which includes blogs detailing the increasing resistance of gonorrhea ( http://blogs.bmj.com/ebm/2016/07/27/primary-care-corner-with-geoffrey-modest-md-gonorrhea-resistance-increasing/ ), a blog from the WHO highlighting that in 3 of the 6 regions of the world there is >25% resistance of gonorrhea to 3rd generation cephalosporins (http://blogs.bmj.com/ebm/2014/07/11/primary-care-corner-with-geoffrey-modest-md-whos-remarkable-scary-report/ ), a blog which questions the recommendation that those with syphilis and HIV get the same treatment as those without HIV (http://blogs.bmj.com/ebm/2015/02/17/primary-care-corner-with-geoffrey-modest-md-syphilis-treatment-in-hiv-positive-patients/ , etc.

Primary Care Corner with Geoffrey Modest MD: Gonorrhea Resistance Increasing?

27 Jul, 16 | by EBM

By Dr. Geoffrey Modest

A rather disturbing MMWR just came out finding that gonorrhea is becoming increasingly resistant to pretty much all of our current antibiotics (see http://www.cdc.gov/mmwr/volumes/65/ss/pdfs/ss6507.pdf ).

Details:

  • The Gonococcal Isolate Surveillance Project (GISP) has been around since 1986 and does sentinel surveillance of antimicrobial sensitivity for N. gonorrhoeae (GC). They check GC cultures and antibiotic susceptibility from the first 25 men with gonococcal urethritis attending each of the participating STD clinics at 27 sites in the US.
  • They are able to extract selected demographic and clinical data
  • Mean age 28, 58% Black/22% white/13%Hispanic-Latino; 37% MSM or MSMF (men who have sex with men, or both men and women)

Results:

  • 5093 isolates were collected in 2014 (all of the resistance patterns were more common in MSM)
    • 3% resistant to tetracyclines
    • 2% resistant to ciprofloxacin (increasing, though there was an initial dip after the CDC stopped recommending its use to treat GC)
      • 2% resistant to penicillin (plasmid-based, chromosomal, or both) — though CDC has not recommended using it for treatment of GC since 1989
    • But of major significance:
      • 5% had reduced susceptibility to azithromycin (0.6% in 2013):
        • In all geographic areas of the US, but most in the Midwest (Midwest about 4%, Northeast about 2.7%, rest about 2%)
        • In all groups of sex partners (MSM about 4.3%, MSMW about 3.2%, and MSW about 1.5%)
        • None of these azithro-resistant isolates had reduced ceftriaxone or cefixime susceptibility
      • 8% had reduced susceptibility to cefixime (0.4% in 2013)
      • 1% had reduced susceptibility to ceftriaxone (no change from 2013), though highest in Northeast (about 0.4%).
      • 38% of isolate exhibited resistance to some antibiotic;  and 10% to 2, 7% to 3 and 0.5% to 4 antibiotics

Commentary:

  • Gonorrhea is the 2nd most commonly reported notifiable disease in the US, with 350,062 cases reported in 2014
  • The role of GISP is especially important, since we have mostly gone to NAAT testing (nucleic acid amplification tests) instead of GC culture, and one needs to grow the GC in culture to test susceptibility
  • Though the numbers of resistant isolates to the azithro and ceftriaxone are still pretty low, it is important to remember that there is a critical threshold (inflection, or tipping point), where the prevalence leads to a dramatic increases in their transmission (which, from my rather distant memory is on the order of 8%). So the 4-fold increase in azithro resistance to 2.5% may be really foreboding
  • Limitations of the study: a big one is that only men with urethritis were tested (and MSM,MSMW were disproportionately represented); another is that we do need to see infectious diseases more and more through a global perspective. What is happening in the US is not isolated from the rest of the world. And though the resistance level to ceftriaxone is still relatively low in the US, in other areas the levels are much higher (the WHO report in 2014 found >25% resistance to 3rd generation cephalosporins in 3 of the 6 regions of the world. See http://blogs.bmj.com/ebm/2014/07/11/primary-care-corner-with-geoffrey-modest-md-whos-remarkable-scary-report/ for details.)  Also, with such low numbers of resistance reported by GISP (especially for ceftriaxone), sampling error could lead to rather large % changes in the numbers (only about 1% of the reported cases were actually sampled, and my guess is that there are many more cases of GC than those reported….)
  • CDC recommendations remain the same: treat GC with ceftriaxone 250mg IM plus azithro 1gm orally (the combined meds are synergistic and cover for each other’s resistance for now, since there are no reported cases of resistance to both). Use azithro 2g plus gentamicin or gemifloxacin if intolerant of cephalosporins. Cefixime had been considered an acceptable cephalosporin to use until 2012, when recommendations changed because of increasing cefixime The decreasing cefixime resistance reported now may not be significant, since it is not simultaneously decreasing in other areas of the world. It is still not recommended by the CDC.
  • And, the striking increase in azithromycin is very concerning because if it continues to increase, the mainstay of GC treatment will become increasingly ineffective, especially in the context of increasing cephalosporin resistance in much of the world. GC may become effectively resistant to all meds we currently have….

For a slew of blogs on antimicrobial resistance, see http://blogs.bmj.com/ebm/category/antimicrobial-resistance/

Primary Care Corner with Geoffrey Modest MD: More Superbugs

28 Jun, 16 | by EBM

By Dr. Geoffrey Modest

Following on the last blogs on colistin-resistant E coli (see http://blogs.bmj.com/ebm/2016/06/21/primary-care-corner-with-geoffrey-modest-md-e-coli-superbug-is-spreading/ and http://blogs.bmj.com/ebm/2016/06/23/primary-care-corner-with-geoffrey-modest-md-response-and-further-comments-on-e-coli-superbug-is-spreading/), Paul Susman sent me the link http://www.coha.org/super-bacteria-in-rio-de-janeiros-olympic-arenas/ on the increasing spread of  Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria, which has been around for many years. A 2011 article (Arnold RS, South Med J 2011; 104: 45) noted at that time that this difficult-to-treat organism, associated with significant morbidity and mortality, had already spread from the northeastern US to most of the world. The CDC commented that 50% of patients infected with this organism will die from it. The current link references the upcoming Olympics in Brazil, noting:

  • KPC is found off the beaches in Rio, where rowing, canoeing and swimming events will take place (i.e., the swimmers, sailors and rowers will be exposed). The source is likely sewage contamination of the waterways
  • 10 samples were taken from five different beaches (Copacabana, Ipanema, Leblon, Botafogo, and Flamengo) and all tested positive for KPC
    • Copababana is the site of the triathlon and open swimming competitions, tested positive in 10% of the samples
    • Botafogo, where sailing and canoeing events are to be held, had 100% of samples positive
    • Ipanema and Leblon, popular tourist beaches, had 50 and 60% of samples positive
    • Flamengo beach, where sailing competitions will be held, 90% tested positive
  • Another study found that Guanabara Bay was contaminated, likely because waste from thousands of households and hospitals that dump into the streams and rivers that empty there. They note that “at least 50% of the untreated sewage from Rio de Janeiro is dumped in to Guanabara Bay.
  • KPC has been found there since 2010. The authorities promised the water would be cleaned. But alas….
  • Another article on Brazil highlights the high rates of methicillin-resistant Staph, vancomycin resistant Enterococci, b-lactamase resistant Klebsiella and E coli, and KPC (see Rossi F. Clinical Infectious Diseases 2011; 9: 1138). They attribute the resistance to: overuse of superantibiotics (e.g. colistin in the ICUs), high total consumption of antibiotics, availability of over-the-counter antibiotics, inadequate dosing of antibiotics, and poor adherence.
  • Also Brazil is the world’s largest beef exporter with the world’s largest commercial cattle herd. The government does regulate antibiotic use (as opposed to the US), though antimicrobial resistance has been found in Brazilian cattle

Commentary:

  • I guess there is more concern about the Olympics than Zika…
  • I don’t mean to single out Brazil by this example. But this example yet again reinforces the big picture of potential outbreaks of untreatable infections caused by antibiotic resistance in common microbes. This is a worldwide phenomenon and really does need to be approached in a coherent worldwide manner

Primary Care Corner with Geoffrey Modest MD: Response and Further Comments On: E. coli Superbug is Spreading

23 Jun, 16 | by EBM

By Dr. Geoffrey Modest

An article was sent by Burak Alsan, from an interview with his wife Marcie Alsan (see http://blogs.plos.org/publichealth/2016/05/31/to-fight-superbugs-fight-poverty). She stresses the connection between socioeconomic disparities and infectious diseases, specifically noting that “out of pocket payments were the most significant correlate of antimicrobial resistance across countries” and that “the entire correlation was driven by countries that had in place a policy by which copayments were imposed in the public sector”. In particular, she found that of 47 countries, out-of-pocket health expenditures were the only factor significantly associated with antibiotic resistance, controlling for socioeconomic and environmental factors (e.g. sanitation, animal husbandry, and poverty) and structural health-care features (e.g. physician density, hospital bed density, total health expenditures). In particular, a “ten point increase in percentage of health expenditures that were out-of-pocket was associated with a 3.2 percentage point increase in resistant isolates”. For details, see Alsan, M. Lancet Infect Dis 2015; 15: 1203.

Commentary

  • I think this is really important. I mentioned out-of-pocket expenses in my rantings on one of the fundamental problems with our health care system: we do not place primary care at its center. Providing easy access to primary care is not only much cheaper to the system but undoubtedly derives better outcomes, with more coordinated, less interventive care that prioritizes a more holistic approach to the broad biopsychosocial aspects of the patient and focuses on the therapeutic benefits of a strong provider-patient relationship. All of this means having free and easy access to primary care (decreasing obstacles to access, such as copayments by patients), as well as reorienting the incentives in the system to promote the training and job satisfaction of primary care providers
  • And, as mentioned before, I have seen way too many patients with treatable conditions (e.g., cellulitis, hypertension…), unable to pay their copays for meds, then hospitalized with serious conditions (sepsis, stroke…). A huge human as well as monetary cost…
  • In the case of antibiotic resistance, there was an article in the Boston Globe recently finding further spread of colistin-resistant E coli, noting a few pretty scary things: this “superbug” was found in another pig in the US, but concerning enough “each of the three US cases (2 in pigs, and the one woman from Pennsylvania) involve different strains of E. coli. The latest animal case suggests the gene is spreading through multiple routes here.” (See https://www.bostonglobe.com/news/nation/2016/06/14/superbug-found-second-pig-sample/OPUjpJ5aMA7ontXAjMW4xL/story.html ). Seems like a pretty urgent thing to tackle….

See http://blogs.bmj.com/ebm/2016/06/21/primary-care-corner-with-geoffrey-modest-md-e-coli-superbug-is-spreading/ for the original blog

Primary Care Corner with Geoffrey Modest MD: E. Coli Superbug is Spreading

21 Jun, 16 | by EBM

By Dr. Geoffrey Modest

Not-so-shockingly, the US government reported the first case of a patient in the US with colistin-resistant E. coli, in a 49 yo Pennsylvania woman with a urinary tract infection. They found a plasmid-mediated piece of DNA which passed along the mcr-1 gene, conferring colistin resistance (see http://www.reuters.com/article/us-health-superbug-idUSKCN0YH2KT . For the case study, see doi:10.1128/AAC.01103-16). This is precisely the issue reported last year in China [see http://blogs.bmj.com/ebm/2015/12/10/primary-care-corner-with-geoffrey-modest-md-troubling-microbiome-changes . This blog looked at the initial report from China, noting that China is the world’s largest producer of poultry and pig products and one of the largest veterinary users or colistin (aka polymixin E), finding this resistant bug in 16 samples from various sites: sputum, urine, ascitic fluid, bile…]. Since the Chinese finding, the  Walter Reed National Military Medical Center has been testing all extended-spectrum b-lactamase-producing E. coli for colistin-resistance.

This current finding and the blog (which goes into detail on the China case) basically make the following points:

  • Antibiotic resistance is a huge and growing problem: >2 million illnesses blamed on antibiotic resistance in the US with 23,000 annual deaths
  • Potential for spread of this E. coli, resistant to the last-line big gun colistin, is real, and highlighted by this case in the US 6 months after the report in China. The concern is that the ability for E. coli to elaborate plasmid-mediated resistance makes it more spreadable than through the prior identified mechanism of chromosomal changes
  • Part of the issue is us guys: more than 1/2 of patients admitted to the hospital get an antibiotic, but 30-50% of the time it is considered unnecessary. Blogs below look at the overuse of antibiotics in the outpatient setting as well.
  • The biggest part of the problem is use/remarkable overuse of antibiotics in agriculture (as in the colistin case), leading to lots of resistant bugs (see blogs below).
  • And there is real concern, as per the CDC, that we may be entering a post-effective antibiotic era
  • Confounding the issue, is the lack of aggressive antibiotic development by drug companies: even expensive antibiotics (the $100-200/pill ones) are typically given for short, and therefore less-profitable, courses of treatment. The $$ is in long-term, preferably lifelong need for meds.  Some of the big drug companies who mostly foreswore against antibiotic drug development have “signed a declaration calling for new incentives from governments to support investment in development of medicines to fight drug-resistant superbugs”. Perhaps the hepatitis c drug model will develop: hugely overpriced drugs, which even for only a few months can develop huge profits…???

See http://blogs.bmj.com/ebm/category/antimicrobial-resistance/ for a litany of articles/critiques on antibiotic overprescribing, resistance, and efforts to combat resistance, including a US White House report from last year

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

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