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Primary Care Corner with Geoffrey Modest MD: 1 shot of penicillin for early syphilis in HIV patients??

13 Apr, 17 | by

by Dr Geoffrey Modest

2 articles of note just came out on syphilis.

MMWR presented data on rates of primary and secondary syphilis in the US in 2015 (see https://www.cdc.gov/mmwr/volumes/66/wr/mm6613a1.htm ). The overall case rate was 7.5/100K population, nearly 4 times the previous lowest documented rate of 2.1/100K in the year 2000, a nadir after which it has increased each year. The rate increased 22% during 2011-13.

Details:

— in 2015, there were 23,872 reported primary and secondary syphilis cases in the United States.

— 81.7% of male primary and secondary syphilis cases were among gay, bisexual, and other men who have sex with men (MSM)

— among the 44 states reporting information on the sex of sex partners for > 70% of male cases, the rates were:

— overall for men over 18 years old: 17.5/100K

— men who have sex only with women: 2.9/100K

— MSM: 309.0/100K, which translates to:

106.0 times the rate among men who have sex with women only, varying by states from 39.2-342.1 times

— 167.5 times the rate among women

— the highest rates of primary and secondary syphilis among MSM were in the South and West, the top 5 being in North Carolina (peaking at 748/100K), Mississippi, Louisiana, South Carolina, and New Mexico

—  the highest rates of primary and secondary syphilis overall were in Louisiana, California, North Carolina, Nevada, Florida, Arizona, Oregon, Maryland, Illinois, and Mississippi.

— As a point of historical reference, the lowest state specific MSM primary and secondary syphilis rate in 2015 was 73.1/100K in Alaska, surpassing the highest overall US primary and secondary syphilis rates in 1946, at 70.9/100K

— this analysis was limited by a few issues: only 44 states had the sex of sex partners reported for >70% of male cases; the number of MSM in each state was estimated based on surveys and there may be significant underestimation; and the incidence of syphilis infections may be underreported.

 

—————————————————–

Another article looked at 1-dose versus 3-dose regimens of intramuscular benzathine penicillin for early syphilis in patients with HIV (See DOI: 10.1093/cid/ciw862).

Details:

— 64 patients were randomized to 2.4 million versus 7.2 million units of intramuscular benzathine penicillin for early syphilis (2.4 million units every week for 3 weeks). The study was from 2009-2013.

–mean age 35, 95% male, 84% MSM, 58% African-American/31% Hispanic/11% white, 6% primary syphilis/61% secondary/33% early latent, 59% had had syphilis before, mean CD4=388/64% on HAART, 49% of those on HAART had undetectable viral loads

— primary syphilis was defined as having compatible genital, anal, or oropharyngeal ulcers; secondary syphilis if they had skin rash or mucosal lesions.  Those with positive serologies (all had positive RPR as well as the more specific TP-PA, T pallidum particle agglutination) were classified as early latent syphilis if they had a documented negative result followed by a positive within 12 months, or at least 4-fold increase in RPR titer.

— median RPR at baseline was 1:128

— RPR and symptoms were monitored every 3 months, and treatment success was defined as at least a fourfold (2 dilution) decrease in RPR during 12 month follow-up.

Results:

— only 9 of the 64 patients had seroconversion (negative RPR after treatment), 4 in the 1-shot and 5 in the 3-shot groups

— intention to treat analysis: treatment success rate was 80% in single-dose versus 93% in 3-dose regimens, absolute difference 13%, but not statistically significant.

— Per protocol analysis: success rates were 93% with single-dose and 100% with 3-dose regimens, also not statistically significant.

— no difference by CD4 counts (< 350 vs >350), HIV viral load, use of HAART at baseline, RPR at baseline (<32 vs >=32), or syphilis stage

— only 1 of 20 (5%) patients with undetectable HIV viral load did not achieve treatment success ; whereas 8 of 44 with detectable HIV did not achieve treatment success, a non-significant difference, but there were 6 in the 1-shot group and 2 in the 3-shot group.

— no severe reactions (eg Jarisch-Herxheimer), and none developed neurologic symptoms during the follow-up period.

— They conclude that the current CDC recommendations for a single-dose of benzathine penicillin is reasonable for HIV-infected patients with early syphilis

Commentary:

— the historic concern here was that:

–Treponema pallidum was and is quite susceptible to penicillin

–essentially all adults with early syphilis have their RPR revert to normal after treatment with 2.4 million units of benzocaine penicillin, i.e. a single dose

— but, in those with HIV infection, about one third do not serorevert.

–there seemed to be a higher rate of abnormal CSF findings as well as clinical neurosyphilis in HIV-positive people at earlier stages of syphilis infection (these data predated  HAART therapies).

— However, clinical failure after 1-shot treatment was actually quite rare, though I saw a report of at least one HIV-infected patient who had progression to neurosyphilis after 2.4 M units of benzathine penicillin for early syphilis infection.

–so, many of us, myself included, automatically prescribed 3 weekly doses, or 7.2 million units. However subsequent data on seroreversion were not much better with this higher dose.

 

–is this study generalizable? And should we just follow the CDC guidelines (ie 1-shot of 2.4 million units of benzathine penicillin)?  There are a few issues:

–really small numbers of patients overall, so above study was underpowered to detect clinically significant differences

–overall a pretty healthy group from CD4 perspective. They did comment that of the 17 patients with CD4 <200 at the time of the syphilis diagnosis, all 11 with 1-shot and 5 of 6 with 3 shots had appropriate serologic response

–but the questions remain: does this apply to those who are more immunocompromized (eg a patient with CD4=50)? or those with detectable viral loads (there was difference noted above, though not statistically significant in this small study)? Does short-term followup of the surrogate marker of RPR titers necessarily correspond to clinical efficacy in the longer-term? Could some of these patients (perhaps with lower CD4 counts) still infect others while their RPR more slowly responds? Should we look at CSF findings (perhaps a better marker of neurosyphilis) and potential long-term neurologic outcomes instead of RPR?

 

So, my conclusions from this study:

— the big conclusion is that syphilis is increasing in MSM around the country, meaning that people seem to be less protected from the spread of other sexually-transmitted infections as well (eg HIV). And the syphilis/HIV coinfection rates are quite high: reported rates of 15.8% in Los Angeles and up to 47.4% in Philadelphia. Sounds like a potential public health (and individual) disaster waiting to happen…

— in terms of the appropriate treatment for syphilis, my guess is that the CDC guidelines are reasonable. But, given the dearth of clear data, my inclination would still be to use 7.2 million units (3 shots) in those more severely immunocompromised (eg CD4 under 200 or so ????, even more so if nonsuppressed HIV viral load). Would be great to have a larger study with more varied patients (different CD4 counts, viral loads, longer term followup including clinical outcomes, etc)

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: Cimetidine for Warts?

4 Apr, 16 | by EBM

By Dr. Geoffrey Modest

I was going through piles of old medical articles, intent on throwing them out in this electronic age, but then found one from 2005 looking at the use of cimetidine for warts (see J Am Podiatr Med Assoc 95(3):229). I have had several very impressive cases where using cimetidine, an H2-blocker but also used in the past as an immunoenhancer for some chemotherapy regimes, really worked. The first case was a 5yo male I saw about 25 years ago with very extensive longstanding perianal warts (condyloma acuminata). The dermatologist was planning rather extensive surgery, but commented to me that there were often responses to cimetidine. The patient took the med and the warts completely vanished within 1-2 weeks. The second case was me, complaining of a rather painful plantar wart. I saw our podiatrist, who tried liquid nitrogen therapy (which exceeded my pain threshold, though I had thought that was very high). So, I tried imiquimod for 6 weeks, to no avail. Given my experience with cimetidine with condyloma, I asked the podiatrist if cimetidine might help, and he produced this paper. So, several weeks after stopping the imiquimod, I began cimetidine 800mg bid and the wart was completely gone, literally within days!! I have recommended cimetidine to several people since then, with variable results (though a few also being quite dramatic. Including a young woman with really bad genital warts, where the warts recurred after extensive cryotherapy, and the dermatologists were at a loss on what to do next. I suggested cimetidine and the warts resolved within days and did not recur). In this light, here is the study I found:

  • 8-year retrospective analysis of cimetidine as first-line therapy for pedal verruca (plantar warts). 216 patients treated, 169 (78%) completed questionnaires a minimum of 15 months post-therapy
  • 90 males, 126 females; 180 were <18 yo, 18 were >25 yo
  • Cimetidine dose: kids –25-40 mg/kg/d in divided doses, adults 800 bid
  • Results:
    • Overall treatment success rate for all age groups: 84.3%
    • ​12 recurrences were after the completion of the study (7.2%): 7 in kids (5%) and 5 in adults (20%); in 2 of the recurrences, retreatment with cimetidine worked without further recurrences
    • Mean duration of treatment was 6.1 weeks in kids and 7.9 weeks in adults
    • In looking at the specific patients involved, 27 patients had personal or family history of autoimmune diseases (treatment success in 81.5%), 13 patients had prior failed surgical excision/curettage (cimetidine worked in 84.6%), 9 patients had successful response despite stopping the cimetidine early because of adverse effects, 5 patients had had symptomatic warts for >100 weeks with 80% success on cimetidine
    • ​Of the 47 patients who did not complete the questionnaires, 40 had documented outcomes by their clinician and 80% were treated successfully
    • Adverse effects: 15.7% (7.4% were GI, rather interestingly for cimetidine).

So, a few points

  • On review of what exists in the literature, there was another open-label study of 47 patients with multiple, nongenital warts treated with oral cimetidine for 3 months (at 30-40 mg/kg and a higher dose of 800mg tid for adults) finding improvement in 87% of children and 68% of adults, and complete clearance in 56% of kids and 44% of adults. followup data showed no recurrences in the 65% of patients they could reach who had complete clearance by the end of the study, though warts recurred if treatment stopped before all warts had cleared (see Clin Exper Dermalol 2000; 25: 183).
  • There were 2 RCTs looking at cimetidine, but the only RCT I could find was of 54 patients with nongenital warts of at least 6 months duration, putting 36 patients on cimetidine 400mg tid vs placebo, finding positive responses in 37% on cimetidine and 25% on placebo, a nonsignificant difference (i.e., though the cimetidine group did better, this was too small a study to draw conclusions (see Arch Dermatol 1997: 133: 533)). Of note, another report (Eur J Dermatol 2003; 13(5): 445) found that only high-dose cimetidine worked clinically (30-40 mg/kg/d vs <20 mg/kg/d), and that those who responded had increased levels of IL-2 and IFN-gamma mRNA levels (as produced by Th1 cells) and decreased IL-16 mRNA levels in tissues of effectively treated warts. And the inconclusive RCT used a lower dose.
  • Overall, cimetidine does seem to work somewhat better in kids (who do have higher likelihood of spontaneous resolution, though the success rate above is impressive). I could not find much data regarding condyloma acuminata, other than occasional anecdotal reports (J Urol 2000; 164:1074, which found 4 of 4 kids with extensive genital warts had resolution with 3 months of cimetidine; though there are also some small reports of failure)​. And bigger, better RCTs are pretty unlikely to happen, given this is a cheap generic drug, hence unlikely to get a drug company to sponsor.
  • How should it be given??? Unclear. I have used the higher doses above (adults: 800mg bid; kids 30-40 mg/kg) until the warts resolve. Of note, in the above studies, most people got the drug for 2-3 months. And some not responding by that time did so by extending the course several months more.
  • I should also add that in my experience, I have had better response to condyloma acuminata with cimetidine than with repeated cryotherapy, or use of caustics such as podophyllin. I have prescribed imiquimod cream with some success, though it is also irritating and very expensive (and only approved for those >12yo)
  • So, it is with some trepidation that I present this study, since the RCTs were not so good, cimetidine is not even listed as an option by the CDC in their sexually-transmitted disease compendium, and Up-To-Date mentions it dismissively. But given the above anecdotes (one quite close to my heart), and given that this is such a benign treatment, it might be worth considering.

Primary Care Corner with Geoffrey Modest MD: M. gentialium

6 Aug, 15 | by EBM

By: Dr. Geoffrey Modest

As a followup to my blog post on the CDC guidelines for sexually-transmitted diseases, there was a recent study looking at Mycoplasma genitalium resistance in the Netherlands (see doi:10.1093/jac/dkv136). And this comes right after the comment from prior my blog noting that M. genitalium  “does respond to 1-g single dose of azithromycin (though resistance is emerging)“. (I will highlight the section on M. genitalium below, since it seems to becoming an increasingly important actor on the STD stage).

Details of the Netherlands study:

–​they looked at all urogenital samples from Feb 2012 to Nov 2014 in the east of the Netherlands to identify the frequency of gene mutations associated with macrolide-resistance

–44 of the 146 samples (30.1% overall, from  55 males and 91 females) had 1 of 3 mutations associated with macrolide resistance

–treatment failure was noted in 4 patients. in 1 patient, using moxifloxacin resulted in microbiologic cure.

In contradistinction to the CDC guidelines, the above authors state: “M. genitalium infections should be treated with the macrolide antibiotic azithromycin, preferably using the 1.5g extended course (500mg once, followed by 250 mg/day for 4 days), since a 1 g single-dose treatment has been shown to lead to a greater development of resistance to macrolide antibiotics“. So, not sure how to reconcile this with the CDC recommendations for the 1 gram single dose. And this is, I think, a pretty important issue, with the emergence of M. gentalium as a major pathogen causing urethritis, cervicitis, PID and possibly infertility in women. The above study was preliminary, since they did not have great specific followup data on the outcomes of therapy.  But this does further raises the issue of emerging azithromycin resistance, and suggests:

–that it would be useful for local labs or the public health department to periodically test samples for M. genitalium and specific gene sites for azithro resistance, and let us know how things are going. and also track clinical resistance to azithro

–I’m not sure what to make of the comment that the 5-day course of azithro is better than a single dose of azitho. In my search I could not find data on the 5-day course for chlamydia (though it would make sense, given the efficacy of longer courses of doxy) , so without that data, I would be hesitant to use the longer course of therapy even for patients who are highly likely to adhere to the longer therapy

–but the real take-home message is that we are likely to see increasing M. genitalium resistance in the US, that we should still treat as we are with azithro and ceftriaxone empirically to cover the major pathogens, but that we should be very aware of potential resistance and switch to moxifloxacin if clinically appropriate….

–it should be noted, however, both that azithro resistance is happening in other countries (eg, a recent study found 39% of specimens were resistant in Australia), and there is the beginning of emergence of moxifloxacin resistance (another Australian study recently found 43% azithro resistance and 15% fluoroquinolone resistance, with documented cases of clinical resistance to azithro and moxifloxacin).​

Primary Care Corner with Geoffrey Modest MD: New STD treatment guidelines

24 Jun, 15 | by EBM

By: Dr. Geoffrey Modest

The CDC just updated their guidelines on the treatment of sexually transmitted diseases (see here).

They offer the usual advice to do detailed risk assessment for STDs and HIV, counseling about prevention, making sure immunizations are up to date (eg HPV, hepatitis A and B — they do limit hepatitis A vaccine to MSM, injection drug users, and those with HIV or chronic liver disease; though those of you privy to my prior blogs know that I strongly favor all getting hepatitis A vaccine, given the occasional outbreaks in the US, the increasing travel to countries where hep A is prevalent, the lack of adverse effects from the vaccine, and the fact that it is now being given to all little kids). They also comment on the use of treating HIV aggressively (treatment as prevention, also see here) and the utility of  pre-exposure prophylaxis (the recent CROI meetings had several important papers on this, including the IPERGAY trial, which showed that 2 tabs of tenofovir/emtracitibine (truvada) 2-24 hours before unprotected sex in serodiscordant couples, then 1 tab in 24 hours, and another in 48 hours was stopped early because of efficacy).

Here are some of the changes over previous guidelines:

–sections on transgender men and women (noting the high prevalence of HIV in transgender women — ie, transgender male to female)

–mycoplasma genitalium, in 15-20% of male urethritis, and 30% of men with recurrent urethritis (ie more common than gonorrhea and chlamydia). Pathogenic role in women less clear, though is found in both asymptomatic and symptomatic women (10-30% of cases of clinical cervicitis and 2-22% of PID cases). Does not respond to beta-lactams such as penicillins/cephalosporins, responds inadequately to a 7-day course of doxycycline  (31% cure rate), but does respond to 1-g single dose of azithromycin (though resistance is emerging). If treatment-resistant, can try moxifloxacin (400mg daily for 7,10, or 14 days). Not tested extensively, but small reports of very high cure rates. Consider 14-d course if treatment-resistant PID. Treat sex-partners.

–patients with HIV should have annual screening for hepatitis C in those at high risk for infection

–urethritis: best test for men is NAAT (nucleic acid amplification test) in urine for GC/chlamydia. Same treatment (azithro 1 gm once or doxycycline 100 bid for 7 days), though M gentalium (the most common cause of persistent or recurrent non-gonococcal urethritis) responds better to azithro (see above). Also consider trichomonas. No NAAT is FDA-approved for men, but can still do a urinary test or just treat empirically (and I have seen several cases of symptomatic presumptive trich urethritis in men, responding to treatment with metronidazole)

–cervicitis: test for cervicitis or PID with NAAT of vaginal, cervical, or urine samples (though you should check with your lab. Ours finds lower sensitivity with urine specimens). First catch urines are more sensitive, esp for chlamydia. Or can do self-collected vaginal swabs. Also evaluate women with cervicitis for BV and trichomonas. Consider treating M genitalium, as above, if persistent cervicitis after using azithro or doxycycline.

–gonorrhea: as in prior guidelines, given emergence of resistance, should be treated with both ceftriaxone 250mg IM, and azithro 1 g (though can use cefixime 400mg if ceftriaxone is not available).

–vaginal discharge: no signif changes that i detect, but they do note that BV can be associated with ureaplasma and mycoplasma, and that all women with BV should be tested for other STDs and HIV. For trich infections: 70-85%  have minimal or no symptoms, 2-3x increased risk for HIV acquisition, and NAAT is the preferred diagnostic method (picking up 3-5x more infections than wet mounts). Candida: nonalbicans candida is pretty common, >50% of women with it are minimally or not symptomatic, and treatment remains unclear (?longer duration of nonfluconazole azoles, using 600mg boric acid).

–PID: now <50% associated with gonorrhea or chlamydia. Lots of “normal” vaginal microorganisms and others (mycoplasma, ureaplasma, CMV, M genitalium) have been implicated. no change in management

–HPV updated section on vaccines and alternative treatments. advised not to use podophyllin (irritation, occ severe systemic toxicity)

–anal cancer screening: data insufficient to recommend routine screening for people with HIV, MSM without HIV, general population

–section on sexual assault and abuse/STDs: pretty complete (to me), includes using NAATs for chlamydia and gonorrhea at sites of penetration, as well as trich. Also check HIV, hep B and syphilis

Overall, this is a very comprehensive, 110-page document (138-page, if include references), with pretty much everything related to STDs including clear and highlighted treatment regimens, and, I think, would be reasonable to download onto your computer desktop if you see patients with sexually transmitted diseases…​

Primary Care Corner with Geoffrey Modest MD: Syphilis treatment in HIV positive patients

17 Feb, 15 | by EBM

By: Dr. Geoffrey Modest

A recent article assessed retrospectively the utility of a single shot of benzathine penicillin 2.4 M units (BPG) for the treatment of early syphilis in HIV positive patients (see DOI: 10.1093/cid/ciu888​), as is recommended by the CDC.

Untitled

Baseline:

–US Military HIV Natural History Study cohort of 350 people with 478 cases of early syphilis diagnosed between 2002-2009 (median year 2006)

–median age 28, 22% white/63% African American, 99% male, and median CD4 count at HIV diagnosis 506 (348-649) and at first syphilis case of 483 (376-636), 59% on HAART at syphilis diagnosis

–30% were treated with one dose of BPG and 52% with >= 2 doses

–early syphilis was defined as converting to a positive nontreponemal test, confirmed by treponemal test, within 365 days of a negative test

–response to treatment at 13 months was defined as a >= 4-fold decline in nontreponemal titers

Results:

–91% responded to treatment by 13 months, 97% by 24 months

–median time to treatment response was 5 months

–no difference in response to treatment by numbers of BPG shots

–multivariate analysis: older age was associated with delayed response; higher pretreatment nontreponemal titer and higher CD4 at time of syphilis diagnosis was associated with shorter time to treatment response. HAART use and HIV viral load were not related to response

The authors note that the CDC recommendations are based on pretty poor data, and that there are no good randomized controlled trials on the question of the best treatment regimen.

So, I remain unconvinced that a single BPG injection should be standard therapy, for the following reasons.

–this is a retrospective analysis. Were there clinical differences between the patients that led the treating provider to choose 1 vs 2+ injections of BPG?? Were those given only one shot fundamentally different/healthier than those given more?

–this group had largely preserved immunologic function, with >50% having CD4 counts of >500, the lowest CD4 count being 348, and had a low viral load (median log of 2.4 copies/ml). And even with that, the study did find that those with lower CD4 counts in this pretty healthy group took longer to respond to treatment. What if their CD4 count were 58?? Would one shot work???

–​there were several case reports awhile ago (probably 20+ years and, as i recollect, prior to HAART) of very rapid progression from syphilis infection to clinical neurosyphilis within 1-2 years in patients treated with only 1-2 shots of BPG (I did find one reference for rapid development of neurosyphilis: Ann Intern Med. 1990;113(11):872). As a result of these early reports, I have been using 3 shots (the same as required for late syphilis) for the few cases I have seen​

–the reason I bring this up is, first, that there has been a significant increase in syphilis cases over the last several years, and, second, that there seems to be a lot of chatter on the internet about how we can now use one one shot of BPG to treat early syphilis in HIV patients, based on the above article. And, it may be true that one shot is sufficient, especially in the era of HAART, but I do not think this article proves it…..

Primary Care Corner with Geoffrey Modest MD: Non-cephalosporin gonorrhea therapies

27 Jan, 15 | by EBM

By: Dr. Geoffrey Modest 

As perhaps a follow-up to the last blog on pelvic exams, there was an article in Journal of Infectious Diseases looking at non-cephalosporin treatments for gonorrhea (see doi: 10.1093/cid/ciu521). This article is important because of the increasing resistance of gonorrhea to multiple agents over the past 50 years (eg, sulfa, penicillins, tetracyclines, cipro). At this time the only recommended treatment by the CDC is cephalosporins (eg, ceftriaxone, since there is too much resistance to cefixime), but there are reports of resistance to ceftriaxone, and it is unclear what to do if the patient has significant cephalosporin allergy. Hence the importance of this study, where 401 patients (mean age 27, 35% MSM, and only 10% women, 60% black, 22% white, 9% HIV positive), from 5 sites across the US with uncomplicated GC aged 15-60 were randomly assigned to gentamicin 240 mg IM plus azithromycin 2 gm orally, or gemifloxacin (a 4th generation fluoroquinolone) 320mg orally plus azithromycin 2 gm orally. Primary outcome was microbiological cure at 10-17 days after treatment. This study was supported by the CDC and NIH. Results:

–202 patients receiving gentamicin/azithro: 100% cure, including 10 of 10 pharyngeal infections and 1 of 1 rectal infections
–199 patients receiving gemifloxacin/azithro: 99.5% cure, including 15 of 15 pharyngeal infections and 5 of 5 rectal infections​ (the one patient who failed therapy probably had a reinfection)
–GI adverse effects were common and pretty similar in both groups: 30+% with nausea, 5% with vomiting, 20% with diarrhea — the vast majority being “mild”. Somewhat more GI toxicity in the gemifloxacin arm, though probably the GI toxicity is largely from the azithro.

So, these may be important therapies in the future. Azithro 2gm has good efficacy as monotherapy, but the concern is that gonorrhea develops resistance to macrolides pretty easily. The above is clearly a preliminary study. there are concerns about the skew of the patients (eg, very few women), and how easily gonorrhea might develop resistance to these meds (though it is heartening that there was a 100% cure rate, and the likelihood of resistance is probably less with double therapy). But this seems pretty reasonable to me for patients either with cephalosporin resistance or intolerance.

Primary Care Corner with Geoffrey Modest MD: CDC Circumcision Guidelines

4 Dec, 14 | by EBM

By: Dr. Geoffrey Modest

The CDC just came out with final recommendations targeting provider counseling regarding male circumcision (not yet available on the CDC website). The focus of these recommendations is to help with prevention of HIV, sexually transmitted infections (STIs), etc.

They note the following:

–The final decision about male circumcision is not only based on health considerations, but includes a variety of social, cultural, ethical and religious considerations

–3 African studies (with very high baseline prevalence of HIV) have shown a 50-60% decreased risk of HIV transmission with circumcision of men engaged in penile-vaginal sex. Additionally, there was a 30% decreased transmission of HSV-2 (herpes simplex virus type-2) and HPV (human papilloma virus). Note: most new HIV infections in the US occur in men who have sex with men (MSM), for which there are no data that circumcision is effective.

Their formal recommendations:

–HIV risk assessment should be done on all who are at risk of acquiring HIV from heterosexual sex (though seems to me that this should include homosexual sex……)

​–Adolescents and men having heterosexual sex should be informed that circumcision reduces but does not eliminate potential transmission of HIV and other STIs, though there are no data for oral or anal sex. Also no data that circumcision reduces risk of transmission to women (though in the US, 10% of new HIV infections are from women to men, so the data suggest these men may benefit)

–After circumcision, avoid sex until the wound is healed

–Although some epidemiologic data suggest protection by circumcision for MSM who have insertive rectal sex, there are no convincing data to confirm this, and it is biologically unlikely that there is any protection for the anal-receptive partner

–Risks and benefits of circumcision should be reviewed with patient​

–In terms of neonatal circumcision, parents should know that circumcised males are less likely to get urinary tract infections (which are pretty uncommon, anyway), balanitis, HIV/STIs as above, penile cancer (also uncommon) and possibly prostate cancer

–Timing of neonatal circumcision: parents should know that neonatal circumcision is safer and heals more rapidly than when done in older boys and men, and costs less. though most of benefits are after the male is sexually active

–Complications: in newborns up to age 9, <0.5% and mostly bleeding/inflammation/need for corrective procedures. In those >10yo, 5% with complications as above and penile wounds. The American Academy of Pediatrics taskforce states that benefits outweigh risks for families who desire it.

baby

Primary Care Corner with Geoffrey Modest MD: Whither the pelvic, again

29 Oct, 14 | by EBM

BMJ had a recent systemic review and meta-analysis of urinary screening for HPV (DOI: 10.1136/bmj.g5264), including 14 studies with 1443 women, comparing urine HPV DNA screen with cervical DNA screen.

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Findings:

–Urine detection of HPV had a pooled sensitivity of 87% (CI: 78-92%), and specificity of 94% (CI: 82-98%)

–Urine detection of high risk HPV (15 serotypes assessed) had a pooled sensitivity of 77% (CI: 68-84%), and specificity of 88% (CI: 58-97%)

–Urine detection of HPV 16/18 (the worst of the high-risk) had a pooled sensitivity of 73% (CI: 56-86%), and specificity of 98% (CI: 91-100%)

–Translation of above: the high specificity suggests that positive test results are 15 times more likely to occur in HPV positive women; the less-high sensitivity suggests that a negative test results would happen only 7 times more frequently in non-infected women. For those with HPV​ 16/18, positive test results are 37 times more likely to occur in HPV positive women and negative test results would happen only 4 times more frequently in non-infected women.

–Sensitivity for urinary HPV testing increased with first void urine, on meta-regression analysis

So, we have moved away from annual pelvic exams for pap smears and gc/ct (gonorrhea/chlamydia) screening of yore to much less frequent pap smears (beginning later, at age 21, and with frequency of every 3-5 years depending on age and HPV testing, and with several European countries currently assessing doing only HPV testing without cytology). And now perhaps we are moving to just doing urine testing for HPV in the future, maybe even as a sole initial screen. And we have transitioned from cervical gc/ct screening to urine gc/ct tests. In addition, women with vaginal discharges are often appropriately self-treating (eg for yeast) or getting medications for various infections without pelvic exams (eg, urine testing for trichomonas, or simply empiric therapy for bacterial vaginosis/BV). As a result, as clinicians we certainly are doing many fewer pelvic exams now as compared to a couple of years ago. Though, clearly, pelvic exams are invasive, uncomfortable procedures that many women would love to avoid, I do have one caveat. I have seen several episodes where a woman has potential PID and the clinician is comfortable with just sending a urine for GC/chlamydia. The issue here is that GC and chlamydia are not the only culprits (the data are a bit murky here, since there are so many potentially infectious pathogens in the vagina, but it is likely that PID is caused by mycoplasmas, ureoplasmas, BV, and, very often, mixed organisms – both aerobic and anaerobic). And there can be other causes of acute pelvic pain besides PID (eg, ovarian cysts, appendicitis, endometriosis, assorted GI problems including bowel obstruction and constipation…). Again, I think it is great that we clinicians need to do fewer pelvic exams. My concern is that this mind-set may lead to not doing one when it is clinically indicated.

Geoff

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