Antibiotic Treatments of Sexually Transmitted Infections So this is going to be a straightforward note set designed to accompany a very straightforward lecture. Dr. Mushatt covered some clinical presentations and treatments of syphilis, gonorrhea, and chlamydia. Any questions, comments or concerns, let me know! [email protected] Case 1 Presentation A 35 year old woman comes to the clinic complaining of red patches on her skin. She has experienced malaise recently and has swollen glands on her neck. She is sexually active with multiple partners and recalls having a small, non-­‐
tender sore on her labium a few months ago which has healed. On physical exam, her vital signs are stable (VSS). Examination of the skin reveals erythematous macules on her palms and soles (example shown at right). Lymph node palpation reveals cervical and axillary lymphadenopathy. Genital exam reveals no genital lesions or urethral discharge. You dutifully send off a sample of her urine for PCR for chlamydia and NAA (nucleic acid amplification) for gonorrhea. (These molecular diagnostic tests are the mainstay now. We no longer swab urethras and send samples to labs or rub them on chocolate agar plates.) Her serum is sent for an RPR (rapid plasma reagin), which comes back positive at a titer of 1:256. Recall from the microbiology block that the RPR test is used as a screening test for asymptomatic syphilis. As a screening test, it is pretty good at picking up people who are positive for syphilis (it has pretty good sensitivity), but it is not the most specific of tests and can be prone to give false positive results, which are especially a problem in certain viral infections [EBV, etc.], the elderly, pregnant women, and others. A good confirmatory test with higher specificity to rule in the diagnosis of syphilis is the TP-­‐PA test (Treponema pallidum particle agglutination assay). In our 35 year old patient, the TP-­‐PA test comes back positive, which confers the diagnosis of secondary syphilis. Clicker Question: Which of the following is the best treatment? a) Doxycycline for 14 days b) Procaine penicillin G IM x 1 c) Azithromycin 1200 mg PO x 1 d) Penicillin VK x 7 days e) Benzathine penicillin G IM x 1 Repository Preparations of Penicillin While doxycycline could be used (if she had an anaphylactic penicillin allergy), it is not as effective as benzathine penicillin G, which is an intramuscular depot preparation of penicillin that has a half life of many days. The compound benzathine allows for an extraordinarily slow release of penicillin from the depot injection so that it takes days to weeks for the penicillin to be released systemically. Thus, benzathine penicillin G maintains therapeutic concentrations of penicillin for 7 to 14 days according to Dr. Mushatt’s lecture (and for up to a month according to PharmWiki), and it is considered the work horse for the treatment of most forms of syphilis short of neurosyphilis. The peak serum concentrations of benzathine | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e S l e a z i e r ” Antibiotic Treatments of Sexually Transmitted Diseases penicillin G are not very high – roughly 0.15 IU/mL – so it couldn’t be used to treat something like pneumococcal pneumonia or group A strep pharyngitis, but it definitely is useful in the treatment of secondary syphilis. Procaine penicillin G is not an appropriate answer to the question of how to treat our syphilitic 35 year old. Procaine is a salt that allows for a gradual release of penicillin from the IM depot, but it has a much shorter half-­‐life of 12 to 24 hours compared to that of benzathine penicllin G. According to PharmWiki, procaine penicillin G is indicated primarily for skin and soft tissue infections, but it’s not used that much any more. Back in the day, procaine penicillin would be used for things like pneumococcal pneumonia, because it can maintain peak serum concentrations of 2 IU/mL (much larger than benzathine penicillin G’s peak concentration). You can see it still being used in the same way in developing countries now, but not so much in the states. The single oral doses of azithromycin or penicillin VK (oral penicillin) would absolutely not be appropriate for secondary syphilis. Stages and Natural History of Syphilis In a fashion similar to TB, soon after primary infection with Treponema pallidum the organisms will disseminate throughout the body, including to the central nervous system. Of course, T. pallidum first grows most at the site of infection, resulting in primary syphilis with its characteristic painless chancre. Untreated primary syphilis will develop into secondary syphilis, which is classically characterized by a disseminated rash and generalized lymphadenopathy. Syphilis however is known as the “great masquerader” and often presents with uncharacteristic symptoms (lacking a rash, lacking lymphadenopathy, etc.). Other symptoms that secondary syphilis can present with include mucous patches (superficial ulcerations in the genital and/or oral mucous membranes), condylomata (wart-­‐like lesion[s], usually near the genitals), alopecia (hair loss), and hepatitis (HBV and HCV negative with a markedly elevated ALP compared to AST and ALT – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1671946/?page=1). Therefore, if you suspect someone might have syphilis because of their history of sexual activity exposures, even if they are not presenting with classic symptoms, you should definitely order one of the screening tests – an RPR or VRDL. The RPR is | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e S l e a z i e r ” Antibiotic Treatments of Sexually Transmitted Infections really cheap so you don’t have an excuse. Remember as well that patients do lie –especially about their sexual history if its been questionable. If you don’t believe me and need validation, you should watch the episode “House vs. God” from Season 2 of House. It’s a good one. In secondary syphilis, the sensitivity of the RPR test approaches 100%, which is not true for when the test is used in any of the other stages of syphilis. As long as the RPR isn’t detecting a false positive, you will almost definitely detect syphilis if the patient is in the secondary phase. Almost all syphilitic patients, if they aren’t treated, will progress from secondary syphilis to an asymptomatic phase called latent syphilis. Latent syphilis simply means that there are no outward manifestations of the infection. About ¾ of latent syphilitics will have no further complications (progression to tertiary syphilis is not a done deal). About ¼ to 1/3 of latent syphilitics are thought to progress to tertiary syphilis. Tertiary syphilitic symptoms are very rare in this country. Dr. Mushatt has never seen cardiovascular syphilis in the US, but it could develop along with other tertiary symptoms such as neurologic complications (general paresis, dementia, tabes dorsalis[http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001742/]) or syphilitic gumma (a collection of spirochetes and lymphocytes that accumulate in an organ). Treatment of Syphilis For primary and secondary syphilis, both of which are forms of early syphilis, a dose of 2.4 million units of benzathine penicillin G is indicated. While official recommendations are for this to be given in a single dose, 2.4 million units is a large amount to be injected into a muscle and can cause considerable pain for the patient, so most practitioners split it up into 2 doses of 1.2 million units each benzathine penicillin G. For treatment of latent syphilis, if you know that the infection has occured within the last year (it’s early latent syphilis), you can give the same dose: 2.4 million units of benzathine penicillin G in a single dose or split up in two doses. However, if you know the infection occured more than a year ago (it’s late latent syphilis) or if you do not know the duration of the latent syphilitic infection, a much larger dose is indicated: 7.2 million units total of benzathine penicillin G administered as 3 doses of 2.4 million units IM each at 1 week intervals. This much larger dose will maintain a higher antibiotic exposure of a longer period of time – greater than 4 weeks. Dealing with Penicillin Allergies -­‐ Doxycycline is an alternative to benzathine penicillin G, but if you are treating a pregnant woman or if you are treating someone who is likely to have poor adherence, you must consider performing a penicillin skin test to evaluate the severity of the allergy and desentizing the patient to penicillin so | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e S l e a z i e r ” Antibiotic Treatments of Sexually Transmitted Diseases you can treat with benzathine penicillin G. The table on the bottom of the previous page shows a desensitization protocol for penicillin. You start with low doses (100 units) of oral penicillin and gradually add until you’ve administered a very high cumulative dose of 1.3 million units, monitoring the patient to make sure anaphylaxis doesnt occur. Interestingly, you can desensitize for most drug allergies. There are a couple of different types of neurosyphilis. If someone comes in with symptoms of meningitis with an inflammatory infiltrate, it’s part of secondary syphilis and is considered syphilitic meningitis. Tertiary syphilis though manifests in tabes dorsalis (gait disturbances, dementia, generalized paresis). Syphilitic meningitis can present within weeks or months of an infection, but tabes dorsalis takes decades to develop. So the treatment of neurosyphilis requires high doses of IV penicillin (aqueous crystalline penicillin G at 18-­‐24 million units per day – administered as 3 to 4 million unit doses every 4 hours or by a continuous infusion). The high IV dose is an attempt to get penicillin to cross the blood brain barrier, since it doesn’t cross very readily. Alternative options include giving daily doses of the procain penicillin at 2.4 million units IM per day along with probenecid. Probenecid, you might recall, blocks renal tubular reabsorption of uric acid and is normally used in the treatment of gout, but in this case we’re using it because it also blocks renal tubular secretion of penicillin, so it helps to maintain high serum levels of penicillin to try to increase the amount of penicillin crossing the BBB. Proof of neurosyphilis is found in a positive blood test for syphilis along with any abnormality of the CSF (like high WBCs or high protein, etc.) plus a positive VDRL of the CSF. Case 2 Presentation A 21 year old college student comes to the clinic complaining of burning urethral discharge for the past few days. On physical exam, there is cloudy discharge from his urethral meatus, but no genital lesions (ulcers or warts) are found. Clicker question: Which of the following is the most appropriate regimen? a) Doxycycline x 7d b) Ciprofloxacin c) Azithromycin 1 g PO x 1 d) Ceftriaxone 250 mg IM x 1 e) Ceftriaxone 250 mg IM x 1 plus azithromycin 1 g PO x 1 The correct answer is ceftriaxone plus azithromycin. The cloudy urethral discharge leads us to believe he likely has gonorrhea, so we empyrically treat for an uncomplicated gonococcal infection with ceftriaxone. However, gonorrhea and chlamydia often travel and infect together, so we need to add azithromycin to cover chlamydia. As we all know, we’re all going to die of gonorrhea because of its increasing antibiotic | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e S l e a z i e r ” Antibiotic Treatments of Sexually Transmitted Infections resistance so oral cefixime and injectible cephalosporins are no longer recommended. Additionally, gonorrhea is becoming increasingly resistant to ciprofloxacin, so don’t use that against gonorrhea either. Chlamydia As for chlamydia, the recommended treatments are high dose azithromycin or doxycycline. The alternative regimens shown in lecture (erythromycin, levofloxacin, ofloxacin) are so rarely used that they didn’t warrant further discussion. Continuing with the case You send the undergraduate’s urine for PCR for Chlamydia trachomatis and Neisseria gonorrheae. Both tests come back positive, confirming that you did the right thing by empyrically treating with both antibiotics. There is at least one caveat to our new molecular diagnostic techniques: Because we are no longer really doing culture isolations for these organisms, we cannot test for antibiotic resistance in them, and so we have to treat with empiric antibiotics to which the organisms we are treating might be resistant. The recommendation is now that if you do have a patient who has refractory gonorrhea that simply can’t be cleared, you do want to culture the organism and determine its MICs. Clicker question: Which of the following should also be tested for? a) HIV b) HIV + RPR c) HIV + RPR + HCV d) HIV + RPR + HCV + HBV e) HIV + RPR + HPV Everyone should have an HIV test at least once in their lifetime if they’re sexually active, and if they’re in a high-­‐risk sexual behavior group, they should likely have 1 a year. Additionally, all sexually active people should probably have a syphilis screening test at some point too. While Hep C and Hep B viruses can be transmitted sexually, the tests for these in this particular instance with a young 21 year old college student are likely not cost effective. Hep B is seen much more often in IVDAs, etc. However, a few months ago, the CDC did come out with new recommendations for screening: for the Baby Boomer generation (born 1945 – 65), the CDC now recommends screening for hepatitis C in addition to the STIs (HIV, syphilis, gonorrhea and chlamydia). This population is the age group at highest risk for hepatitis C primarily because at the time the blood supply was not being tested for hepatitis and many people received infected transfusions. Good luck on Friday! | T 2 F o r D u m m i e s , “ M a k i n g S e c o n d Y e a r a L i t t l e S l e a z i e r ” 

Double-blind trial of amoxycillin and ampicillin plus probenecid in

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YOUTH AND SEXUALITY All cultures are affected by