1. Updates in Infectious Diseases Sandra A. Kemmerly, MD, MACP, FIDSA 26 June, 2015

2. Disclosure of Financial Relationship Sandra Kemmerly, Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients

3. Objective: Select clinical infectious diseases papers of interest to general internists and family physicians.

4. Amoxicillin for acute rhinosinusitis. A randomized controlled trial. Garbutt JM, Banister C, Spitznagel E, Piccirillo JF JAMA 2012;307:685-692.

5. Background: 1 in 5 antibiotic prescriptions for US adults is for treatment of sinusitis. Antibiotic resistance increasing, want to limit use to those for whom it will provide help. Trials of antibiotics for sinusitis have had conflicting results. ‒ Those requiring confirmatory tests like sinus x-rays tended to show antibiotic benefit ‒ Those using clinical diagnostic criteria tend to show no or minimal benefit ‒ CDC expert panel’s evidence-based guidelines recommended clinical criteria for diagnosis and antibiotics only for those with moderately severe or severe symptoms. Use narrow spectrum antibiotic

6. Methods: Randomized, placebo-controlled trial in 166 adults with uncomplicated, acute rhinosinusitis from 10 community primary-care office practices. Diagnosis: maxillary pain or tenderness, purulent nasal secretions, and rhinosinusitis symptoms for 7 days or more; but not more than 28 days. Amoxicillin 500mg tid vs. placebo for 10 days. All got week supply of symptomatic treatments for pain, fever, cough and nasal congestion. Primary outcome: quality of life after 3 days of treatment assessed by Sinonasal Outcome Test-16 (SNOT-16).

7. Results: No significant difference between antibiotic and placebo: At day 3*, same (37% Abx better vs 34% placebo). At day 7, antibiotic group better (74% vs 56%). At day 10, same (78% vs 80%). * Primary outcome

8. Take home message: First trial of antibiotics for sinusitis to assess improvement in disease-specific quality of life as primary outcome (what patients want). In both groups, sinus symptoms improved over time with no difference at 10 days. No differences in work days missed, satisfaction with treatment, rate of relapse, or amount of additional medical care. Don’t give antibiotic to usual patient with acute sinusitis.

9. Most prescribed antibiotics for adults US: Top Antibiotic Drugs, Adults, BCBSM, 2009 Product Name Total Spending in 2009 Number of Prescriptions Price per Course Azithromycin$4,234,950.16292,797$14.46 Amoxicillin$920,529.32184,921$4.98 Cephalexin$577,347.89113,861$5.07 Ciprofloxacin$392,565.25107,295$3.66 Amoxicillin-Clavulanate$2,131,969.6888,257$24.16 Trimethoprim- Sulfamethoxazole $384,944.2187,423$4.40 Doxycycline$532,470.6275,536$7.05 Levofloxacin$6,566,226.7859,525$110.31 Clindamycin$498,133.1853,473$9.32 Penicillin V$246,756.4242,614$5.79

10. Azithromycin and the risk of cardiovascular death. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. N Engl J Med 2012;366:1881-1890

11. Background: The macrolide antibiotics erythromycin and clarithromycin can increase the risk of serious ventricular arrhythmias and are associated with an increased risk of sudden death. Azithromycin, a widely-used macrolide, has been thought to be free of cardiac toxicity; adverse event reports gathered by the FDA suggest otherwise. Authors’ hypothesis: patients who took azithromycin would have an increased risk of sudden death when compared with persons who didn’t take antibiotics and with patients who took other selected antibiotics.

12. Methods: Retrospective cohort study of azithromycin use and mortality. Included persons aged 30-74 enrolled in Tennessee Medicaid Program who got azithromycin between 1992 and 2006 and who had no life-threatening noncardiovascular illness. Also included matched control periods during which there was no use of study antibiotics (four control periods for each azithromycin prescription). Also included control groups who took amoxicillin (including amox-clav), ciprofloxacin, and levofloxacin.

13. Results: Cohort: 347,795 persons with azithromycin prescriptions. ‒ 1,391,180 matched control periods with no antibiotic ‒ 1,348,672 amoxicillin prescriptions ‒ 264,626 ciprofloxacin prescriptions ‒ 193,906 levofloxacin prescriptions Azithromycin users mostly women (77.5%) Mean cardiovascular risk scores : ‒ Azithromycin 9.3 ‒ Amoxicillin 9.5 ‒ Ciprofloxacin 10.3 ‒ Levofloxacin 10.6

14. Results: Most azithromycin use for ENT infections and bronchitis; same for amoxicillin (62 and 63% of prescriptions). Sudden cardiac deaths during five-day course of treatment : ‒ Azithro: 65 per 1 million courses (n=22) ‒ No abx: 24 per 1 million periods (n=33) ‒ Amoxicillin: 22 per 1 million courses (n=29 )

15. Cumulative Incidence of Cardiovascular Death among Patients Who Took Azithromycin and Persons Who Did Not Take Study Antibiotics during a 10-Day Period. Ray WA et al. N Engl J Med 2012;366:1881-1890

16. Cumulative Incidence of Cardiovascular Death for Patients Who Took Azithromycin or Amoxicillin during a 10-Day Period. Ray WA et al. N Engl J Med 2012;366:1881-1890

17. Results: Azithromycin patients had an estimated 47 additional cardiovascular deaths per 1 million 5-day courses of therapy. As compared with amoxicillin, those who got ciprofloxacin had no increased risk of cardiovascular death; there was a nonsignificant trend toward increased cardiovascular death risk for levofloxacin. Death risk for azithromycin varied according to baseline risk for cardiovascular disease. ‒ Those in the highest decile of risk, had 245 additional cardiovascular deaths per 1 million courses.

18. Excess Risk of Cardiovascular Death with Azithromycin as Compared with Amoxicillin, According to Decile of Cardiovascular Risk Score. Ray WA et al. N Engl J Med 2012;366:1881-1890

19. Take home message: A short course of azithromycin was associated with an increase in cardiovascular deaths. Although the risk was small, it was greater than with amoxicillin. The increased risk for cardiovascular death didn’t persist after the course of therapy ended. Physicians should think twice about prescribing azithromycin for patients with cardiovascular disease and should first ask whether the patient needs an antibiotic at all.

20. Azithromycin for Prevention of Exacerbations of COPD N Engl J Med 2011; 365:689-698 Conclusions: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Based on the previous study, one wonders how many deaths there might be in this group!!!

21. CBS News/ March 12, 2013, 1:59 PM FDA warns azithromycin "Z-pack“ antibiotics could lead to deadly heart rhythms for some.

22. Early surgery versus conventional treatment for infective endocarditis. Kang D-H, Kim Y-J, Kim S-H, Sun BJ, Kim D-H, Yun S-C, Song J-M, Choo SJ, Chung C-H, Song J- K, Lee J-W, Sohn D-W. N Engl J Med 2012;366:2466-2473

23. Background: Guidelines advocate early surgery for patients with infective endocarditis and heart failure. Indications for surgery to prevent embolism are not clearly defined and debate continues. ACC-AHA* 2006: early surgery as Class IIa recommendation in those with recurrent emboli and persistent vegetation. European Society of Cardiology: early surgery as Class IIb recommendation for those with isolated, large vegetations (>15mm). *American College of Cardiology-American Heart Association

24. Background: There has been no randomized trial to make clear the indications for surgery and timing of surgery. Designed this study to compare surgery with conventional treatment in those with left-sided endocarditis and a high risk of embolism. Hypothesis was that early surgery would reduce the rate of death or embolic events.

25. Methods: Prospective, randomized trial at two centers. All had blood cultures and TTE within 24 hours of hospitalization. Enrolled consecutive patients 18-80 years old with native valve endocarditis defined by modified Duke criteria and severe mitral or aortic valve disease and a vegetation >10mm. Excluded those with: moderate-severe CHF, heart block, aortic abscess, penetrating lesions requiring urgent surgery, fungal endocarditis, coexisting major embolic stroke, right-sided vegetations, prosthetic valve or referral from another institution more than seven days after diagnosis of endocarditis.

26. Methods: Surgery done within 48 hours after randomization. Conventional group: surgery only if complications requiring urgent surgery developed during medical treatment or if symptoms persisted after end of antibiotics. Followed in hospital; then 4 weeks, 6 weeks, 3 months, 6 months and one year; then six month intervals until Sept 2011. Primary end point: composite of hospital death or clinical embolic events within 6 weeks of randomization. (didn’t count skin lesions or metastatic abscesses as embolic events).

27. Results: 37 in surgery group; 39 conventional Mean age 47; 67% men Mitral valve in 45; aortic in 22; both in 9. Severe regurgitation: 97% surgery; 92% conventional. Organisms: ‒ viridans streptococci……… 33% ‒ Other streptococci………… 31% ‒ Staphylococcus aureus….. 13% ‒ Enterococcus……………….. 3% ‒ Other………………………….3% ‒ Culture negative……………18%

28. Results: Primary end point of in-hospital death or emboli within the first 6 weeks after randomization: ‒ Surgery: 1 patient ‒ Conventional: 9 patients (P=0.03) ‒ At 6 weeks, rate of embolism 0% in surgery group and 21% in conventional treatment group (P=0.005).

29. Kang D et al. N Engl J Med 2012;366:2466-2473.

30. Cumulative Probabilities of Death and of the Composite End Point at 6 Months, According to Treatment Group. Kang D et al. N Engl J Med 2012;366:2466-2473. No difference in all cause mortality at 6 months. Composite end point of death from any cause, embolic events, recurrence of endocarditis, or repeat hospitalization due to CHF was: 3% in early surgery group and 28% in conventional treatment group (P=0.02).

31. Editorial: “..implication of this study for early surgery is profound..” “..endocarditis is a dangerous condition and the benefits of timely surgical intervention in patients with large vegetations and severe valvular dysfunction, even if they do not have congestive heart failure, outweigh the additional risk of surgery in patients with active infection.” Gordon SM, Pettersson GB. NEJM 2012;366:2519-2521.

32. Take home message: Early surgery in patients with left-sided endocarditis, severe valve dysfunction and a large vegetation (but without heart failure) reduced systemic embolization (the second most common cause of endocarditis death). Limitations: only applies to a subset of endocarditis patients. Less S. aureus than in most series. Don’t know how long from symptoms to randomization. Early surgery seems appropriate in the subset examined in this study. I would recommend it.

33. The role of asymptomatic bacteriuria in young women with recurrent urinary tract infections: to treat or not to treat? Cai T, Mazzoli S, Mondaini N, Meacci F, Nesi G, D’Elia C, Malossini G, Boddi V, Bartoletti R. Clin Infect Dis 2012;55:771-777

34. Background: Asymptomatic bacteriuria (AB) is the presence of bacteria in the urine without signs or symptoms of a UTI (independent of pyuria). AB is associated with adverse outcomes in pregnant women, and treatment of AB in this group decreases risk of pyelonephritis. Been assumed that AB defines a population at risk, and that elimination of bacteriuria will minimize risk for symptomatic illness. But, the role of treatment of AB in young women with recurrent UTIs has not been evaluated.

35. Methods: Evaluated the impact of AB treatment on UTI rates in young women with recurrent UTIs. Screened women attending an STD center for recurrent UTIs. Selected sexually active women 18-40; Hx of UTI in previous year but at least one month prior to enrollment; currently asymptomatic; had significant bacteriuria (10 5 CFUs/ml of single uropathogen) in 2 consecutive voided midstream urines.

36. Methods: Randomly assigned to: ‒ Group A = not treated (treated if got UTI) ‒ Group B = treated (based on susceptibility) Follow-up with cultures at 3, 6 and 12 months. Principal outcome: recurrence free rate at end of study period.

37. Results: Group A (not treated): 330 women Group B (treated): 369 women Development of symptomatic UTIs ‒ At 3 months: 3.5% group A; 8.8% group B ‒ At 6 months: 7.6% group A; 29.7% group B ‒ At 1 year: 14.7% group A; 73.1% group B Treatment of AB due to E. faecalis was associated with development of multi-drug resistant E. coli.

38. Probability of being recurrence-free Cai T et al. Clin Infect Dis. 2012;55:771-777

39. Caution: The study population was one that attended an STD clinic and had a history of multiple antibiotic courses for recurrent UTIs. (most had more than 3 UTIs/year). There was no control group of healthy young women. Nevertheless…..

40. Take home message: In healthy, sexually active young women with recurrent urinary tract infections, the treatment of asymptomatic bacteriuria increases the risk of subsequent infection and is associated with the development of resistant organisms. Don’t look for or treat asymptomatic bacteriuria in young women with recurrent UTIs.

41. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW et al. for the Partners PrEP Study Team. N Engl J Med 2012;367:399-410

42. Background: To impact the global HIV epidemic effective primary prevention strategies are critical. Antiretroviral prophylaxis is a potential HIV prevention strategy for uninfected persons given either as postexposure prophylaxis after high-risk occupational or nonoccupational exposure or as preexposure prophylaxis for those who have ongoing HIV exposure such as an HIV-seronegative person in a partnership with someone already infected (serodiscordant couple).

43. Methods: Randomized trial of antiretrovirals for preexposure prophylaxis among HIV-1 discordant couples in Kenya and Uganda. At enrollment, seropositive partner not eligible for treatment, according to national guidelines. Median CD4 495 (375-662). Seronegative partner (male in 62% of couples) assigned one of three regimens: ‒ Daily tenofovir (N=1584) ‒ Tenofovir plus emtricitabine (N=1579) ‒ Placebo (N=1584) Followed monthly up to 36 months.

44. Results: 82 HIV infections occurred: ‒ 17 in tenofovir group ‒ 13 in tenofovir-emtricitabine group ‒ 52 in placebo group Relative reduction of HIV infection in treatment groups 67%-75% (P<0.001). Protective effects not significantly different in two treatment arms. Eight of those treated were found to have been infected at baseline; antiretroviral resistance developed in two.

45. Cumulative Probability of HIV infection in the Modified Intention-to-Treat Analysis Baeten JM et al. N Engl J Med 2012;367:399-410.

46. Results: Better results than some other similar studies. Why??? Comprehensive package of HIV prevention services: counseling before and after testing, risk reduction counseling, screening and treatment for STIs, free condoms with training, referral for male circumcision and postexposure prophylaxis. Monthly visits with HIV testing, dispensing of 30 days of meds, adherence counseling, collection of prior months unused meds, pregnancy testing. 97% of study medication was taken. Condom use increased.

47. Take home message: In heterosexual, HIV discordant couples, oral prophylaxis with both daily tenofovir or tenofovir combined with emtricitabine protect against HIV transmission in both women and men. Preexposure prophylaxis can reduce HIV acquisition in heterosexual persons. High adherence is essential!!! Synergy between medication, risk-reduction counseling, methods to increase adherence.

48. New Germs

49. Lober, circ 1980s

50. Lorber B. Ann Intern Med 1996; 125:844-851. MERS Ebola Chikungunya virus SARS West Nile Virus Metapneumovirus Bird Flu Monkey Pox Novel H1N1 Dengue XDR Tb 21 st century

51. Chikungunya (CDC Bulletin May 14, 2015) What is the current situation? In December 2013, French Guiana reported locally transmitted cases for the first time in South America. Local transmission means that mosquitoes in the area have been infected with chikungunya and are spreading it to people. Local transmission of chikungunya is now being reported in other countries in the South America. As of February 23, 2015, the following South American countries have reported cases of chikungunya:

52. Chikungunya Virus

53. Chikungunya Transmission South America Bolivia Brazil Colombia Ecuador French Guiana Guyana Paraguay Peru Suriname Venezuela CDC Bulletin May 14, 2015

55. “New truths become evident when new tools become available” Rosalyn Yalow Nobel Laureate 1977