Update in Infectious Diseases 2012

1. Update in Infectious Diseases 2012 Keith B. Armitage, MD Professor of Medicine Case Western Reserve University

2. Disclosures • No conflicts

3. Topics • Clostridium difficile infection (CDI) • Update on antimicrobial agents • Miscellaneous updates

4. Clostridium difficile infection • CDI > MRSA for nosocomial infection • Long term care facilities • “Epidemic strain” • NEJM 12/05; NAP1 strain • Increase in frequency and severity • 10x increase in reports of CDI as primary cause of death 1999-2009 • Change in antimicrobial risk • Quinolones >> cephalosporins > clindamycin

5. Clostridium difficile • New testing method • PCR 85 % to 95 % sensitive; quick turnaround time • Prior toxin assays- 28 % sensitive! • Relapses- 20 %- predicted by age, severity of presentation, hospital exposure, prior CDI relapse • New therapies • Fidaxomicin • Stool transplants

6. Audience Response Question • For hospitalized patients with suspected or proven mild to moderate CD- I most often start with : • 1. oral metronidazole • 2. oral vancomycin • 3. IV metronidazole • 4. oral vanco + IV metronidazole • 5. fidaxomicin

7. Clostridium difficile- treatment options • Oral or IV metronidazole • Mild to moderate • Inferior to vancomycin for severe CDI • Oral vancomycin • 125 mg dose adequate • Impact on the gastrointestinal microbiome • Cost- more and more pharmacies are compounding • vs. Fidaxomicin

8. Clostridium difficile • Fidaxomicin • First in class macrocyclic antibiotic • Theoretical advantages • More active against NAP1 strain • Inhibits spore and toxin production • Less impact on the normal flora • Decrease VRE colonization • High fecal concentration with minimal systemic absorption • Cost • $ 2800 for a 10 day course

9. Fidaxomicin • Initial two licensing studies- non inferior to vancomycin with fewer relapses in the non-NAP1 strain • Meta-analysis – superior for recurrence and global cure, including NAP1, but no difference in an intention to treat analysis • Subgroup analysis suggests benefit

10. Fidaxomicin • Recent multicenter trial in 1164 patients with first recurrence- vancomycin vs. fidaxomicin • Same response to therapy • Superior in preventing second relapse • ? More data needed to justify cost?

11. Clostridium difficile-multiple relapses • Long tapering courses • Fidaxomicin ? • Probiotics • Not helpful in patients with relapses • Stool transplants • Strong results in case series • Sonication, filter, instill via nasogastric tube • No comparator trials

12. Clostridium difficile- treatment options • Nitazoxanide • Rifaximin • Used as chaser in multiple recurrences- small study • Tigecycline • Dose not promote CD growth despite broad spectrum • Very limited data in CDI

13. Clostridium difficile • CDI and PPIs • 2012 FDA warning • 1.4 to 2.75x risk in patients on PPIs • Relationship of dose and duration unknown • FDA recommends lowest dose for lowest duration in patients at risk for CDI

14. Update on antimicrobial agents • New antimicrobial agents for gram positive infections in the past fifteen years • Daptomycin • Linezolid • Synercid • Ceftaroline • Telavancin • Tigecycline

15. Update on antimicrobial agents • New antimicrobial agents for gram negative infections in the past decade, or in the pipeline………. Tigecycline ? otherwise

16. Audience Response Question • For outpatients with suspected Staphylococcus aureus skin and soft tissue infections, I most prescribe: • 1. Augmentin • 2. Bactrim • 3. Clindamycin • 4. Doxycycline • 5. Linezolid • 6. One of the above plus Keflex

17. New antimicrobial agents for gram positive infections • Linezolid • Not new, but…… • Best oral bioavailability • SSRIs • Cytopenias • Cost

18. New antimicrobial agents for gram positive infections • Daptomycin • IV only • Not in the lung • Once a day • Weekly CPK • Tends to not be particularly helpful in the VISA strains

19. Vancomycin dosing/levels • New dosing recommendations • Vancomycin levels • Serious infections; increased MICs- trough 15-20 • ‘minor infections’- 5-10 • Dosing apps

20. Ceftaroline • Novel cephalosporin that has activity against MRSA • Maintains the broad spectrum gram negative activity of advanced generation cephalosporins • Skin and soft tissue, community acquired pneumonia

21. Tigecycline • Tetracycline antibiotic • Broad spectrum, including MRSA • Does not cover “P P P” • Pseudomonas, Proteus, Providencia • Used primarily in patients intolerant to other antibiotics; multiple allergies • 2012 meta-analysis- small increase in mortality • Tolerance

22. Telavancin • semi-synthetic derivative of vancomycin • Once a day • Meta-Analysis- Telavancin vs. vancomycin • Non inferior vs. vancomycin • Associated with higher eradication rates and trend towards better clinical response • All cause mortality equivalent • High rate of adverse events, including elevations in serum creatinine

23. Brief Updates-2012 FDA advisories • Cefepime/seizures- Too high doses in patients with renal impairment • Azithromycin/cardiovascular risk • Class effect on QT; torsades de pointes • Large database- increased cardiovascular death vs. amoxicillin • Similar to quinolones • Highest in patients with cardiovascular risk factors • Quinolones/retinal detachment • Possible increased risk

24. Vaccines • HSV vaccine trial- no efficacy • Zoster vaccination • New age recommendation • ACIP > 60 (FDA > 50) • Currently contraindicated in high level immunosuppression • Safe in low levels of Imuran, mtx, steroids • > 20 mg prednisone for 3 weeks • Large database analysis of patient with Crohn’s and RA showed no risk of adverse reactions • Larger trials needed for confirmation

25. Vaccines • Pertussis vaccination in adults • 2012 ACIM recommends T-dap booster for all adults- regardless of age • Pneumococcal conjugate vaccine in healthy adults • 13-valent conjugate vaccine approved December 2011 in adults > 50 • Antibody responses =/> than pneumococcal polysaccharide vaccine • Recommended by ACIP for routine use in adults- pending additional data • June 2012- ACIP recommended use in immunocompromised adults age > 19 • May give in addition to polysaccharide vaccine- one or more year later • Evolving recommendations- recommend ACIP web site or app

26. Vaccines • Influenza 2012-2013 • 2010: all persons > 6 • A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), and B/Wisconsin/1/2010 • Vaccinate as soon as vaccine available…… • Fluzone high dose- indicated for persons age > 65 • 4x antigen • Shown to invoke stronger immune response, but protective efficacy not clear; studies ongoing • Do not use in patients with prior vaccine reaction • Egg allergy- hives only • 30 minutes observation • trivalent inactivated vaccine only

27. Mycobacterium • New recommendation for latent TB • Rifapentine- longer half life and greater potency than rifampin • Three month course of weekly directly observed therapy of rifapentine/INH non-inferior to nine months of INH • CDC recommends rifapentine/INH as alternative to nine months of INH in patients > 12 months • Advantage of DOT

28. Chronic Fatigue Syndrome- 2012 • Retraction of two studies that initially associated CFS with retrovirus infection

29. HIV • Rapid in-home testing approved but not yet commercially available • 2012 US Department of Health and Human Services recommended therapy for HIV infected patients regardless of CD4 count • Pre-exposure prophylaxis: • July 2012 FDA approved tenofovir-emtricitabine (truvada) among confirmed HIV negative individuals at high risk for sexually acquired HIV • Counseling about factors • Evaluation for HIV prior to initiation crucial to avoid selection of mutations

30. H3N2 Variant Influenza • CDC reports > 150 cases of H3N2 variant influenza caused by reassortment of swine H3N2 and H1N1; most cases have occurred since July 2012 • All patients reported contact with swine (including fairs) • Mild diseases- two hospitalizations; no deaths • CDC recommends frequent hand washing and avoiding contact with pigs that appear ill