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2013 Antimicrobial Update Oklahoma ACP Chapter October 18, 2013

2013 Antimicrobial Update Oklahoma ACP Chapter October 18, 2013. Michelle R. Salvaggio MD FACP Associate Professor, Medicine Section of Infectious Diseases OUHSC. Outline. Clostridium difficile Methicillin resistant Staphylococcus aureus Hepatitis C HIV

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2013 Antimicrobial Update Oklahoma ACP Chapter October 18, 2013

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  1. 2013 Antimicrobial UpdateOklahoma ACP Chapter October 18, 2013 Michelle R. Salvaggio MD FACP Associate Professor, Medicine Section of Infectious Diseases OUHSC

  2. Outline • Clostridium difficile • Methicillin resistant Staphylococcus aureus • Hepatitis C • HIV • I will be discussing off-label use of some medications.

  3. Question 1 • A 66 yo WM was recently admitted to the hospital for pneumonia. While admitted he was also diagnosed with C difficile diarrhea and has now completed a course of metronidazole. He is calling your office complaining of continued diarrhea. What do you do? • Tell him take a probiotic and Immodium. • Have him come to the office and submit stool for testing. • Retreat with an extended course of metronidazole. • Ask him if he has money saved, if he says yes, prescribe oral vancomycin. • Call your GI colleague and arrange for fecal transplantation.

  4. C. difficilebackground • Gram-positive, anaerobic, spore-forming bacillus(“Difficile” because it is difficult to culture) • Accounts for 20-30% cases of antibiotic-Major cause of hospital infection, morbidity and mortality. • Present epidemic strain (BI/NAP1/027)first reported in the US in 2005 • Now reported from 40 US states and all Canadian providences • Comprises 36% of all C difficileinfection (CDI) associated • Rates continue to increase in North America Gerding D Infect Control Hosp Epidemiol 2010; 31(S1):S32-S34

  5. CDI Clinical manifestations • Range from symptomless carriage to fatal pseudomembranous colitis • 96% have received antibiotics within the previous 14 days • Fever, abdominal cramps, peripheral leukocytosis, and hypoalbuminemia • WBC can exceed 30,000-50,000 cells/mL and be indicative of severity Kelly CP and JT LaMont. NEJM 2008; 359: 1932-1940.

  6. CDI Treatment Adapted from Cohen et al. ICHE 2010; 31: 431-455 and Kelly CP. NEJM 2008; 359: 1932-1940.

  7. Fidaxomicin (Dificid) • FDA approved in 2011: treatment of Clostridium difficileassociated diarrhea • Granted New Technology Add On-Payment by CMS (August 2012) • Mechanism of action • Bacteriocidal against C. dificilein vitro, inhibiting RNA synthesis by RNA polymerases • Macrolide but does not confer cross-resistance • Low rate of spontaneous resistance (although specific mutation Val-II43-Gly has been identified) Dificid Package Insert: http://www.dificid.com/sites/default/files/prescribing.pdf

  8. Fidaxomicin facts • Dose is 200mg po twice daily x 10 days • Retail cost: $4000/course (cash) • Very little systemic absorption, essentially no dose adjustment with various other medications, no adjustment with renal or hepatic impairment • Warnings: hypersensitivity reaction (dyspnea, rash, pruritis, angioedema of mouth, throat, face), may report previous allergy to macrolides • Adverse events/side effects: same rate of blood dyscrasias, GI symptoms (N/V/abd pain/GI bleed) as vancomycin Dificid Package Insert: http://www.dificid.com/sites/default/files/prescribing.pdf

  9. Fidaxomicin data • Two randomized, double-blinded controlled studies • Non-inferiority design • Fidaxomicin 200mg po BID vsvancomycin 125 mg poqid x 10 days in patients with CDAD Dificid Package Insert: http://www.dificid.com/sites/default/files/prescribing.pdf

  10. Other CDAD Treatment Options • Rifaximin- 400 mg BID for 14 days • Nitazoxanide- 500mg BID for 7 – 10 days • Fecal transplant - successful in uncontrolled series • Monoclonal antibodies - against toxins A&B • NontoxigenicC difficile 1. Kelly CP and JT LaMont. NEJM 2008; 359: 1932-1940.2. Cohen et al. ICHE 2010; 31: 431-455.

  11. Question 2 • In mid January, a 54 yo woman presents to the hospital with increasing shortness of breath, productive cough and fever. She was diagnosed with influenza 1 month prior and treated with oseltamivir. Her chest Xray is consistent with lobar pneumonia. Sputum is positive for gram positive cocci in pairs. What is the best course of action at this time? • Give her another course of oseltamivir • Prescribe linezolid and send her home. • Do a chest CT with angiography to assess for PE. • Admit her, start vancomycin, pip/tazo and cipro. • You lost me at gram positive cocci…

  12. Ceftaroline (teflaro) • FDA approved 2010: • treatment of acute bacterial skin and skin structure infections • community acquired bacterial pneumonia • Mechanism action: • cephalosporin (β-lactam) prodrug • bacteriocidal against S aureusdue to affinity for PBP2a • bacteriocidal against S pneumoniaedue to affinity to PBP2x Teflaro Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

  13. Ceftaroline dosing • Dosing: 600mg IV every 12 hours to be infused over one hour • Dosing in renal impairment: • CrCl > 50ml/min no adjustment • CrCl >30 to ≤ 50 ml/min 400mg IV every 12 hours • CrCl ≥15 to ≤ 30ml/min 300mg IV every 12 hours • ESRD including HD 200mg IV every 12 hours • Ceftaroline is dialyzable and should be given after HD • No dosing adjustment with hepatic disease Teflaro Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

  14. CEFtaroline warnings • Hypersensitivity reactions: to ceftaroline and to other β-lactams • Cephalosporins • Pencillins • carbapenems • C difficileassociated diarrhea • Direct Coombs’s test seroconversion • Monitor for drug induced hemolytic anemia • Teflaro Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

  15. Ceftarolinespectrum of activity • Gram positive: S aureus(MRSA, MSSA), Streptococcus species • Gram negative: E coli, Klebsiella species, H influenzae(possibly Citrobacter, Enterobacter, Proteus) • DOES NOT COVER • Enterococcus (including VRE) • Anaerobes • Pseudomonas species • Any ESBL, KPC, etc • Teflaro Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

  16. Ceftaroline data – Acute Bacterial Skin and Skin Structure Infections • Lesion size ≥ 75 cm2 • Major abscess with ≥ 5cm surrounding erythema • Wound infection • Deep/extensive cellulitis • Teflaro Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

  17. Ceftaroline Data- Community Acquired Bacterial Pneumonia • 2 studies comparing ceftriaxone to ceftaroline • 1 study allowed macrolide on first day, the other did not • No MRSA allowed • Teflaro Package Insert: http://www.frx.com/pi/teflaro_pi.pdf

  18. Question 3 • A 62 yo WF presents to your clinic complaining of fatigue. She asks you test her for everything. You order • TSH, B12, cbc, sed rate • Vit D • HIV, Hep C • Nothing. She needs reassurance alone. • Referral to therapist.

  19. Screening for Hepatitis C: Recommendations • CDC Issued on May 18, 2012 • USPSTF issued on June 25, 2013 • Routine HCV screening for all adults born from 1945 through 1965 (currently aged 48 – 68). • Numbers of diagnosed patients expected to double, possibly triple http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcfinalrs.htm

  20. Screening: Identifying Estimated 170 Million Persons With HCV Infection Worldwide Europe 8.9 million (1.03%) Western Pacific 62.2 million (3.9%) Americas 13.1 million (1.7%) Southeast Asia 32.3 million (2.15%) Eastern Mediterranean 21.3 million (4.6%) Africa 31.9 million (5.3%) World Health Organization. Wkly Epid Rec .1999;74:425-427. World Health Organization. Hepatitis C: Global Prevalence: Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16.

  21. HCV Overview/epidemiology • “Silent Epidemic” - Approximately 3.9 million in the US • 170 million globally • HIV—1 million US • Majority of patients in US have Genotype 1 (75%), few G2 and G3 • G2—10-15%; Europe • G3—4-6%; Australia • G4—Middle East, Africa • G5—South Africa • G6—Hong Kong • Predominant cause of chronic liver disease, HCC, and death in US; leading indication for liver transplant • Transmission • Blood • Sexual contact • Mother-to-child • Six genotypes • Response to treatment dependent on genotype Ghany MG et al. 2006. Hepatology 49: 1335-1374.

  22. Clinical Manifestations of Hepatitis C

  23. Telaprevir (Incivek)Boceprevir (victrelis) • FDA Approved 2011: • treatment of Hepatitis C genotype 1 in adults with compensated liver disease including cirrhosis • May be used in treatment naïve, those who have previously been treated with an interferon-based therapy including prior null responders, partial responders and relapsers • only in combination with peginterferon and ribavirin • Mechanism of action • NS3/4A protease inhibitor IncivekPackage Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf VictrelisPackage Insert:http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

  24. dosing Telaprevir BOceprevir Dose Week 1 -4 peginterferon and ribavirin then add boceprevir 800mg orally every 8 hours with meal or snack Response, prior response and disease stage dictate course of all 3 meds(total of 28 – 52 weeks) Hepatic impairment No dose adjustment for mild, moderate or severe impairment Renal Impairment No dose adjustment for renal impairment • Dose • Standard—750mg orally every 8 hours weeks 1-12, with food, not low fat • Response and prior response dictate course of peg-interferon and ribavirin (12 to 36 more weeks) • Hepatic impairment • No dose adjustment for mild impairment, Child-Pugh A (score 5-6) • Renal impairment • No dose adjustment for CrCl > 50 ml/min Peg-interferon has only been studied in adults with CrCl > 50ml/min and is approved for use in compensated cirrhosis only IncivekPackage Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf VictrelisPackage Insert:http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

  25. WARNings Telaprevir Boceprevir Adverse Effects Anemia Neutropenia Dysgeusia Cost (30 day supply) Standard dose $4,600 With peg-interferon + ribavirin = $7000 • Adverse Effects • Black box: rash (Stevens Johnson, DRESS, TEN) • Anemia • GI: nausea, vomiting, diarrhea, anorectal discomfort, dysgeusia • Cost (30-day supply) • Standard dose $18,350 • With peg-interferon + ribavirin = $21,000 IncivekPackage Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf VictrelisPackage Insert:http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

  26. Telaprevir and Boceprevir drug interactions • Antiarrythmics: lidocaine, flecainide, amiodarone, digoxin • Antibacterials: clarithromycin • Anticoagulants: warfarin • Anticonvulsants: carbamazepine, phenytoin • Antidepressants: escitalopram, trazodone • Antifungals: itraconazole, posaconazole, voriconazole • Antigout: colchicine • Antimycobacterial: rifabutin • Benzodiazepines: alprazolam, IV midazolam, zolpidem • Calcium channel blockers: amlodipine, all others • Corticosteroids: prednisone, nasal fluticasone/butesanide • HMG co-reductase inhibitors: atorvastatin, all others • Hormonal contraceptives: ethinyl estradiol IncivekPackage Insert: http://pi.vrtx.com/files/uspi_telaprevir.pdf VictrelisPackage Insert:http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

  27. SVR Rates With BOC or TVR in Genotype 1 Treatment-Naive Patients 100 80 63-75 60 SVR (%) 38-44 40 20 0 PegIFN/RBV BOC or TVR + PegIFN/RBV Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

  28. SVR Rates With BOC or TVR in GT1 Treatment-Experienced Patients 100 PegIFN + RBV 69-83 BOC or TVR + PegIFN + RBV 80 40-59 60 SVR (%) 40 29-38 24-29 20 7-15 5 0 NullResponders Relapsers Partial Responders Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.Vierling JM, et al. AASLD 2011. Abstract 931.

  29. Hepatitis C Treatment Options • First-line therapy • Genotype 1 • Telaprevir or Boceprevir + Pegylated interferon/Ribavirin • Genotypes 2/3 • Pegylated interferon/Ribavirin • Treatment Duration • Response-guided therapy • Not to be used in cirrhotic and/or null responders • Determined by early virologic decline • RVR—undetectable HCV RNA at week 4 • eRVR—undetectable HCV RNA at weeks 4 and 12

  30. Question 4 • A 28 yo man presents to your office. He states he has heard about a medicine that will keep him from getting HIV. He would like for you to prescribe that to him. You • Refer him to Infectious Diseases. • Ask him why he thinks he is going to be infected with HIV. • Ask him if he is infected with HIV. • Give him a package of condoms.

  31. US National HIV strategy released July 2010 http://www.whitehouse.gov/files/documents/nhas-implementation.pdf

  32. July 16, 2012 • FDA approves first drug for reducing the risk of sexually acquired HIV infection • Truvada™ is indicated in combination with safer sex practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adults at high risk. Originally approved 2004 for use in combination with other antiretrovirals for the treatment of HIV-1 in adults and children > 12 years. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm

  33. emtricitabine/tenofovirdisoproxilfumarate(Truvada) facts • Combination product of two different nucleoside analogs emtricitabine (200mg) and tenofovir (300mg) • Given orally once daily (regardless of indication) • Retail cost: $1500/month • Dosing in renal impairment: • CrCl ≥ 50ml/min no adjustment • CrCl 30 – 49 one tablet every 48 hours • CrCl < 30 should not be used (includes HD pts) Truvada Package Insert: https://www.gilead.com/~/media/Files/pdfs/medicines/hiv/truvada/truvada_pi.pdf

  34. FTC/TDF Black Box warnings • Lactic acidosis and severe hepatomegaly (including fatal cases) • Severe exacerbations of hepatitis B have been reported in ptscoinfected with hep B and HIV who discontinued FTC/TDF • TRUVADA used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and periodically (at least every 3 months) during use. Drug-resistant HIV-1 variants have been identified with use of TRUVADA for a PrEP indication following undetected acute HIV-1 infection. Do not initiate TRUVADA for a PrEP indication if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed. Truvada Package Insert: https://www.gilead.com/~/media/Files/pdfs/medicines/hiv/truvada/truvada_pi.pdf

  35. Acute antiretroviral syndrome VanhemsP, et al. 2002. JAIDS 31: 318- 321.

  36. FTC/TDF adverse events/warnings • New onset or worsening renal impairment • Fanconi syndrome • Avoid concurrent nephrotoxic agents • Decreased in bone mineral density • Redistribution/accumulation of body fat • Side effects in HIV positive patients (in combination with other agents): diarrhea, nausea, rash • Side effects in HIV-negative patients: no significant difference from placebo Truvada Package Insert: https://www.gilead.com/~/media/Files/pdfs/medicines/hiv/truvada/truvada_pi.pdf

  37. FTC/TDF nPrep data

  38. Before Truvada REMS: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/UCM312304.pdf

  39. Before Truvada REMS: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/UCM312304.pdf

  40. Beginning Truvada REMS: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/UCM312304.pdf

  41. Follow-up Truvada REMS: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/UCM312304.pdf

  42. Discontinuing Truvada REMS: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/UCM312304.pdf

  43. Question 1 • A 66 yo WM was recently admitted to the hospital for pneumonia. While admitted he was also diagnosed with C difficilediarrhea and has now completed a course of metronidazole. He is calling your office complaining of continued diarrhea. What do you do? • Tell him take a probiotic and Immodium. • Have him come to the office and submit stool for testing. • Retreat with an extended course of metronidazole. • Ask him if he has money saved, if he says yes, prescribe fidaxomicin. • Call your GI colleague and arrange for fecal transplantation.

  44. Question 2 • In mid January, a 54 yo woman presents to hospital with increasing shortness of breath, productive cough and fever. She was diagnosed with influenza 1 month prior and treated with oseltamivir. Her chest Xray is consistent with lobar pneumonia. Sputum is positive for gram positive cocci in pairs. She takes paroxetine daily. What is the best course of action at this time? • Give her a another course of oseltamivir • Prescribe linezolid and send her home. • Do a chest CT to assess for empyema. • Admit her, start vancomycin, pip/tazo and cipro. • Admit her, start ceftaroline.

  45. Question 3 • A 62 yo WF presents to your clinic complaining of fatigue. She asks you test her for everything. You order • TSH, B12, cbc, sed rate • Vit D • HIV, Hep C • Nothing. She needs reassurance alone. • Referral to therapist.

  46. Question 3b • You test the patient from the previous question for Hepatitis C. Her Hep C IgG is positive, viral load is 600,000 and her genotype is 1a. Her US shows mild cirrhosis and her LFTs are 1.5 ULN. What is the next step in her management? • Test for HIV, Hepatitis A and B and syphilis. • Have her come back in 6 months and repeat testing. • Schedule her for a liver biopsy. • Refer her to ANYONE treating Hepatitis C. • Start her on telaprevir with peg-interferon and ribivirin.

  47. Question 4 • A 28 yo man presents to your office. He states he has heard about a medicine that will keep him from getting HIV. He would like for you to prescribe that to him. You • Refer him to Infectious Diseases. • Ask him why he thinks he is going to be infected with HIV. • Ask him if he is infected with HIV. • Give him a package of condoms. • Prescribe FTC/TDF.

  48. Summary • C difficileremains a serious health issue. Vancomycin and metronidazole remain the mainstays of therapy. Fidaxomicin (Dificid) is another treatment option. • MRSA skin and lung infections remain a serious health issues. Ceftaroline (Teflaro) has been approved for SSTI and may be used in pneumonia. • Ceftaroline = cefazolin + MRSA coverage • Screen everyone for Hepatitis C. • If ab positive, get viral load and genotype then send to specialist. • Screen everyone for HIV. Encourage safe sex practices to all of your patients. • If pre-exposure prophylaxis questions come up, send the patient to us.

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