What's New in Infectious Diseases Pharmacotherapy?

Transcription

1 Disclosure What's New in Infectious Diseases Pharmacotherapy? Nothing to Disclose Douglas Slain, Pharm.D., BCPS, FCCP, FASHP Associate Professor Infectious Diseases Clinical Specialist West Virginia University Outline Methicillin Resistant Staphylococcus aureus (MRSA) Treatment of MRSA Clostridium difficile infection Influenza therapy Mechanism: Produce an altered PBP (2 or 2a) Encoded by the mec A gene lactams have a very low affinity for these altered PBP Traditional DOC: Vancomycin PBP = Penicillin Binding Protein, DOC= Drug of Choice Killing Vancomycin Difficulty in dosing / monitoring drug MIC creep? Higher failure rates or slower cures at higher susceptible MICs Heteroresistance (h VISA) Alternatives: Daptomycin, Linezolid, Tigecycline, Ceftaroline Vancomycin vs.staphylococcus aureus Definition of vancomycin resistance: Sensitive < 2 g/ml Intermediate 4 8 g/ml Resistant > 16 g/ml Vancomycin Therapeutic Guidelines support a pharmacodynamic target AUC/MIC ratio 400 Trough concentrations 15 to 20 mcg/ml may be desired in several situations Clin Infect Dis 2009;49:325-7, AJHP 2009;66:

2 Vancomycin Intermediate Resistant Staphylococcus aureus (VISA or GISA) In vitro definition: MIC of 4 8 g/ml. Mechanism: Thickened cell walls. Many patients treated with Vancomycin + another agent. Heteroresistance is becoming common Susceptible VISA Vancomycin Pharmacodynamics Probability of achieving AUC/MIC ratio 400 for vancomycin regimens of varying intensity when Cmin values were between 15 and 20 mg/l. Adapted from: Patel Et al. Clin Infect Dis 2011;52: Linezolid (Zyvox) Oxazolidinone Class Bacteriostatic Unique site of action (protein synthesis) Indicated for pneumonia and skin infections Toxicity: thrombocytopenia, neutropenia, Neurotoxicity, lactic acidosis x1 Serotonin syndrome related drug interactions SSRI antidepressants Meperidine Daptomycin Bactericidal Indications: skin infections, complicated bacteremia and endocarditis Daptomycin is not indicated for the treatment of pneumonia Dosage: 4 6 mg/kg IV q 24 hr Myopathy Observed in < 0.2% treated patients (2 patients) in clinical studies Rare: Eosinophilic pneumonia Reports of resistance to daptomycin and linezolid in MRSA Resistance to linezolid due to: 23S rrna mutation Acquisition of cfr gene Antimicrob. Agents Chemother. 2006;50: , J Antimicrob Chemother 2013;68:4-11 Tigecycline (Tygacil) IV only Glycylcycline Gm positives: Enterococcus faecalis, Staph aureus (including MRSA), Streptococcus spp. Gm negatives: Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, etc. (no Pseudomonas) Atypicals: Mycoplasma and Chlamydophila Anaerobes Stable to many tetracycline resistant strains FDA: Skin, intra abdominal, and CAP Infections Not good for bacteremia x2 2

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4 Ceftaroline(Teflaro) 5 th Generation?? Broad spectrum 1 st β lactam that has MRSA activity No Pseudomonas activity Limited activity against anaerobes Can induce and be impaired by ESBL, AmpC, and KPC producing organisms C. Difficile Infection Traditional Approach (pre 2008) Replace fluid / electrolytes Avoid anti peristaltic agents Metronidazole 500 mg q8h x 7 10 days, Re treat first time recurrences with the same regimen Avoid vancomycin as 1 st line Cost No difference in most studies No metronidazole resistance VRE risk (1995 HICPAC Guidelines) New Hypervirulent Strain BI/NAP 1/027 More resistant to fluoroquinolones Higher MICs to metronidazole Increased morbidity & mortality More virulent Increased toxin A and B production Associated with a deletion in the tcdc gene Increased sporulation Longer courses of treatment needed? Produces a binary toxin? Recurrence 20 30% rates of recurrence within 60 days with metronidazole and vancomycin 2 Many have multiple recurrences Usually is relapse instead of reinfection 1 Continuation of antibiotics increases risk of recurrence Other risks: age and proton pump inhibitor use Important factors: spores, toxin, failure to reestablish flora, and/or host immune function Is Metronidazole Still Effective Therapy for Treating CDI? Never approved by the FDA for CDI. Meta analysis of randomized trials show no difference in efficacy between metronidazole and oral vancomycin (response rates 90 98%)* If only studies since 2004 are considered response rates of CDI to metronidazole have decreased 62 84% Aslam S, et al. Lancet Infect Dis. 2005;5: Clin Infect Dis 2011;53: J Infect 1989;159: *Nelson RL Cochrane Database Syst Rev Jul 8;(3):CD

5 Oral Metronidazole Lumen Exposure vs. MICs Scientific Support for Current Oral Vancomycin Dosing Oral Metronidazole is extensively absorbed in the GI tract and fecal penetration is poor Dependent on bowel inflammation Luminal concentrations are low (range ug/g) C. difficile usually appears susceptible in vitro ( ug/ml) C. difficile isolates have rarely been documented in vitro as resistant to metronidazole of ug/ml 19 Vancocin capsules approved based on small non clinical pharmacokinetic study in healthy subjects No well designed trials on dose response Recommended oral vancomycin dosing very broad Daily dosage: 500 mg to 2 g in 3 or 4 divided doses Fekety et al. Am J Med 1989;86: mg q 6 hours (n=28) vs. 500mg q 6 hours (n=28) No difference inferred [though small study], leading to 125mg recommendation [Sanford Guide, etc] Fecal vancomycin concentrations exceed organism MIC by times J Clin Pharm Ther 1987;12:27 31 Vancomycin vs. Metronidazole Metronidazole vs. Vancomycin Outcomes from US hospital Database Time to resolution of diarrhea is shorter in patients treated with oral vancomycin compared to metronidazole (3.0 vs 4.6 d, p<0.01) US Hospitals 32,325 cases CDI Treated Metronidazole 89%; Vancomycin 11% Metronidazole vs. Vancomycin Increased length of stay (12.8 vs d, p<0.0001) Increased mortality (7.9% vs. 6.8%, p<0.02) Longer ICU stay (23.2 vs d, p<0.0001) Wilcox MH. J Antimicrob Chemther. 1995; 36: Lahue BJ. Euro Cong Clin Micro. Abst Metronidazole vs. Vancomycin Randomized, Double Blind Trial (n=150) Metronidazole vs. Vancomycin Randomized, Double Blind Trial (n=150) Metronidazole PO 250mg QID Vancomycin PO 125mg QID Severe if > 2points x3 Endoscopically-proven pseudomembranes (2 points) ICU patient (2 points) Age > 60 years (1 point) Temp > 38.3 C (1 point) Albumin < 2.5mg/dL (1 point) Peripheral WBC > 15,000 (1 point) Response Rate (%) P = 0.36 P = 0.02 Relapse rates were similar Zar et al. Clin Infect Dis 2007;45: Zar et al. Clin Infect Dis 2007;45:

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7 Severe Disease SHEA / IDSA C. Difficile Guidelines WBC > 15,000 cells/mm 3 SCr 1.5 times baseline Age > 65 yrs Hypoalbuminemia Immunocompromised SHEA / IDSA C. Difficile Treatment Guidelines Clinical Presentation Initial Episode (Mild Moderate) Initial Episode (Severe) Initial Episode Complicated Regimen Metronidazole 500mg PO q 8 hrs Vancomycin 125mg PO QID Vancomycin 500mg PO /NG QID + Metronidazole 500mg IV q 8 hrs ± Rectal Vancomycin (if Ileus) Strength of Recommendation A I B I C III First Recurrence Same as initial A II Second Recurrence Vancomycin in taper or pulse dosing B III Fidaxomicin (OPT 80) Macrocyclic Agent Inhibits RNA polymerase/protein synthesis Bactericidal against C. difficile Narrow spectrum of activity Less effect on microbiota (B. fragilis, etc) Long post antibiotic effect Bioavailability < 10% Fecal Concentration 2983 mcg/ml C. difficile MIC about mcg/ml Cohen et al. Infect Control Hosp Epidemiol 2010;31: Antimicrob Agents Chemother 2006;50:401-2,; 2009;53:223-8; 2011;55: J Med Microbiol 2011;55:4427-9, Fidaxomicin vs. Vancomycin Phase III Trail Prospective, blinded multicenter trial (n=629) Toxin positive symptomatic patients Excluded fulminant CDI Randomized to 10 days of therapy Fidaxomicin 200mg PO BID Vancomycin 125mg PO QID Clinical cure: resolution of diarrhea for duration of therapy and no further requirement for therapy Global cure: resolution of diarrhea without recurrence Fidaxomicin vs. Vancomycin Phase III Trail ADRs: No clinical difference Both agents were well tolerated Statistically significant difference in laboratory abnormalities 4.7% vs. 1.2% (p=0.01) Hyperuricemia and elevated transaminases (3 fidaxomicin patients) Louie et al. NEJM 2011;364:

8 Fidaxomicin vs. Vancomycin Response Rates Fidaxomicin vs. Vancomycin Recurrence Rates (up to 28 days) Response Rate (%) P = P = Recurrence Rate (%) P < Recurrence: Reappearance of diarrhea within 4 weeks Stool toxin positivity Need for retreatment Louie et al. NEJM 2011;364: Per protocol analysis Louie et al. NEJM 2011;364: Fidaxomicin vs. Vancomycin Recurrence Rates In Patients x4 Receiving Concomitant Antibiotics (CAs) Fecal Transplant Recurrence Rate (%) P<0.001 P=0.48 P<0.001 P=0.54 Randomized, open label trial (n=42) Trial stopped early due to better outcomes in fecal transplant patients Regimen Cure (%) Vancomycin 500mg PO QID x 4 days, lavage, Fecal NG infusion 13/16 (81%) Vancomycin 500mg PO QID x 14 days 4/13 (31%) Vancomycin 500mg PO QID x 14 days + lavage 3/13 (23%) Fecal infusion improved patients microbiota diversity Mullane et al. Clin Infect Dis 2011;53: NEJM 2013; 368: Influenza Surface Proteins Neuraminidase Influenza Treatment Hemagglutinin RNA M 2 protein (only on type A) 6

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10 Pathology of Influenza Infection A. Binding to Sialic Acid B. Entering Cell C. Replication D. Release From Cell Adamantanes Amantadine (Symmetrel ) Rimantadine (Flumadine ) Active against Influenza A only Mechanism not well understood Block uncoating of viral genome and viral entry Inhibit M 2 ion channel functions Decrease symptom duration by 1 2 days (post exposure). Resistance has limited the usefulness of this class Amantadine 90% excreted unchanged in the urine ADRs: Nausea /vomiting CNS > 5 10 % Insomnia Altered concentration Seizures Suicidal ideation? Rimantadine 20% excreted unchanged in the urine ADRs: Nausea /vomiting CNS < 3 6 % Insomnia Altered concentration seizures Neuraminidase Inhibitors Oseltamivir Zanamivir (Tamiflu) (Relenza) Indication Treatment in adults, Treatment in adults, adolescents and adolescents and children 1 yr children 7 yrs Prophylaxis in adults Prophylaxis in adults and adolescents 1 yr and adolescents 5 yrs Spectrum Type A, type B Type A, type B Administration Oral Inhaled *both drugs are contraindicated in pregnancy Pregnancy Category C Role of Viral Neuraminidase Neuraminidase (Sialidase) Inhibitors A destroying enzyme that cleaves terminal sialic acid from cell surface receptors and permits release of progeny virus from infected host cells Oseltamivir has a unique binding to the Glu276 residue in the sialic acid binding pocket of neuraminidase 7

11 Active Site in Neuraminidase Pocket Oseltamivir Neuraminidase Treatment Outcomes Oseltamivir and Zanamivir Shorten symptoms days Reduce viral shedding Decrease hospitalizations Decreased secondary infections Decreased usage of antibiotics Best results: Begun within 48 hours of symptom onset In patients with Influenza confirmed Used with permission: Yarlagadda S. Babu, Ph.D., BioCryst Pharmaceuticals Clin Infect Dis 2009;48: , Lancet 2000;355; , J Infect Dis 2007;196: Osteltamivir (Tamiflu) Only oral Neuraminidase Inhibitor Nausea /Vomiting Less with food Serious Rash (rare) FDA Warning: Rare neuropsychiatric effects / Suicide in Children Oseltamivir Dosing Standard Treatment Dosage Standard: 75 mg bid 5 days CrCl ml/min: Reduce dose to 75 mg qd 5 days There are published hemodialysis and CRRT dosing recommendations Standard Prophylaxis Dosage Postexposure: 75 mg qd 7 days within 2 days of exposure Seasonal (during community outbreak): 75 mg qd Protection lasts as long as dosing continued CrCl ml/min: Reduce dose to 75 mg qod Caution: Tamiflu oral Syringe in mg Zanamivir (Relenza ) Dry powder inhaler Treatment dose: 10mg inhaled BID Prophylaxis dose : once daily No renal adjustments Can cause bronchospasm Caution in asthma and COPD patients Experimental IV formulation Treatment with Antiviral Agents Begin within 2 days of illness onset in otherwise healthy individuals All four drugs reduce duration of uncomplicated illness by about 1 2 days. Limited human data with Influenza B (NIs) Treat all hospitalized Flu+ patients Neuraminidase inhibitors treatment duration: 5 days uncomplicated non critically ill Longer for critically ill 8

12 Oseltamivir Resistance ( ) H1N1 virus strains ( ) 12.3% resistance H1N1 virus strains ( ) 98.5% resistance H274Y /H275Y mutation in viral neuraminidase No link to previous oseltamivir use by patient Zanamavir and adamantane susceptible Still effective against H3N2 strains Recommendation: Zanamavir Oseltamivir + Rimantadine Swine Flu Pandemic H1N1 (ph1n1) A/California/04/2009 Pig to human, human to human Serious infections in young patients, pregnant, and obese patients Resistant to adamantanes Sensitive to neuraminidase Inhibitors JAMA 2009;301: Influenza in South Carolina Treating Influenza in Critically Ill There is a benefit from starting drug > 48 hours Decreased mortality? Treatment duration will typically need to be longer than 5 days Larger doses of oseltamivir may be requested Suspension can be made from oseltmivir capsules Intravenous zanamivir may be available for oseltamivir resistant infections Clin Infect Dis 2012;55: , J Infect Dis 2011;204:777-82, Crit Care Med 2010;38:e43-51 Influenza Resources CDC Fluview World Health Organization State/County Health Department 9