Top 5 Papers in Infectious Diseases Pharmacotherapy: A Review of 2013 for the General Practitioner Sharanie V. Sims, Pharm.D., BCPS (AQ-ID) Infectious Diseases Clinical Pharmacy Specialist Louis Stokes Cleveland VA Medical Center Friday, May 2, 2014

Objectives Review data from recent studies using various antimicrobial agents/dosing strategies and its effects on clinical outcomes Discuss the benefits of optimizing cefepime dosing for the treatment of infections caused by Pseudomonas aeruginosa Compare clinical outcomes in patients with methicillin – resistant Staphylococcus aureus bacteremia (MRSAB) treated with vancomycin vs. daptomycin

Extended – Infusion Cefepime Reduces Mortality in Patients with Pseudomonas aeruginosa Infections Retrospective quasi – experimental Primary outcome: incidence of mortality in intermittent infusion (II) vs. extended infusion (EI) cefepime Secondary outcomes: duration of mechanical ventilation, length of stay (LOS), cost Inclusion ≥18 years old, bacteremia and/or pneumonia, cefepime MIC ≤8 µg/mL, cefepime w/in 72 hrs of onset of Gram – negative (GN) infection, cefepime ≥48 hours Exclusion Concurrent β-lactam with Gram-negative activity w/in 2 days of Cefepime initiation, incarceration, or receipt of both intermittent- and extended infusion Antimicrob Agents Chemother 2013; 57(7):

Baseline Characteristics 592 patients with (+) blood and/or sputum culture with GN organisms No difference in baseline characteristics, ICU admission, LOS, hospital cost, or mortality (17% vs. 20%; p= 0.31) 87 patients with (+) blood and/or sputum with P. aeruginosa No difference in baseline characteristics Antimicrob Agents Chemother 2013; 57(7):

Subgroup Analysis: Clinical and Economic Outcomes Antimicrob Agents Chemother 2013; 57(7):

Subgroup Analysis: Predictors of Hospital Mortality Antimicrob Agents Chemother 2013; 57(7): Multivariate analysis

Author’s Conclusion & Critique Cefepime EI provides increased clinical and economic benefits in the treatment of invasive infections due to P. aeruginosa Retrospective, single centered Small sample size Included 2 different time periods Excluded patients with intermediate or resistant MICs Antimicrob Agents Chemother 2013; 57(7):

Early Use of Daptomycin vs. Vancomycin for Methicillin – Resistant Staphylococcus aureus Bacteremia (MRSAB) Retrospective, matched cohort study Primary outcome: clinical failure Secondary outcomes: 90 day survival, in-hospital mortality, re- admission, recurrent MRSAB, duration of bacteremia, emergence of decreased MRSA susceptibility, cost Inclusion: ≥18 years old, susceptible MRSA blood isolate, VAN MIC >1 µg/mL, VAN or DAP for >72 hours Exclusion: IV catheter or pneumonia primary source, on renal replacement therapy, ≥72 hours of alternative MRSA therapy prior to VAN or DAP initiation (including those switched from VAN to DAP) Clin Infect Dis 2013;56(11):

Baseline Characteristics Clin Infect Dis 2013;56(11):

Clinical Outcomes Clin Infect Dis 2013;56(11):

Clinical Failure & Mortality Clin Infect Dis 2013;56(11):

Author’s Conclusion & Critique Early initiation of daptomycin was associated with significantly less clinical failure in patients with MRSAB with high vancomycin MICs Retrospective, single centered Excluded patients with IV catheter/access device Median vancomycin trough levels 18.1 µg/mL Median daptomycin dosage 8.4 mg/kg Utilized 2 different susceptibility testing methods Clin Infect Dis 2013;56(11):

Azithromycin and CV – related Death Prospective, historical cohort Primary outcome: cardiovascular death Secondary outcomes: non – cardiovascular death Inclusion: 18 – 64 year old, living in Denmark, oral azithromycin or penicillin V between 1997 – 2010 Exclusion: Hospitalization or any antibiotic within 30 days of index date, >1 antibiotic prescription filled on the index date N Engl J Med 2013;368(18):

Baseline Characteristics N Engl J Med 2013;368(18):

Risk of Death from CV Causes: Azithromycin vs. No Antibiotic or Penicillin V N Engl J Med 2013;368(18):

Risk of Death from CV Causes: A Subgroup Analysis N Engl J Med 2013;368(18):

Author’s Conclusion & Critique Use of azithromycin does not significantly increase the risk of death from CV – related causes in young and middle aged adults Data from the study does not support the author’s conclusions Large study; young – middle aged patients Used multiple strategies to minimize confounders Patient population significantly different than previous studies Results may not be generalizable N Engl J Med 2013;368(18):

Double-dose Oseltamivir for Severe Influenza Prospective, multicentered, double-blinded, randomized Primary Endpoint: proportion of patients with no detectable viral RNA on day 5 Secondary Outcomes: mortality, mechanical ventilation, ICU admission, virologic endpoints Inclusion: ≥ 1 years old, respiratory illness ≤ 10 days, lab confirmed influenza, evidence of severe influenza Exclusion: pregnancy, (+) hCG in urine, actively breastfeeding, >72 hours before treatment, Crcl <10 mL/min BMJ 2013:346:f3039:1-16

Primary and Secondary Endpoints No difference in clinical failure (9.9% vs. 13%; p=0.44) or mortality (6.4% vs. 7.3%; p=0.54) 30% of all patients required O 2, 18% admitted to ICU, 12% mechanical ventilation Oseltamivir resistance: none in patients with H1N1-pdm09 or H5N1 Seasonal H1N1: 32/38 sequenced 18 with H275Y mutation at baseline No difference in viral detection or outcome associated with mutation Double Dose (n = 159) Standard Dose (n = 154) P-value Negative Viral RNA at Day 5115/159 (72.3%)105/154 (68.2%)P = 0.42 BMJ 2013:346:f3039:1-16

Author’s Conclusion & Critique Double dose oseltamivir is well tolerated but does not confer additional virologic or clinical benefit over standard dose Heterogeneous population; mostly children Median presentation 5 days after onset 25% of patients received prior neuraminidase inhibitors Viral RNA detection in upper respiratory track may not reflect replication in lower tract BMJ 2013:346:f3039:1-16

Duodenal Infusion for Treatment of Clostridium difficile Open – labeled, randomized, controlled trial Primary outcome: cure without relapse within 10 weeks after initiation of therapy Secondary outcomes: cure without relapse after 5 weeks Inclusion: ≥ 18 years of age, > 3 month life expectancy, relapse of C. difficile, ≥ 3 loose stools/day or ≥ 8 in 48 hrs, (+) C. difficile toxin Exclusion: recent chemotherapy, HIV with CD4 <240, prolonged use of prednisolone (≥ 60 mg/day), pregnancy, concomitant antibiotics, ICU admission, need for vasopressor N Engl J Med 2013;368(5):

Baseline Characteristics N Engl J Med 2013;368(5):

Cure at 10 Weeks without Relapse Overall cure rate Donor – feces Infusion vs. Vancomycin 3.05 (99.9% CI 1.08 – ) Donor – feces Infusion vs. Vancomycin + Bowel Lavage 4.05 (99.9% CI 1.21 – ) N Engl J Med 2013;368(5):

Author’s Conclusion & Critique Infusion of donor feces is a potential therapeutic strategy against recurrent C. difficile infections Elderly population Excluded several groups at high risk of C. difficile Many patients had several relapses prior to inclusion N Engl J Med 2013;368(5):

Summary Maximize PK/PD of antimicrobial agents in the treatment of Gram – negative infections Mortality in patients with infections due to MRSA with elevated vancomycin MIC may warrant alternate therapy Risk of cardiovascular death in patients actively treated with azithromycin remains controversial Donor infusions are a promising option for treating recurrent/relapse C. difficile infection No benefit of using double dose oseltamivir for the treatment of severe influenza