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 CenterFriday, 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): 2907-2912

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): 2907-2912

Subgroup Analysis: Clinical and Economic Outcomes

Antimicrob Agents Chemother 2013; 57(7): 2907-2912

Subgroup Analysis:Predictors of Hospital Mortality

Antimicrob Agents Chemother 2013; 57(7): 2907-2912

• 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): 2907-2912

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):1562-1569

Baseline Characteristics

Clin Infect Dis 2013;56(11):1562-1569

Clinical Outcomes

Clin Infect Dis 2013;56(11):1562-1569

Clinical Failure & Mortality

Clin Infect Dis 2013;56(11):1562-1569

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):1562-1569

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):1704-17012

Baseline Characteristics

N Engl J Med 2013;368(18):1704-17012

Risk of Death from CV Causes: Azithromycin vs. No Antibiotic or Penicillin V

N Engl J Med 2013;368(18):1704-17012

Risk of Death from CV Causes: A Subgroup Analysis

N Engl J Med 2013;368(18):1704-17012

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):1704-17012

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 O2, 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 5 115/159 (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):407-415

Baseline Characteristics

N Engl J Med 2013;368(5):407-415

Cure at 10 Weeks without Relapse

Overall cure rateDonor – feces Infusion vs. Vancomycin

3.05 (99.9% CI 1.08 – 290.05)

Donor – feces Infusion vs. Vancomycin + Bowel Lavage

4.05 (99.9% CI 1.21 – 290.12)

N Engl J Med 2013;368(5):407-415

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):407-415

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