IH Pharmacy Live Rounds

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1 IH Pharmacy Live Rounds Effect of Vancomycin plus Rifampicin in the Treatment of Nosocomial Methicillin-resistant Staphylococcus aureus Pneumonia Sandra Katalinic, Pharmacy Resident Kelowna General Hospital April 20, 2010

2 Overview Journal article Title, journal, authors, funding Abstract Introduction Methods Results Discussion Critique or evaluation General interpretation Recommendation

3 Title Effect of Vancomycin plus Rifampicin in the Treatment of Nosocomial Methicillin-resistant Staphylococcus aureus Pneumonia Journal Background Critical Care Medicine Publication Timeline Submitted: unavailable Accepted: unavailable Published online January, 2010

4 Authors Background Young Ju Jung, Younsuck Koh, Sang-Bum Hong, Joo Won Chung, Sang Ho Choi, Nam Joong Kim, Mi-Na Kim, Ik Su Choi, Song Yi Han, Won-Dong Kim, Sung Cheol Yun, Chae-Man Lim Younsuck Koh, Sang-Bum Hong, Joo Won Chung previously published in well respected journals Funding from Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea Authors do not have any conflicts of interest

5 Summary Introduction MRSA common nosocomial pathogen >20% mortality, greatest in pneumonia and bacteremia Vancomycin is gold standard treatment of MRSA Big bulky molecule, hydrophilic, poor lung penetration cause of tx failure

6 Summary Introduction Rifampin good efficacy on gram positives including MRSA Success with rifampin + vancomycin and demonstrated in endocarditis, shunt infections, bacteremia Rifampin + vancomycin in pneumonia not yet thoroughly evaluated

7 Purpose Introduction To investigate whether adding rifampicin * to vancomycin could cure more patients with nosocomial methicillin resistant staphylococcus aureus pneumonia compared with vancomycin-only. *Rifampicin is the International Non-proprietary Name (INN) of rifampin, used by the WHO

8 Null hypothesis Methods The vancomycin + rifampicin combination does not differ from the vancomycin alone in the cure rate of MRSA pneumonia Research hypothesis The vancomycin + rifampicin combination is more effective than vancomycin alone in the cure rate of MRSA pneumonia Cure is defined in symptom resolution and CXR improvement of 50% in amount of consolidation

9 Design Approved by the Institutional Review Board Written, informed consent was obtained from patients or their family Setting Methods Conducted at the medical ICU of Asan Medical Center, Seoul, Korea July December 2006

10 Population Methods Inclusion criteria e.g. > 18 y/o, CXR w/ new or progressive infiltrates/ consolidation, +/- pleural effusion, and 2/3 of: 1) Cough, purulent sputum, or auscultatory pulmonary consolidation 2) Dyspnea, tachypnea, or hypoxemia 3) Identification of Gm + cocci (resp. tract, sputum, or blood)

11 Methods Population At least two of the following: 1) T 38 C or <36 C) 2) RR 30 breaths/min 3) SBP <90 mm Hg 4) HR 120 beats/min 5) Altered mental status 6) Need for mechanical ventilation; 7) WBC 10,000/mm 3 or <4000/mm 3 or 15% bands

12 Population Exclusion criteria: Methods 1) Pneumonia with pathogen resistant to rifampicin 2) Meningitis, endocarditis, or osteomyelitis 3) CD4 count <200 cells/mm 3 secondary to HIV 4) Vancomycin treatment for 48 hrs for any reason in the preceding week 5) Elevated liver enzymes ( 5x ULN) or total bili 2.0 mg/dl; severe neutropenia (<500 cells/mm 3 ) 6) Gram + pneumonia caused by bacteria other than MRSA

13 Methods Screening/recruitment Adult patients 18 y/o screened daily for clinical signs and symptoms of nosocomial pneumonia, >48 hrs after admission Patients were randomly assigned to treatment

14 Treatment allocation Methods Method of randomization not adequately described; unsure who or what did the randomization Patients were allocated in a 1:1 block randomization No concealment due to side effects of rifampin (i.e. orange urine)

15 Blinding Methods Study was conducted as open label no blinding Due to characteristic orange urine with rifampin, blinding not possible Interventions Vancomycin 1g IV q12h + rifampicin 300mg PO q12h Vancomycin 1g IV q12h Vanco trough >10; adjusted for elderly / renal fxn Other antibiotics given if req d for gram neg organisms as per ATS / ISDA guidelines

16 Study definitions Methods a) Cure resolution of the entry clinical signs and symptoms of pneumonia with improvement of chest radiography (decrease 50% in the extent or density of the initial pneumonic infiltrates) by day 14 b) Failure No cure by day 14, death, or change of antibiotics to linezolid because of a deteriorating clinical course

17 Outcome measures Methods a) Primary Clinical cure on day 14 b) Secondary Intensive care unit mortality on days 28 and 60, and microbiological eradication of MRSA on day 14 No subgroup analyses done

18 Methods Study procedures (Broad overview) At randomization: physical exam, ECG, Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, CXR, recent medications, antibiotics and duration of mechanical ventilation before enrolment Daily: Vitals, entry sx, abdominal sx, CXR, side effects of abx, until discharge or death Vancomycin trough on days 3, 7, and 14 Lab testing (sputum and blood) at baseline and every 3 days Stool for C. difficile toxin at day 6, 10, 21 (if diarrhea) Patient interviews 21 days after completion of study medication

19 Methods Statistical considerations a) Sample size calculation not done!

20 Statistical considerations b) Statistical tests Methods Categorical variables (i.e. cure, mortality) were compared, using the chi-square test or Fisher s exact test using the SPSS statistical analysis program. Continuous variables (i.e. % microbial eradication) were compared, using the Student s t test or Mann- Whitney U test. All reported p values were two-sided

21 No MRSA on culture: 4 Rifampicin resistance: 1 Dropouts: 11 Switch to linezolid: 2 Elevated bili: 5 Intolerance of oral feeding: 1 Deaths: 2 Transfer: 1 1 Trial Flow Diagram Number assessed for eligibility n = 183 Vanco + Rif ITT n = 46 Number randomized n = 93 Vanco ITT n = 47 mitt n = 41 mitt n = 42 Per protocol n = 30 Pre Protocol n = 34 Ineligibility: 90 Refuse to participate: 20 Total bili > 2 mg/dl: 28 Use of previous study med: 23 Neutropenia: 4 Others: 15 No MRSA on culture: 4 MRSA judged as colonizer: 1 No MRSA: 4 MRSA colonizer:1 Dropouts: 8 Switch to linezolid: 5 Deaths: 2 Transfer: 1

22 Baseline Characteristics Dates of recruitment not stated, only duration of trial Additional follow up done 21 days after discharge Comparable baseline characteristics Co-interventions Results Patients were given other antibiotics as required for gram negatives Some broad spectrum

23 Crit. Care Med. 2010; 38:

24 Analysis Results Primary endpoint was analyzed both on an intention-to-treat and a per protocol basis Per protocol group: received the tx for 5 days and 10 doses of study medication Secondary endpoint Microbiological eradication also analyzed on mitt and per protocol populations Mortality analysis based on MRSA association

25 Results n = 150 evaluated ( Efficacy analysis) n = 40 VANCO n = 38 METRO Crit. Care Med. 2010; 38:

26 Results Ouctome Vanco + Rif Vanco Only p-value Microbial Eradication Modified ITT 28/39 (71.8%) 24/39 (61.5%) Per Protocol 20/29 (69.0%) 21/33 (63.6%) Day Mortality MRSA pneum. related 6/41 (14.7%) 12/24 (50%) >0.999 MRSA pneum. unrelated 3/41 (7.3%) 4/42 (9.5%) Day Mortality MRSA pneum. related 7/41 (17.1%) 15/42 (35.7%) MRSA pneum. unrelated 4/41 (9.7%) 6/42 (14.3%) >0.999

27 Results Similar rate of adverse events in both Vanco + rif and vanco alone Not statistically significant difference (p 0.183) Vanco + rif 11 pts (23.9%) Vanco alone 6 pts (12.8%) RSS 2001

28 Authors Summary Discussion Vancomycin treatment failure rates around 40% have been reported for MRSA pneumonia Authors suggest high failure rates may be due to poor lung penetration and ++ Vd in critically ill patients worsen poor tissue penetration

29 Authors Summary Discussion Increasing vanco dose may not overcome poor penetration, and increase risk of SE s Authors suggest adding or changing antimicrobial agents Vanco + rif combo has been used in other MRSA infections (i.e. endocarditis) Limitations: unblinded, single centre, small patient population, could not measure MIC <2 μg/ml

30 Authors Summary Discussion Authors conclude vancomycin plus [rifampicin] regimen could result in a better clinical outcome than vancomycin-only therapy in patients with MRSA pneumonia... a larger and multicenter clinical study is warranted to determine this preliminary result.

31 Critique Title and Abstract Title should state that this is an RCT Abstract is structured into headings, easy to read, succinctly provides pertinent information for a quick screening

32 Critique Introduction Discusses vancomycin resistance, treatment failure and epidemiology briefly Does not say where these resistance and failure stats come from (Korea Vs US Vs world wide) Discusses pharmacokinetics and chemical properties of vancomycin (i.e. large size = poor penetration) No null or alternate (research) hypothesis stated

33 Critique Methods Randomized Did not tell us how randomization was carried out (i.e. by investigator vs outsider, coin toss vs computer) Ethical (IRB approval, patient consent) Unblinded: Study drugs unable to be concealed No power or sample size calculation done Trial flow diagram provided Inclusion criteria consistent with sx of pneumonia

34 Critique Methods Carried out at one centre in S. Korea May not representative of us in BC or Canada Sampling not described: Unclear if consecutive patients sampled, or if it was based on convenience Stated all inclusion, exclusion criteria Very specific / homogenous patient population (ICU inpatient) can we use this info for all MRSA pneumonias? Small sample size collected reliability of results? No power calc.

35 Critique Methods Only evaluated vancomycin or vanco + rif; no other antibiotic evaluated, even though the author suggested this as a solution to vancomycin treatment failure Did not provide details of role of study personnel

36 Critique Methods Patients assessed daily for both clinical improvement and side effects of medication Specific information on microbial assessment, susceptibility testing and R/O tuberculosis (time for TB cultures realistic to study timeline?) Time to cure rate consistent with recommended duration of treatment Comprehensive description of types of statistical calculations used to analyze collected data appropriate tests

37 Critique Results Small trial, only ~40 pts in each intervention group (mitt) Well balanced baseline Vanco characteristics + Rifampin Vancomycin overall p-values calculated for baseline characteristics Used validated scores to assess patient characteristics Reasons for drop out on non-inclusion stated Stated vanco trough levels similar between both groups medians are similar; large range

38 Critique Results Other antibiotics briefly mentioned in methods, not in results Carbapenems, tazobactam 3 rd and 4 th gen cephalosporins, ciprofloxacin Did they have any impact on results? Not addressed

39 Critique Discussion Do discuss important study limitations, which are a threat to the internal validity of study Small size, discrepancy between microbial eradication and cure rate, inability to test MIC s <2, could this have skewed results? No obvious hypothesis stated Fail to discuss concerns around generalizability of results to patients with pneumonia NOT in ICU Stated conclusion not consistent with data

40 General Interpretation Summary Significant methodological limitations cause the reader to question its reliability The quality of evidence here does not convince me Large difference in cure rate V + R is 2x that of vancomycin alone Such small population, is this a reliable result? A larger study: multiple centers (to account for variable resistance patterns), and comparisons to other treatments for MRSA pneumonia Establish more conclusive recommendations

41 Summary Recommendation Based on this study, there is insufficient evidence to suggest that the addition of rifampin would provide a significant benefit in MRSA pneumonia No other data to help support these results

42 Summary Recommendation At point time, the IDSA HAP, VAP, HCAP guidelines suggest vancomycin (15mg/kg q12h; target trough μg/ml) or using an alternate drug (linezolid 600mg q12h) No mention of rifampin as an add-on therapy Continue with previously established recommendations