JCM Accepts, published online ahead of print on 7 May 2008 J. Clin. Microbiol. doi:10.1128/jcm.00801-08 Copyright 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. 1 The Impact of meca Gene Testing and Infectious Diseases Pharmacists Intervention on the Time to Optimal Antimicrobial Therapy for AUTHORS: Staphylococcus aureus Bacteremia at a University Hospital Peggy L. Carver, Pharm.D., FCCP* Clinical Pharmacist in Infectious Diseases and Associate Professor University of Michigan Health System and College of Pharmacy Shu-Wen Lin, M.S., Pharm.D. (No middle initial) At the time of the study: Specialty Resident in Infectious Diseases and Clinical Instructor University of Michigan Health System and College of Pharmacy Departments of Pharmacy Services and Clinical Sciences University of Michigan Health System Current position: Pharmacist and Lecturer National Taiwan University Hospital and Graduate Institute of Clinical Pharmacy Daryl D. DePestel, Pharm.D. Clinical Pharmacist in Infectious Diseases and Clinical Assistant Professor University of Michigan Health System and College of Pharmacy
2 Duane W. Newton, Ph.D., D(ABMM) Director, Clinical Microbiology Laboratories and Assistant Professor Department of Pathology University of Michigan Health System and Medical School Corresponding Author and Author to whom Reprint Requests should be directed: Peggy L. Carver, Pharm.D., FCCP Clinical Pharmacist in Infectious Diseases and Associate Professor University of Michigan Health System and College of Pharmacy Address: University of Michigan College of Pharmacy, Department of Clinical Sciences 428 Church Street Ann Arbor, MI 48109-0008 Phone: (734) 764-9384 Fax: (734) 763-2022 Email: peg@umich.edu No funding or conflict of interest information to disclose with respect to this publication. Presented as a poster at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC, December 16-19, 2005.
3 Running title: meca Testing and Time to Optimal Antimicrobial Therapy Key words: meca gene, gram-positive, methicillin-resistant, Staphylococcus aureus, methicillin-susceptible, susceptibility testing, intervention, antimicrobial pharmacist, optimal antimicrobial therapy
1 1 Abstract 2 3 4 5 In patients with Staphylococcus aureus bacteremia, Infectious Diseases pharmacist intervention based on the results of meca tests resulted in a a 25.4 hour reduction in the time to optimal antimicrobial therapy, from 64.7 ± 36.8 to 39.3 ± 15.5 hours (p = 0.002), which may result in decreased mortality.
2 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Although the most accurate testing method for the detection of MRSA, the meca gene test is not widely used at hospitals, and many clinicians lack knowledge regarding the appropriate and timely application of meca gene test results for the selection of optimal antimicrobial therapy (OAT) against S. aureus infections. Our microbiology laboratory routinely performs meca gene polymerase chain reaction (PCR) testing on all staphylococci once daily, 6 days/week; results are generally available within 36 hours after growth of the organism in culture. However, an additional 2-4 days elapse before the availability of final in vitro susceptibility testing results (i.e., oxacillin susceptibility using cefoxitin as the indicator drug). We hypothesized that the use of an ID clinical pharmacist to alert physicians and to provide clinical recommendations regarding specific antimicrobial therapy at the time of meca gene test availability would decrease the time to receipt of optimal OAT. We compared the time to prescribing of OAT following positive blood culture results with or without ID pharmacist intervention, to evaluate the impact of an ID pharmacistbased meca result notification program on the percentage of patients receiving optimal anti-staphylococcal therapy as compared to a historical control group (standard of care). The study consisted of 2 consecutive, prospective study phases. Phase I was a pilot phase with concurrent quality-assurance surveillance of antimicrobial agents in patients with SAB, without ID pharmacist intervention. During Phase II, the ID pharmacist was alerted daily by the microbiology laboratory when the results of the meca gene tests were available. At that time, patient records were assessed to determine target patients, defined as those who were not currently receiving OAT. The
3 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 target patients physician was contacted by phone to explain the interpretation of the meca gene test result, and to offer recommendations for therapy. All target patients who met the selection criteria were enrolled into the study. During Phase II (but not Phase I), all patients received ID pharmacist intervention. Institutional review board (IRB) approval was obtained for this study. For purposes of this investigation, appropriate antimicrobial therapy was defined as microbiologically documented SAB that was effectively treated with antimicrobials at the time of its identification, and optimal antimicrobial therapy as any regimen containing vancomycin for MRSA bacteremia, and any regimen containing nafcillin, - lactam/ -lactamase inhibitor combinations, first-, or fourth-generation cephalosporins, or vancomycin for MSSA. Vancomycin was not considered optimal therapy for MSSA SAB except in patients with true allergic reactions or severe adverse reactions (eg, neutropenia) to -lactam antibiotics. Vancomycin alternatives (e.g. linezolid, quinupristin/dalfopristin, or daptomycin) were considered optimal if patients had a true vancomycin allergy, were vancomycin intolerant, or had a documented treatment failure on vancomycin. Additionally, only nafcillin was considered optimal therapy if the patient had concurrent meningitis or endocarditis due to MSSA. The primary objective of this study was to evaluate the impact of infectious diseases (ID) pharmacists interventions on the adjustment of antimicrobial therapy based on meca gene tests, and the primary endpoint was the difference in time (hours) to optimal anti-staphylococcal antimicrobial therapy for SAB between Phases I and II. Secondary endpoints included the time to OAT and the rate of application of
4 51 52 meca gene test results to antimicrobial regimen adjustment in the period prior to or with the ID pharmacist s interventions. 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 Statistical analysis was performed utilizing Statview 5.0.1 (SAS Institute Inc., Cary, NC). The t test (or Mann-Whitney U test for nonparametric data) was used to compare the differences in time to optimal antibiotic therapy prior to and after implementation of pharmacy intervention. The Pearson chi-square test was applied on categorical variables of target groups between the two study phases with 2 2 tables. A p-value less than 0.05 was considered significant. The time to optimal antimicrobial therapy following the drawing of a SAB was 64.7 ± 36.8 hours in Phase I and 39.3 ± 15.5 hours in Phase II (p=0.002), a 25.4 h reduction in the time to optimal antimicrobial therapy. (Table 1, Figure 1). The sample size of this study is insufficient to evaluate or compare infection-related outcomes or mortality; however, and a trend towards a decrease in the duration of SAB was observed. An additional benefit during the intervention phase was the discontinuation or de-escalation of inappropriate therapy, which can more effectively target the causative pathogen, resulting in decreased inappropriate antimicrobial exposure. Timely use of appropriate empiric antimicrobial therapy and of specific antimicrobial therapy-based susceptibility results are important determinants of clinical outcomes in S. aureus bacteremia (SAB). In a retrospective cohort study of 64 patients with MSSA and 103 patients with MRSA, delayed treatment of hospitalacquired SAB was associated with a higher infection-related mortality and a longer length of hospital stay (p = 0.05). The breakpoint between early and delayed treatment was 44.75 hours from the draw time of the first positive SAB blood culture
5 74 75 76 (1). The strongest clinical evidence to date supporting the concept that vancomycin is inferior to nafcillin in treating MSSA SAB is from Chang et al (2), who found that nafcillin was superior to vancomycin in preventing persistent bacteremia or relapse in 77 patients with MSSA SAB. More recently, Stryjewski and colleagues (3) noted that 78 hemodialysis-dependent patients treated with cefazolin (vs vancomycin) for MSSA 79 bacteremia experienced a lower risk of treatment failure. 80 The meca PCR test provides rapid identification of MRSA compared to 81 traditional susceptibility testing methods and can be used to tailor OAT in a timely 82 fashion. Novel methods to detect and differentiate between MSSA and MRSA directly 83 from blood culture bottles have recently become available (4). However, the clinician s 84 utilization of this information is vital for tailoring the timely use of optimal antimicrobial 85 treatment. Despite the availability of the meca test, prescribers failed to utilize the 86 results without pharmacists intervention. Pharmacists intervention based on the 87 meca gene test resulted in a 25.4 h reduction in the time to OAT, and a trend towards 88 a decrease in the duration of SAB. These results may result in decrease morbidity and 89 mortality in patients with SAB; further clinical study is needed in order to assess this possibility. 90
6 91 References 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 1. Lodise T.P., P.S. McKinnon, L. Swiderski, and M.J. Rybak. 2003. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin. Infect. Dis. 36:1418-1423. 2. Chang F.Y., B.B. MacDonald, J.E. Peacock Jr, D.M. Musher, P. Triplett, J.M. Mylotte, A. O'Donnell, M.M. Wagener, and V.L. Yu. 2003. A prospective multicenter study of Staphylococcus aureus bacteremia: incidence of endocarditis, risk factors for mortality, and clinical impact of methicillin resistance. Medicine (Baltimore). 82:322-332. 3. Stryjewski M.E., L.A. Szczech, D.K. Benjamin Jr, J.K. Inrig, Z.A. Kanafani, J.J. Engemann, V.H. Chu, M.J. Joyce, L.B. Reller, G.R. Corey, and Fowler V.G. Jr. 2007. Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin. Infect. Dis. 44:190-196. 4. Huletsky A., P. Lebel, F.J. Picard, M. Bernier, M. Gagnon, N. Boucher, and M.G. Bergeron. 2005. Identification of methicillin-resistant Staphylococcus aureus carriage in less than 1 hour during a hospital surveillance program. Clin. Infect. Dis. 40:976-981.
7 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 Table 1 Demographic characteristics, comorbidities, antimicrobial therapy, and species of staphylococci identified for 46 patients with Staphylococcus aureus bacteremia enrolled in the study. a Phase I Phase II P Demographic Characteristic (no.=30) (no.=16) Age in years (mean ± SD) 49.3 ± 20.4 40.2 ± 23.8 0.20 Range in years 0.25-85 0.17-82 --- Male sex 20 (66.6) 8 (50.0) 0.27 MSSA (meca gene absent) 24 (80.0) 15 (93.8) 0.22 Duration of Staphylococcus aureus 3.2 ± 4.0 1.8 ± 1.3 0.08 bacteremia (days) ID consult service b 13 (43.3) 10 (62.5) 0.24 Empiric antimicrobial therapy Vancomycin 23 (76.7) 15 (94.4) 0.77 -lactam/ -lactamase inhibitor 3 (10.0) 0 (0.0) 0.19 1/4 generation cephalosporin c 0 (0.0) 0 (0.0) ---- 125 Other antimicrobial agents 4 (13.3) 1 (6.3) 0.50 126 Specific antimicrobial therapy 127 Vancomycin 6 (20.0) 1 (6.3) 0.18 128 Nafcillin 12 (40.0) 7 (43.8) 0.74
8 129 -lactam/ -lactamase inhibitor 4 (13.3) 3 (18.8) 0.66 130 131 132 133 134 135 136 137 1/4 generation cephalosporin 6 (20.0) 5 (31.3) 0.39 Other antimicrobial agents 2 (6.7) 0 (0.0) 0.29 a Data are presented as the number (percentage) of patients b Patient was seen by the Infectious Diseases consult service c 1/4 generation cephalosporin = first or fourth generation anti-staphylococcal cephalosporin MSSA = methicillin susceptible Staphylococcus
9 138 139 140 Figure 1. Time frame for the collection of SAB blood cultures, the reporting of meca gene test and susceptibility tests for S. aureus, and time to optimal antimicrobial therapy during Phases I and II. Data are reported in hours.
Time to optimal antimicrobial therapy Phase II Phase I P value* Hours after + meca gene test 7.7±11.8 36.6 ± 37.8 0.0004 Hours after + blood culture 39.3 ± 15.5 64.7 ± 36.8 0.002 Blood culture Positive meca gene Preliminary Final Drawn Blood culture test report susceptibility susceptibility I: 26.8 ± 14.4 II: 26.9 ± 10.4 (P=0.96) I: 28.1 ± 12.4 II: 28.5 ± 11.5 (P=0.90) I: 18.2 ± 1.4 II: 18.3 ± 1.3 (P=0.92) I: 49.7 ± 30.6 II: 53.8 ± 39.3 (P=0.72) I: 46.3 ± 12.9 II: 45.7 ± 12.6 (P=0.87) *Phase I vs Phase II