- Email: [email protected]
Impact of an antimicrobial stewardship program with multidisciplinary cooperation in a community public teaching hospital in Taiwan
American Journal of Infection Control 41 (2013) 1069-72
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
journal homepage: www.ajicjournal.org
Major article
Impact of an antimicrobial stewardship program with multidisciplinary cooperation in a community public teaching hospital in Taiwan Yu-Shiuan Lin MSc a, I-Fen Lin DrPH b, c, Yung-Feng Yen MD, MPH b, d, e, *, Pei-Ching Lin MD f, g, Yu-chih Shiu BSN d, Hsing-Yi Hu BSN d, Ying-Pi Yang MSc a a
Department of Pharmacy, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan Institute of Public Health, National Yang-Ming University, Taipei, Taiwan Biostatistical Consultation Centre, National Yang-Ming University, Taipei, Taiwan d Committee of Infection Control, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan e Department of Infectious Disease, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan f Department of Clinical Pathology and Laboratory Medicine, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan g Department of Pediatrics, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan b c
Key Words: Program development Education Multidisciplinary Clinical pharmacists Feedback Cost-benefit Drug utilization evaluation
Background: Reports of antimicrobial stewardship programs (ASPs) in community hospitals are limited, with the major focus on specific agents, small settings, or short time periods. Here we present the outcomes of cost control, consumption restraint, and quality of care after a 3-year multidisciplinary ASP in a 415-bed community public teaching hospital. Methods: Three strategies for improving antimicrobial stewardship were implemented: education, clinical pharmacists-based intervention, and regular outcome announcement. The steering panel of the program was a committee composed of infection specialists, attending physicians, clinical pharmacists, nurses, and medical laboratorists. Results: Semiannual data from July 2009 to June 2012 was analyzed. Antibiotic costs declined from $21,464 to $12,146 per 1,000 patient-days (43.4%). Approximately $2.5 million was saved in 3 years, and estimated labor cost was $3,935 per month. Defined daily dose per 1,000 patient-days were diminished from 906.7 to 717.5 (20.9%). Significant reductions were found in the consumption of aminoglycosides, first-generation cephalosporins, and aminopenicillins. However, through comprehensive auditing, increasing consumption of fourth-generation cephalosporins and fluoroquinolones was noticed. No significant difference in the quality of care (ie, length of stay, incidence of health care associated infections, and mortality) was observed. Conclusions: The multidisciplinary ASP was beneficial to reduce antibiotic cost and consumption. The strategies were practical and worthy to be recommended to community health care settings. Copyright Ó 2013 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
The utilization of antibiotic agents is of particular concern in hospitals. Substantial reports demonstrate the causal relationships among antibiotic consumption, selective pressure of resistant organisms,1-3 adverse drug events, and health care costs.4 This led to the wide application of antimicrobial stewardship programs (ASPs) in health care settings. Benefits of institutional ASPs to infection control, cost restraint, and improvement of quality of caredespecially with an interdisciplinary cooperationdhave been well presented.5-8 * Address correspondence to Yung-Feng Yen, MD, MPH, Department of Infectious Disease, Taipei City Hospital Yang-Ming Branch, 105 Yu, Sheng St, Shi Lin District, Taipei City 111, Taiwan. E-mail address: [email protected] (Y.-F. Yen). Conflicts of interest: None to report.
However, a recent survey conducted by the Infectious Disease Society of America Emerging Infections Network9 noticed that ASPs were mostly in place in medical centers or university teaching hospitals. In Asian countries, most of the ASP reports were displayed by medical centers as well, demonstrating the efficacy of short-term intensive strategies,10,11 specific antibiotic control,12 or hospital-wide computerized antimicrobial approval programs.13 Experience of community health care settings is limited, with the major focus on specific antimicrobial agents,14 in small-sized institutions,15 or over short time periods.16,17 Comprehensive utilization analysis of antimicrobial agents is also insufficient. Given that the ASPs in community-based settings have gained attention in recent years,18 we here provide our experience of ASP practice in a community public teaching hospital in Taipei, Taiwan.
0196-6553/$36.00 - Copyright Ó 2013 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajic.2013.04.004
1070
Y.-S. Lin et al. / American Journal of Infection Control 41 (2013) 1069-72
METHODS Study designs Taipei City Hospital Yang-Ming branch is a 415-bed, nonuniversityaffiliated community teaching hospital subordinate to the Taipei City Government. Taipei City Hospital Yang-Ming branch is active in community, geriatric, chest medicine, and long-term acute-care service. Unit drug dose dispensing with nominative delivery form is provided to all patients. During 2006-2008, cost of antibiotic agents was around $17-$19 per patient-day with an upward trend. It surged to $21 per patient-day during the first quarter of 2009. To increase the quality of antimicrobial prescriptions, as well as restrain the cost and consumption of antibiotic agents, an ASP was introduced in July 2009. The steering panel of this program was a committee of infection control composed of infection specialists, attending physicians, clinical pharmacists, infection control nurses, and medical laboratorists. Intervention The program was based on three components: provide systematic education on the stewardship concept, enhance pharmacists’ participation in antimicrobial use evaluation, and report outcomes of the program regularly to all staff. We provided systematic education to all staff, especially the prescribers, to enhance general adherence with the program. Semiannual plenary speeches were mainly on the rational use of antibiotics and infection control. In the forums, a 4-category control policy for antimicrobial prescribing was described: first-line antibiotics (includes antistaphylococcal penicillins, first-generation cephalosporins, and aminoglycosides) are used in clinical situations by all prescribers. Second-line antibiotics (such as aminopenicillines with enzyme inhibitors and second-generation cephalosporins) are prescribed according to the diagnosis (ICD-9 code) on the chart. For instance, amoxicillin/clavulanate is recommended for patients with community-acquired pneumonia according to the diagnosis (ICD-9 code 481) at admission. Third-line antibiotics are broad-spectrum agents such as antipseudomonal penicillins with enzyme inhibitors, third- and fourth-generation cephalosporins, and fluoroquinolones. Physicians are required to submit applications to the ASP steering panel through the healthcare information system while prescribing. Fourth-line agents, namely imipenem, meropenem, colistin, linezolid, and tigecycline, are restricted to treat multiple drug-resistant organisms exclusively. Infection specialists will conduct a bedside evaluation before approving prescriptions online. However, to not impede treatment for severely ill patients, emergent antibiotic prescriptions for <1 day are available to instant dispensing. To enhance pharmacists’ participation in antimicrobial use evaluation, inappropriate selection of agents, dose, frequency, or duration of antimicrobials was reported by pharmacists via telephone calls upon the delivery of computerized prescriptions. Antimicrobial regimens were reevaluated weekly in general wards. Two clinical pharmacists joined ward rounds with infectious and intensive care medical teams 1-4 times a week, providing explicit therapeutic recommendations, especially in antibiotic use. Druge drug interactions and adverse drug events were consulted as needed. After the chief pharmacist submitted an analysis report to the committee of infection control during the quarterly meeting, it was presented to all staff, especially attending physicians, via the in-hospital Web site. Costs, consumption (defined daily dose [DDD]/1,000 patient-days), the percentage of antimicrobial agents in total drug costs, and a brief antimicrobial use evaluation were
included. Use of controlled agents was monitored by retrospective chart review and sample survey. Potentially inappropriate prescriptions were discussed during the quarterly meeting, and directors of associated medical departments were informed, if needed. Data analysis To compare our data with international data, the expenditures related to medication were converted from New Taiwan dollars to US dollars at a ratio of 1:30.19. All values presented here are thus presented in US dollars. Unit price of medication kept steady except for a slight adjustment managed by the Bureau of National Health Insurance of Taiwan during December 2011. Consumption of antibiotics was translated by DDD according to the Anatomical, Therapeutic, and Chemical classification system/DDD system of the World Health Organization19 and expressed as DDD/1,000 patient-days. Quality indicators To ensure the safety of this program, selective quality indicators were monitored by infection control nurses, including length of stay (LoS), patient mortality, incidence of health-care associated infections (HAIs) (defined as infections occurred >3 days after admission) and prevalence of health care-associated drug resistant organisms (HA-DROs). Target HA-DROs are namely oxacillin-resistant Staphylococcus aerous, Escherichia coli producing extended-spectrum b-lactamase, and pan-drug-resistant Acinetobacter baumannii,20 which was cultured 3 days after admission. Statistical analysis Linear regression was used to examine the trend of semiannual antibiotics cost, DDD, LoS, mortality, incidence of HAIs, and HA-DROs before and after the program. Pearson’s correlation coefficient was used to determine the relationship between the program implementation, and trends in antibiotic costs as well as consumption. A P value .05 was considered statistically significant. Analyses were done with SPSS version 19.0 statistical software (IBM Corp, Armonk, NY). RESULTS During July 2009 through June 2012, there were 6 monitoring sessions, 12 panel meetings, and 6 education forums. Quarterly reports of antimicrobial use evaluation were presented by the chief pharmacist. There was no change in the antimicrobial categories under the controlling policy. Cost savings after implementing the ASP Cost of antibiotics during the study period is shown in Table 1. During the first half (H1) of 2009, mean cost of antimicrobials was $21,464/1,000 patient-days. 98.5% of the budget was spent for antibacterials. After 1 year of ASP practice, antibiotic cost per 1,000 patient-days was decreased remarkably (25.8%), and we saved $607,140. The costs kept downgrading. In 2012 H1, the cost of antimicrobials reached the lowest point (43.4%; P ¼ .02). The percentage of expenses on antimicrobial agents to total medication declined as well. After the intervention, mean value of the proportions of antibiotic costs was 56.4% (6.2% to 13.0%). Based on the expenditure records in 2009 H1, estimated financial preservation of the program was $2,495,954 in 3 years.
Y.-S. Lin et al. / American Journal of Infection Control 41 (2013) 1069-72
1071
Table 1 Costs* per 1,000 patient-days before and during the antimicrobial stewardship program Before
Cost of antimicrobial agents Antibacterials Antifungals Antivirals Reduction ratey (%) Cost of total medication Percentage of cost of antimicrobials to total medication
During
Trend analysis
2009 H1
2009 H2
2010 H1
2010 H2
2011 H1
2011 H2
2012 H1
r
P
b
21,464 21,139 157 168 32,161 66.7%
14,043 13,860 60 123 34.6 25,376 55.3%
15,934 15,701 166 67 25.8 26,329 60.5%
15,651 15,526 48 77 27.1 28,338 55.2%
12,173 11,965 133 75 43.3 22,645 53.8%
11,434 11,160 118 156 46.7 20,809 54.9%
12,146 11,851 145 150 43.4 20,753 58.5%
0.82 0.83 0.08 0.04 0.73 0.87 0.59
.02 .02 .87 .94 .10 .01 .16
1,319.04 1,321.43 1.68 0.71 3.51 1,680.07 1.24
H1, first half of the year; H2, second half of the year. *Costs are presented in US dollars (US dollars:New Taiwan dollars ¼ 1:30.19). y Reduction rate of the cost of antimicrobial agents was compared with the data of 2009 H1.
Table 2 Significant changes of defined daily dose per 1,000 patient-days of antimicrobials during the antimicrobial stewardship program Before
Antibacterial Aminoglycosides All cephalosporins First generation cephalosporin Miscellaneous* Colistin Penicillins Aminopenicillins Antifungals Antivirals Total
During
Trend analysis
2009 H1
2009 H2
2010 H1
2010 H2
2011 H1
2011 H2
2012 H1
r
P
b
899.0 55.0 301.0 140.0 0.0 0.0 304.0 169.0 7.2 0.5 906.7
748.0 61.0 294.0 147.0 0.0 0.0 220.0 128.0 5.6 0.9 754.5
804.0 53.0 310.0 124.0 0.1 0.1 239.0 132.0 11.6 0.9 816.5
879.0 52.0 335.0 134.0 4.8 4.4 252.0 119.0 8.9 0.7 888.6
666.0 42.0 235.0 86.0 7.2 5.7 199.0 110.0 8.2 0.5 674.7
677.0 33.0 238.0 96.0 10.4 8.9 208.0 119.0 9.3 0.8 687.1
705.0 28.0 223.0 91.0 8.8 8.4 217.0 118.0 9.6 2.9 717.5
0.70 0.93 0.74 0.88 0.94 0.94 0.71 0.76 0.43 0.77 0.69
0.08 0.00 0.06 0.01 0.00 0.00 0.07 0.05 0.34 0.04 0.09
30.79 5.29 14.93 10.25 1.93 1.71 11.61 6.89 0.39 0.32 30.29
H1, first half of the year; H2, second half of the year. *Miscellaneous includes colistin, linezolid, and tigecycline.
In contrast with the significant decline of antibacterial expenditures (P ¼ .02), costs of antifungal and antiviral agents were steady.
indicators deviated significantly from the record of 2009 H1, except a steady increase of total patient-days (from 47,698 to 53,336; P ¼ .02).
DDD/1,000 patient-days
DISCUSSION
The significant changes of antimicrobial consumption are presented in Table 2. After 3 years of ASP intervention, DDDs of antibiotics declined from 906.7 to 717.5/1,000 patient-days. Remarkable decreases were found in the consumption of aminoglycosides (P < .01), first-generation cephalosporins (P ¼ .01), and aminopenicillins (P ¼ .05). Insignificant declines were also noticed in the use of glycopeptides (from 20.0 to 14.3; P ¼ .06), total cephalosporins (from 301.0 to 223.0; P ¼ .06), total penicillins (from 314.0 to 217.0; P ¼ .07), and carbapenems (from 34.7 to 21.4; P ¼ .24). Slight increases were observed in piperacillin/tazobactam (from 29.0 to 37.0; P ¼ .85), fluoroquinolones (from 79.7 to 87.6; P ¼ .46), and fourth-generation cephalosporins (ie, cefepime and cefpirome [from 16.0 to 26.0]; P ¼ .15). Colistin, antifungal, and antiviral agents presented growing trends based on their extremely small quantities before the program. In general, first- and second-line antibiotics remained as the widely used agents before and during the program.
ASPs have been suggested to restrain the costs of medication as well as antimicrobial resistance in health care institutions.21,22 Our report describes the strategies and outcomes of an ASP in a community public teaching hospital. The program contained 3 domains, based on the recommendation of Infectious Diseases Society of America/Society for Healthcare Epidemiology of America in 200721; that is, 2 core strategies (ie, prospective audit with intervention and feedback by infectious disease physicians and clinical pharmacists, formulary restriction, and preauthorization) and 1 supplying element (ie, education). Besides having an infection specialist as the program leader, assistance from clinical pharmacists and infection control nurses was pivotal. After 3 years of practice, the multidisciplinary program was efficient at curbing the cost and consumption of antimicrobials without interfering with quality of care. To assess the economic benefit of the program, we estimated the expense of our institution by labor costs.23 We calculated it by salary and proportion time spent on the ASP by an infection specialist ($2,650 60% 1 ¼ $1,590), 2 pharmacists ($1,656 50% 2 ¼ $1,656), and 2 infection control nurses ($1,722 20% 2 ¼ $689). Total labor cost was $3,935 per month. Because we saved $2,495,954 in 3 years, the benefit ratio was 1:17.6. Therefore, we found a positive financial effect of the interdisciplinary program. Some points are worthy of note. First, a substantial decrease in expenditure was observed during the initial 6 months, accounting for more than one-third of the money savings. Expenditure fluctuated before reaching stable status over a prolonged period. The
Quality indicators From 2009 H1 to 2012 H1, numbers of admissions fluctuated between 3,874 and 4,965 semiannually (P ¼ .31). LoS was kept between 10.6 and 12.2 days. Mortality rate was consistent between 2.6 and 3.9 per 100 admissions. HAIs were extremely rare in our hospital. Incidence of HAIs was 1.9 cases per 1,000 patient-days in 2009 H1, slightly swinging to reach a lower point of 1.3 cases per 1,000 patient-days in 2012 H1 (P ¼ .29). Target HA-DROs were between 15 and 24 cases semiannually. None of the quality
1072
Y.-S. Lin et al. / American Journal of Infection Control 41 (2013) 1069-72
maximum cost reduction was noticed during the third year, which was behind a slight rebound period. Similar oscillation was also seen in ASP reports from other health care settings.14,24 Second, significant declines in antibiotic consumption were mainly found in first- and second-line agents. The use of board-spectrum agents was relatively rigid to control. Furthermore, compared with the reports worldwide,14,24-27 it is evident that ASPs had significant lowering effects on the consumption of a number of broadspectrum antibacterials, yet some others may slip up.17,25 In our experience, the consumption of fourth-generation cephalosporins and fluoroquinolones seemed to creep. The finding supports the necessity of regular and comprehensive analysis of the consumption of antimicrobial agents during ASP practice. Quality of care was not altered significantly during the 3 years. Incidence of HAIs was slightly descending, and prevalence of HA-DROs was kept stable. Besides our program, 2 infection control projects may have contributed to the change in our institution: a care bundle of urinary tract infection in the intensive care unit (2011) and a hand-washing promotion in every ward (2010). Certain limitations should be considered when interpreting our results. The monetary preservation outcome was a cost-benefit analysis rather than a cost-effectiveness or a cost-utility one.22 Additionally, according to the study design, we monitored the appropriateness of antimicrobial prescription by retrospective chart review and sample survey. The improvement in the quality of antimicrobial prescriptions after the ASP was launched was not measured in detail. Neither was the program adherence by prescribers. Lastly, because of the extremely rare strains of health care-associated microorganisms, we were unable to infer the relationship, if any, between the decreasing antibiotic use and the prevalence of HA-DROs. CONCLUSIONS We provided a report of a positive experience of an ASP in a community hospital. Although there are studies showing vast contribution of modern technologies to antibiotic control,13,28 it is not easy for community health care institutions to apply for/attain the considerable amount of financial subsidies necessary to implement those technologies. By enforcing the overall concept of antimicrobial stewardship via education, interdisciplinary teamwork, and giving feedback regarding the ASP outcomes to staff regularly, we successfully curtailed the expenditure related to and use of antimicrobial agents. Based on our experience, we recommend these practical strategies to other community-based health care settings. Acknowledgments The authors thank the following people for their help in developing and maintaining the ASP: Wen-Li Yang, MD (president of the hospital), Hung-Meng Huang (vice president of the hospital), and Chia-Li Wang (vice director, Division of Clinical Pathology and Laboratory). References 1. Lai CC, Wang CY, Chu CC, Tan CK, Lu CL, Lee YC, et al. Correlation between antibiotic consumption and resistance of Gram-negative bacteria causing healthcare-associated infections at a university hospital in Taiwan from 2000 to 2009. J Antimicrob Chemother 2011;66:1374-82. 2. Iosifidis E, Antachopoulos C, Tsivitanidou M, Katragkou A, Farmaki E, Tsiakou M, et al. Differential correlation between rates of antimicrobial drug consumption and prevalence of antimicrobial resistance in a tertiary care hospital in Greece. Infect Control Hosp Epidemiol 2008;29:615-22. 3. Rogues AM, Dumartin C, Amadeo B, Venier AG, Marty N, Parneix P, et al. Relationship between rates of antimicrobial consumption and the incidence of antimicrobial resistance in Staphylococcus aureus and Pseudomonas aeruginosa
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18. 19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
isolates from 47 French hospitals. Infect Control Hosp Epidemiol 2007;28: 1389-95. Ben-David D, Novikov I, Mermel LA. Are there differences in hospital cost between patients with nosocomial methicillin-resistant Staphylococcus aureus bloodstream infection and those with methicillin-susceptible S. aureus bloodstream infection? Infect Control Hosp Epidemiol 2009;30:453-60. Nowak MA, Nelson RE, Breidenbach JL, Thompson PA, Carson PJ. Clinical and economic outcomes of a prospective antimicrobial stewardship program. Am J Health Syst Pharm 2012;69:1500-8. Saizy-Callaert S, Causse R, Furhman C, Le Paih MF, Thebault A, Chouaid C. Impact of a multidisciplinary approach to the control of antibiotic prescription in a general hospital. J Hosp Infect 2003;53:177-82. Griffith M, Postelnick M, Scheetz M. Antimicrobial stewardship programs: methods of operation and suggested outcomes. Expert Rev Anti Infect Ther 2012;10:63-73. Pope SD, Dellit TH, Owens RC, Hooton TM. Results of survey on implementation of Infectious Diseases Society of America and Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Infect Control Hospital Epidemiol 2009;30:97-8. Johannsson B, Beekmann SE, Srinivasan A, Hersh AL, Laxminarayan R, Polgreen PM. Improving antimicrobial stewardship: the evolution of programmatic strategies and barriers. Infect Control Hosp Epidemiol 2011;32:367-74. Chang MT, Wu TH, Wang CY, Jang TN, Huang CY. The impact of an intensive antimicrobial control program in a Taiwanese medical center. Pharm World Sci 2006;28:257-64. Ng CK, Wu TC, Chan WM, Leung YS, Li CK, Tsang DN, et al. Clinical and economic impact of an antibiotics stewardship programme in a regional hospital in Hong Kong. Qual Saf Health Care 2008;17:387-92. Wu HH, Liu HY, Lin YC, Hsueh PR, Lee YJ. Correlation between levofloxacin consumption and the incidence of nosocomial infections due to fluoroquinolone-resistant Escherichia coli. J Microbiol Immunol Infect. 2012 May 4 [Epub ahead of print]. Chan YY, Lin TY, Huang CT, Deng ST, Wu TL, Leu HS, et al. Implementation and outcomes of a hospital-wide computerised antimicrobial stewardship programme in a large medical centre in Taiwan. Int J Antimicrob Agent 2011;38: 486-92. Philmon C, Smith T, Williamson S, Goodman E. Controlling use of antimicrobials in a community teaching hospital. Infect Control Hospital Epidemiol 2006;27:239-44. Pate PG, Storey DF, Baum DL. Implementation of an antimicrobial stewardship program at a 60-bed long-term acute care hospital. Infect Control Hosp Epidemiol 2012;33:405-8. Malani AN, Richards PG, Kapila S, Otto MH, Czerwinski J, Singal B. Clinical and economic outcomes from a community hospital’s antimicrobial stewardship program. Am J Infect Control 2012;41:145-8. Storey DF, Pate PG, Nguyen AT, Chang F. Implementation of an antimicrobial stewardship program on the medical-surgical service of a 100-bed community hospital. Antimicrob Resist Infect Control 2012;1:32. Septimus EJ, Owens RC Jr. Need and potential of antimicrobial stewardship in community hospitals. Clinical Infect Dis 2011;53(Suppl 1):S8-14. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2012. Available from: http://www.whocc.no/atc_ddd_index/. Accessed October 8, 2012. Falagas ME, Karageorgopoulos DE. Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology. Clin Infect Dis 2008;46:1121-2. Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin infect Dis 2007;44:159-77. Stevenson KB, Balada-Llasat JM, Bauer K, Deutscher M, Goff D, Lustberg M, et al. The economics of antimicrobial stewardship: the current state of the art and applying the business case model. Infect Control Hosp Epidemiol 2012;33:389-97. Beardsley JR, Williamson JC, Johnson JW, Luther VP, Wrenn RH, Ohl CC. Show me the money: long-term financial impact of an antimicrobial stewardship program. Infect Control Hosp Epidemiol 2012;33:398-400. Standiford HC, Chan S, Tripoli M, Weekes E, Forrest GN. Antimicrobial stewardship at a large tertiary care academic medical center: cost analysis before, during, and after a 7-year program. Infect Control Hosp Epidemiol 2012;33: 338-45. Niwa T, Shinoda Y, Suzuki A, Ohmori T, Yasuda M, Ohta H, et al. Outcome measurement of extensive implementation of antimicrobial stewardship in patients receiving intravenous antibiotics in a Japanese university hospital. Int J Clin Pract 2012;66:999-1008. Velickovic-Radovanovic R, Petrovic J, Kocic B, Antic S, Mitic R. Analysis of antibiotic utilization and bacterial resistance changes in a surgical clinic of Clinical Centre. Nis. J Clin Pharm Ther 2012;37:32-6. Ababneh M, Harpe S, Oinonen M, Polk RE. Trends in aminoglycoside use and gentamicin-resistant gram-negative clinical isolates in US academic medical centers: implications for antimicrobial stewardship. Infection Control Hosp Epidemiol 2012;33:594-601. Thursky K. Use of computerized decision support systems to improve antibiotic prescribing. Expert Rev Anti Infect Ther 2006;4:491-507.
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
journal homepage: www.ajicjournal.org
Major article
Impact of an antimicrobial stewardship program with multidisciplinary cooperation in a community public teaching hospital in Taiwan Yu-Shiuan Lin MSc a, I-Fen Lin DrPH b, c, Yung-Feng Yen MD, MPH b, d, e, *, Pei-Ching Lin MD f, g, Yu-chih Shiu BSN d, Hsing-Yi Hu BSN d, Ying-Pi Yang MSc a a
Department of Pharmacy, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan Institute of Public Health, National Yang-Ming University, Taipei, Taiwan Biostatistical Consultation Centre, National Yang-Ming University, Taipei, Taiwan d Committee of Infection Control, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan e Department of Infectious Disease, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan f Department of Clinical Pathology and Laboratory Medicine, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan g Department of Pediatrics, Taipei City Hospital Yang-Ming Branch, Taipei City Government, Taipei, Taiwan b c
Key Words: Program development Education Multidisciplinary Clinical pharmacists Feedback Cost-benefit Drug utilization evaluation
Background: Reports of antimicrobial stewardship programs (ASPs) in community hospitals are limited, with the major focus on specific agents, small settings, or short time periods. Here we present the outcomes of cost control, consumption restraint, and quality of care after a 3-year multidisciplinary ASP in a 415-bed community public teaching hospital. Methods: Three strategies for improving antimicrobial stewardship were implemented: education, clinical pharmacists-based intervention, and regular outcome announcement. The steering panel of the program was a committee composed of infection specialists, attending physicians, clinical pharmacists, nurses, and medical laboratorists. Results: Semiannual data from July 2009 to June 2012 was analyzed. Antibiotic costs declined from $21,464 to $12,146 per 1,000 patient-days (43.4%). Approximately $2.5 million was saved in 3 years, and estimated labor cost was $3,935 per month. Defined daily dose per 1,000 patient-days were diminished from 906.7 to 717.5 (20.9%). Significant reductions were found in the consumption of aminoglycosides, first-generation cephalosporins, and aminopenicillins. However, through comprehensive auditing, increasing consumption of fourth-generation cephalosporins and fluoroquinolones was noticed. No significant difference in the quality of care (ie, length of stay, incidence of health care associated infections, and mortality) was observed. Conclusions: The multidisciplinary ASP was beneficial to reduce antibiotic cost and consumption. The strategies were practical and worthy to be recommended to community health care settings. Copyright Ó 2013 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
The utilization of antibiotic agents is of particular concern in hospitals. Substantial reports demonstrate the causal relationships among antibiotic consumption, selective pressure of resistant organisms,1-3 adverse drug events, and health care costs.4 This led to the wide application of antimicrobial stewardship programs (ASPs) in health care settings. Benefits of institutional ASPs to infection control, cost restraint, and improvement of quality of caredespecially with an interdisciplinary cooperationdhave been well presented.5-8 * Address correspondence to Yung-Feng Yen, MD, MPH, Department of Infectious Disease, Taipei City Hospital Yang-Ming Branch, 105 Yu, Sheng St, Shi Lin District, Taipei City 111, Taiwan. E-mail address: [email protected] (Y.-F. Yen). Conflicts of interest: None to report.
However, a recent survey conducted by the Infectious Disease Society of America Emerging Infections Network9 noticed that ASPs were mostly in place in medical centers or university teaching hospitals. In Asian countries, most of the ASP reports were displayed by medical centers as well, demonstrating the efficacy of short-term intensive strategies,10,11 specific antibiotic control,12 or hospital-wide computerized antimicrobial approval programs.13 Experience of community health care settings is limited, with the major focus on specific antimicrobial agents,14 in small-sized institutions,15 or over short time periods.16,17 Comprehensive utilization analysis of antimicrobial agents is also insufficient. Given that the ASPs in community-based settings have gained attention in recent years,18 we here provide our experience of ASP practice in a community public teaching hospital in Taipei, Taiwan.
0196-6553/$36.00 - Copyright Ó 2013 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajic.2013.04.004
1070
Y.-S. Lin et al. / American Journal of Infection Control 41 (2013) 1069-72
METHODS Study designs Taipei City Hospital Yang-Ming branch is a 415-bed, nonuniversityaffiliated community teaching hospital subordinate to the Taipei City Government. Taipei City Hospital Yang-Ming branch is active in community, geriatric, chest medicine, and long-term acute-care service. Unit drug dose dispensing with nominative delivery form is provided to all patients. During 2006-2008, cost of antibiotic agents was around $17-$19 per patient-day with an upward trend. It surged to $21 per patient-day during the first quarter of 2009. To increase the quality of antimicrobial prescriptions, as well as restrain the cost and consumption of antibiotic agents, an ASP was introduced in July 2009. The steering panel of this program was a committee of infection control composed of infection specialists, attending physicians, clinical pharmacists, infection control nurses, and medical laboratorists. Intervention The program was based on three components: provide systematic education on the stewardship concept, enhance pharmacists’ participation in antimicrobial use evaluation, and report outcomes of the program regularly to all staff. We provided systematic education to all staff, especially the prescribers, to enhance general adherence with the program. Semiannual plenary speeches were mainly on the rational use of antibiotics and infection control. In the forums, a 4-category control policy for antimicrobial prescribing was described: first-line antibiotics (includes antistaphylococcal penicillins, first-generation cephalosporins, and aminoglycosides) are used in clinical situations by all prescribers. Second-line antibiotics (such as aminopenicillines with enzyme inhibitors and second-generation cephalosporins) are prescribed according to the diagnosis (ICD-9 code) on the chart. For instance, amoxicillin/clavulanate is recommended for patients with community-acquired pneumonia according to the diagnosis (ICD-9 code 481) at admission. Third-line antibiotics are broad-spectrum agents such as antipseudomonal penicillins with enzyme inhibitors, third- and fourth-generation cephalosporins, and fluoroquinolones. Physicians are required to submit applications to the ASP steering panel through the healthcare information system while prescribing. Fourth-line agents, namely imipenem, meropenem, colistin, linezolid, and tigecycline, are restricted to treat multiple drug-resistant organisms exclusively. Infection specialists will conduct a bedside evaluation before approving prescriptions online. However, to not impede treatment for severely ill patients, emergent antibiotic prescriptions for <1 day are available to instant dispensing. To enhance pharmacists’ participation in antimicrobial use evaluation, inappropriate selection of agents, dose, frequency, or duration of antimicrobials was reported by pharmacists via telephone calls upon the delivery of computerized prescriptions. Antimicrobial regimens were reevaluated weekly in general wards. Two clinical pharmacists joined ward rounds with infectious and intensive care medical teams 1-4 times a week, providing explicit therapeutic recommendations, especially in antibiotic use. Druge drug interactions and adverse drug events were consulted as needed. After the chief pharmacist submitted an analysis report to the committee of infection control during the quarterly meeting, it was presented to all staff, especially attending physicians, via the in-hospital Web site. Costs, consumption (defined daily dose [DDD]/1,000 patient-days), the percentage of antimicrobial agents in total drug costs, and a brief antimicrobial use evaluation were
included. Use of controlled agents was monitored by retrospective chart review and sample survey. Potentially inappropriate prescriptions were discussed during the quarterly meeting, and directors of associated medical departments were informed, if needed. Data analysis To compare our data with international data, the expenditures related to medication were converted from New Taiwan dollars to US dollars at a ratio of 1:30.19. All values presented here are thus presented in US dollars. Unit price of medication kept steady except for a slight adjustment managed by the Bureau of National Health Insurance of Taiwan during December 2011. Consumption of antibiotics was translated by DDD according to the Anatomical, Therapeutic, and Chemical classification system/DDD system of the World Health Organization19 and expressed as DDD/1,000 patient-days. Quality indicators To ensure the safety of this program, selective quality indicators were monitored by infection control nurses, including length of stay (LoS), patient mortality, incidence of health-care associated infections (HAIs) (defined as infections occurred >3 days after admission) and prevalence of health care-associated drug resistant organisms (HA-DROs). Target HA-DROs are namely oxacillin-resistant Staphylococcus aerous, Escherichia coli producing extended-spectrum b-lactamase, and pan-drug-resistant Acinetobacter baumannii,20 which was cultured 3 days after admission. Statistical analysis Linear regression was used to examine the trend of semiannual antibiotics cost, DDD, LoS, mortality, incidence of HAIs, and HA-DROs before and after the program. Pearson’s correlation coefficient was used to determine the relationship between the program implementation, and trends in antibiotic costs as well as consumption. A P value .05 was considered statistically significant. Analyses were done with SPSS version 19.0 statistical software (IBM Corp, Armonk, NY). RESULTS During July 2009 through June 2012, there were 6 monitoring sessions, 12 panel meetings, and 6 education forums. Quarterly reports of antimicrobial use evaluation were presented by the chief pharmacist. There was no change in the antimicrobial categories under the controlling policy. Cost savings after implementing the ASP Cost of antibiotics during the study period is shown in Table 1. During the first half (H1) of 2009, mean cost of antimicrobials was $21,464/1,000 patient-days. 98.5% of the budget was spent for antibacterials. After 1 year of ASP practice, antibiotic cost per 1,000 patient-days was decreased remarkably (25.8%), and we saved $607,140. The costs kept downgrading. In 2012 H1, the cost of antimicrobials reached the lowest point (43.4%; P ¼ .02). The percentage of expenses on antimicrobial agents to total medication declined as well. After the intervention, mean value of the proportions of antibiotic costs was 56.4% (6.2% to 13.0%). Based on the expenditure records in 2009 H1, estimated financial preservation of the program was $2,495,954 in 3 years.
Y.-S. Lin et al. / American Journal of Infection Control 41 (2013) 1069-72
1071
Table 1 Costs* per 1,000 patient-days before and during the antimicrobial stewardship program Before
Cost of antimicrobial agents Antibacterials Antifungals Antivirals Reduction ratey (%) Cost of total medication Percentage of cost of antimicrobials to total medication
During
Trend analysis
2009 H1
2009 H2
2010 H1
2010 H2
2011 H1
2011 H2
2012 H1
r
P
b
21,464 21,139 157 168 32,161 66.7%
14,043 13,860 60 123 34.6 25,376 55.3%
15,934 15,701 166 67 25.8 26,329 60.5%
15,651 15,526 48 77 27.1 28,338 55.2%
12,173 11,965 133 75 43.3 22,645 53.8%
11,434 11,160 118 156 46.7 20,809 54.9%
12,146 11,851 145 150 43.4 20,753 58.5%
0.82 0.83 0.08 0.04 0.73 0.87 0.59
.02 .02 .87 .94 .10 .01 .16
1,319.04 1,321.43 1.68 0.71 3.51 1,680.07 1.24
H1, first half of the year; H2, second half of the year. *Costs are presented in US dollars (US dollars:New Taiwan dollars ¼ 1:30.19). y Reduction rate of the cost of antimicrobial agents was compared with the data of 2009 H1.
Table 2 Significant changes of defined daily dose per 1,000 patient-days of antimicrobials during the antimicrobial stewardship program Before
Antibacterial Aminoglycosides All cephalosporins First generation cephalosporin Miscellaneous* Colistin Penicillins Aminopenicillins Antifungals Antivirals Total
During
Trend analysis
2009 H1
2009 H2
2010 H1
2010 H2
2011 H1
2011 H2
2012 H1
r
P
b
899.0 55.0 301.0 140.0 0.0 0.0 304.0 169.0 7.2 0.5 906.7
748.0 61.0 294.0 147.0 0.0 0.0 220.0 128.0 5.6 0.9 754.5
804.0 53.0 310.0 124.0 0.1 0.1 239.0 132.0 11.6 0.9 816.5
879.0 52.0 335.0 134.0 4.8 4.4 252.0 119.0 8.9 0.7 888.6
666.0 42.0 235.0 86.0 7.2 5.7 199.0 110.0 8.2 0.5 674.7
677.0 33.0 238.0 96.0 10.4 8.9 208.0 119.0 9.3 0.8 687.1
705.0 28.0 223.0 91.0 8.8 8.4 217.0 118.0 9.6 2.9 717.5
0.70 0.93 0.74 0.88 0.94 0.94 0.71 0.76 0.43 0.77 0.69
0.08 0.00 0.06 0.01 0.00 0.00 0.07 0.05 0.34 0.04 0.09
30.79 5.29 14.93 10.25 1.93 1.71 11.61 6.89 0.39 0.32 30.29
H1, first half of the year; H2, second half of the year. *Miscellaneous includes colistin, linezolid, and tigecycline.
In contrast with the significant decline of antibacterial expenditures (P ¼ .02), costs of antifungal and antiviral agents were steady.
indicators deviated significantly from the record of 2009 H1, except a steady increase of total patient-days (from 47,698 to 53,336; P ¼ .02).
DDD/1,000 patient-days
DISCUSSION
The significant changes of antimicrobial consumption are presented in Table 2. After 3 years of ASP intervention, DDDs of antibiotics declined from 906.7 to 717.5/1,000 patient-days. Remarkable decreases were found in the consumption of aminoglycosides (P < .01), first-generation cephalosporins (P ¼ .01), and aminopenicillins (P ¼ .05). Insignificant declines were also noticed in the use of glycopeptides (from 20.0 to 14.3; P ¼ .06), total cephalosporins (from 301.0 to 223.0; P ¼ .06), total penicillins (from 314.0 to 217.0; P ¼ .07), and carbapenems (from 34.7 to 21.4; P ¼ .24). Slight increases were observed in piperacillin/tazobactam (from 29.0 to 37.0; P ¼ .85), fluoroquinolones (from 79.7 to 87.6; P ¼ .46), and fourth-generation cephalosporins (ie, cefepime and cefpirome [from 16.0 to 26.0]; P ¼ .15). Colistin, antifungal, and antiviral agents presented growing trends based on their extremely small quantities before the program. In general, first- and second-line antibiotics remained as the widely used agents before and during the program.
ASPs have been suggested to restrain the costs of medication as well as antimicrobial resistance in health care institutions.21,22 Our report describes the strategies and outcomes of an ASP in a community public teaching hospital. The program contained 3 domains, based on the recommendation of Infectious Diseases Society of America/Society for Healthcare Epidemiology of America in 200721; that is, 2 core strategies (ie, prospective audit with intervention and feedback by infectious disease physicians and clinical pharmacists, formulary restriction, and preauthorization) and 1 supplying element (ie, education). Besides having an infection specialist as the program leader, assistance from clinical pharmacists and infection control nurses was pivotal. After 3 years of practice, the multidisciplinary program was efficient at curbing the cost and consumption of antimicrobials without interfering with quality of care. To assess the economic benefit of the program, we estimated the expense of our institution by labor costs.23 We calculated it by salary and proportion time spent on the ASP by an infection specialist ($2,650 60% 1 ¼ $1,590), 2 pharmacists ($1,656 50% 2 ¼ $1,656), and 2 infection control nurses ($1,722 20% 2 ¼ $689). Total labor cost was $3,935 per month. Because we saved $2,495,954 in 3 years, the benefit ratio was 1:17.6. Therefore, we found a positive financial effect of the interdisciplinary program. Some points are worthy of note. First, a substantial decrease in expenditure was observed during the initial 6 months, accounting for more than one-third of the money savings. Expenditure fluctuated before reaching stable status over a prolonged period. The
Quality indicators From 2009 H1 to 2012 H1, numbers of admissions fluctuated between 3,874 and 4,965 semiannually (P ¼ .31). LoS was kept between 10.6 and 12.2 days. Mortality rate was consistent between 2.6 and 3.9 per 100 admissions. HAIs were extremely rare in our hospital. Incidence of HAIs was 1.9 cases per 1,000 patient-days in 2009 H1, slightly swinging to reach a lower point of 1.3 cases per 1,000 patient-days in 2012 H1 (P ¼ .29). Target HA-DROs were between 15 and 24 cases semiannually. None of the quality
1072
Y.-S. Lin et al. / American Journal of Infection Control 41 (2013) 1069-72
maximum cost reduction was noticed during the third year, which was behind a slight rebound period. Similar oscillation was also seen in ASP reports from other health care settings.14,24 Second, significant declines in antibiotic consumption were mainly found in first- and second-line agents. The use of board-spectrum agents was relatively rigid to control. Furthermore, compared with the reports worldwide,14,24-27 it is evident that ASPs had significant lowering effects on the consumption of a number of broadspectrum antibacterials, yet some others may slip up.17,25 In our experience, the consumption of fourth-generation cephalosporins and fluoroquinolones seemed to creep. The finding supports the necessity of regular and comprehensive analysis of the consumption of antimicrobial agents during ASP practice. Quality of care was not altered significantly during the 3 years. Incidence of HAIs was slightly descending, and prevalence of HA-DROs was kept stable. Besides our program, 2 infection control projects may have contributed to the change in our institution: a care bundle of urinary tract infection in the intensive care unit (2011) and a hand-washing promotion in every ward (2010). Certain limitations should be considered when interpreting our results. The monetary preservation outcome was a cost-benefit analysis rather than a cost-effectiveness or a cost-utility one.22 Additionally, according to the study design, we monitored the appropriateness of antimicrobial prescription by retrospective chart review and sample survey. The improvement in the quality of antimicrobial prescriptions after the ASP was launched was not measured in detail. Neither was the program adherence by prescribers. Lastly, because of the extremely rare strains of health care-associated microorganisms, we were unable to infer the relationship, if any, between the decreasing antibiotic use and the prevalence of HA-DROs. CONCLUSIONS We provided a report of a positive experience of an ASP in a community hospital. Although there are studies showing vast contribution of modern technologies to antibiotic control,13,28 it is not easy for community health care institutions to apply for/attain the considerable amount of financial subsidies necessary to implement those technologies. By enforcing the overall concept of antimicrobial stewardship via education, interdisciplinary teamwork, and giving feedback regarding the ASP outcomes to staff regularly, we successfully curtailed the expenditure related to and use of antimicrobial agents. Based on our experience, we recommend these practical strategies to other community-based health care settings. Acknowledgments The authors thank the following people for their help in developing and maintaining the ASP: Wen-Li Yang, MD (president of the hospital), Hung-Meng Huang (vice president of the hospital), and Chia-Li Wang (vice director, Division of Clinical Pathology and Laboratory). References 1. Lai CC, Wang CY, Chu CC, Tan CK, Lu CL, Lee YC, et al. Correlation between antibiotic consumption and resistance of Gram-negative bacteria causing healthcare-associated infections at a university hospital in Taiwan from 2000 to 2009. J Antimicrob Chemother 2011;66:1374-82. 2. Iosifidis E, Antachopoulos C, Tsivitanidou M, Katragkou A, Farmaki E, Tsiakou M, et al. Differential correlation between rates of antimicrobial drug consumption and prevalence of antimicrobial resistance in a tertiary care hospital in Greece. Infect Control Hosp Epidemiol 2008;29:615-22. 3. Rogues AM, Dumartin C, Amadeo B, Venier AG, Marty N, Parneix P, et al. Relationship between rates of antimicrobial consumption and the incidence of antimicrobial resistance in Staphylococcus aureus and Pseudomonas aeruginosa
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18. 19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
isolates from 47 French hospitals. Infect Control Hosp Epidemiol 2007;28: 1389-95. Ben-David D, Novikov I, Mermel LA. Are there differences in hospital cost between patients with nosocomial methicillin-resistant Staphylococcus aureus bloodstream infection and those with methicillin-susceptible S. aureus bloodstream infection? Infect Control Hosp Epidemiol 2009;30:453-60. Nowak MA, Nelson RE, Breidenbach JL, Thompson PA, Carson PJ. Clinical and economic outcomes of a prospective antimicrobial stewardship program. Am J Health Syst Pharm 2012;69:1500-8. Saizy-Callaert S, Causse R, Furhman C, Le Paih MF, Thebault A, Chouaid C. Impact of a multidisciplinary approach to the control of antibiotic prescription in a general hospital. J Hosp Infect 2003;53:177-82. Griffith M, Postelnick M, Scheetz M. Antimicrobial stewardship programs: methods of operation and suggested outcomes. Expert Rev Anti Infect Ther 2012;10:63-73. Pope SD, Dellit TH, Owens RC, Hooton TM. Results of survey on implementation of Infectious Diseases Society of America and Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Infect Control Hospital Epidemiol 2009;30:97-8. Johannsson B, Beekmann SE, Srinivasan A, Hersh AL, Laxminarayan R, Polgreen PM. Improving antimicrobial stewardship: the evolution of programmatic strategies and barriers. Infect Control Hosp Epidemiol 2011;32:367-74. Chang MT, Wu TH, Wang CY, Jang TN, Huang CY. The impact of an intensive antimicrobial control program in a Taiwanese medical center. Pharm World Sci 2006;28:257-64. Ng CK, Wu TC, Chan WM, Leung YS, Li CK, Tsang DN, et al. Clinical and economic impact of an antibiotics stewardship programme in a regional hospital in Hong Kong. Qual Saf Health Care 2008;17:387-92. Wu HH, Liu HY, Lin YC, Hsueh PR, Lee YJ. Correlation between levofloxacin consumption and the incidence of nosocomial infections due to fluoroquinolone-resistant Escherichia coli. J Microbiol Immunol Infect. 2012 May 4 [Epub ahead of print]. Chan YY, Lin TY, Huang CT, Deng ST, Wu TL, Leu HS, et al. Implementation and outcomes of a hospital-wide computerised antimicrobial stewardship programme in a large medical centre in Taiwan. Int J Antimicrob Agent 2011;38: 486-92. Philmon C, Smith T, Williamson S, Goodman E. Controlling use of antimicrobials in a community teaching hospital. Infect Control Hospital Epidemiol 2006;27:239-44. Pate PG, Storey DF, Baum DL. Implementation of an antimicrobial stewardship program at a 60-bed long-term acute care hospital. Infect Control Hosp Epidemiol 2012;33:405-8. Malani AN, Richards PG, Kapila S, Otto MH, Czerwinski J, Singal B. Clinical and economic outcomes from a community hospital’s antimicrobial stewardship program. Am J Infect Control 2012;41:145-8. Storey DF, Pate PG, Nguyen AT, Chang F. Implementation of an antimicrobial stewardship program on the medical-surgical service of a 100-bed community hospital. Antimicrob Resist Infect Control 2012;1:32. Septimus EJ, Owens RC Jr. Need and potential of antimicrobial stewardship in community hospitals. Clinical Infect Dis 2011;53(Suppl 1):S8-14. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2012. Available from: http://www.whocc.no/atc_ddd_index/. Accessed October 8, 2012. Falagas ME, Karageorgopoulos DE. Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: need for international harmonization in terminology. Clin Infect Dis 2008;46:1121-2. Dellit TH, Owens RC, McGowan JE Jr, Gerding DN, Weinstein RA, Burke JP, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin infect Dis 2007;44:159-77. Stevenson KB, Balada-Llasat JM, Bauer K, Deutscher M, Goff D, Lustberg M, et al. The economics of antimicrobial stewardship: the current state of the art and applying the business case model. Infect Control Hosp Epidemiol 2012;33:389-97. Beardsley JR, Williamson JC, Johnson JW, Luther VP, Wrenn RH, Ohl CC. Show me the money: long-term financial impact of an antimicrobial stewardship program. Infect Control Hosp Epidemiol 2012;33:398-400. Standiford HC, Chan S, Tripoli M, Weekes E, Forrest GN. Antimicrobial stewardship at a large tertiary care academic medical center: cost analysis before, during, and after a 7-year program. Infect Control Hosp Epidemiol 2012;33: 338-45. Niwa T, Shinoda Y, Suzuki A, Ohmori T, Yasuda M, Ohta H, et al. Outcome measurement of extensive implementation of antimicrobial stewardship in patients receiving intravenous antibiotics in a Japanese university hospital. Int J Clin Pract 2012;66:999-1008. Velickovic-Radovanovic R, Petrovic J, Kocic B, Antic S, Mitic R. Analysis of antibiotic utilization and bacterial resistance changes in a surgical clinic of Clinical Centre. Nis. J Clin Pharm Ther 2012;37:32-6. Ababneh M, Harpe S, Oinonen M, Polk RE. Trends in aminoglycoside use and gentamicin-resistant gram-negative clinical isolates in US academic medical centers: implications for antimicrobial stewardship. Infection Control Hosp Epidemiol 2012;33:594-601. Thursky K. Use of computerized decision support systems to improve antibiotic prescribing. Expert Rev Anti Infect Ther 2006;4:491-507.