Advertisement

The need for an antibiotic stewardship program in a hospital using a computerized pre-authorization system

Open AccessPublished:March 04, 2019DOI:https://doi.org/10.1016/j.ijid.2019.02.044

      Highlights

      • A unique pre-authorization system has been used in Turkey since 2003.
      • This system alone had an important role in decreasing inappropriate antimicrobial use.
      • Using prospective audit and feedback further decreased the days of therapy.
      • A combination of the two systems improved appropriate antibiotic usage.

      Abstract

      Objectives

      Antimicrobial stewardship programs (ASPs) have an important role in the appropriate utilization of antibiotics. Some of the core strategies recommended for ASPs are pre-authorization and prospective audit and feedback. In Turkey, a unique nationwide antibiotic restriction program (NARP) has been in place since 2003. The aim of this study was to measure the effect of a prospective audit and feedback strategy system along with the NARP.

      Methods

      A prospective quasi-experimental study was designed and implemented between March and June 2017. A computerized pre-authorization system was used as an ASP strategy to approve the antibiotics. During the baseline period, patients with intravenous (IV) antibiotic use ≥72 h were monitored without intervention. In the second period, feedback and treatment recommendations were given to attending physicians in the case of IV antibiotic use ≥72 h. The modified criteria of Kunin et al. and Gyssens et al. were followed for appropriateness of prescribing. Days of therapy (DOT) and length of stay (LOS) were calculated and compared between the two study periods.

      Results

      A total of 866 antibiotic episodes among 519 patients were observed. A significant reduction in systemic antibiotic consumption was observed in the intervention period (575 vs. 349 DOT per 1000 patient-days; p <  0.001). On multivariate analysis, prospective audit and feedback (odds ratio 1.5, 95% confidence interval 1.09–2.04; p = 0.011) and pre-authorization of restricted antibiotics (odds ratio 1.7; 95% confidence interval 1.2–2.31; p =  0.002) were the predictors of appropriate antimicrobial use. Mean LOS was decreased by 2.9 days (p =  0.095).

      Conclusions

      This study showed that the antimicrobial restriction program alone was effective, but the system should be supported by a tailored ASP, such as prospective audit and feedback.

      Keywords

      Introduction

      Antibiotics are one of the most frequently used drugs among hospitalized patients. Excessive and inappropriate use of antibiotics results in the emergence of resistant microorganisms, adverse events, drug interactions, increased length of stay, and increased costs (
      • Fishman N.
      Antimicrobial stewardship.
      ). Antimicrobial resistance is an emerging threat to public health worldwide and limits the choices of treatment; furthermore, it increases the mortality rate because of complications (
      • Barlam T.F.
      • Cosgrove S.E.
      • Abbo L.M.
      • MacDougall C.
      • Schuetz A.N.
      • Septimus E.J.
      • et al.
      Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
      ). To overcome the unnecessary use of antimicrobials, an antimicrobial stewardship program (ASP) should be implemented. Such programs are coordinated interventions to improve and measure the appropriate use of antimicrobials with an optimal regimen, dose, and duration (
      • IDSA, USA
      Promoting Antimicrobial Stewardship in Human Medicine.
      ).
      The favorable effects of ASPs on prescribing and microbiological outcomes have been shown repeatedly in the literature (
      • Davey P.
      • Brown E.
      • Charani E.
      • Fenelon L.
      • Gould I.M.
      • Holmes A.
      • et al.
      Interventions to improve antibiotic prescribing practices for hospital inpatients.
      ). However the practice in Turkey for combating inappropriate antibiotic use provides a unique experience. In February 2003, the Ministry of Health of Turkey initiated a nationwide antibiotic restriction program (NARP) based on a computerized pre-authorization system. According to this program, parenteral carbapenems, piperacillin–tazobactam, glycopeptides, colistin, and antifungals (except fluconazole) have been restricted without prior approval of an infectious disease specialist (IDS). Physicians from all medical specialties can prescribe parenteral third-generation cephalosporins, quinolones, and amikacin antimicrobials for the first 72 h, but further use requires IDS approval. According to recent reports, Turkey has the highest rate of antibiotic consumption among the OECD countries (Organization for Economic Co-operation and Development) (

      OECD. (2018). Stemming the Superbug Tide: Just A Few Dollars More, OECD Publishing, Paris. https://doi.org/10.1787/9789264307599-en

      ,
      • Versporten A.
      • Bolokhovets G.
      • Ghazaryan L.
      • Abilova V.
      • Pyshnik G.
      • Spasojevic T.
      • et al.
      Antibiotic use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe.
      ). The aim of this study was to assess the contribution of antimicrobial stewardship interventions in addition to the NARP.

      Methods

      The study was conducted in a university hospital with 650 beds. A prospective, quasi-experimental study was designed and implemented between March and June 2017. Wards were grouped as medical, surgical, and intensive care units (ICUs). Medical wards included in the study were internal medicine and neurology, while surgical wards were general surgery, urology, gynecology/obstetrics, neurosurgery, and thoracic surgery. Patient characteristics such as age, sex, weight, height, admission and discharge dates, antibiotics prescribed and their dosages, and antibiotic indications were recorded in a standardized form. Indications for antibiotics were: (1) surgical prophylaxis; (2) medical prophylaxis, including prophylaxis of immunosuppressive patients during chemotherapy; (3) empirical treatment, i.e., initial treatment for suspected bacterial infections prior to microbiology results becoming available; (4) preemptive treatment, for patients with radiological or laboratory findings of infection, but no microbiological documentation; (5) microbiologically documented infection. Decisions on the authorization of restricted antimicrobials, including the initiation and discontinuation of antibiotic therapy, were performed by the routine infectious diseases consultants.
      Each intravenous (IV) antibiotic use corresponded to a single episode. The assessment of the antibiotic prescriptions was performed by two infectious diseases physicians, one of whom was blind. The assessment was done according to clinical guidelines and the modified criteria of Kunin et al. and Gyssens et al. (
      • Gyssens I.C.
      • van den Broek P.J.
      • Kullberg B.J.
      • Hekster Y.
      • van der Meer J.W.
      Optimizing antimicrobial therapy. A method for antimicrobial drug use evaluation.
      ,
      • Kunin C.M.
      • Tupasi T.
      • Craig W.A.
      Use of antibiotics. A brief exposition of the problem and some tentative solutions.
      ): (1) agree with the choice of antibiotic, but the dosage is inappropriate according to the literature; (2) disagree with the choice of antibiotics because the spectra of the antibiotics overlap; (3) disagree with the choice of antibiotic because the spectrum is not broad enough; (4) disagree with the choice of antibiotic because the spectrum is overly broad; (5) disagree with the need for an antibiotic.
      During the baseline period (March to April 2017), the medical records of the study patients who received more than 3 days of IV systemic antimicrobial therapy were observed without intervention. During the intervention period (May to June 2017), the ASP team audited the medical records of study patients. Feedback and treatment recommendations were given to each patient in the wards. These interventions included stopping extended surgical prophylaxis or unnecessary antibiotics, correcting inappropriate antibiotic dosages, and de-escalation/escalation according to the modified Kunin and Gyssens criteria (
      • Gyssens I.C.
      • van den Broek P.J.
      • Kullberg B.J.
      • Hekster Y.
      • van der Meer J.W.
      Optimizing antimicrobial therapy. A method for antimicrobial drug use evaluation.
      ,
      • Kunin C.M.
      • Tupasi T.
      • Craig W.A.
      Use of antibiotics. A brief exposition of the problem and some tentative solutions.
      ).
      Antimicrobial use was expressed as the days of therapy (DOT) per 1000 patient-days. The numerator was the antimicrobial days, which was the sum of the days of antibiotic use. The denominator was the patient days (
      • Centers for Disease Control and Prevention
      National Healtcare Safety Network (NHSN). Surveillance for antimicrobial use and antimicrobial resistance options. Protocols: Antimicrobial use and resistance (AUR) module.
      ,
      • Centers for Disease Control and Prevention
      National Healthcare Safety Network (NHSN). Surveillance for C. difficile, MRSA, and other Drug-Resistant Infections. Protocols: Multidrug-resistant Organism & Clostridium difficile Infection (MDRO/CDI) module.
      ,
      • Cohen A.L.
      • Calfee D.
      • Fridkin S.K.
      • Huang S.S.
      • Jernigan J.A.
      • Lautenbach E.
      • et al.
      Recommendations for metrics for multidrug-resistant organisms in healthcare settings: SHEA/HICPAC Position paper.
      ). One DOT represented the administration of a single antimicrobial on a given day regardless of the number of doses. If a single patient received two antibiotics, this was recorded as two DOTs. The data were normalized to 1000 patient-days. Monthly unit DOTs and the length of stay (LOS) of the patients were compared between the two periods. The primary outcome was the effect of prospective audit and feedback on the duration of IV antibiotic usage, and the secondary outcome was LOS. The study protocol was approved by the local ethics committee of Marmara University School of Medicine. A waiver of consent was granted, since all patients were routinely evaluated by the IDS team and the person could be enrolled in the study without any additional risk beyond their standard care.

      Statistical analysis

      In the univariate analysis, categorical data were tested by Chi-square test and the t-test was used for the comparison of the means of two groups. In the multivariate analysis, logistic regression analysis was performed to determine the predictors of appropriate antibiotic use. The independent variables included in the model were the effect of the intervention (post vs. pre intervention), antibiotics restricted by NARP, and medical vs. surgical ward. Stata version 11 was used for the statistical analysis (Stata, version 11, TX, USA). The level of statistical significance was set at <0.05.

      Results

      A total 519 patients who had been prescribed IV antibiotics for longer than 72 h were enrolled and a total 866 antibiotic episodes were observed (Table 1). Of the 519 patients, 280 were male (54%). The mean age of the patients was 56 years (standard deviation 18 years).
      Table 1Distribution of patients and antibiotic episodes in the wards.
      PatientsAntibiotic episodes
      n = 519 (%)n = 866 (%)
      Medical wards299 (58%)567 (65%)
      Internal medicine280 (54%)542 (62%)
      Neurology19 (4%)25 (3%)
      Surgical wards220 (42%)299 (35%)
      Thoracic surgery62 (12%)67 (8%)
      General surgery50 (10%)73 (9%)
      Neurosurgery40 (8%)43 (5%)
      Gynecology/obstetrics36 (7%)71 (8%)
      Urology32 (6%)45 (5%)
      In both periods, 15 different groups of antibiotics were prescribed. The most frequently prescribed antibiotic group was third and fourth-generation cephalosporins (18%), followed by ampicillin–sulbactam (13%), piperacillin–tazobactam (12%), carbapenems (10%), quinolones (8%), first-generation cephalosporins (6%), glycopeptides (5%), aminoglycosides (4%), and colistin (1%).
      The indications for antibiotic use were preemptive (42%), documented infection (26%), empirical (17%), surgical prophylaxis (12%), and medical prophylaxis (2%). Further analysis of these indications revealed that 98% of surgical prophylaxis was inappropriate due to an extended antimicrobial duration. Seventy percent of 151 empirical antibiotics were inappropriate, and the most common reason was the absence of a source of infection. In contrast, justifications for medical prophylaxis, preemptive use, and documented infections were mostly appropriate (90%, 91%, and 91%, respectively). Respiratory tract (34%), intra-abdominal (14%), urinary tract (10%), bloodstream (8%), and skin and soft tissue (7%) were the infection sites identified.
      Overall, the rate of inappropriate antibiotic use was 30% (261 episodes); the rate was 33% (162 episodes) in the observation period and 27% (99 episodes) in the intervention period (p =  0.036). The unnecessary use of antibiotics was 54% in both study periods. The most common reasons for inappropriateness were extended surgical prophylaxis (32%), necessity of de-escalation (10%), necessity of escalation (3%), and inappropriate doses (1%). During the observation period, the inappropriate use of antibiotics was 23% for restricted drugs, while it was 39% for unrestricted antibiotics (p <  0.001). In the intervention period, these rates were 19% (restricted drugs) and 31% (unrestricted drugs), respectively (p =  0.013).
      The most frequent microorganisms were Pseudomonas aeruginosa (20%), Escherichia coli (15%), Enterococcus spp (9%), Klebsiella pneumoniae (8%), Acinetobacter baumannii (5%), and Candida spp (3%).
      The mean DOT was 349 days in the intervention period and 576 days in the observation period (p <  0.001). The LOS decreased, although this was not statistically significant (17.4 days in the intervention period vs. 20.3 days in the observation period; p =  0.095).
      During the intervention period, the DOT decreased significantly in all wards, except gynecology/obstetrics and general surgery (p <  0.001). Since the antimicrobial modifications were done before 72 h in the ICUs, they were analyzed separately. The DOT also decreased significantly in both the medical (p =  0.02) and surgical (p =  0.001) ICUs during the intervention period (Table 2).
      Table 2Comparison of DOTs for the effects of the intervention.
      RR95% CIp-Value
      Internal medicine0.740.70–0.77<0.001
      Thoracic surgery0.740.65–0.84<0.001
      Gynecology/obstetrics0.910.81–1.010.10
      Urology0.640.53–0.76<0.001
      Neurosurgery0.290.24–0.34<0.001
      General surgery0.930.82–1.070.36
      Neurology0.430.31–0.59<0.001
      Medical ICU0.890.80–0.980.02
      Surgical ICU0.850.78–0.930.001
      DOT, days of therapy; RR, risk ratio; CI, confidence interval; ICU, intensive care unit.
      In the multivariate analysis, the feedback strategy after ≥72 h of IV antibiotic use (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.09–2.04; p =  0.011), antibiotics restricted by NARP (OR 1.7, 95% CI 1.2–2.31; p =  0.002), and being hospitalized in a medical vs. surgical ward (OR 3, 95% CI 2.2–4.11; p <  0.001) were found to be predictors of appropriate antibiotic use (Table 3).
      Table 3Univariate and multivariate analyses for the predictors of appropriate antibiotic use.
      Univariate analysisMultivariate analysis
      OR95% CIp-ValueOR95% CIp-Value
      Prospective audit and feedback1.41.02–1.840.0361.51.09–2.040.011
      Antibiotics restricted by NARP21.51–2.82<0.0011.71.2–2.310.002
      Medical vs. surgical wards (excluding ICU)3.22.34–4.28<0.00132.2–4.11<0.001
      OR, odds ratio; CI, confidence interval; NARP, nationwide antibiotic restriction program; ICU, intensive care unit.

      Discussion

      This study demonstrated a decrease in inappropriate antibiotic use from 33% during the observation period to 27% during the intervention period (p = 0.036). In both periods, restricted antibiotics were used less inappropriately. Thus, the NARP alone had a significant role in decreasing inappropriate antibiotic use in both periods. Similarly, Ozkurt et al. found that inappropriate antibiotic use was higher among unrestricted antibiotics than restricted ones in a previous study performed in Turkey (
      • Ozkurt Z.
      • Erol S.
      • Kadanali A.
      • Ertek M.
      • Ozden K.
      • Tasyaran M.A.
      Changes in antibiotic use, cost and consumption after an antibiotic restriction policy applied by infectious disease specialists.
      ). Other studies showed that the NARP was effective in lowering costs and preventing antibiotic resistance (
      • Altunsoy A.
      • Aypak C.
      • Azap A.
      • Ergonul O.
      • Balik I.
      The impact of a nationwide antibiotic restriction program on antibiotic usage and resistance against nosocomial pathogens in Turkey.
      ,
      • Arda B.
      • Sipahi O.R.
      • Yamazhan T.
      • Tasbakan M.
      • Pullukcu H.
      • Tunger A.
      • et al.
      Short-term effect of antibiotic control policy on the usage patterns and cost of antimicrobials, mortality, nosocomial infection rates and antibacterial resistance.
      ). Previous studies have reported the system of approval by IDS to be the most effective control method for minimizing antimicrobial use (
      • Hirschman S.Z.
      • Meyers B.R.
      • Bradbury K.
      • Mehl B.
      • Gendelman S.
      • Kimelblatt B.
      Use of antimicrobial agents in a university teaching hospital. Evolution of a comprehensive control program.
      ,
      • McGowan Jr, J.E.
      Minimizing antimicrobial resistance: the key role of the infectious diseases physician.
      ).
      In the multivariate analysis, performing prospective audit and feedback after 72 h of IV antibiotics as an ASP intervention and antibiotics restricted by NARP were found to be the independent predictors of appropriate antibiotic use. Prospective audit and feedback and restrictive approaches have been found to be the most effective ways to reach the goals of the ASP (
      • Barlam T.F.
      • Cosgrove S.E.
      • Abbo L.M.
      • MacDougall C.
      • Schuetz A.N.
      • Septimus E.J.
      • et al.
      Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
      ,
      • Davey P.
      • Brown E.
      • Charani E.
      • Fenelon L.
      • Gould I.M.
      • Holmes A.
      • et al.
      Interventions to improve antibiotic prescribing practices for hospital inpatients.
      ).
      In the present study, the main reason for inappropriateness was unnecessary antibiotic use (54%). Previous studies have demonstrated that the administration of antibiotics to uninfected patients accounts for 32–60% of irrational antibiotic use (
      • Dunagan W.C.
      • Woodward R.S.
      • Medoff G.
      • Gray J.L.
      • Casabar E.
      • Lawrenz C.
      • et al.
      Antibiotic misuse in two clinical situations: positive blood culture and administration of aminoglycosides.
      ). Fleming-Dutra et al. reported that nearly half of hospitalized patients receive at least one antimicrobial and up to 30–50% of this antimicrobial use is unnecessary (
      • Fleming-Dutra K.E.
      • Hersh A.L.
      • Shapiro D.J.
      • Bartoces M.
      • Enns E.A.
      • File Jr, T.M.
      • et al.
      Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011.
      ).
      In the present study, the majority of the patients and antibiotic consumption occurred in the internal medicine ward. The most frequently prescribed antibiotic group was third and fourth-generation cephalosporins. Since the parenteral form of ceftriaxone was not restricted for the first 72 h of therapy by the NARP, the consumption of this antibiotic was unsurprisingly high in this study. In a study that included Eastern European countries, Versporten et al. found that the country most commonly prescribing cephalosporins was Turkey (
      • Versporten A.
      • Bolokhovets G.
      • Ghazaryan L.
      • Abilova V.
      • Pyshnik G.
      • Spasojevic T.
      • et al.
      Antibiotic use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe.
      ).
      This study demonstrated a total mean decrease in DOT with the intervention, from 575 DOT to 349 DOT (p <  0.001), reflecting a decrease in the consumption of parenteral antibiotics. Although other outcomes were not investigated in this study, it is safe to assume that with this intervention, antibiotic-related adverse events, the prevalence of resistant microorganisms, and antibiotic costs would also have decreased. Several studies have demonstrated a decrease in inappropriate antibiotic usage with the implementation of an ASP (
      • Chrysou K.
      • Zarkotou O.
      • Kalofolia S.
      • Papagiannakopoulou P.
      • Chrysos G.
      • Themeli-Digalaki K.
      • et al.
      First-year results of an antibiotic stewardship program in a Greek tertiary care hospital.
      ,
      • Ting J.Y.
      • Paquette V.
      • Ng K.
      • Lisonkova S.
      • Hait V.
      • Shivanada S.
      • et al.
      Reduction of inappropriate antimicrobial prescriptions in a tertiary neonatal intensive care unit following antimicrobial stewardship care bundle implementation.
      ). Chrysou et al. found that after implementing an ASP, total antibiotic use decreased by 16.7% owing to a 19.1% reduction in unrestricted antibiotics and 13.8% in restricted antibiotics (
      • Chrysou K.
      • Zarkotou O.
      • Kalofolia S.
      • Papagiannakopoulou P.
      • Chrysos G.
      • Themeli-Digalaki K.
      • et al.
      First-year results of an antibiotic stewardship program in a Greek tertiary care hospital.
      ). In the present study, when each ward was assessed separately, it was found that the DOT was significantly decreased in all wards, except in gynecology/obstetrics and general surgery.
      A decrease in LOS from 20.3 to 17.4 was demonstrated with the intervention, but this was not statistically significant (p =  0.095), probably due to the sample size. In a meta-analysis, it was shown that interventions reduced LOS by 1.12 days (
      • Davey P.
      • Brown E.
      • Charani E.
      • Fenelon L.
      • Gould I.M.
      • Holmes A.
      • et al.
      Interventions to improve antibiotic prescribing practices for hospital inpatients.
      ). In another study, it was demonstrated that a prospective audit and feedback intervention reduced median LOS in patients with community-acquired pneumonia by nearly 0.5 days (
      • DiDiodato G.
      • McAthur L.
      Transition from a dedicated to a non-dedicated, ward-based pharmacist antimicrobial stewardship programme model in a non-academic hospital and its impact on length of stay of patients admitted with pneumonia: a prospective observational study.
      ). The overall reduction in LOS was 19.4%. The effectiveness and economic impact of ASPs have also been shown in previous studies (
      • Dik J.W.
      • Vemer P.
      • Friedrich A.W.
      • Hendrix R.
      • Lo-Ten-Foe J.R.
      • Sinha B.
      • et al.
      Financial evaluations of antibiotic stewardship programs-a systematic review.
      ,
      • Schuts E.C.
      • Hulscher M.
      • Mouton J.W.
      • Verduin C.M.
      • Stuart J.
      • Overdiek H.
      • et al.
      Current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis.
      ). In a meta-analysis, it was found that there was a reduction in the duration of antibiotic therapy ranging from 0.6 to 3.3 days and it was not associated with clinical outcomes (
      • Lee C.F.
      • Cowling B.J.
      • Feng S.
      • Aso H.
      • Wu P.
      • Fukuda K.
      • et al.
      Impact of antibiotic stewardship programmes in Asia: a systematic review and meta-analysis.
      ).
      There are several limitations to this study. First, a time-series analysis was not performed, but logistic regression was performed. There was no seasonal change during the study period, as it was performed during the four spring months. Second, the duration of the study was too short to assess changing antibiotic resistance patterns and Clostridium difficile infections. In a systematic review, Kaki et al. found that ASP interventions reduced antimicrobial resistance if they were applied beyond 6 months (
      • Kaki R.
      • Elligsen M.
      • Walker S.
      • Simor A.
      • Palmay L.
      • Daneman N.
      Impact of antimicrobial stewardship in critical care: a systematic review.
      ). Finally, observing outcome measures such as mortality and complications such as re-admissions would not be possible in a shorter time. The results of this study emphasize the significance of an ID approval system.
      In conclusion, although the NARP alone had a significant role in decreasing inappropriate antimicrobial use, the implementation of prospective audit and feedback as an ASP strategy along with the NARP may further improve appropriate antimicrobial use.

      Funding source

      There is no funding source in this study.

      Ethical approval

      The study protocol was approved by the local ethics committee of Marmara University School of Medicine (reference number 09.2017.231).

      Conflict of interest

      The authors declare that they have no conflicts of interest.

      References

        • Altunsoy A.
        • Aypak C.
        • Azap A.
        • Ergonul O.
        • Balik I.
        The impact of a nationwide antibiotic restriction program on antibiotic usage and resistance against nosocomial pathogens in Turkey.
        Int J Med Sci. 2011; 8: 339-344
        • Arda B.
        • Sipahi O.R.
        • Yamazhan T.
        • Tasbakan M.
        • Pullukcu H.
        • Tunger A.
        • et al.
        Short-term effect of antibiotic control policy on the usage patterns and cost of antimicrobials, mortality, nosocomial infection rates and antibacterial resistance.
        J Infect. 2007; 55: 41-48
        • Barlam T.F.
        • Cosgrove S.E.
        • Abbo L.M.
        • MacDougall C.
        • Schuetz A.N.
        • Septimus E.J.
        • et al.
        Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America.
        Clin Infect Dis. 2016; 62: e51-77
        • Centers for Disease Control and Prevention
        National Healtcare Safety Network (NHSN). Surveillance for antimicrobial use and antimicrobial resistance options. Protocols: Antimicrobial use and resistance (AUR) module.
        2017 (Available from: https://www.cdc.gov/nhsn/acute-care-hospital/aur/index.html. [Accessed 04.30.18 2018])
        • Centers for Disease Control and Prevention
        National Healthcare Safety Network (NHSN). Surveillance for C. difficile, MRSA, and other Drug-Resistant Infections. Protocols: Multidrug-resistant Organism & Clostridium difficile Infection (MDRO/CDI) module.
        2018 (Available from: https://www.cdc.gov/nhsn/ltach/cdiff-mrsa/index.html. [Accessed 05.01.2018 2018])
      1. OECD. (2018). Stemming the Superbug Tide: Just A Few Dollars More, OECD Publishing, Paris. https://doi.org/10.1787/9789264307599-en

        • Chrysou K.
        • Zarkotou O.
        • Kalofolia S.
        • Papagiannakopoulou P.
        • Chrysos G.
        • Themeli-Digalaki K.
        • et al.
        First-year results of an antibiotic stewardship program in a Greek tertiary care hospital.
        Eur J Clin Microbiol Infect Dis. 2018; 37: 333-337
        • Cohen A.L.
        • Calfee D.
        • Fridkin S.K.
        • Huang S.S.
        • Jernigan J.A.
        • Lautenbach E.
        • et al.
        Recommendations for metrics for multidrug-resistant organisms in healthcare settings: SHEA/HICPAC Position paper.
        Infect Control Hosp Epidemiol. 2008; 29: 901-913
        • Davey P.
        • Brown E.
        • Charani E.
        • Fenelon L.
        • Gould I.M.
        • Holmes A.
        • et al.
        Interventions to improve antibiotic prescribing practices for hospital inpatients.
        Cochrane Database Syst Rev. 2013; CD003543
        • DiDiodato G.
        • McAthur L.
        Transition from a dedicated to a non-dedicated, ward-based pharmacist antimicrobial stewardship programme model in a non-academic hospital and its impact on length of stay of patients admitted with pneumonia: a prospective observational study.
        BMJ Open Qual. 2017; 6e000060
        • Dik J.W.
        • Vemer P.
        • Friedrich A.W.
        • Hendrix R.
        • Lo-Ten-Foe J.R.
        • Sinha B.
        • et al.
        Financial evaluations of antibiotic stewardship programs-a systematic review.
        Front Microbiol. 2015; 6: 317
        • Dunagan W.C.
        • Woodward R.S.
        • Medoff G.
        • Gray J.L.
        • Casabar E.
        • Lawrenz C.
        • et al.
        Antibiotic misuse in two clinical situations: positive blood culture and administration of aminoglycosides.
        Rev Infect Dis. 1991; 13: 405-412
        • Fishman N.
        Antimicrobial stewardship.
        Am J Infect Control. 2006; 34 (discussion S4-73): S55-63
        • Fleming-Dutra K.E.
        • Hersh A.L.
        • Shapiro D.J.
        • Bartoces M.
        • Enns E.A.
        • File Jr, T.M.
        • et al.
        Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010-2011.
        JAMA. 2016; 315: 1864-1873
        • Gyssens I.C.
        • van den Broek P.J.
        • Kullberg B.J.
        • Hekster Y.
        • van der Meer J.W.
        Optimizing antimicrobial therapy. A method for antimicrobial drug use evaluation.
        J Antimicrob Chemother. 1992; 30: 724-727
        • Hirschman S.Z.
        • Meyers B.R.
        • Bradbury K.
        • Mehl B.
        • Gendelman S.
        • Kimelblatt B.
        Use of antimicrobial agents in a university teaching hospital. Evolution of a comprehensive control program.
        Arch Intern Med. 1988; 148: 2001-2007
        • IDSA, USA
        Promoting Antimicrobial Stewardship in Human Medicine.
        2015 (Available from: http://www.idsociety.org/Stewardship_Policy/. [Accessed 04.30.2018 2018])
        • Kaki R.
        • Elligsen M.
        • Walker S.
        • Simor A.
        • Palmay L.
        • Daneman N.
        Impact of antimicrobial stewardship in critical care: a systematic review.
        J Antimicrob Chemother. 2011; 66: 1223-1230
        • Kunin C.M.
        • Tupasi T.
        • Craig W.A.
        Use of antibiotics. A brief exposition of the problem and some tentative solutions.
        Ann Intern Med. 1973; 79: 555-560
        • Lee C.F.
        • Cowling B.J.
        • Feng S.
        • Aso H.
        • Wu P.
        • Fukuda K.
        • et al.
        Impact of antibiotic stewardship programmes in Asia: a systematic review and meta-analysis.
        J Antimicrob Chemother. 2018; 73: 844-851
        • McGowan Jr, J.E.
        Minimizing antimicrobial resistance: the key role of the infectious diseases physician.
        Clin Infect Dis. 2004; 38: 939-942
        • Ozkurt Z.
        • Erol S.
        • Kadanali A.
        • Ertek M.
        • Ozden K.
        • Tasyaran M.A.
        Changes in antibiotic use, cost and consumption after an antibiotic restriction policy applied by infectious disease specialists.
        Jpn J Infect Dis. 2005; 58: 338-343
        • Schuts E.C.
        • Hulscher M.
        • Mouton J.W.
        • Verduin C.M.
        • Stuart J.
        • Overdiek H.
        • et al.
        Current evidence on hospital antimicrobial stewardship objectives: a systematic review and meta-analysis.
        Lancet Infect Dis. 2016; 16: 847-856
        • Ting J.Y.
        • Paquette V.
        • Ng K.
        • Lisonkova S.
        • Hait V.
        • Shivanada S.
        • et al.
        Reduction of inappropriate antimicrobial prescriptions in a tertiary neonatal intensive care unit following antimicrobial stewardship care bundle implementation.
        Pediatric Infect Dis J. 2018; 38: 54-59
        • Versporten A.
        • Bolokhovets G.
        • Ghazaryan L.
        • Abilova V.
        • Pyshnik G.
        • Spasojevic T.
        • et al.
        Antibiotic use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe.
        Lancet Infect Dis. 2014; 14: 381-387