Journal of Antimicrobial Chemotherapy Advance Access published April 14, 2008

Journal of Antimicrobial Chemotherapy Advance Access published April 14, 2008 Journal of Antimicrobial Chemotherapy doi:10.1093/jac/dkn164 Control of extended-spectrum b-lactamase-producing Klebsiella pneumoniae using a computer-assisted management program to restrict third-generation cephalosporin use Jeong Yeon Kim 1, Jang Wook Sohn 1,2, Dae Won Park 1,2, Young Kyung Yoon 1, Young Mi Kim 3 and Min Ja Kim 1,2 * 1 Division of nfectious Diseases, Korea University Medical Center, Seoul, Republic of Korea; 2 nstitute of Emerging nfectious Diseases, Korea University, Seoul, Republic of Korea; 3 Department of Pharmacy, Korea University Medical Center, Seoul, Republic of Korea Received 13 November 2007; returned 9 January 2008; revised 11 March 2008; accepted 19 March 2008 Objectives: The aim of this study was to evaluate the control of extended-spectrum b-lactamase (ESBL)-producing Klebsiella pneumoniae and antimicrobial resistance through a computerized antibiotic control program. Methods: An ambidirectional intervention study was conducted at a 750-bed university hospital in Korea from February 2004 to April 2006. n November 2004, hospital-wide restriction of third-generation cephalosporin use was integrated into a pre-existing computerized antibiotic prescription program that included an approval system for 15 antimicrobials. The proportions of ESBL-producing K. pneumoniae and other multidrug-resistant clinical isolates were compared during three phases (9 months per phase): Phase ( pre-intervention), Phase (intensive-intervention) and Phase (maintenance). Results: Third-generation cephalosporin use decreased significantly from 103.2 to 84.9 antibiotic use density (AUD, defined daily dose/1000 patient-days) between Phase and Phase (P < 0.05), whereas use of carbapenems and b-lactam/b-lactamase inhibitors increased from 14.5 to 18.2 AUD and from 53.3 to 62.6 AUD, respectively. The proportion of ESBL-producing K. pneumoniae isolates increased significantly from 8.1% (47/578) in Phase to 32.0% (188/587) in Phase, and then decreased significantly to 20.6% (97/470) in Phase (P < 0.05). n addition, the proportions of imipenem- or piperacillin/tazobactamresistant Pseudomonas aeruginosa and Acinetobacter baumannii isolates decreased significantly over the same period (P < 0.05). Conclusions: The computerized antibiotic control program appears to be an effective tool for modifying antibiotic consumption, which may in turn prevent the spread of resistant pathogens. Keywords: antibacterial agents, bacterial drug resistance, cephalosporins, b-lactamases ntroduction Extended-spectrum b-lactamase (ESBL)-producing Klebsiella pneumoniae has emerged as a problematic nosocomial pathogen. ESBL production causes resistance to most b-lactam antibiotics and is often associated with resistance to aminoglycosides, trimethoprim/sulfamethoxazole and fluoroquinolones. 1,2 Risk factors for the emergence of these strains include previous exposure to antibiotics, the presence of intravascular catheters, jejunostomy tube, gastrointestinal colonization, urinary catheter, ventilator assistance and length of hospital or intensive care unit stay. 1 4 Furthermore, some third-generation cephalosporins are strong inducers of ESBL-producing strain outbreaks in hospitals and long-term care facilities. 5 8 Guidelines have emphasized aggressive infection control measures to limit the emergence and spread of resistant bacteria within the hospital. However, such measures alone often fail to reverse the trend of increasing antibiotic resistance. Therefore, several antibiotic control strategies have been advocated as an adjunctive to improve antibiotic use by physicians. 9 11 Studies have... *Correspondence address. Division of nfectious Diseases, Department of nternal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1 5-ga, Anam-dong, Sungbuk-gu, Seoul 136-705, Korea. Tel: þ82-2-920-5685; Fax: þ82-2-920-5616; E-mail: macropha@korea.ac.kr... Page 1 of 6 # The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Kim et al. shown that a change of empirical antibiotics may reduce the antibiotic resistance of Enterobacteriaceae including Klebsiella spp. 12 18 A sudden increase in the number of ESBL-producing K. pneumoniae isolates since August 2004 was detected by monthly surveillance at Korea University Anam Hospital. The proportion of ESBL-producing K. pneumoniae isolates, which ranged between 2.1% and 7.7%, began to increase in August 2004 and eventually reached 12% or more. The hospital committee for antimicrobial use and control introduced restrictions on the use of third-generation cephalosporins as a control measure beginning in November 2004. This intervention study aimed to evaluate whether restrictions on the use of third-generation cephalosporins with a computerized antibiotics control program could significantly reduce the prevalence of ESBL-producing K. pneumoniae. n addition, we monitored the occurrence of other multidrug-resistant nosocomial pathogens and the usage trends of other antibiotics. Materials and methods Setting This study was conducted at the 750-bed Korea University Anam Hospital in Seoul, Republic of Korea, from 1 February 2004 to 30 April 2006. This acute care hospital has medical and surgical wards, including three intensive care units with 56 beds. Study design An ambidirectional (before and after) comparative study of intervention was set up following introduction of a computerized program to restrict third-generation cephalosporin use as an intervention in November 2004, as the prevalence of ESBL-producing K. pneumoniae increased to 12% or more in the hospital. Beginning in February 2004, the 9 month Phase ( pre-intervention), the 9 month Phase (intensive-intervention) and the 9 month Phase (maintenance) periods were instituted. Primary and secondary outcome measures were the prevalence of ESBL-producing K. pneumoniae and multidrug-resistant Gram-negative bacilli, respectively, among clinical isolates per phase. The number of new cases as an outcome measure was too small to sufficiently demonstrate the outcome of the intervention. nterventions Our hospital introduced a computerized antibiotic prescription system in 2002. This system blocks repeated copied prescriptions, so the doctors prescribe antibiotics using the system every 3 days. The hospital controls proper antibiotic usage through a restricted Figure 1. Summary table of population, clinical setting, nature and timing of interventions. Page 2 of 6

ESBL K. pneumoniae control by antibiotic restriction antimicrobial program for 15 agents: ceftazidime, cefepime, carbapenems (4), piperacillin/tazobactam, glycopeptides (2), aztreonam, arbekacin, quinupristin/dalfopristin, linezolid, itraconazole and caspofungin. This system automatically stops the prescription of these antibiotics if an infectious disease specialist does not approve the prescription. n the pre-intervention period (February 2004 October 2004), third-generation cephalosporins, with the exception of ceftazidime, were not among the restricted antibiotics, and thus could be used without approval through the computerized prescription system. For the intervention, we developed a new program to restrict third-generation cephalosporin use and merged it into the hospitalwide computerized antibiotic prescription system. The policies regarding prescribing antibiotic and providing feedback during the intervention periods are presented in Figure 1. Data collection The amounts of antibiotics used were collected from hospital pharmacy records for each period of the study and were expressed as the antimicrobial use density (AUD; the number of defined daily doses per 1000 patient-days). The antibiotics included third-generation cephalosporins and other substitute agents that were suggested to physicians as alternatives to third-generation cephalosporins. The hospital infection control unit surveyed for ESBL-producing K. pneumoniae and other multidrug-resistant pathogens among clinical isolates during the entire study period. Cultures were obtained according to clinical indications. One isolate was recorded per body site per patient. All isolates were identified by standard microbiological methods, and susceptibility testing was performed using the Clinical and Laboratory Standards nstitute disc-diffusion method and an automated antimicrobial susceptibility testing system (Vitek; biomérieux Vitek, Hazelwood, MO, USA). Computer-generated hospital clinical microbiology antibiograms were used to determine the prevalence of resistance to antibiotics. The proportions of ESBL-producing K. pneumoniae and other multidrug-resistant Gram-negative bacilli among clinical isolates per phase were compared. Reasons for prescription of third-generation cephalosporins were analysed from the computer-based records of the intensiveintervention period. Others, defined as reasons other than the suggested indications, was further analysed by an infectious disease doctor through medical record review. Statistical analyses Statistical analyses were performed using SPSS 10.0 for Windows (SPSS nc., Chicago, L, USA). Values were presented as the mean + SD (continuous variables) or as a percentage of a specific group (categorical variables). We used one-way analysis of variance (or ANOVA) with Tukey s multiple comparison to assess the significance of the change in antibiotic use. The change in the proportions of resistant organisms was analysed by logistic regression. All P values,0.05 were considered statistically significant. Results Changes in antibiotic use (Table 1) The use of third-generation cephalosporins decreased significantly from 103.2 AUD in Phase to 84.9 AUD in Phase (P, 0.05), but increased to 115.1 AUD in Phase (P, 0.05), indicating Table 1. Change in antibiotic use in study periods Phase/antibiotics AUD (+SD) P 1st generation cephalosporins 30.3 + 3.8 a 34.3 + 3.8 b 0.0124 27.3 + 5.8 ab 2nd generation cephalosporins 102.1 + 14.5 a 121.2 + 15.0 b 0.0054 95.3 + 17.5 a 3rd generation cephalosporins 103.2 + 10.2 a 84.9 + 10.0 b 0.0000 115.1 + 8.4 c 4th generation cephalosporins 5.8 + 2.9 4.6 + 1.8 0.2245 6.6 + 2.4 Aminoglycosides 188.0 + 12.7 ab 195.1 + 16.2 b 0.0150 169.6 + 22.6 a Carbapenems 14.5 + 3.9 18.2 + 5.6 0.1083 20.6 + 7.7 Quinolones 31.0 + 3.1 a 37.5 + 4.2 b 0.0025 33.1 + 3.5 a b-lactam/b-lactamase inhibitors 53.3 + 7.3 62.6 + 5.7 0.0800 60.7 + 12.1 Piperacillin/tazobactam 6.4 + 2.5 a 11.1 + 1.8 b 0.0010 7.6 + 2.8 a a,b,c Same letters indicate statistical insignificance based on Tukey s multiple comparison. P value is for one-way analysis of variance (or ANOVA). that the effect of the intervention was lost during the maintenance period. n contrast, the use of second-generation cephalosporins, quinolones and piperacillin/tazobactam as substitutes increased significantly in Phase and then decreased in Phase. Changes in ESBL-producing K. pneumoniae isolates Figure 2 shows the status of ESBL-producing K. pneumoniae isolates obtained during the study period from February 2004 to April 2006. The number of clinical isolates of ESBL-producing K. pneumoniae began to increase in August 2004 and showed an increasing tendency during extensive restrictions on the use of third-generation cephalosporins. Page 3 of 6

Kim et al. Figure 2. ESBL-producing K. pneumoniae isolates and third-generation cephalosporin use during study periods. The proportion of ESBL-producing K. pneumoniae isolates reached its peak of 50% (33/66) in May 2005 and then subsided during the remainder of the intensive-intervention period (Phase ). The decreasing tendency continued during the maintenance period (Phase ) and the proportion remained at 13.2% (7/53) in April 2006. Comparing the intensive-intervention and maintenance periods, the proportion of ESBL-producing K. pneumoniae isolates decreased significantly from 32.0% (188/587) in Phase to 20.6% (97/470) in Phase, which reflected a decline of 35.6% (P, 0.05). However, the ESBL rate in Phase was still higher than that in Phase (Table 2). Changes in antimicrobial resistance (Table 2) The proportion of imipenem-resistant Pseudomonas aeruginosa isolates increased in Phase and then declined significantly in Phase. The proportion of piperacillin/tazobactam-resistant P. aeruginosa isolates decreased significantly from Phase through Phase. The proportions of imipenem- or piperacillin/ tazobactam-resistant Acinetobacter baumannii isolates did not change significantly between Phase and Phase, but decreased significantly in Phase. Reasons for selecting third-generation cephalosporins Analysis of the reasons for prescribing third-generation cephalosporins showed that others accounted for 64.4% of the reasons and thus ranked first. Bacterial meningitis (14.5%) and intra-abdominal infection (13.5%) were the second and third reasons, respectively. Among doctors who selected others, the majority of doctors selected uncertain reasons (92.1%). Further analysis of third-generation cephalosporin use for uncertain reasons through medical record review revealed that prophylactic use for surgery or procedure and empirical use for the treatment of infections accounted for 86.8% and 13.2%, respectively. Discussion n this intervention study, we observed that our hospital-wide computerized antibiotic control program effectively reduced third-generation cephalosporin use and that the occurrence of ESBL-producing K. pneumoniae decreased significantly. n addition, the proportions of other multidrug-resistant organisms such as imipenem-resistant or piperacillin/tazobactam-resistant P. aeruginosa and A. baumannii decreased significantly. n this study, we implemented a hospital-wide intervention to restrict third-generation cephalosporin use through a computerized antibiotic prescription program. Doctors were alerted to the increase in ESBL-producing K. pneumoniae and were asked to choose from a list of indications or to choose one of the alternatives. The intervention effectively reduced third-generation cephalosporin use, although 64% of third-generation cephalosporins were still prescribed with no specific indications. This might be due to doctors good compliance with the program and to the inconvenience of the prescription process. However, the effect of the intervention was lost during Phase, when doctors compliance with the program decreased in the absence of adequate feedback from the peer group. We believe that continuous feedback might be an important component for preserving the effect of the intervention. n our study, the proportion of ESBL-producing K. pneumoniae isolates increased during the intensive-intervention period and then significantly decreased in the maintenance period. Nevertheless, Page 4 of 6

ESBL K. pneumoniae control by antibiotic restriction Table 2. Change in proportions of multidrug-resistant nosocomial isolates in study periods Phase/organism No. of isolates (%) Comparison OR 95% C P value* P value** ESBL-producing K. pneumoniae 47/578 (8.13) versus 5.32 3.77 7.52,0.0001 188/587 (32.03) versus 2.94 2.02 4.26,0.0001,0.0001 97/470 (20.64) versus 1.81 1.37 2.40,0.0001 ESBL-producing E. coli 53/1110 (4.77) versus 1.65 1.15 2.37 0.0063 78/1020 (7.65) versus 1.46 0.99 2.14 0.0538 0.0177 58/851 (6.82) versus 1.13 0.80 1.61 0.4905 mipenem-resistant P. aeruginosa 154/676 (22.78) versus 1.26 0.97 1.64 0.0865 144/532 (27.07) versus 0.68 0.52 0.89 0.0052,0.0001 113/676 (16.72) versus 1.85 1.40 2.44,0.0001 TZP-resistant P. aeruginosa 143/676 (21.15) versus 0.35 0.25 0.50,0.0001 46/532 (8.65) versus 0.13 0.08 0.21,0.0001,0.0001 23/676 (3.40) versus 2.69 1.61 4.49 0.0002 mipenem-resistant A. baumannii 70/513 (13.65) versus 1.12 0.77 1.62 0.5544 62/413 (15.01) versus 0.45 0.28 0.71 0.0007 0.0001 27/410 (6.59) versus 2.51 1.56 4.03 0.0001 TZP-resistant A. baumannii 276/513 (53.80) versus 1.16 0.90 1.51 0.2536 236/410 (57.56) versus 0.72 0.56 0.94 0.0151 0.0024 189/413 (45.76) versus 1.61 1.22 2.12 0.0007 ESBL, extended-spectrum b-lactamase; TZP, piperacillin/tazobactam. *P value is for odds ratio (comparison with reference category). **P value is for logit model (or logistic model). that proportion was still higher than that in Phase. This suggests that traditional infection control measures are important in combination with antibiotic use control for more effective control of ESBL-producing K. pneumoniae. We also noted that the proportion of ESBL-producing K. pneumoniae began to decrease 6 months after the intervention started. n other studies, a lag of 1 year was noted after restriction of third-generation cephalosporins. 8,19 Previous studies reported that rigorous restriction of cephalosporin use to control ESBL-producing K. pneumoniae was accompanied by an increase in the use of carbapenems or b-lactam/b-lactamase inhibitors and the proportion of imipenem resistance in P. aeruginosa. 16 18 This phenomenon has been described as squeezing the balloon, namely the replacement of a third-generation cephalosporin with a different class of antibiotic and the emergence of a different type of antibiotic resistance. 20 n contrast to those studies, in this study, carbapenem use did not change significantly before and after the intervention, and the antimicrobial susceptibility patterns were rather improved among other Gram-negative pathogens such as Pseudomonas and Acinetobacter. We strictly controlled carbapenem use through the pre-existing computerized antibiotic prescription approval system. Using a more comprehensive antibiotic control strategy than previous studies, which focused only on a single antibiotic, we could direct the squeeze towards more ecologically favourable antibiotics. n this study, we have not established a link between the reduction of third-generation cephalosporin use and the decreased occurrence of ESBL-producing K. pneumoniae in terms of a cause-and-effect relationship. An intervention model or interrupted time series model would be the most appropriate analysis model in our study design, 21,22 but we did not have enough data to fit the model. Moreover, we did not consider possible confounders such as changes in length of stay, bed occupancy, staffing levels, hand-hygiene compliance and so on. On the basis of our observations and previous studies, however, we hypothesize that reduction of third-generation cephalosporin use was associated with decreased occurrence of ESBLproducing K. pneumoniae. Conclusions This study suggests that the computerized antibiotic control program is an effective tool for modifying antibiotic consumption to control multidrug-resistant pathogens in hospitals. n addition, it could easily provide us with the ability to monitor and analyse the effect of the intervention and for it to be developed as a hospital-wide program. Acknowledgements This study was presented previously as an abstract at the 44th Annual Meeting of the nfectious Diseases Society of America (DSA), (E abstract No. 954). The authors thank Byung Chul Chun for his advice and support in the statistical analysis of this study. Page 5 of 6

Kim et al. Funding This study was partly funded by City of Seoul grant #10920 and by KCOS project (Battelle nstitute, Korea University) grant. Transparency declarations None to declare. References 1. Colodner R. Extended-spectrum b-lactamases: a challenge for clinical microbiologists and infection control specialists. Am J nfect Control 2005; 33: 104 7. 2. Sturenburg E, Mack D. Extended-spectrum b-lactamases: implications for the clinical microbiology laboratory, therapy, and infection control. J nfect 2003; 47: 273 95. 3. Lautenbach E, Patel JB, Bilker WB et al. Extended-spectrum b-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection and impact of resistance on outcomes. Clin nfect Dis 2001; 32: 1162 71. 4. Lin MF, Huang ML, Lai SH. Risk factors in the acquisition of extended-spectrum b-lactamase Klebsiella pneumoniae: a case control study in a district teaching hospital in Taiwan. J Hosp nfect 2003; 53: 39 45. 5. Asensio A, Oliver A, Gonzalez-Diego P et al. Outbreak of a multiresistant Klebsiella pneumoniae strain in an intensive care unit: antibiotic use as risk factor for colonization and infection. Clin nfect Dis 2000; 30: 55 60. 6. Meyer KS, Urban C, Eagan JA et al. Nosocomial outbreak of Klebsiella infection resistant to late-generation cephalosporins. Ann ntern Med 1993; 119: 353 8. 7. Pena C, Pujol M, Ardanuy C et al. Epidemiology and successful control of a large outbreak due to Klebsiella pneumoniae producing extended-spectrum b-lactamases. Antimicrob Agents Chemother 1998; 42: 53 8. 8. Rice LB, Willey SH, Papanicolaou GA et al. Outbreak of ceftazidime resistance caused by extended-spectrum b-lactamases at a Massachusetts chronic-care facility. Antimicrob Agents Chemother 1990; 34: 2193 9. 9. Aubert G, Carricajo A, Vautrin AC et al. mpact of restricting fluoroquinolone prescription on bacterial resistance in an intensive care unit. J Hosp nfect 2005; 59: 83 9. 10. Duncan RA. Controlling use of antimicrobial agents. nfect Control Hosp Epidemiol 1997; 18: 260 6. 11. Kollef MH, Vlasnik J, Sharpless L et al. Scheduled change of antibiotic classes: a strategy to decrease the incidence of ventilatorassociated pneumonia. Am J Respir Crit Care Med 1997; 156: 1040 8. 12. Bisson G, Fishman NO, Patel JB et al. Extended-spectrum b-lactamase-producing Escherichia coli and Klebsiella species: risk factors for colonization and impact of antimicrobial formulary interventions on colonization prevalence. nfect Control Hosp Epidemiol 2002; 23: 254 60. 13. Calil R, Marba ST, von Nowakonski A et al. Reduction in colonization and nosocomial infection by multiresistant bacteria in a neonatal unit after institution of educational measures and restriction in the use of cephalosporins. Am J nfect Control 2001; 29: 133 8. 14. Du B, Chen D, Liu D et al. Restriction of third-generation cephalosporin use decreases infection-related mortality. Crit Care Med 2003; 31: 1088 93. 15. Lan CK, Hsueh PR, Wong WW et al. Association of antibiotic utilization measures and reduced incidence of infections with extendedspectrum b-lactamase-producing organisms. J Microbiol mmunol nfect 2003; 36: 182 6. 16. Lee SO, Lee ES, Park SY et al. Reduced use of third-generation cephalosporins decreases the acquisition of extended-spectrum b-lactamase-producing Klebsiella pneumoniae. nfect Control Hosp Epidemiol 2004; 25: 832 7. 17. Patterson JE, Hardin TC, Kelly CA et al. Association of antibiotic utilization measures and control of multiple-drug resistance in Klebsiella pneumoniae. nfect Control Hosp Epidemiol 2000; 21: 455 8. 18. Rahal JJ, Urban C, Horn D et al. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial Klebsiella. JAMA 1998; 280: 1233 7. 19. Ma MY, Goldstein EJ, Friedman MH et al. Resistance of Gram-negative bacilli as related to hospital use of antimicrobial agents. Antimicrob Agents Chemother 1983; 24: 347 52. 20. Burk JP. Antibiotic resistance squeezing the balloon? JAMA 1998; 280: 1270 1. 21. Mol PG, Wieringa JE, Nannanpanday PV et al. mproving compliance with hospital antibiotic guidelines: a time-series intervention analysis. J Antimicrob Chemother 2005; 55: 550 7. 22. Ansari F, Gray K, Nathwani D et al. Outcomes of an intervention to improve hospital antibiotic prescribing: interrupted time series with segmented regression analysis. J Antimicrob Chemother 2003; 52: 842 8. Page 6 of 6