American Journal of Infection Control 43 (2015) 358-64
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
journal homepage: www.ajicjournal.org
Major article
Influence of antimicrobial consumption on gram-negative bacteria in inpatients receiving antimicrobial resistance therapy from 2008-2013 at a tertiary hospital in Shanghai, China Wei Guo MD, PhD a, Qian He MD, PhD a, Zhiyong Wang MS b, Min Wei MS b, Zhangwei Yang PhD c, Yin Du MS b, Cheng Wu MD, PhD a, *, Jia He MD, PhD a, * a b c
Department of Health Statistics, Second Military Medical University, Shanghai, China Department of Information, Changhai Hospital, Second Military Medical University, Shanghai, China Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China
Key Words: Antimicrobial stewardship policy Time-series analysis Cross-correlation analysis Resistance reversal Infection control
Background: Irrational use of antimicrobial agents is a major cause of increased antimicrobial resistance. Effective antibiotic stewardship strategies nationwide or in local health care settings are necessary to reduce antibiotic use and bacteria resistance. Methods: We evaluated the effectiveness of China’s antimicrobial stewardship policy on antimicrobial use and applied time-series analysis methodology to determine the temporal relationship between antibiotic use and gram-negative bacteria resistance at Changhai Hospital from 2008-2013. Isolates investigated included Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Results: Consumption of 7 restricted-use antibiotics was dramatically reduced. Resistance to ceftazidime in P aeruginosa and A baumannii and resistance to ciprofloxacin in P aeruginosa significantly decreased. By using cross-correlation analysis, associations between ciprofloxacin resistance in P aeruginosa and fluoroquinolones consumption (r ¼ 0.48; lag ¼ 0; P ¼ .02), ceftazidime resistance in P aeruginosa and third-generation cephalosporins consumption (r ¼ 0.54; lag ¼ 1; P ¼ .01) were identified. No substantial association between other pairs was found. Conclusions: Enhanced nationwide antimicrobial stewardship campaigns launched in 2011 have made great achievements in regard to antibiotic use but have had limited effects on the reversal of gramnegative bacteria resistance in health care settings. Sound infection prevention and control programs to reduce the transmission of resistant pathogens for hospitals in China are urgently needed. Copyright Ó 2015 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
The increasing incidence of antimicrobial-resistant gram-negative organisms is a major public health problem.1 Hospital-acquired infections caused by gram-negative bacteria are of particular concern. In China, gram-negative bacteria are amongst the most commonly isolated pathogens from nosocomial infections.2 Irrational use of
* Address correspondence to Cheng Wu, MD, PhD and Jia He, MD, PhD, Department of Health Statistics, Second Military Medical University, 800 Xiangyin Road, Shanghai, China 200433. E-mail addresses: [email protected] (C. Wu), [email protected] (J. He). WG, QH, ZW, and MW contributed equally to this work. This study was funded by grants from the Key Discipline Construction of Evidence-Based Public Health (No. 12GWZX0602), the Key Program of Shanghai Soft Science Research (No. 14692101700), and the Foundation of Faculty of Health Service, Second Military Medical University (No. 2014WK02), all based in Shanghai, China. Conflicts of interest: None to report.
antimicrobial agents is the major cause of increased antimicrobial resistance and it has been proposed that effective antibiotic stewardship strategies nationwide or in local health-care settings would enable clinicians to reduce antibiotic use and reverse bacteria resistance. China has a high rate of antibiotic use for hospital inpatients. It is estimated that 75% of patients with seasonal influenza are prescribed antibiotics and the rate of antibiotic prescription for inpatients is 80%.3 To curb the abuse of antibiotics in health-care settings, the Chinese health administrative authorities implemented a series of professional strategies over the past decade, including guides for hospital drug therapeutic committees (2002), principles for clinical use of antibiotics (2004), and a national formulary (2008).4,5 However, antimicrobial agents have remained the most prescribed institutional medicine and antimicrobial resistance has continued to increase.5,6 To promote the rational use of
0196-6553/$36.00 - Copyright Ó 2015 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.2014.12.010
W. Guo et al. / American Journal of Infection Control 43 (2015) 358-64
antibiotic agents and contain antimicrobial resistance, the Ministry of Health of China (MOH) launched a 3-year nationwide campaign in 2011, with a special task force to overhaul the use of antibiotics in health-care settings. This nationwide special campaign protocol mainly consists of strengthening regulations on antibiotic agent use at the clinical level, clarifying the responsibility of hospital management staff, introducing legal penalties, setting targets for antibiotic management, implementing the classification management of antibiotics, developing antibiotic surveillance networks, and establishing antibiotic stewardship departments in hospitals. On August 1, 2012, China formally implemented a decree issued by MOH on administrative regulations for clinical use of antimicrobial agents to ensure sustainable progress toward the rational use of antimicrobial agents.7 To enforce the formulary restrictions mandated in the protocol Changhai Hospital developed a computerized antibiotics control program in 2011 with the cooperation of information technology engineers, clinical physicians, pharmacists, and infectious disease experts. Our retrospective study aimed to evaluate the effectiveness of China’s antimicrobial stewardship policy on the use of antimicrobial agents at Changhai Hospital over a 6-year period. In addition, we attempted to determine the temporal relationship between antibiotic use and gram-negative bacteria resistance in inpatients at this institution by applying time-series analysis methodology. MATERIALS AND METHODS Ethics statement This study was approved by the institutional ethics committee of Changhai Hospital. The committee waived the need for informed consent (both written and oral) from participants because this was a retrospective observational study, involved very minimal risk to participants, did not include intentional deception, and did not involve sensitive populations or topics; this waiver does not adversely affect the rights and welfare of the participants. Setting Our study was conducted between January 2008 and December 2013 at Changhai Hospital located in eastern China, a 1,800-bed tertiary care teaching hospital that includes 49 clinical departments with approximately 600,000 admissions annually. The hospital developed a computer-assisted program and integrated the antibiotic classification management function into an electronic prescription system during 2011. Based on Guidelines for Clinical Use of Antibiotics, antimicrobial agents are divided into 3 levels: nonrestricted-use, restricted-use, and special-use antibiotics. Prescribers have accredited prescription rights for different antibiotic classes determined by their job titles; generally, prescribers at all levels have permission to prescribe nonrestricted-use antibiotics depending on their requirements in their clinical work and restricted-use drugs can only be prescribed by prescribers with intermediate and senior specialized technical qualifications, including attending physicians, associate chief physicians, and chief physicians. The stewardship of special-use antibiotics is even stricter and only physicians with senior specialized technical qualifications; for example, associate chief physicians and chief physicians, can prescribe them after consultation with the Antibiotic Management Working Group. Antimicrobial consumption Antibiotic use data were obtained from all clinical departments except for pediatric wards. Antibiotic prescription data were
359
gathered from the hospital electronic prescription system and converted into defined daily doses (DDD) per 1,000 inpatient-days according to the 2012 World Health Organization anatomic therapeutic chemical classification system.8 Hospital inpatient-days were obtained from the hospital’s administrative records and used as the denominator for each quarter. Antimicrobial agents used throughout the time period were tracked and analyzed individually and in combination classes, including b-lactam-b-lactamase inhibitor combinations (ie, amoxicillin/clavulanate, cefoperazone/sulbactam, and piperacillin/tazobactam), second-generation cephalosporins (ie, cefoxitin, cefuroxime, cefaclor, cefdinir, and cefmetazole), thirdgeneration cephalosporins (ie, ceftazidime and ceftriaxone), fourth-generation cephalosporins (ie, cefpirome and cefepime), aztreonam, carbapenems (ie, imipenem and meropenem), aminoglycosides (ie, amikacin and gentamicin), and fluoroquinolones (ie, ciprofloxacin and levofloxacin). Only antibiotics achieving systemic treatment concentrations (oral and injectable) were employed and any agents prescribed as a topical solution was excluded. Antimicrobial susceptibility testing The number of nonduplicated isolates was obtained from the database of the Microbiology Department of the hospital clinical laboratory. Duplicate isolatesddefined as the same bacterial species from the same inpatient during the same inpatient staydwere excluded from analysis, and only the first isolate was included in the analysis. The microorganisms tracked included Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Bacterial isolates from inpatients were tested for susceptibility to a range of antimicrobial classes during the whole period, including b-lactam-b-lactamase inhibitor combinations (represented by piperacillin/tazobactam), third-generation cephalosporins (represented by ceftazidime), carbapenems (represented by imipenem), and fluoroquinolones (represented by ciprofloxacin). Identification and susceptibility testing were performed using the automated Vitek-2 system (biomérieux, l’Etoile, France), supplemented by the Kirby-Bauer Disk Diffusion Agar method, following guidelines recommended by the Clinical and Laboratory Standards Institute in 2009 (M100-S19).9 Isolates were classified as susceptible or resistant (all the intermediate resistance isolates were grouped as resistant isolates in this study). Although minimum inhibitory concentration susceptibility breakpoints for carbapenems, aztreonam, and some cephalosporins were changed after 2010, the laboratory did not change to the new guidelines because the panels for the commercial system in use did not have concentration wells that were low enough to allow interpretation at the lower breakpoints. Antimicrobial resistance was expressed as the percentage of the number of isolates that were resistant to certain antibiotics to the total number of isolates tested per quarter. E coli ATCC 25922 and P aeruginosa ATCC 27853 were used as quality control strains for each batch of tests. Statistical analysis Trends for antimicrobial consumption and the antimicrobial resistance series were first explored by linear regression within the study period. When a trend was identified as statistically significant (P < .05), we used the Box-Jenkins approach to fit the quarterly time series of antibiotic resistance and corresponding antibiotic class into autoregressive-integrated moving average (ARIMA) models.10-12 Then we cross-correlated the residual of each model to explore the strength of associations between selected clinically meaningful antibiotic consumption and resistance series in pairs by taking into account quarterly time lags of up to 3 quarters to avoid spurious correlations.
360
W. Guo et al. / American Journal of Infection Control 43 (2015) 358-64
Table 1 Characteristics and trends in the antimicrobial agent consumption time series at Changhai Hospital (January 2008-December 2013) World Health Organization classification J01
J01CR
J01DC
J01DD
J01DE J01DF
J01DH
J01 GB
J01 MA
Antimicrobial agent(s) Total Amoxicillin/clavulanate Cefoperazone/sulbactam Piperacillin/tazobactam b-lactamase inhibitor combinations Cefoxitin Cefuroxime Cefaclor Cefdinir Cefmetazole Second-generation cephalosporins Ceftazidime Ceftriaxone Third-generation cephalosporins Cefpirome Cefepime Fourth-generation cephalosporins Aztreonam Imipenem Meropenem Carbapenems Amikacin Gentamicin Aminoglycosides Ciprofloxacin Levofloxacin Fluoroquinolones
Prescription level* Nonrestricted Restricted Restricted
Restricted Nonrestricted Nonrestricted Restricted Restricted
Average usey 320.71 9.78 12.75 48.44 96.57 11.79 12.72 2.32 1.15 8.88 82.20
(210.45-489.28) (6.76-18.71) (6.05-17.41) (1.81-141.80) (30.58-180.40)
Gradientz 19.59 0.47 0.65 11.29 11.75
(3.10-20.70) (10.87-20.77) (1.96-3.29) (0.18-2.12) (5.79-11.97) (72.76-97.09)
1.69 2.58 0.10 0.06 0.05 0.00
P value
Trend
(24.73 to 14.45) (1.02 to 0.09) (0.92 to 0.36) (13.70 to 8.87) (13.75 to 9.75)
Contents lists available at ScienceDirect
American Journal of Infection Control
American Journal of Infection Control
journal homepage: www.ajicjournal.org
Major article
Influence of antimicrobial consumption on gram-negative bacteria in inpatients receiving antimicrobial resistance therapy from 2008-2013 at a tertiary hospital in Shanghai, China Wei Guo MD, PhD a, Qian He MD, PhD a, Zhiyong Wang MS b, Min Wei MS b, Zhangwei Yang PhD c, Yin Du MS b, Cheng Wu MD, PhD a, *, Jia He MD, PhD a, * a b c
Department of Health Statistics, Second Military Medical University, Shanghai, China Department of Information, Changhai Hospital, Second Military Medical University, Shanghai, China Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, China
Key Words: Antimicrobial stewardship policy Time-series analysis Cross-correlation analysis Resistance reversal Infection control
Background: Irrational use of antimicrobial agents is a major cause of increased antimicrobial resistance. Effective antibiotic stewardship strategies nationwide or in local health care settings are necessary to reduce antibiotic use and bacteria resistance. Methods: We evaluated the effectiveness of China’s antimicrobial stewardship policy on antimicrobial use and applied time-series analysis methodology to determine the temporal relationship between antibiotic use and gram-negative bacteria resistance at Changhai Hospital from 2008-2013. Isolates investigated included Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Results: Consumption of 7 restricted-use antibiotics was dramatically reduced. Resistance to ceftazidime in P aeruginosa and A baumannii and resistance to ciprofloxacin in P aeruginosa significantly decreased. By using cross-correlation analysis, associations between ciprofloxacin resistance in P aeruginosa and fluoroquinolones consumption (r ¼ 0.48; lag ¼ 0; P ¼ .02), ceftazidime resistance in P aeruginosa and third-generation cephalosporins consumption (r ¼ 0.54; lag ¼ 1; P ¼ .01) were identified. No substantial association between other pairs was found. Conclusions: Enhanced nationwide antimicrobial stewardship campaigns launched in 2011 have made great achievements in regard to antibiotic use but have had limited effects on the reversal of gramnegative bacteria resistance in health care settings. Sound infection prevention and control programs to reduce the transmission of resistant pathogens for hospitals in China are urgently needed. Copyright Ó 2015 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
The increasing incidence of antimicrobial-resistant gram-negative organisms is a major public health problem.1 Hospital-acquired infections caused by gram-negative bacteria are of particular concern. In China, gram-negative bacteria are amongst the most commonly isolated pathogens from nosocomial infections.2 Irrational use of
* Address correspondence to Cheng Wu, MD, PhD and Jia He, MD, PhD, Department of Health Statistics, Second Military Medical University, 800 Xiangyin Road, Shanghai, China 200433. E-mail addresses: [email protected] (C. Wu), [email protected] (J. He). WG, QH, ZW, and MW contributed equally to this work. This study was funded by grants from the Key Discipline Construction of Evidence-Based Public Health (No. 12GWZX0602), the Key Program of Shanghai Soft Science Research (No. 14692101700), and the Foundation of Faculty of Health Service, Second Military Medical University (No. 2014WK02), all based in Shanghai, China. Conflicts of interest: None to report.
antimicrobial agents is the major cause of increased antimicrobial resistance and it has been proposed that effective antibiotic stewardship strategies nationwide or in local health-care settings would enable clinicians to reduce antibiotic use and reverse bacteria resistance. China has a high rate of antibiotic use for hospital inpatients. It is estimated that 75% of patients with seasonal influenza are prescribed antibiotics and the rate of antibiotic prescription for inpatients is 80%.3 To curb the abuse of antibiotics in health-care settings, the Chinese health administrative authorities implemented a series of professional strategies over the past decade, including guides for hospital drug therapeutic committees (2002), principles for clinical use of antibiotics (2004), and a national formulary (2008).4,5 However, antimicrobial agents have remained the most prescribed institutional medicine and antimicrobial resistance has continued to increase.5,6 To promote the rational use of
0196-6553/$36.00 - Copyright Ó 2015 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.2014.12.010
W. Guo et al. / American Journal of Infection Control 43 (2015) 358-64
antibiotic agents and contain antimicrobial resistance, the Ministry of Health of China (MOH) launched a 3-year nationwide campaign in 2011, with a special task force to overhaul the use of antibiotics in health-care settings. This nationwide special campaign protocol mainly consists of strengthening regulations on antibiotic agent use at the clinical level, clarifying the responsibility of hospital management staff, introducing legal penalties, setting targets for antibiotic management, implementing the classification management of antibiotics, developing antibiotic surveillance networks, and establishing antibiotic stewardship departments in hospitals. On August 1, 2012, China formally implemented a decree issued by MOH on administrative regulations for clinical use of antimicrobial agents to ensure sustainable progress toward the rational use of antimicrobial agents.7 To enforce the formulary restrictions mandated in the protocol Changhai Hospital developed a computerized antibiotics control program in 2011 with the cooperation of information technology engineers, clinical physicians, pharmacists, and infectious disease experts. Our retrospective study aimed to evaluate the effectiveness of China’s antimicrobial stewardship policy on the use of antimicrobial agents at Changhai Hospital over a 6-year period. In addition, we attempted to determine the temporal relationship between antibiotic use and gram-negative bacteria resistance in inpatients at this institution by applying time-series analysis methodology. MATERIALS AND METHODS Ethics statement This study was approved by the institutional ethics committee of Changhai Hospital. The committee waived the need for informed consent (both written and oral) from participants because this was a retrospective observational study, involved very minimal risk to participants, did not include intentional deception, and did not involve sensitive populations or topics; this waiver does not adversely affect the rights and welfare of the participants. Setting Our study was conducted between January 2008 and December 2013 at Changhai Hospital located in eastern China, a 1,800-bed tertiary care teaching hospital that includes 49 clinical departments with approximately 600,000 admissions annually. The hospital developed a computer-assisted program and integrated the antibiotic classification management function into an electronic prescription system during 2011. Based on Guidelines for Clinical Use of Antibiotics, antimicrobial agents are divided into 3 levels: nonrestricted-use, restricted-use, and special-use antibiotics. Prescribers have accredited prescription rights for different antibiotic classes determined by their job titles; generally, prescribers at all levels have permission to prescribe nonrestricted-use antibiotics depending on their requirements in their clinical work and restricted-use drugs can only be prescribed by prescribers with intermediate and senior specialized technical qualifications, including attending physicians, associate chief physicians, and chief physicians. The stewardship of special-use antibiotics is even stricter and only physicians with senior specialized technical qualifications; for example, associate chief physicians and chief physicians, can prescribe them after consultation with the Antibiotic Management Working Group. Antimicrobial consumption Antibiotic use data were obtained from all clinical departments except for pediatric wards. Antibiotic prescription data were
359
gathered from the hospital electronic prescription system and converted into defined daily doses (DDD) per 1,000 inpatient-days according to the 2012 World Health Organization anatomic therapeutic chemical classification system.8 Hospital inpatient-days were obtained from the hospital’s administrative records and used as the denominator for each quarter. Antimicrobial agents used throughout the time period were tracked and analyzed individually and in combination classes, including b-lactam-b-lactamase inhibitor combinations (ie, amoxicillin/clavulanate, cefoperazone/sulbactam, and piperacillin/tazobactam), second-generation cephalosporins (ie, cefoxitin, cefuroxime, cefaclor, cefdinir, and cefmetazole), thirdgeneration cephalosporins (ie, ceftazidime and ceftriaxone), fourth-generation cephalosporins (ie, cefpirome and cefepime), aztreonam, carbapenems (ie, imipenem and meropenem), aminoglycosides (ie, amikacin and gentamicin), and fluoroquinolones (ie, ciprofloxacin and levofloxacin). Only antibiotics achieving systemic treatment concentrations (oral and injectable) were employed and any agents prescribed as a topical solution was excluded. Antimicrobial susceptibility testing The number of nonduplicated isolates was obtained from the database of the Microbiology Department of the hospital clinical laboratory. Duplicate isolatesddefined as the same bacterial species from the same inpatient during the same inpatient staydwere excluded from analysis, and only the first isolate was included in the analysis. The microorganisms tracked included Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Bacterial isolates from inpatients were tested for susceptibility to a range of antimicrobial classes during the whole period, including b-lactam-b-lactamase inhibitor combinations (represented by piperacillin/tazobactam), third-generation cephalosporins (represented by ceftazidime), carbapenems (represented by imipenem), and fluoroquinolones (represented by ciprofloxacin). Identification and susceptibility testing were performed using the automated Vitek-2 system (biomérieux, l’Etoile, France), supplemented by the Kirby-Bauer Disk Diffusion Agar method, following guidelines recommended by the Clinical and Laboratory Standards Institute in 2009 (M100-S19).9 Isolates were classified as susceptible or resistant (all the intermediate resistance isolates were grouped as resistant isolates in this study). Although minimum inhibitory concentration susceptibility breakpoints for carbapenems, aztreonam, and some cephalosporins were changed after 2010, the laboratory did not change to the new guidelines because the panels for the commercial system in use did not have concentration wells that were low enough to allow interpretation at the lower breakpoints. Antimicrobial resistance was expressed as the percentage of the number of isolates that were resistant to certain antibiotics to the total number of isolates tested per quarter. E coli ATCC 25922 and P aeruginosa ATCC 27853 were used as quality control strains for each batch of tests. Statistical analysis Trends for antimicrobial consumption and the antimicrobial resistance series were first explored by linear regression within the study period. When a trend was identified as statistically significant (P < .05), we used the Box-Jenkins approach to fit the quarterly time series of antibiotic resistance and corresponding antibiotic class into autoregressive-integrated moving average (ARIMA) models.10-12 Then we cross-correlated the residual of each model to explore the strength of associations between selected clinically meaningful antibiotic consumption and resistance series in pairs by taking into account quarterly time lags of up to 3 quarters to avoid spurious correlations.
360
W. Guo et al. / American Journal of Infection Control 43 (2015) 358-64
Table 1 Characteristics and trends in the antimicrobial agent consumption time series at Changhai Hospital (January 2008-December 2013) World Health Organization classification J01
J01CR
J01DC
J01DD
J01DE J01DF
J01DH
J01 GB
J01 MA
Antimicrobial agent(s) Total Amoxicillin/clavulanate Cefoperazone/sulbactam Piperacillin/tazobactam b-lactamase inhibitor combinations Cefoxitin Cefuroxime Cefaclor Cefdinir Cefmetazole Second-generation cephalosporins Ceftazidime Ceftriaxone Third-generation cephalosporins Cefpirome Cefepime Fourth-generation cephalosporins Aztreonam Imipenem Meropenem Carbapenems Amikacin Gentamicin Aminoglycosides Ciprofloxacin Levofloxacin Fluoroquinolones
Prescription level* Nonrestricted Restricted Restricted
Restricted Nonrestricted Nonrestricted Restricted Restricted
Average usey 320.71 9.78 12.75 48.44 96.57 11.79 12.72 2.32 1.15 8.88 82.20
(210.45-489.28) (6.76-18.71) (6.05-17.41) (1.81-141.80) (30.58-180.40)
Gradientz 19.59 0.47 0.65 11.29 11.75
(3.10-20.70) (10.87-20.77) (1.96-3.29) (0.18-2.12) (5.79-11.97) (72.76-97.09)
1.69 2.58 0.10 0.06 0.05 0.00
P value
Trend
(24.73 to 14.45) (1.02 to 0.09) (0.92 to 0.36) (13.70 to 8.87) (13.75 to 9.75)
