Research Original Investigation
Antibiotics Use in Primary Health Care in China
drug use evaluation. J Antimicrob Chemother. 1992; 30(5):724-727.
hospital [in Chinese]. Chin J Nosocomiol. 2013;23 (15):3729-3731.
11. Willemsen I, Groenhuijzen A, Bogaers D, Stuurman A, van Keulen P, Kluytmans J. Appropriateness of antimicrobial therapy measured by repeated prevalence surveys. Antimicrob Agents Chemother. 2007;51(3):864-867.
17. Sharma M, Eriksson B, Marrone G, Dhaneria S, Lundborg CS. Antibiotic prescribing in two private sector hospitals; one teaching and one non-teaching: a cross-sectional study in Ujjain, India. BMC Infect Dis. 2012;12:155.
12. National Bureau of Statistics of China. The State Statistical Yearbook (2009) [in Chinese]. http: //data.stats.gov.cn/workspace/index?m=fsnd. Accessed July 10, 2013.
18. Sohn HS, Oh OH, Kwon JW, Lee YS. Higher systemic antibiotic consumption in a population of South Korea (2008-2009). Int J Clin Pharmacol Ther. 2013;51(7):585-592.
13. Xiao Y, Zhang J, Zheng B, Zhao L, Li S, Li L. Changes in Chinese policies to promote the rational use of antibiotics. PLoS Med. 2013;10(11):e1001556.
19. Polk RE, Hohmann SF, Medvedev S, Ibrahim O. Benchmarking risk-adjusted adult antibacterial drug use in 70 US academic medical center hospitals. Clin Infect Dis. 2011;53(11):1100-1110.
14. Li CH, Wu AH, Wen XM, et al. National health care-associated infection surveillance system point-prevalence trend of antibacterial use in Chinese hospitals 2001-2010 [in Chinese]. Chin J Nosocomiol. 2012;22(21):4859-4861. 15. Mao XH, Ye Q, Han JJ, et al. Antibiotics usage in outpatient department after new antibiotic policy [in Chinese]. Chin J Nosocomiol. 2013;23(15): 3739-3741. 16. Liu LP, Yang YR, Hu W, et al. Current status of clinical use of antibiotics in an A-level tertiary
20. Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005;365(9459):579-587. 21. Hu S, Tang S, Liu Y, Zhao Y, Escobar ML, de Ferranti D. Reform of how health care is paid for in China: challenges and opportunities. Lancet. 2008; 372(9652):1846-1853.
Cooperative Medical Scheme and its implications for rural primary healthcare: multivariate difference-in-difference analysis. BMJ. 2010;341: c5617. 23. Liu GY, Chai D, Jiao Q, et al. Investigation on knowledge level of antibacterials rational use among health professionals [in Chinese]. Adv D React J. 2005;7(3):175-179. 24. National Health and Family Planning Commission of the People's Republic of China. Further supervision and administration of antibiotics clinical use (2012-03-05) [in Chinese]. http://wsb.moh.gov.cn/mohyzs/s3586/201206 /55062.shtml. Accessed July 10, 2013. 25. Dong L, Yan H, Wang D. Antibiotic prescribing patterns in village health clinics across 10 provinces of Western China. J Antimicrob Chemother. 2008; 62(2):410-415. 26. Hadi U, Duerink DO, Lestari ES, et al; Antimicrobial Resistance in Indonesia: Prevalence and Prevention. Audit of antibiotic prescribing in two governmental teaching hospitals in Indonesia. Clin Microbiol Infect. 2008;14(7):698-707.
22. Babiarz KS, Miller G, Yi H, Zhang L, Rozelle S. New evidence on the impact of China’s New Rural
Invited Commentary
Antibiotic Misuse A Global Crisis Michael Bell, MD
Antibiotics are an essential medical resource. The ability to treat infections not only saves lives but provides a safety net for medical advances that now seem routine: trauma surgery, cancer chemotherapy, and stem cell and organ transplantation—each inherently reliant on effective antibiotics in order to deliver their life-saving potential. Antibiotic resistance has developed and Related article page 1914 spread predictably since the advent of the first antibiotics and with each new drug brought to market. To make matters worse, Clostridium difficile infection as a consequence of antibiotic misuse is resulting in increasingly severe disease.1 Whereas the selective pressure of antibiotics on human pathogens inevitably drives the development of resistance, it must not be allowed to happen as rapidly as it has. Particularly at a time when alternatives to existing antibiotic classes are limited, we have an obligation to preserve the effectiveness of available drugs for as long as possible. In this issue of JAMA Internal Medicine, Wang et al2 describe a striking and widespread example of medical misuse of antibiotics that can rapidly drive the acquisition and spread of antibiotic resistance. They assessed China’s primary care system, a network of mostly rural facilities that provide two-thirds of that country’s health care— amounting to more than 3.7 billion outpatient encounters each year. More than 60% of antibiotic prescriptions were found to be inappropriate, with 78% to 93% of 1920
respiratory infections being treated with antibiotics. In addition, they describe a system supported by staff with limited training and education; their ability to restrict inappropriate antibiotic use is further hampered by an innate conflict of interest wherein the facility must sell antibiotics to sustain its operating budget. Unfortunately, China’s situation is not unique. It represents many of the major drivers of medical misuse of antibiotics worldwide. Underlying this are systemic factors that include lack of microbiologic diagnosis to support precise use of antibiotics in hospitals, unrestricted availability of antibiotics in the community, and payment policies that promote clinician prescribing of antibiotics. Diagnostic standards3 and best practices for antibiotic stewardship4 for the treatment of infections are increasingly being adopted in many parts of the world. However, substantial challenges remain in many places where professional culture, access to clinical expertise, and administrative factors can limit the potential for success. Ideally, antibiotics should be selected on the basis of accurate and timely microbiologic identification and antibiotic susceptibility testing. Many basic aspects of medical care, such as first aid and uncomplicated obstetrics, can be provided without substantial laboratory infrastructure; however, clinical microbiology laboratory capacity is an essential component of advanced medical care, eg, intensive care support and hemodialysis. Unfortunately, this crucial capability is often overlooked or undersupported. The need for reliable supplies of
JAMA Internal Medicine December 2014 Volume 174, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 05/28/2015
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Antibiotics Use in Primary Health Care in China
Original Investigation Research
quality-assured media, knowledgeable technicians with advanced training, quality assurance of protocols, and proficiency testing make microbiology laboratory capacity a greater sustainability challenge than other elements of laboratory diagnosis such as biochemical and hematological analysis. Where microbiology laboratory capabilities are either absent or perceived as unreliable, clinicians are not trained to rely on or demand access to such testing, relying instead on empirical antimicrobial therapy alone. Without data to guide precise antibiotic treatment or scaling back from broad initial therapy, broad-spectrum antibiotics are likely to be favored for routine use. Treatment failures lead to escalation of antibiotic choices, a pattern that guarantees systematic promotion of antibiotic resistance. A related challenge is that of overuse driven by unrestricted availability of antibiotics. In resource-limited and remote areas where clinicians are not accessible, antibiotic availability “over the counter” can be life-saving but is also associated with excessive and imprecise use of antibiotics, a situation in which resistance quickly develops. Health care payment practices can drive unintended consequences. Whereas there have been recent successes in using payment and policies to drive quality improvement in health care,5 the United States has also had federal payment policies wherein expensive medications were included in a bundled payment structure that drove attempts to scavenge reimbursable doses by pooling residual medication, leading to contamination and severe infections among recipients.6 Similarly, systems wherein clinicians or facilities have a financial incentive to prescribe antibiotics, as described by Wang et al,2 can drive additional overuse. Interventions to slow the advance of antibiotic resistance must be safe for patients, tailored to local needs, and sustainable by facilities, clinicians, and governments. Short-term options include strong and consistent public and clinician information campaigns to highlight the negative consequences of antibiotic misuse and change the underlying demand for unnecessary antibiotics. Appropriate attention to individual and environmental hygiene, and standard infection control practices, should be applied by personnel in all facilities to preARTICLE INFORMATION Author Affiliation: Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia. Corresponding Author: Michael Bell, MD, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, 1600 Clifton Rd, A-7, Atlanta, GA 30333 ([email protected]). Published Online: October 6, 2014. doi:10.1001/jamainternmed.2014.3289. Conflict of Interest Disclosures: None reported. REFERENCES 1. See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis. 2014;58(10):1394-1400.
jamainternalmedicine.com
vent cross-transmission and amplification of pathogens, including resistant organisms, in health care settings. In addition, facilities can assess the quality of their microbiology laboratory resources and personnel to identify gaps and areas of need; even limited diagnostic microbiologic analysis capacity could be applied to perform periodic prevalence surveys to produce antibiograms to guide clinical staff. An approach to unrestricted access to antibiotics in places where clinical experts are not available can include consideration of whether a few basic antibiotics should remain accessible without a prescription, in order to ensure that patients have access to urgently needed treatments while the remaining antibiotics are held in reserve by requiring a prescription for dispensing. Such an approach will benefit from alignment among governments, international organizations, and aid organizations, similar to the essential medications lists7 published by the World Health Organization. In the longer term, a reassessment of medical and pharmacy professional curricula is needed, with renewed attention to pragmatic elements of microbiology content and antimicrobial use. Governments can support rational antibiotic use by ensuring that costs of sustaining clinical microbiology laboratories and reimbursement for appropriate diagnostic culture and susceptibility testing are addressed at the level of national policy; regional reference laboratories can be an intermediate step toward sufficient diagnostic capacity. In addition, newer technologies such as matrix-assisted laser desorption ionization time-of-flight8 and molecular diagnostics can increase the accessibility of accurate microbiologic diagnosis and facilitate susceptibility testing among a wider range of laboratories. Governments can also assess whether payment strategies have created unintended drivers of excessive antibiotic dispensing, ideally disassociating prescription from the sales and dispensing process. Ultimately, we as clinicians must face up to the harm that we can do with every antibiotic we administer, whether immediate in the form of severe C difficile infections or by bringing us all closer to the impending return to an era of untreatable infections. There is a limited and dwindling opportunity to change our trajectory; we must not allow it to slip by.
2. Wang J, Wang P, Wang X, Zheng Y, Xiao Y. Use and prescription of antibiotics in primary health care settings in China [published online October 6, 2014]. JAMA Intern Med. doi:10.1001 /jamainternmed.2014.5214. 3. Jones RN, Stilwell MG, Wilson ML, Mendes RE. Contemporary tetracycline susceptibility testing: doxycycline MIC methods and interpretive criteria (CLSI and EUCAST) performance when testing Gram-positive pathogens. Diagn Microbiol Infect Dis. 2013;76(1):69-72. 4. Srinivasan A. Engaging hospitalists in antimicrobial stewardship: the CDC perspective. J Hosp Med. 2011;6(suppl 1):S31-S33.
coordination in healthcare-associated infection prevention. Clin Infect Dis. 2012;55(3):426-431. 6. Grohskopf LA, Roth VR, Feikin DR, et al. Serratia liquefaciens bloodstream infections from contamination of epoetin alfa at a hemodialysis center. N Engl J Med. 2001;344(20):1491-1497. 7. World Health Organization. Essential medicines. 2014. http://www.who.int/medicines/services /essmedicines_def/en/. Accessed June 23, 2014. 8. Carbonnelle E, Mesquita C, Bille E, et al. MALDI-TOF mass spectrometry tools for bacterial identification in clinical microbiology laboratory. Clin Biochem. 2011;44(1):104-109.
5. Srinivasan A, Craig M, Cardo D. The power of policy change, federal collaboration, and state
JAMA Internal Medicine December 2014 Volume 174, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 05/28/2015
1921
Antibiotics Use in Primary Health Care in China
drug use evaluation. J Antimicrob Chemother. 1992; 30(5):724-727.
hospital [in Chinese]. Chin J Nosocomiol. 2013;23 (15):3729-3731.
11. Willemsen I, Groenhuijzen A, Bogaers D, Stuurman A, van Keulen P, Kluytmans J. Appropriateness of antimicrobial therapy measured by repeated prevalence surveys. Antimicrob Agents Chemother. 2007;51(3):864-867.
17. Sharma M, Eriksson B, Marrone G, Dhaneria S, Lundborg CS. Antibiotic prescribing in two private sector hospitals; one teaching and one non-teaching: a cross-sectional study in Ujjain, India. BMC Infect Dis. 2012;12:155.
12. National Bureau of Statistics of China. The State Statistical Yearbook (2009) [in Chinese]. http: //data.stats.gov.cn/workspace/index?m=fsnd. Accessed July 10, 2013.
18. Sohn HS, Oh OH, Kwon JW, Lee YS. Higher systemic antibiotic consumption in a population of South Korea (2008-2009). Int J Clin Pharmacol Ther. 2013;51(7):585-592.
13. Xiao Y, Zhang J, Zheng B, Zhao L, Li S, Li L. Changes in Chinese policies to promote the rational use of antibiotics. PLoS Med. 2013;10(11):e1001556.
19. Polk RE, Hohmann SF, Medvedev S, Ibrahim O. Benchmarking risk-adjusted adult antibacterial drug use in 70 US academic medical center hospitals. Clin Infect Dis. 2011;53(11):1100-1110.
14. Li CH, Wu AH, Wen XM, et al. National health care-associated infection surveillance system point-prevalence trend of antibacterial use in Chinese hospitals 2001-2010 [in Chinese]. Chin J Nosocomiol. 2012;22(21):4859-4861. 15. Mao XH, Ye Q, Han JJ, et al. Antibiotics usage in outpatient department after new antibiotic policy [in Chinese]. Chin J Nosocomiol. 2013;23(15): 3739-3741. 16. Liu LP, Yang YR, Hu W, et al. Current status of clinical use of antibiotics in an A-level tertiary
20. Goossens H, Ferech M, Vander Stichele R, Elseviers M; ESAC Project Group. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet. 2005;365(9459):579-587. 21. Hu S, Tang S, Liu Y, Zhao Y, Escobar ML, de Ferranti D. Reform of how health care is paid for in China: challenges and opportunities. Lancet. 2008; 372(9652):1846-1853.
Cooperative Medical Scheme and its implications for rural primary healthcare: multivariate difference-in-difference analysis. BMJ. 2010;341: c5617. 23. Liu GY, Chai D, Jiao Q, et al. Investigation on knowledge level of antibacterials rational use among health professionals [in Chinese]. Adv D React J. 2005;7(3):175-179. 24. National Health and Family Planning Commission of the People's Republic of China. Further supervision and administration of antibiotics clinical use (2012-03-05) [in Chinese]. http://wsb.moh.gov.cn/mohyzs/s3586/201206 /55062.shtml. Accessed July 10, 2013. 25. Dong L, Yan H, Wang D. Antibiotic prescribing patterns in village health clinics across 10 provinces of Western China. J Antimicrob Chemother. 2008; 62(2):410-415. 26. Hadi U, Duerink DO, Lestari ES, et al; Antimicrobial Resistance in Indonesia: Prevalence and Prevention. Audit of antibiotic prescribing in two governmental teaching hospitals in Indonesia. Clin Microbiol Infect. 2008;14(7):698-707.
22. Babiarz KS, Miller G, Yi H, Zhang L, Rozelle S. New evidence on the impact of China’s New Rural
Invited Commentary
Antibiotic Misuse A Global Crisis Michael Bell, MD
Antibiotics are an essential medical resource. The ability to treat infections not only saves lives but provides a safety net for medical advances that now seem routine: trauma surgery, cancer chemotherapy, and stem cell and organ transplantation—each inherently reliant on effective antibiotics in order to deliver their life-saving potential. Antibiotic resistance has developed and Related article page 1914 spread predictably since the advent of the first antibiotics and with each new drug brought to market. To make matters worse, Clostridium difficile infection as a consequence of antibiotic misuse is resulting in increasingly severe disease.1 Whereas the selective pressure of antibiotics on human pathogens inevitably drives the development of resistance, it must not be allowed to happen as rapidly as it has. Particularly at a time when alternatives to existing antibiotic classes are limited, we have an obligation to preserve the effectiveness of available drugs for as long as possible. In this issue of JAMA Internal Medicine, Wang et al2 describe a striking and widespread example of medical misuse of antibiotics that can rapidly drive the acquisition and spread of antibiotic resistance. They assessed China’s primary care system, a network of mostly rural facilities that provide two-thirds of that country’s health care— amounting to more than 3.7 billion outpatient encounters each year. More than 60% of antibiotic prescriptions were found to be inappropriate, with 78% to 93% of 1920
respiratory infections being treated with antibiotics. In addition, they describe a system supported by staff with limited training and education; their ability to restrict inappropriate antibiotic use is further hampered by an innate conflict of interest wherein the facility must sell antibiotics to sustain its operating budget. Unfortunately, China’s situation is not unique. It represents many of the major drivers of medical misuse of antibiotics worldwide. Underlying this are systemic factors that include lack of microbiologic diagnosis to support precise use of antibiotics in hospitals, unrestricted availability of antibiotics in the community, and payment policies that promote clinician prescribing of antibiotics. Diagnostic standards3 and best practices for antibiotic stewardship4 for the treatment of infections are increasingly being adopted in many parts of the world. However, substantial challenges remain in many places where professional culture, access to clinical expertise, and administrative factors can limit the potential for success. Ideally, antibiotics should be selected on the basis of accurate and timely microbiologic identification and antibiotic susceptibility testing. Many basic aspects of medical care, such as first aid and uncomplicated obstetrics, can be provided without substantial laboratory infrastructure; however, clinical microbiology laboratory capacity is an essential component of advanced medical care, eg, intensive care support and hemodialysis. Unfortunately, this crucial capability is often overlooked or undersupported. The need for reliable supplies of
JAMA Internal Medicine December 2014 Volume 174, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 05/28/2015
jamainternalmedicine.com
Antibiotics Use in Primary Health Care in China
Original Investigation Research
quality-assured media, knowledgeable technicians with advanced training, quality assurance of protocols, and proficiency testing make microbiology laboratory capacity a greater sustainability challenge than other elements of laboratory diagnosis such as biochemical and hematological analysis. Where microbiology laboratory capabilities are either absent or perceived as unreliable, clinicians are not trained to rely on or demand access to such testing, relying instead on empirical antimicrobial therapy alone. Without data to guide precise antibiotic treatment or scaling back from broad initial therapy, broad-spectrum antibiotics are likely to be favored for routine use. Treatment failures lead to escalation of antibiotic choices, a pattern that guarantees systematic promotion of antibiotic resistance. A related challenge is that of overuse driven by unrestricted availability of antibiotics. In resource-limited and remote areas where clinicians are not accessible, antibiotic availability “over the counter” can be life-saving but is also associated with excessive and imprecise use of antibiotics, a situation in which resistance quickly develops. Health care payment practices can drive unintended consequences. Whereas there have been recent successes in using payment and policies to drive quality improvement in health care,5 the United States has also had federal payment policies wherein expensive medications were included in a bundled payment structure that drove attempts to scavenge reimbursable doses by pooling residual medication, leading to contamination and severe infections among recipients.6 Similarly, systems wherein clinicians or facilities have a financial incentive to prescribe antibiotics, as described by Wang et al,2 can drive additional overuse. Interventions to slow the advance of antibiotic resistance must be safe for patients, tailored to local needs, and sustainable by facilities, clinicians, and governments. Short-term options include strong and consistent public and clinician information campaigns to highlight the negative consequences of antibiotic misuse and change the underlying demand for unnecessary antibiotics. Appropriate attention to individual and environmental hygiene, and standard infection control practices, should be applied by personnel in all facilities to preARTICLE INFORMATION Author Affiliation: Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia. Corresponding Author: Michael Bell, MD, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, 1600 Clifton Rd, A-7, Atlanta, GA 30333 ([email protected]). Published Online: October 6, 2014. doi:10.1001/jamainternmed.2014.3289. Conflict of Interest Disclosures: None reported. REFERENCES 1. See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis. 2014;58(10):1394-1400.
jamainternalmedicine.com
vent cross-transmission and amplification of pathogens, including resistant organisms, in health care settings. In addition, facilities can assess the quality of their microbiology laboratory resources and personnel to identify gaps and areas of need; even limited diagnostic microbiologic analysis capacity could be applied to perform periodic prevalence surveys to produce antibiograms to guide clinical staff. An approach to unrestricted access to antibiotics in places where clinical experts are not available can include consideration of whether a few basic antibiotics should remain accessible without a prescription, in order to ensure that patients have access to urgently needed treatments while the remaining antibiotics are held in reserve by requiring a prescription for dispensing. Such an approach will benefit from alignment among governments, international organizations, and aid organizations, similar to the essential medications lists7 published by the World Health Organization. In the longer term, a reassessment of medical and pharmacy professional curricula is needed, with renewed attention to pragmatic elements of microbiology content and antimicrobial use. Governments can support rational antibiotic use by ensuring that costs of sustaining clinical microbiology laboratories and reimbursement for appropriate diagnostic culture and susceptibility testing are addressed at the level of national policy; regional reference laboratories can be an intermediate step toward sufficient diagnostic capacity. In addition, newer technologies such as matrix-assisted laser desorption ionization time-of-flight8 and molecular diagnostics can increase the accessibility of accurate microbiologic diagnosis and facilitate susceptibility testing among a wider range of laboratories. Governments can also assess whether payment strategies have created unintended drivers of excessive antibiotic dispensing, ideally disassociating prescription from the sales and dispensing process. Ultimately, we as clinicians must face up to the harm that we can do with every antibiotic we administer, whether immediate in the form of severe C difficile infections or by bringing us all closer to the impending return to an era of untreatable infections. There is a limited and dwindling opportunity to change our trajectory; we must not allow it to slip by.
2. Wang J, Wang P, Wang X, Zheng Y, Xiao Y. Use and prescription of antibiotics in primary health care settings in China [published online October 6, 2014]. JAMA Intern Med. doi:10.1001 /jamainternmed.2014.5214. 3. Jones RN, Stilwell MG, Wilson ML, Mendes RE. Contemporary tetracycline susceptibility testing: doxycycline MIC methods and interpretive criteria (CLSI and EUCAST) performance when testing Gram-positive pathogens. Diagn Microbiol Infect Dis. 2013;76(1):69-72. 4. Srinivasan A. Engaging hospitalists in antimicrobial stewardship: the CDC perspective. J Hosp Med. 2011;6(suppl 1):S31-S33.
coordination in healthcare-associated infection prevention. Clin Infect Dis. 2012;55(3):426-431. 6. Grohskopf LA, Roth VR, Feikin DR, et al. Serratia liquefaciens bloodstream infections from contamination of epoetin alfa at a hemodialysis center. N Engl J Med. 2001;344(20):1491-1497. 7. World Health Organization. Essential medicines. 2014. http://www.who.int/medicines/services /essmedicines_def/en/. Accessed June 23, 2014. 8. Carbonnelle E, Mesquita C, Bille E, et al. MALDI-TOF mass spectrometry tools for bacterial identification in clinical microbiology laboratory. Clin Biochem. 2011;44(1):104-109.
5. Srinivasan A, Craig M, Cardo D. The power of policy change, federal collaboration, and state
JAMA Internal Medicine December 2014 Volume 174, Number 12
Copyright 2014 American Medical Association. All rights reserved.
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1921
![[Antibiotic resistance: A global crisis].](/assets/img/hold.png)
