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| ORIGINAL ARTICLE |
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| Year : 2020 | Volume
: 11
| Issue : 1 | Page : 5-9 |
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Implementation of antimicrobial stewardship activities in India
Arzoo Sahni1, Arti Bahl2, Rashi Martolia1, Sudhir Kumar Jain2, Sujeet Kumar Singh3
1 Department of Epidemiology, National Centre for Disease Control, Ministry of Health and Family Welfare, Delhi, India
2 Division of Epidemiology, National Centre for Disease Control, Ministry of Health and Family Welfare, Delhi, India
3 National Centre for Disease Control, Ministry of Health and Family Welfare, Delhi, India
| Date of Submission | 06-Sep-2019 |
| Date of Decision | 25-Nov-2019 |
| Date of Acceptance | 23-Dec-2019 |
| Date of Web Publication | 12-Feb-2020 |
Correspondence Address:
Dr. Arti Bahl
Division of Epidemiology, National Centre for Disease Control, 22, Shamnath Marg, Civil Lines, Delhi -110 054
India
 Source of Support: None, Conflict of Interest: None  | 5 |
DOI: 10.4103/INJMS.INJMS_118_19
Introduction: The ease of availability of antimicrobials and their excessive use is a growing issue which has significantly contributed to antimicrobial resistance (AMR). This is a matter of public health concern as the burden of AMR is far outpacing the research and development work done to develop new antimicrobials. India, being one of the top consumers of antimicrobials, now faces this threat which can only be curtailed through the implementation of antimicrobial stewardship program (AMSP). To address this issue, this systematic review attempts to study the implementation activities of AMSP in the country by the means of literature review. Methods: A comprehensive research using web-based search engines was performed employing a combination of search string: AMSP, ASP, implementation, impact, antibiotic stewardship, antimicrobial surveillance, infection control, and resistance control. The search yielded thirty papers between the time period of 2008 and 2019. 17 papers fulfilling the inclusion-exclusion criteria were taken up for review, employing PRISMA framework. Results: Results from different studies conducted on implementation of AMSP and its components were consolidated and analyzed to track the extent of AMSP activities. Moreover, by studying AMSP practices, gaps in implementation activities were identified by highlighting the AMSP components that were not fully utilized in the country. Conclusion: The results show that implementation of AMSP in India is still in its nascent stage as all the stewardship components are yet to be fully applied in the country. There seems to be a lot of scope in improving the implementation activities by building and strengthening of components such as use of information technology in monitoring and surveillance, use of antibiotic cycling and sensitizing staff, and broadening the role of different staff members to develop an effective program in the nation which meets the goals of National Action Plan-AMR.
Keywords: Antimicrobial resistance, antimicrobial stewardship, infection control
How to cite this article:
Sahni A, Bahl A, Martolia R, Jain SK, Singh SK. Implementation of antimicrobial stewardship activities in India. Indian J Med Spec 2020;11:5-9 |
How to cite this URL:
Sahni A, Bahl A, Martolia R, Jain SK, Singh SK. Implementation of antimicrobial stewardship activities in India. Indian J Med Spec [serial online] 2020 [cited 2023 Jun 9];11:5-9. Available from: http://www.ijms.in/text.asp?2020/11/1/5/278085 |
| Introduction | |  |
Antimicrobial resistance (AMR) is a threatening public health phenomenon which is presently among the biggest burden on the health-care system, considering it will render the old medicines ineffective and the new ones unaffordable.[1],[2],[3] India is the leading antibiotic consumer of world for humans (with 12.9 × 109 units consumption every year) and animals (among the top five antibiotic consumers).[4],[5]
Antimicrobials stewardship programs (AMSPs) are being initiated to optimize the use of antimicrobials and improve patient outcomes.[6] AMSP is defined as “the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance.”[7]
In 2018, the Indian Council of Medical Research (ICMR) formulated the AMSP guidelines consisting of the main components application which will reduce the effects of AMR.[8] This review attempts to address the issue of AMR by highlighting the need for AMSP. Through this review, the implementation of various AMSP strategies in India will be assessed along with the present shortcomings in the application of AMSP in India.
Objectives
Through the medium of this review, three objectives were worked upon. These objectives were designed to identify and illustrate the need and means to promote AMSP to control the growing surge of AMR in India. The objectives addressed are as follows:
- To highlight the need of AMSPs
- To explore the implementation of AMSPs in India
- To identify the possibly missing components of AMSP implementation in India.
| Methodology | | |
To address the objectives of this review, means of literature review was used to first identify appropriate research papers which accessed the implementation of AMSP or at least one of its components in health-care facilities in India. Literature review was used to address all the objectives as it led to comprehensive findings in the desired field area with substantial emphasis on AMSP. It also led to identification of the recent work done in a more systematic manner.[9]
Comprehensive research using web-based search engines such as Google Scholar and Ovid was conducted using a combination of search string: AMSP, ASP, implementation, impact, antibiotic stewardship, antimicrobial surveillance, infection control, and resistance control. The preliminary search on PubMed was conducted using MeSH terms such as “antimicrobial drug resistance AND antimicrobial stewardship in India AND antibiotic stewardship. The search yielded thirty papers between the time period of 2008 and 2019 which were shortlisted on the basis of abstract of these studies. To further filter the studies, PICO inclusion and exclusion criteria were set up as demonstrated in [Table 1].
Based on the inclusion–exclusion criteria, 17 papers were taken up for this review. [Figure 1] outlines the flowchart for selection of these 17 studies based on the PRISMA statement guideline.[10]
Data from these papers were extracted on the basis of characteristics of the area of study, type of intervention, the main findings of the articles, and the general characteristics of study such as publication year, study design, and author's name. For further supplementation of information, the following websites were used for gray literature: The World Health Organization, Centre for Disease Control and Prevention and ICMR.
| Results | | |
The findings of this review indicate that implementation of AMSP in India is still in the nascent stage. Out of the 17 studies included, only 35% (6 studies) were based on the entire AMSP implementation, whereas other studies included the implementation of at least one of the AMSP components as depicted in [Figure 2]. | Figure 2: Distribution of reviewed studies based on the components of antimicrobial stewardship program implemented
Click here to view |
The review yielded that AMSP (35.2%) has not been fully implemented in the country. Infection control (23.5%), application of clinical guidelines (17.6%), and prospective audit (11.%) are some of the components of AMSP that are more frequently being studied and applied across health-care settings in the country.[11],[12],[13],[14],[15],[16],[17],[18],[19] No major work was identified on components such as antimicrobial cycling, doze optimization, use of microbiological labs for surveillance and monitoring due to which these components were not included in this review. Thus, there is a need for the implementation of these components in the Indian context.
The results from 17 studies depicted some common trends about the AMSP implementation pertaining to the Indian scenario. First, there is fragmented application of AMSP in India which can be resolved by developing and improving infrastructure and further strengthening the surveillance and monitoring process.[20],[21] Moreover, better results were reported to have been achieved when the stewardship activities were taken under the guidance of an infectious disease (ID) physician or microbiologist. Presence of specialist staff also contributes in education and training of other staff members and led to positive attitude of staff in taking up AMSP strategies.[18] Lastly, implementation of infection control as an intervention was the most adopted component for stewardship activities which attributed to highly positive results.[11],[12],[13],[14]
| Implementation of Antimicrobial Stewardship Programs in Health Facilities | | |
All the six studies which were based on the implementation of AMSP in India showed that proper implementation of AMSP guidelines in health-care facilities was key to reduction in the usage of antibiotics/antimicrobials and also yielded economic benefits.[21],[22],[23],[24],[25],[26] In 2019, Baubie et al. conducted a study on AMSP implementation in a tertiary care hospital located in Kerala by interviewing 45 hospital faculty members to understand the key facilitators that assisted in the uptake of stewardship activities as well as the challenges the hospital faced in the implementation of stewardship program.[23] Studies conducted by Singh et al. (conducted a quasi-experimental study in a tertiary care hospital in Kerala in 2019), Afzal et al. (conducted a case study in a tertiary care hospital situated in Hyderabad in 2017), and Walia and Ohri (conducted a survey in 2015) revealed that the initial compliance to AMSP was at least 40%–50% in all the hospitals, which gradually increased in the postinterventional period.[20],[21],[24] A study conducted by Jaggi et al. in Gurugram, Haryana, in 2012 depicted that AMSP was a major contributor in restricting the growth of extended spectrum beta-lactamase enzymes which break down the active ingredients in antimicrobials and render them ineffective, ultimately leading to reductions in costs.[25]
| Infection Control | | |
In case of infection control, most of the studies were conducted in tertiary care hospital where application of infection control guidelines played a crucial role in curtailing costs. The hospital staff played a pivotal role in implementation of these guidelines and had a positive attitude toward interventions and information and education and communication campaigns directed toward infection control.[11],[12],[13],[14] These strategies led to positive outcomes in three out of four studies where significant reductions were seen in infection control in the postinterventional period. Results from a study conducted in 2011 by Anchalia and D'Ambruoso in Gujarat depicted a significant reduction in the surgical infection control from 30% in the preinterventional phase to 4.4% in the postinterventional phase.[11] Results from a study conducted by Agarwal et al. in Nagpur in 2008 to determine the impact of infection control guidelines in curbing the expenditure associated with disinfectants revealed that infection control guidelines were successful in bringing down the costs from 6.2% to 1.95%.[14] In case of a study by Saramma et al. (conducted a study in 2011 in Kerala), a slight difference in infection control was observed when alcohol-based hand rub was taken as an intervention to reduce infection.[12]
| Clinical Guidelines | | |
Analysis of studies based on clinical guidelines as intervention in health-care facilities provided contradicting results. While two of the three studies showed that application of clinical guidelines alone did not decrease the dependence on antibiotic/antimicrobial use, application of multiple AMSP components and strategies was required to attain positive outcomes; only one study proved that development and application of clinical guidelines reduced the dependency on antimicrobials and led to its judicious use.[15],[16],[17] Wattal et al. conducted two studies on clinical guidelines as a measure to implement stewardship activities in a tertiary care hospital in Delhi between 2015 and 2017. In both these studies, the results were not at par; the study conducted in 2017 revealed that clinical guidelines did not have an impact on the prescribing practices of the doctors. Low prescribers continued to prescribe antibiotics at a low rate, and high prescribers continued to prescribe at a high rate.[15] The study conducted in 2015 also reflected similar results where compliance to clinical guidelines resulted in only 1.88% decrease in antibiotic consumption.[16] On the other hand, Jimmy et al. conducted a study in Manipal, Karnataka, in 2008, which showed that implementation of guidelines in antibiotic use caused compliance of 93% for indication, 94% for dose, 98% frequency of administration, 90% for duration of therapy, and 86% for conversion of IV to oral therapy in postimplementation phase.[17]
| Prospective Audit | | |
Use of prospective audit as an AMSP component was seen in only two studies. Both the studies revealed that results of the audits conducted under the supervision of stewardship specialist team members such as ID specialist and microbiologist showed significant reductions in the dependence of antimicrobials in the form of decrease in days on antimicrobial therapy (Days on Therapy [DOT]) and choice of drug and dose.[18],[19] Results from a study conducted by Rupali et al. in a tertiary care hospital in Vellore, Tamil Nadu, in 2018 depicted that antimicrobial use decreased from 831.5 during baseline to 717 DOT (days on antimicrobial therapy per 1000 patient-days during intervention period).[18] On similar lines, Ravi et al. reviewed 121 prescriptions at a tertiary care center located in Kolkata in 2017, in which the choice of drug was deemed appropriate in 97% of prescriptions, correct dose in 96% of prescriptions, appropriate duration in 97% of cases, the route of suitable administration in 98% of prescriptions, and the combination of drugs appropriate for 95% of patients.[19]
| Education and Training | | |
Only one study was found for components such as education and training and four dimensions (4D: right drug, right dose, dosing interval, and right duration). In the case of education and training, there is a need for more endorsement of this component as education and training activities in AMSP were found to be fragmented with conditions being worse off in public health-care facilities. In 2019, surveys and interviews were conducted by Singh et al. in Kerala; results from the study revealed that 69% (27/39) of the respondents had received education and training in relation to AMSP during undergraduate or postgraduate education, whereas 88% (15/17) had not received any education at induction or training. Thus, there seems to be more scope in the utilization of education and training as a measure to strengthen stewardship activities.[20]
Four dimensions: Right drug, right dose, dosing interval, and right duration
Finally, implementation of 4Ds (right drug, right dose, dosing interval, and right duration) in a tertiary care hospital in Kerala was studied by Singh et al. 2017. A total of 868 patients were targeted, of which compliance with 4Ds policies was 50%. Nearly 51% of prescriptions required adjustment for drug selection, route, dose, or duration. This caused decrease in costs pertaining to antibiotics as adherence to proper drug selection route, dose, and duration increased.[27]
| Discussion | | |
In the Indian scenario, work on stewardship activities accelerated with the formation of National Action Plan (NAP)-AMR and the recent formulation of ICMR guidelines for stewardship activities.[8] Over the years, several initiatives in the form of formation of NAP on AMR, signing of Chennai declaration, formation of India Indian Clinical Epidemiology Network, and Indian Initiative for Management of Antibiotic Resistance in collaboration with WHO have been launched to generate some quality data on AMR.[28] Despite these developments, there is an urgent need to develop adequate infrastructure for proper disease surveillance and monitoring and to initiate more research and development on AMR at the grassroots level. The results of this review clearly indicate that implementation of AMSP activities in India needs further strengthening. Presently, very few research studies are being conducted to study the use of antimicrobials and evaluate the evidence of the effectiveness of the implementation of stewardship activities in India.[29],[30]
The results from this review also indicate that there is a need to implement all the components of AMSP. Components such as antimicrobial cycling, computerized data collection for surveillance, and appropriate use of microbiology labs are required to further consolidate the implementation of AMSP. Use of components such as information technology in stewardship activities is essential as it will assist in harnessing microbiology and antimicrobial use data for the purpose of detecting instances needing intervention and to assist in measuring the effect of the program.[31] Hospitals in the USA have adopted computer surveillance and decision support systems related to antimicrobial prescribing. The developed program is linked to electronic records and makes recommendations for antimicrobial regimen and assists with dosage and interval along with potential drug interactions based on patient's hepatic and renal function. This system also helps in generating recommendations and warnings regarding allergies in specific patients. Adaptation of such computer-based system are not only cost-effective as it helps in the reduction of hospital stay lengths but also increase the adherence to practice guidelines, which lead to timely and appropriate use of antimicrobials which increased to 99.1% from 40% in the case of hospitals in the USA.[32]
To improve the overall uptake of AMSP in India, there is a need to actively involve, sensitize, and support the entire health-care facility staff in curbing AMR by clearly indicating the roles and responsibilities of each of the staff members. In this aspect, nurses have a crucial role to play.[33] AMSP implementation activities highly complement the workload of nurses. For example, during admitting the patients, nurses can perform initial triage and take necessary steps to identify medications, allergy reactions, and history in a documented form. Moreover, nurses monitoring patients 24 × 7 can contribute in restraining AMR by ensuring that patients are given appropriate dose of prescribed medications in a timely manner and be gradually moved from intravenous to oral therapy.[33]
The methodologies used for this article have certain set of strengths and limitations. The strength of this article is the comprehensive search strategy used to provide an overview of the present studies available regarding the implementation of AMSP in India. The analysis in this review acts as a mechanism to understand the shortcomings of the ways in which AMSP activities are tackled in India.
However, this article is constrained by a few limitations as well. The synthesis of studies presented in this article is only one interpretation of the set of studies. Different interpretations for the same set of studies would be possible and could be equally valid. To remove this limitation, the synthesis of result was done by different investigators independently to ensure that the result presented was the most appropriate interpretation. A major limitation of this review is caused by the limited research of overall work done to study the implementation of AMSP in India, especially after the formation of NAP-AMR. This article is just an overview of the extent to which AMSP activities are being conducted in the country. Therefore, there is an urgent need to have research studies conducted on the progress made on AMSP activities and to check the progress made to achieve the targets enlisted in NAP-AMR.
| Conclusion | | |
AMR is a global threat which is accelerating in India; to tackle this issue, it is paramount that there is an uptake of stewardship activities in the country. The results of this review clearly demonstrate the urgent need for the Indian government and policymakers to undertake measures to ensure that AMR in India decreases.[5] The present AMSP activities in India indicate that there is a lot of scope of improvement as the ICMR guidelines are not uniformly implemented throughout the nation. Active participation with proper education and training of all the staff members including nurses, microbiologists, and ID physicians can further be strengthened by stronger implementation of prescription guidelines with proper annual surveillance and monitoring of the system.[18],[33] Moreover, to accelerate the stewardship program, it is essential that all the components of AMSP are implemented.
Lastly, to ensure the fulfillment of NAP-AMR targets, there is a dire need to take up more research and development activities on a regular basis to not only understand the effectiveness of the program, but also to identify challenges and barriers and to find strategies to address them.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Centers for Disease Control and Prevention. What Exactly is Antibiotic Resistance? Centers for Disease Control and Prevention; 2018. Available from: https://www.cdc.gov/drugresistance/about.html. [Last accessed on 2019 May 26].  |
| 2. | |
| 3. | MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev 2005;18:638-56. |
| 4. | Van Boeckel TP, Gandra S, Ashok A, Caudron Q, Grenfell BT, Levin SA, et al. Global antibiotic consumption 2000 to 2010: An analysis of national pharmaceutical sales data. Lancet Infect Dis 2014;14:742-50. |
| 5. | Ayukekbong JA, Ntemgwa M, Atabe AN. The threat of antimicrobial resistance in developing countries: Causes and control strategies. Antimicrob Resist Infect Control 2017;6:47. |
| 6. | Gandra S, Joshi J, Trett A, Lamkang A, Laxminarayan R. Scoping Report on Antimicrobial Resistance in India. Washington DC: Center for Disease Dynamics, Economics & Policy; 2017. |
| 7. | Gerding DN. The search for good antimicrobial stewardship. Jt Comm J Qual Improv 2001;27:403-4. |
| 8. | |
| 9. | |
| 10. | Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009;6:e1000097. |
| 11. | Anchalia MM, D'Ambruoso L. Seeking solutions: Scaling-up audit as a quality improvement tool for infection control in Gujarat, India. Int J Qual Health Care 2011;23:464-70. |
| 12. | Saramma PP, Krishnakumar K, Sarma PS. Alcohol-based hand rub and surgical site infection after elective neurosurgery: An intervention. Neurol India 2011;59:12-7. [ PUBMED] [Full text] |
| 13. | Joshi SC, Diwan V, Tamhankar AJ, Joshi R, Shah H, Sharma M, et al. Qualitative study on perceptions of hand hygiene among hospital staff in a rural teaching hospital in India. J Hosp Infect 2012;80:340-4. |
| 14. | Agarwal V, Gharpure K, Thawani V, Makhija S, Thakur A, Powar R. Economic impact of interventional study on rational use of antiseptics and disinfectants in super speciality hospital of Nagpur. Indian J Pharmacol 2008;40:78-83. [ PUBMED] [Full text] |
| 15. | Wattal C, Khanna S, Goel N, Oberoi JK, Rao BK. Antimicrobial prescribing patterns of surgical speciality in a tertiary care hospital in India: Role of persuasive intervention for changing antibiotic prescription behaviour. Indian J Med Microbiol 2017;35:369-75. [ PUBMED] [Full text] |
| 16. | Wattal C, Goel N, Khanna S, Byotra SP, Laxminarayan R, Easton A. Impact of informational feedback to clinicians on antibiotic-prescribing rates in a tertiary care hospital in Delhi. Indian J Med Microbiol 2015;33:255-9. [ PUBMED] [Full text] |
| 17. | Jimmy B, Jose J, Parthasarthi G. Drug utilization evaluation of third generation cephalosporins in a tertiary care hospital in South India. Indian J Pharma Educ Res 2008;42:295-300. |
| 18. | Rupali P, Palanikumar P, Shanthamurthy D, Peter JV, Kandasamy S, Zacchaeus NG, et al. Impact of an antimicrobial stewardship intervention in India: Evaluation of post-prescription review and feedback as a method of promoting optimal antimicrobial use in the intensive care units of a tertiary-care hospital. Infect Control Hosp Epidemiol 2019;40:512-9. |
| 19. | Ravi N, Laha A, Chatterjee S. Exploring the prescribing behaviours and he mind of antibiotic prescribers in critical for a successful antibiotic stewardship programme: Results of a survey from Eastern India. Indian J Med Microbiol 2017;35:299-301. [ PUBMED] [Full text] |
| 20. | Singh S, Charani E, Wattal C, Arora A, Jenkins A, Nathwani D. The state of education and training for antimicrobial stewardship programs in Indian hospitals-a qualitative and quantitative assessment. Antibiotics (Basel) 2019;8. pii: E11. |
| 21. | Walia K, Ohri V. Antibiotic stewardship activities in India: Current scenario. Int J Infect Dis 2014;21:214. |
| 22. | Harrison TS, Thompson NW. Multiple endocrine adenomatosis-I and II. Curr Probl Surg 1975;1:51. |
| 23. | Baubie K, Shaughnessy C, Kostiuk L, Varsha Joseph M, Safdar N, Singh SK, et al. Evaluating antibiotic stewardship in a tertiary care hospital in Kerala, India: A qualitative interview study. BMJ Open 2019;9:e026193. |
| 24. | Afzal M, Tenali J, Burri RR. Antibiotic stewardship program in a tertiary private hospital in India – A case study. Infect Dis Health 2017;22:S3. |
| 25. | Jaggi N, Sissodia P, Sharma L. Control of multidrug resistant bacteria in a tertiary care hospital in India. Antimicrob Resist Infect Control 2012;1:23. |
| 26. | Walia K, Ohri VC, Mathai D; Antimicrobial Stewardship Programme of ICMR. Antimicrobial stewardship programme (AMSP) practices in India. Indian J Med Res 2015;142:130-8. [ PUBMED] [Full text] |
| 27. | Singh S, Menon V, Kumar A, Nampoothiri V, Mohamed Z, Sudhir S, et al. Implementation of antibiotic stewardship: A South Indian experience. Open Forum Infect Dis 2017;4 Suppl 1:S267-8. |
| 28. | Kumar SG, Adithan C, Harish BN, Sujatha S, Roy G, Malini A. Antimicrobial resistance in India: A review. J Nat Sci Biol Med 2013;4:286-91. |
| 29. | |
| 30. | Reddaiah VP, Kapoor SK. Effectiveness of ARI control strategy on underfive mortality. Indian J Pediatr 1991;58:123-30. |
| 31. | Doron S, Davidson LE. Antimicrobial stewardship. Mayo Clin Proc 2011;86:1113-23. |
| 32. | Pestotnik SL, Classen DC, Evans RS, Burke JP. Implementing antibiotic practice guidelines through computer-assisted decision support: Clinical and financial outcomes. Ann Intern Med 1996;124:884-90. |
| 33. | Kumar A, Sahu M, Sahoo PR, Wig N. Under-explored Dimensions of Anti-microbial Stewardship in India. J Assoc Physicians India 2018;66:69-71. |
[Figure 1], [Figure 2]
[Table 1]
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