Antibiotic use and resistance : patterns, perceptions, policy and the price to pay

Background: Antibiotic resistance is a major health challenge especially in low and middle income countries such as India. Inappropriate antibiotic use is one important factor contributing to resistance. Strategies to improve use would help contain resistance. In order to develop strategies that are feasible and appropriate, knowledge is needed about patterns and perceptions of antibiotic use, the consequences of resistance and impact of policy guidelines. Current knowledge and evidence is limited in India. Aim: To improve knowledge on the patterns and perceptions of antibiotic use in the community, the consequences of resistance in individual patients, and the impact of policy guidelines on hospital antibiotic use, so as to identify potential interventional targets, generate key messages and subsequently develop appropriate strategies towards improving use and containing resistance. The specific objectives were: 1. To determine patterns of antibiotic use through a surveillance system in the community and challenges faced while developing the system. (I) 2. To ascertain the perceptions of stakeholders in antibiotic use and resistance and highlight the challenges to changing practice. (II) 3. To assess the impact of antibiotic resistance on cost burden and health consequences in patients with suspected sepsis. (III) 4. To determine patterns of inpatient antibiotic use over a decade and evaluate the impact of policy guidelines and modes of dissemination on antibiotic use. (IV) Methods: The first two studies (Paper I & II) for this thesis were done in urban and rural areas of Vellore district, south India and the two other studies (Paper III & IV) at Christian Medical College, Vellore (CMC), a not for profit, university teaching hospital with 2140 beds. Surveillance of antibiotic use patterns (prescriptions and dispensations) in thirty community healthcare facilities for 2 years was conducted with a repeated cross-sectional design (I). A qualitative study with eight focus group discussions among doctors, pharmacists and public explored perceptions about resistance, antibiotic use practices, factors driving use, and strategies for appropriate use (II). A one year observational study on inpatients with a preliminary diagnosis of suspected sepsis and a positive blood culture report analysed costs and health consequences in two groups, ‘resistant’ and ‘susceptible’ based on susceptibility of causative bacteria to the empiric antibiotic given (III). A time series segmented regression analysis of antibiotic use across a decade revealed the patterns of use over time segments and the impact of differing modes of policy guideline development and implementation (IV). Findings: Surveillance in community healthcare facilities (I) revealed that among 52,788 patients, 40.9% were prescribed or dispensed antibiotics (antibiotic encounters). There were significant differences among facilities types and areas. Fluoroquinolones and penicillins were widely used, co-trimoxazole more in rural hospitals and cephalosporins in urban private hospitals. 41.1% of antibiotics were for respiratory infections. Focus group discussions (II) revealed that the public had limited awareness of infection, antibiotics and resistance and wanted quick relief through antibiotics. Doctors prescribed antibiotics for perceived patient expectations and quick recovery. Business concerns promoted antibiotic sales by pharmacists. Improving public awareness, provider communication, diagnostic support, and strict regulatory implementation were suggested strategies. Among 220 patients admitted into the hospital with suspected sepsis (III), the median difference between ‘resistant’ and ‘susceptible’ groups in overall costs, antibiotic costs and pharmacy costs was Rs. 41,993 (p = 0.001), 8,315 (p < 0.001) and 21,492 (p < 0.001) respectively. Length of stay, intensive care admissions, complications and mortality were significantly higher in ‘resistant’ group by 3 days (p = 0.027), 23% (p < 0.001), 19% (p = 0.006) and 10% (p = 0.011). The overall antibiotic use in the hospital (IV), expressed in DDD per 100 bed days, increased monthly during Segments 1 (0.95), 2 (0.21) and 3 (0.31), stabilized in Segment 4 (0.05) and declined in Segment 5 (-0.37). Pairwise segmented regression adjusted for seasonality showed a drop in antibiotic use of 0.401 (SE=0.089; p < 0.001) for Segment 5 (guidelines booklet and online intranet guidelines) compared to Segment 4 (guidelines booklet alone). Conclusion: The level of antibiotic use is significant in the community, especially for respiratory infections and fluoroquinolone use. Patterns of antibiotic use varied among healthcare facilities and stakeholders. Knowledge and understanding of resistance was limited. Patient demand and competitive pressures were some of the main challenges expressed in changing practice. Antibiotic resistance had significant impact on cost and health consequences in patients. Containment of rising inpatient antibiotic use was possible with guideline dissemination through intranet computer network. LIST OF PUBLICATIO S I. Chandy SJ, Thomas K, Mathai E, Antonisamy B, Holloway KA, Stalsby Lundborg C. Patterns of antibiotic use in the community and challenges of antibiotic surveillance in a lower-middle-income country setting: a repeated cross-sectional study in Vellore, south India. J Antimicrob Chemother. 2013 Jan;68(1):229-36. PMID: 22945913 II. Chandy SJ, Mathai E, Thomas K, Faruqui AR, Holloway K, Stalsby Lundborg C. Antibiotic Use and Resistance: perceptions and ethical challenges among doctors, pharmacists and the public in Vellore, South India. Indian J Medical Ethics. 2013 Jan-Mar;10(1):20-27. PMID: 23439193 III. Chandy SJ, Naik GS, Balaji V, Jeyaseelan V, Thomas K, Stalsby Lundborg C. High Cost Burden and Health Consequences of Antibiotic Resistance – The Price to Pay. Resubmitted after revision. IV. Chandy SJ, Naik GS, Charles R, Jeyaseelan V, Naumova EN, Thomas K, Stalsby Lundborg C. The Impact of Policy Guidelines on Hospital Antibiotic Use over a Decade: A Segmented Time Series Analysis. PLoS One. 2014 Mar 19;9(3):e92206. doi:10.1371/journal.pone. 0092206. PMID:24647339 These papers will be referred to in the text by their Roman numerals (I-IV). Published papers were reproduced with permission from the publisher. ABBREVIATIO S AIDS – Acquired Immunodeficiency Syndrome AMR – Antimicrobial Resistance ASHA – Accredited Social Health Activist ASPIC – Antibiotic Stewardship Prevention of Infection and Control AYUSH – Ayurveda, Unani, Siddha, Homeopathy BPL – Below Poverty Line CDC – Centers for Disease Control and Prevention CDSCO Central Drugs Standard Control Organization CHC – Community Health Centre CI – Confidence Interval DDD – Defined Daily Dose DTC – Drugs and Therapeutics Committee ESBL – Extended Spectrum Beta-Lactamases EU – European Union FGD – Focus Group Discussion GDP – Gross Domestic Product GNB – Gram Negative Bacteria GP – General Practitioner GPB – Gram Positive Bacteria HAI – Hospital Acquired Infections HIC – High Income Countries HIS – Hospital Information Systems HICC – Hospital Infection Control Committee HIV – Human Immunodeficiency Virus HPLC – High Performance Liquid Chromatography HSEP – Higher Socioeconomic Public ICU – Intensive Care Unit ISM – Indian Systems of Medicine IT – Information Technology LMIC – Low and Middle Income Countries LSEP – Lower Socioeconomic Public MDR – Multi-Drug Resistance MRSA – Methicillin Resistant Staphylococcus aureus NDM-1 New Delhi Metallo-beta-lactamase-1 NLEM – National List of Essential Medicines NFGNB – Non Fermenting Gram Negative Bacteria NGO – Non Governmental Organization NRHM – National Rural Health Mission OOP – Out Of Pocket OPD – Outpatient Department OTC – Over The Counter PHC – Primary Health Centre POC – Point Of Care RDT – Rapid Diagnostic Testing RMP – Registered Medical Practitioner SC – Sub-Centre STG – Standard Treatment Guidelines USD – United States Dollar