Discussion

Several models exist for antimicrobial stewardship in LMICs, each with their own merits and demerits. A systematic review of interventions for ASP in low- and middle-income countries in 2021 elaborated upon single and multicomponent interventions. ^{Reference Cuevas, Batura, Putu, Wulandari, Khan and Wiseman11} The most commonly utilized single-component interventions were education, training, guideline formulation, implementation, prescription auditing, and prospective audit with feedback. The predominant multicomponent interventions were combination of education and training followed by audit and feedback. Although education and training were easy to implement, the impact was not sustainable without constant reinforcement or supervision. Auditing of prescriptions showed the general trend of antibiotic use but provided no direct feedback in real time that could modify the behavior of the individual prescribers. In our study, we chose to implement a multipronged intervention approach that included a combination of education, training, guideline formulation, and laboratory augmentation, culminating in a prospective audit with feedback system.

Implementation of and sustaining a successful ASP in a low-resource setting has many barriers and challenges. A general lack of awareness regarding the short- and long-term implications of antimicrobial resistance among various senior administrators and healthcare workers has led to poor acceptance and implementation of an ASP. A lack of emphasis on rational antimicrobial prescribing in the undergraduate and postgraduate curricula is also a major lacuna, though recent efforts have been made to modify this. In the United States, a survey of medical schools revealed that antimicrobial stewardship was taught in only 66% of academic centers. ^{Reference Melber, Teherani and Schwartz12} Surprisingly, even among ID fellows, only half felt comfortable in leading stewardship programs at the completion of their training programs. ^{Reference Nori, Madaline and Munjal13} A written assessment among practicing physicians found a singular lack of knowledge regarding appropriate antibiotic prescribing. ^{Reference Ohl and Luther14} Education and reinforcing optimal antibiotic use by senior and junior practicing physicians are key to improving antibiotic stewardship. Surveys reveal that >70% of prescribers were keen to improve their knowledge of antibiotics, ^{Reference Singh, Charani, Wattal, Arora, Jenkins and Nathwani15} suggesting that periodic training is useful. Very few structured training programs specifically cater to ASPs in India, ¹⁶ although an attempt has been made by the Indian Medical Council to add ASPs to existing curricula. ¹⁶ Training courses using interactive programs with case studies and prescribing methods are effective tools in ASP implementation, and often they are not part of even postdoctoral infectious diseases training programs. ^{Reference Nori, Madaline and Munjal13,Reference Ohl and Luther14} Thus, our customized ASP curriculum, with both online interactive modules and hands-on, case-based training of study physicians, demonstrated a significant reduction in antimicrobial usage in the postintervention phase. Training local physicians and pharmacists overcame the barrier of the absence of an infectious disease specialist and empowered them as ASP champions to lead their team in implementing a successful ASP.

Inadequate laboratory infrastructure and expertise also impair the ability of physicians to avoid empirical use, and to de-escalate or modify antibiotics according to susceptibility patterns. In addition, the nonavailability of laboratory information management systems in health settings can hamper the creation and development of an antibiogram. The Infectious Diseases Society of America emphasizes the critical role played by diagnostic stewardship and outlines 6 important components: a stratified antibiogram, cascade reporting, rapid viral testing for respiratory infections, rapid diagnostic serological tests, and serial monitoring of procalcitonin in ICU patients. ^{Reference Barlam, Cosgrove and Abbo17,Reference Dellit, Owens and McGowan18} However, these components may not be accessible or possible in all settings. A carefully phased adoption of these components could be cost-effective in the long run; hence, healthcare settings should be encouraged and mentored regarding their implementation. We were able to demonstrate this in our study: each center was assisted in developing their own antibiogram annually based on their own cultures using WHO-net with expertise from the main center.

In our study, common infectious syndromes noted in the secondary care in 75% of the cases were lower respiratory (25.2%), genitourinary (18.1%), and intra-abdominal infections (16.1%), followed by skin and soft-tissue infections (13.3%). Community-acquired infections predominated in both during the baseline phase and the postintervention phase (74.8% and 68.8%). The prevalences of MDR organisms in our study were 1.5% for carbapenem-resistant Enterobacteriaceae (CRE) in secondary-care hospitals and 57.4% in established tertiary-care centers, and for extended-spectrum β-lactamases (ESBLs) the prevalences were 9.6% in secondary-care hospitals versus 14.8% in established tertiary-care centers. ^{Reference Rupali, Palanikumar and Shanthamurthy19} Hence, in a secondary-care, low-resource setting, empiric use of high-end antibiotics can be restricted to microbiologically confirmed infectious disease syndromes in the community setting and in nosocomial infections. Both the WHO and the CDC recommend treatment guidelines as a priority for the judicious use of antibiotics, making it a critical component of any ASP program. ^20,21 Our project focused on creating treatment guidelines targeting specific infectious disease syndromes that are treated at these secondary-care hospitals considering their local antibiogram. Empirical antibiotics seemed to be justified in 80% of the cases at 48 hours in the postintervention arm, which was due to the implementation of a facility-based antibiotic policy and study physicians taking the lead in implementing the policy as well as performing a postprescription audit and feedback for specific areas in the healthcare setting.

Antibiotic consumption significantly decreased, with a marked reduction in use observed with cephalosporins, macrolides, and quinolones. However, an increase in β-lactam/β-lactamase inhibitor consumption was observed, possibly due to the higher rates of de-escalation and discontinuation of inappropriate use. ^{Reference Rupali, Palanikumar and Shanthamurthy19} No significant decrease in consumption of reserve antibiotics (carbapenem and colistin) was noted. Thus, cost and access prevented excess use when not indicated, proving that ASP efforts at secondary-care settings need to be directed toward the Access and Watch groups of antibiotics rather than the Reserve group. ^{Reference Huang, Chen and Hu22} Overall, we achieved a significant improvement in optimal antibiotic use after our intervention.

Antibiotic-related adverse events and overall mortality were similar in both groups in our study, but infection-related mortality showed a trend toward favorable outcome in the postintervention group compared to the baseline group (43.8% vs 61%; P = .193), suggesting that optimizing antibiotic therapy does not lead to poor outcomes. A similar study in the United States also showed no difference in in-hospital mortality between preintervention and postintervention arms (11% and 14%; P = .44), suggesting that mortality did not increase with ASPs. ^{Reference Cosgrove, Seo and Bolon23}

Our study has proven that ASP can be successfully implemented with good outcomes in resource-limited, secondary-care hospitals by adopting a hub-and-spoke model. We leveraged freely available laboratory information management systems like WHO-net to create an antibiogram and to develop facility-specific antibiotic guidelines. We also augmented laboratory services through existing external quality control systems, and we trained ASP teams to recognize and treat infections through a blended training course that enabled them to do so with the least disruption to their routine busy clinical patient-care duties.

Thus, we created a sustainable intervention package that involves increasing local capacity building and creating skill sets both in the laboratory and clinical settings. This intervention led to a decrease in antibiotic consumption without any significant increase in mortality or morbidity and a decrease in infection-related mortality, improving the overall quality of care. This ASP model could be replicated with tertiary-care centers acting as nodal and support centers for multiple selected secondary-care centers for the implementation of ASPs.