DTI Drug Target Insights 2022; 16: 78-80 ISSN 1177-3928 | DOI: 10.33393/dti.2022.2532 SHORT COMMUNICATION Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti © 2022 The Authors. This article is published by AboutScience and licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.aboutscience.eu Focus on Antimicrobial Resistance (AMR) Unmet needs for management of drug-resistant infections: low- and middle-income countries’ viewpoint Monica Sharma1, Kamini Walia1, Nitin Bansal2 1Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi - India 2Rajiv Gandhi Cancer Institute and Research Centre, New Delhi - India ABSTRACT Drug-resistant infections are a serious threat globally which demands cost-effective solutions to meet the unmet needs in their diagnosis and treatment. Gram-negative pathogens, drug-resistant tuberculosis, and multidrug- resistant Salmonella typhi have been reported as cause of resistant infections in developing countries. Here, we discuss the priority pathogens and conditions for which feasible solutions adaptable to low-resource settings are required to address the antimicrobial resistance in pathogens. These solutions will be helpful in containing the spread of antimicrobial resistance and better patient outcomes. Keywords: Antibiotic, Antimicrobial resistance, Diagnostics, India, Infection, Low- and middle-income countries Received: November 30, 2022 Accepted: December 26, 2022 Published online: December 31, 2022 Corresponding author: Dr. Monica Sharma Division of Epidemiology and Communicable Diseases Indian Council of Medical Research Ansari Nagar, New Delhi, PIN 110029 - India sharmasankhyan@gmail.com Escherichia coli, Klebsiella pneumoniae, Acinetobacter bau- mannii, Pseudomonas aeruginosa, and Enterobacter spp. have become public health concerns (3,7,8) that are difficult to control due to acquisition of different resistance markers. Streptococcus pneumoniae infections have been associated with high mortality in children aged below 5 years, and in 2015, 50% of all pneumococcal deaths were reported in four countries of Africa and Asia (3,9). In neonates, antimicrobial- resistant infections have been associated with approximately 23% of deaths, with over 55% of AMR prevalence among sepsis-causing pathogens (3,10). Published data from India have reported concerning rates of AMR among pathogens including Enterococcus faecium, Staphylococcus aureus, Enterobacter spp., Salmonella Typhi, etc. (7,11,12). An increase in infections due to carbapenem- resistant K. pneumoniae and A. baumannii has been reported from India and other countries (7,11,13). Hospital-acquired infections (HAIs) are another major concern especially in resource-constrained low-income settings where higher infection rates due to gram-negative pathogens have been reported than in developed countries (11,14). A recent HAI surveillance study from India reported high rates of car- bapenem resistance in Klebsiella spp., Acinetobacter spp., and Pseudomonas spp. (15) and observed reduced suscep- tibility to extended-spectrum cephalosporins. This study also highlights Candida auris as an emerging multidrug-resistant threat in bloodstream infection (BSI) and urinary tract infec- tion (UTI). Therefore, fungal pathogens such as Candida spp. require close monitoring for trends of infections, outbreaks, and susceptibility. Introduction Drug-resistant infections are major public health con- cerns that are associated with high morbidity and mortal- ity in patients, and result in exorbitant health and economic burden (1,2). In 2019, 4.95 million deaths were estimated due to resistant bacterial infections (3). The burden of drug- resistant infections remains high in low-resource health- care settings, especially in low- and middle-income countries (LMICs) including India (3,4,1,5). Rampant misuse of antimi- crobials (in humans and animal husbandry), unregulated over- the-counter availability, poor healthcare facilities and infection control practices, and lack of accurate diagnostics to support treatment decisions are few of the major drivers of antimicro- bial resistance (AMR) in communities and hospitals (5,6). In the past few years, reports on multidrug-resistant infec- tions due to gram-negative bacteria have increased globally (3,4), which represent a critical unmet medical need, for which interventions are required. Gram-negative pathogens https://doi.org/10.33393/dti.2022.2532 https://creativecommons.org/licenses/by-nc/4.0/legalcode mailto:sharmasankhyan@gmail.com Sharma et al Drug Target Insights 2022; 16: 79 © 2022 The Authors. Published by AboutScience - www.aboutscience.eu Enteric fever and especially typhoidal Salmonella endemic to South and Southeast Asia and sub-Saharan Africa require continuous monitoring where changing resistance trends have been reported due to fluoroquinolones and cephalo- sporins (16, 17). Drug-resistant bacteria such as third-gener- ation cephalosporin-resistant E. coli, carbapenem-resistant A. baumannii, fluoroquinolone-resistant E. coli, carbapenem- resistant K. pneumoniae, and third-generation cephalosporin- resistant K. pneumoniae represent serious challenges in patient management, especially in critically ill patient with comorbidities (3,4,7,11,14). Treating these drug-resistant infections exerts high eco- nomic burden on healthcare and patients. Therefore, patho- gens exhibiting resistance to antimicrobials for which there are limited treatment options represent a critical unmet medical need for diagnostics and therapeutic interventions. However, the priority pathogens or conditions as well as healthcare settings need to be prioritized as per local health- care systems and burden of resistant infections. Managing and containing drug-resistant infections in low-resource healthcare settings requires a multipronged approach consisting of the following steps: • Effective surveillance systems are required to provide cor- rect estimates of drug-resistant infections at national and regional levels. • Strengthening of existing healthcare facilities by improv- ing availability of laboratory services, diagnostics, and trained health personnel and, in parallel, enabling new health facilities at peripheral settings. • Supporting research and innovations to develop rapid diagnostics and new treatment options such as drug mol- ecules, targeted therapies, vaccines, and repurposing old antibiotics. • Effective socio-behavioral tools and systems to create awareness among prescribers and general public to enable judicious utilization of existing antimicrobials. Addressing the diagnostic gap Improving diagnosis helps in generating evidence-based prescriptions to reduce empirical use of antimicrobials. There is a need for quality diagnostics with fast turnaround time for pathogen identification and susceptibility testing to address the problem of AMR (18). In LMICs, accurate and affordable diagnostic tests to differentiate viral and bacte- rial infections are a priority where resources and capacities are limited, and antibiotics are routinely misused for viral infections. Diagnostics for diagnosis of sepsis and typhoid fever are urgently required to contain spread of resistant infections and reduce morbidity and mortality, especially in neonatal sepsis. Typhoid and enteric fever are major con- cerns for LMICs with poor sanitation practices. Rapid diag- nostic tests for UTIs, fever, and respiratory infections (lower and upper tract) are another unmet need, where empiri- cal treatments result in heavy misuse of antibiotics. Global burden study in 2019 has also reported the dominance of lower respiratory infections, BSIs, and intra-abdominal infections as major infections attributable to AMR (3). Over the last decade, several molecular diagnostics have been developed for pathogen identification and detection of genes(s) or gene mutations for presence or absence of resis- tance to antimicrobials (19). Despite the expedited diagno- sis, these tests are expensive and need infrastructure and trained resources to provide results, thus limiting their use in resource-limiting settings. In LMICs, indigenously devel- oped low-cost diagnostics have potential to fill this diagnostic gap and help in containing AMR (18). However, indigenous efforts in developing new diagnostics for AMR need to be supported and guided by delineating the local priorities and facilitators as per country’s disease burden and healthcare requirements. Need of new and reformulated antimicrobials and alternatives The reliance on new drugs or combinations to fight AMR will only provide momentary relief as pathogens will evolve mechanisms to acquire resistance to antimicrobials. Analyzing and reducing antibiotic consumptions across human and ani- mal husbandry sectors, research on intervention strategies and resistance rates can help in tailoring strategies and infec- tion-specific treatment guidelines. The existing antibiotics also need to be utilized for developing new formulations to improve patient outcomes. There is a need to determine top combinations of antibiotics for BSI and study the efficacy of these combinations, preferably with contemporary isolates to provide effective combinations for the treatment of resis- tant infections. Pharmacokinetic/pharmacodynamic (PK/PD) and safety data on antibiotics and their combinations in dif- ferent age groups are essential to effectively treat resistant infections. It is also imperative to understand that the need for new antibiotics for LMIC is different from those of high-income countries as in countries like India, for example, predomi- nant carbapenemase present in gram-negative isolates are metallo-β-lactamases (NDM, VIM) and not KPC (7). This also holds true for P. aeruginosa as the newer drugs for gram- negatives (ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) do not have activity against metallo-β-lactamases. This becomes an important aspect for drug developers for consideration with regard to LMICs. Low-cost solutions are therefore urgently needed to preserve the efficacy of available antibiotics/antibiotic alternatives such as virulence blockers, immune modulators, vaccines, etc. Research efforts need to be prioritized for new treat- ment strategies such as re-appropriation of old drugs, deliv- ery strategies and for resistance mechanisms such as efflux pump inhibitors, and bacteriophage treatment. Strengthening surveillance of drug-resistant infections Tracking resistance trends is important to reduce the burden of infections in hospitals and community settings. Data generated through surveillance can be used in defining guidance for treatment in common syndromes and diagnosis of infections. It is important to implement infection preven- tion and control, antimicrobial stewardship practices, and Management of resistant infections80 © 2022 The Authors. Drug Target Insights - ISSN 1177-3928 - www.aboutscience.eu/dti immunization program and reduce over- and misuse of anti- microbials. National estimates of resistant infections, etiology of infections, type of infections, and local resistance rates and patterns can be utilized to set research priorities regarding challenges and opportunities to tackle resistant pathogens in different healthcare and community settings. 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