29 November 2024

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Antimicrobial resistance (AMR) is one of the most significant global health threats of the 21st century. As an often-overlooked silent pandemic, it poses a huge challenge to global health security, economic development and prosperity. Addressing AMR is critical in the pursuit of universal health coverage, and attainment of the Sustainable Development Goals (SDGs) by countries.1,2 Due to the increased use of antibiotics and the subsequent rising levels of resistance, the effectiveness of these drugs is under threat.3 However, the discovery and manufacturing pipeline faces numerous challenges, from scientific and economic barriers to regulatory complexities.  

According to the Global burden of bacterial antimicrobial resistance 1990–2021 report, it was estimated that 4.71 million (95% UI 4.23–5.19) deaths were associated with bacterial AMR, including 1.14 million (1.00–1.28) deaths attributable to bacterial AMR, putting the global burden of AMR in sharper focus.4 From these estimates, the highest burdens attributable to, and associated with, AMR occurred in sub-Saharan Africa and south Asia; The AMR burden is forecast to be highest in the south, east and southeastern regions of Asia, Oceania, and sub-Saharan Africa, with a cumulative AMR attributable death burden from 2025 to 2050 at 11.8 million (95% UI 9.43–14.4), 8.96 million (7.45–10.4), and 6.63 million (5.00–8.66), respectively. This makes low- and middle-income countries (LMICs) particularly vulnerable to the impacts of AMR due to higher infectious disease burden, poor sanitation, limited access to clean water and limited healthcare infrastructure. In addition, the misuse and overuse of antibiotics are prevalent in situations lacking adequate diagnostic capacity, further escalating AMR. A perfect example of the evolution of AMR is in Vibrio cholerae, a cause of endemic cholera disease in the sub-Saharan Africa region. Before 2004, all the V. cholerae isolates were susceptible to all commonly available antimicrobials but from 2005 85% of strains were multidrug-resistant (MDR) and carried a large plasmid that bears the extended spectrum beta-lactamase (ESBL)-producing CTX-M-15 gene acquired from other Enterobacterales.3  

The role of new treatments 

The development of new and affordable antibiotics is critical for addressing drug-resistant infections especially in LMIC settings where the burden is highest and more potent antimicrobials are either too expensive or altogether unavailable. Examples of new molecular entities acting on novel targets or with new modes of action that, if affordable, may address the challenge of AMR in LMICs include gepotidacin, zoliflodacin, ibezapolstat, MGB-BP-3, CRS-3123, afabicin, zosurabalpin and TXA-709, which are currently in clinical trials.5 However, the current antibiotic development pipeline is insufficient to address increasing resistance of priority pathogens, especially for MDR Gram-negative bacteria and more needs to be done in research and development.  

The value of old treatments for LMICs 

In the face of economic and logistical challenges associated with developing new treatments especially in LMIC settings, optimizing the use of existing antibiotics is a practical and necessary approach to preserve the effectiveness of antimicrobial agents. Many older antibiotics remain effective against certain infections and can be repurposed, repositioned, re-profiled or re-tasked, or used in combination therapies with other antibiotics to enhance their efficacy and reduce the likelihood of resistance emerging.6 For instance, revisiting older antibiotics such as chloramphenicol for the treatment of typhoid fever in Southeast Asia is a possibility after a 30-year break during which time the pathogen has become susceptible again.7,8 The use of combination antibiotics has proven helpful in the face of evolution of resistance caused by spontaneous mutations against one antibiotic. For instance, use of a β-lactam-aminoglycoside combination which has been extensively applied to combat infections caused by resistant Gram-negative bacteria. Another example is intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms.6 Also, combination therapy is the cornerstone of treatment of tuberculosis with desired therapeutic effects and reduction of resistance.7 There is, however, an urgent need for clinical trial evidence to support the combination of “old” antibiotics in the absence of new antibiotics. 

The development of new and affordable antibiotics is critical for addressing drug-resistant infections especially in LMIC settings where the burden is highest and more potent antimicrobials are either too expensive or altogether unavailable.

Access for LMICs with high infectious disease burden 

In our interaction with health managers, the cost element came out as a key challenge that often limits access to potential life-saving antibiotic treatments, exacerbating health disparities. Due to the global evolution in the supply chain after the COVID-19 pandemic, there have been significant challenges that have led to inconsistent supply and insufficient stock which can hinder the effective distribution of life-saving antibiotics. Ensuring the quality and efficacy of antibiotics is a significant concern as we lack robust regulatory frameworks and have a limited capacity to enforce regulations.8 In our settings, for instance, nearly a third of the antimicrobials commonly available may come through the porous borders without customs inspection, thereby compromising quality controls and that can be a driver for resistance.  

Balancing new and old treatments for LMICs: A holistic approach  

We require a balanced approach that leverages both new and old treatments due to the unique system challenges. This will require not only developing new, affordable antibiotics but also optimizing the use of existing ones through robust diagnostics and antimicrobial stewardship (AMS) programmes. This is essential for prolonging the efficacy of current treatments and ensuring that antibiotics remain effective, while achieving optimal patient outcomes and implementing water, sanitation and hygiene (WASH) and infection, prevention and control (IPC) interventions.9,10 

Phage therapy has recently been revitalized in higher-income countries with many successful applications in personalized medicine against multi-drug-resistant bacterial infections. However, for this approach to work in LMICs, we will require dedicated laboratories that will test candidate phages against infectious pathogens in individual patients who fail treatment due to pan-resistance.11 Concerted efforts by stakeholders in the health sector are required to ensure support and funding for these approaches in personalized medicine.  

In the context of infectious diseases, monoclonal antibodies12 can neutralize pathogens, modulate host immune responses, or disrupt pathogen-host interactions. Use of monoclonal antibodies is an approach that has gained prominence for the prevention and treatment of infectious diseases such as influenza, respiratory syncytial virus and Clostridioides difficile. They offer potential advantages such as high specificity, reduced risk of resistance development, and the ability to tailor treatment to individual patients. However, the technology is expensive and is still largely confined to well-resourced settings and LMICs will require to adopt more affordable approaches  

Vaccines have also proven to be an effective tool against emergence and spread of AMR.13 By stimulating the immune system to produce protective antibodies against specific pathogens, vaccines can prevent infections from occurring in the first place, thereby reducing the reliance on antibiotics and the risk of resistance emergence. The development and widespread adoption of vaccines against bacterial pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis, have contributed to reductions in burden of diseases, antibiotic use and resistance rates in many LMIC settings.11 

Due to the global evolution in the supply chain after the COVID-19 pandemic, there have been significant challenges that have led to inconsistent supply and insufficient stock which can hinder the effective distribution of life-saving antibiotics.

Conclusion 

AMR is a complex, multifaceted challenge disproportionately affecting LMIC settings, a problem compounded by high disease burden, weak WASH infrastructure, poverty and limited investments in healthcare. An approach encompassing the research and development of new affordable antimicrobial agents, personalized medicine utilizing bacteriophage and monoclonal antibody approaches, and the use of vaccines for prevention of endemic infectious diseases offers the best hope to minimize disparities in access to both new and old antibiotics. By fostering innovation, enhancing stewardship, and strengthening global partnerships, we can create sustainable strategies to combat AMR and to ensure that both new and old treatments remain viable tools in the fight against infections, ultimately safeguarding global health for future generations. 

References

  1. Okeke IN, de Kraker MEA, Van Boeckel TP, Kumar CK, Schmitt H, Gales AC, Bertagnolio S, Sharland M, Laxminarayan R. The scope of the antimicrobial resistance challenge. Lancet. 2024 Jun 1;403(10442):2426-2438. doi: 10.1016/S0140-6736(24)00876-6. 
  2. Rupasinghe, N., C. Machalaba, T. Muthee, and A. Mazimba. Stopping the Grand Pandemic: A Framework for Action. Addressing Antimicrobial Resistance through World Bank Operations. Washington, DC: World Bank; 2024. 
  3. Kariuki S, Wairimu C, Mbae C. Antimicrobial Resistance in Endemic Enteric Infections in Kenya and the Region, and Efforts Toward Addressing the Challenges. J Infect Dis. 2021 Dec 20;224(12 Suppl 2):S883-S889. 
  4. GBD 2021 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. Lancet. 2024 Sep 28;404(10459):1199-1226.  
  5. Ruggieri F, Compagne N, Antraygues K, Eveque M, Flipo M, Willand N. Antibiotics with novel mode of action as new weapons to fight antimicrobial resistance. Eur J Med Chem. 2023 Aug 5;256:115413. 
  6. Meschiari M, Faltoni M, Kaleci S, Tassoni G, Orlando G, Franceschini E, Burastero G, Bedini A, Serio L, Biagioni E, Melegari G. Intravenous fosfomycin in combination regimens as a treatment option for difficult-to-treat infections due to multi-drug-resistant Gram-negative organisms: A real-life experience. International Journal of Antimicrobial Agents. 2024 May 1;63(5):107134. 
  7. Morales-Durán N, León-Buitimea A, Morones-Ramírez JR. Unraveling resistance mechanisms in combination therapy: A comprehensive review of recent advances and future directions. Heliyon. 2024 Mar 11. 
  8. World Bank. Drug-Resistant Infections: A Threat to Our Economic Future. 2017;13:833005.
  9. Talat, A., Bashir, Y., Khan, A.U. Repurposing of Antibiotics: Sense or Non-sense. Front Pharmacol. 2022 Feb 21  
  10. Regional Guidance for the Establishment and Implementation of Antimicrobial Stewardship Programs. 2nd Edition, East Central and Southern Africa Health Community, 2024 
  11. Fabiyi K, Sintondji K, Agbankpe J, Assogba P, Koudokpon H, Lègba B, Gbotche E, Baba-Moussa L, Dougnon V. Harnessing Bacteriophages to Combat Antibiotic-Resistant Infections in Africa: A Comprehensive Review. Antibiotics (Basel). 2024 Aug 23;13(9):795. 
  12. Troisi M, Marini E, Abbiento V, Stazzoni S, Andreano E, Rappuoli R. A new dawn for monoclonal antibodies against antimicrobial resistant bacteria. Front Microbiol. 2022 Dec 14;13:1080059.  
  13. Frost I, Balachandran A, Paulin-Deschenaux S, Sati H, Hasso-Agopsowicz M. The approach of World Health Organization to articulate the role and assure impact of vaccines against antimicrobial resistance. Hum Vaccin Immunother. 2022 Nov 30;18(6):2145069. 

Samuel Kariuki has been the Director of Drugs for Neglected Diseases initiative (DNDi) in Eastern Africa since 2023. Additionally, he is a visiting Professor in Tropical Microbiology, Nuffield Department of Medicine, University of Oxford and the Ohio State University One-Health Initiative, and Honorary Fellow, Wellcome Trust Sanger Institute, Cambridge, the United Kingdom. He is also a member of the WHO Strategic Advisory Group (SAG-AMR) on AMR.

Samuel has carried out research on epidemiologic characterization of enteric infections outbreaks, utilizing whole genome sequencing to better understand ecology, and transmission dynamics of bacteria and antimicrobial resistance. He led the initiative to develop the National Action Plan for reduction and control of Antimicrobial Resistance and sits on the National Antimicrobial Stewardship Advisory Committee that advises Ministries of Health and Agriculture on policy on prudent use of Antimicrobials in human and veterinary medicine.

In addition, he has published on the local epidemiology of antimicrobial resistance especially relating to the human-animal interface. He has co-authored 185 manuscripts in peer-reviewed journals and written chapters in four text books in related fields of antimicrobial resistance and food safety.

He holds a Bachelor of Veterinary degree from the University of Nairobi, a Master of Science in Pharmacology & Toxicology from the same university, and a PhD in Tropical Medicine from the University of Liverpool, UK. He is a fellow of the African Academy of Sciences, a member of the American Society for Tropical Medicine and Hygiene and the American Society for Microbiology. 

Robert Onsare is the Acting Deputy Director, One Health Approach Research Program at the Kenya Medical Research Institute (KEMRI) and Principal Research Scientist at the Centre for Microbiology Research, KEMRI.

He has over 18 years of research experience focusing on a One Health approach to AMR surveillance and monitoring, molecular and epidemiologic characterization of enteric pathogens obtained from hospitals, community and food animals in both outbreak and non-outbreak settings. The pathogens he is currently focused on are Salmonella, V. Cholera, Campylobacter, and E. coli, among others.

Robert also teaches and supervises post-graduate courses on sessional/invitation basis and serves as external examiner of post-graduate students. He is passionate about One Health research issues and monitoring up and coming young scientists. He has a PhD in microbiology, a BSc in Biological Sciences and a MSc in Microbiology.

Evelyn Wesangula works with the East Central and Southern Africa Health Community (ECSA- HC) based in Arusha, Tanzania, as a senior AMR Control Specialist, strengthening the implementation of Infection Prevention Control Strategies and National Action Plans on Antimicrobial Resistance in the region. Evelyn is a passionate pharmacist with an Msc. in Tropical and Infectious Diseases.

Evelyn serves as the Vice Chairperson, Infection Prevention Network-Kenya and is a member of the African Union Taskforce on AMR, the Technical Advisory Group of the UK aid programme The Fleming Fund. She is also a Chatham House Africa Public Health Leaders Fellow, Fleming Fund Policy Fellow and an International Ambassador of the Society of Hospital Epidemiology of America.

She previously worked at the Ministry of Health in Kenya as the National AMR focal point where she championed the development and implementation of the first NAP-AMR. She has supported the World Health Organization in developing AMS guidance documents supporting implementation of NAPs.

Evelyn serves as a volunteer mentor for the Commonwealth Partnerships for Antimicrobial Stewardship (CwPAMS) ALFA Fellowship programme.

The authors declare that they do not have any relationships or affiliations that could be construed as a potential conflict of interest.