AMR and the need for new and old treatments for drug-resistant infections in LMICs
– by Samuel Kariuki, Robert Onsare and Evelyn Wesangula

PLEASE NOTE: The Viewpoints on our website are to be read and freely shared by all. If they are republished, the following text should be used: “This Viewpoint was originally published on the REVIVE website revive.gardp.org, an activity of the Global Antibiotic Research & Development Partnership (GARDP).”

The views and opinions expressed in this article are solely those of the original author(s) and do not necessarily represent those of GARDP, their donors and partners, or other collaborators and contributors. GARDP is not responsible for the content of external sites.

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.