Public Health Challenges

RESEARCH ARTICLE

A Landscaping Assessment and Call-to-Action to Improve

Access to Novel Reserve Antibiotics in 14 Low- and
Middle-Income Countries
Fabrizio Motta1 Summiya Nizamuddin2 Ejaz Khan3 Tracie Muraya4 Silvio Vega5 Joseph Fadare6
Shaffi F. Koya7 Maria Virginia Villegas8 Faisal Sultan2 Tara Lumley9 Rahul Dwivedi10 Lauren Jankelowitz10
Jennifer Cohn10

1
Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil 2 Shaukat Khanum Memorial Cancer Hospital and Research Centres (SKMCH&RC), Lahore,
Pakistan 3 Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad, Pakistan 4 REACT Africa, Lusaka, Zambia 5 Complejo Hospitalario
Metropolitano, Caja de Seguro Social, Sistema Nacional de Investigadores (SNI), Panama City, Panama 6 Department of Pharmacology and Therapeutics, Ekiti
State University/Ekiti State University Teaching Hospital, Ado-Ekiti, Nigeria 7 Global Institute of Public Health, Thiruvananthapuram, Kerala, India 8 Grupo
de Investigaciones en Resistencia Antimicrobiana y Epidemiología Hospitalaria (RAEH), Universidad el Bosque, Bogotá, Colombia 9 L.E.K. Consulting Group,
London, UK 10 Global Antibiotic R&D Partnership (GARDP), Geneva, Switzerland

Correspondence: Jennifer Cohn ([email protected])

Received: 10 January 2024 Revised: 18 August 2024 Accepted: 25 August 2024

Funding: This research was supported by Direktion für Entwicklung und Zusammenarbeit

Keywords: access | antimicrobial resistance | low- and middle-income country (LMIC) | Reserve antibiotics

ABSTRACT
Background: Antimicrobial resistance (AMR) presents a significant global mortality burden which particularly affects the low-
and middle-income countries (LMICs). Enhancing diagnostics to identify drug-resistant infections and improving appropriate
access to novel Reserve antibiotics in LMICs can address AMR-related morbidity, mortality and healthcare costs. This article
characterizes the AMR landscape across 14 LMICs and describes an introductory pathway for novel Reserve antibiotics.
Methods: This mixed-method study was completed in 14 LMICs in Africa, the Americas, Asia and Europe through a combination
of qualitative interviews with physicians and public health experts (PHEs), and a quantitative survey of physicians, supported by
an assessment of secondary materials relating to antibiotic introduction and AMR burden.
Results: A total of 54 physicians and 17 PHEs were interviewed, and 209 physicians participated in the survey. Top unmet needs
across public and private settings were as follows: access to new antibiotics to better manage drug-resistant infections; affordability;
adequate safety profile for prescribed antibiotics. Access to diagnostics and antibiotic susceptibility testing was noted as a barrier,
with large tertiary and private centres experiencing better access. Implementation of antibiotic stewardship programmes was
variable and limited by insufficient funding, shortage of infectious disease physicians, poor AMR education and lack of restrictions
to limit antibiotic use. Antibiotic access varies by sector, centre type, location and strength of individual state procurement systems.
In particular, private sector facilities have better access to Reserve products. In most countries, most Reserve antibiotics included
in WHO’s Essential Medicines List (EML) were not included in national EMLs or not registered in countries.
Conclusion: This study has helped to identify common barriers and pathways to Reserve antibiotic access, irrespective of the
level of preparedness of countries. The data offer insights into possible solutions to improve access and highlight opportunities to

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly
cited.
© 2024 The Author(s). Public Health Challenges published by John Wiley & Sons Ltd.

Public Health Challenges, 2024; 3:e70005 1 of 13

https://doi.org/10.1002/puh2.70005
 strengthen access pathways and expedite access, for example, by identifying priority antibiotics based on national public health
need. A six-step introductory pathway for novel Reserve antibiotics is described.

1 Introduction Action Plan developed or implemented according to the WHO

Global Database for Tracking AMR Country Self-Assessment
Antimicrobial resistance (AMR) presents a significant global Survey [12]) [2], whether the country has documented evidence
mortality burden, directly leading to 1.27 million deaths in 2019, of significant AMR by prevalence of carbapenem-resistant (CR)
making it the third most common underlying cause of death organisms (>20% CR organisms in surveillance samples, such as
worldwide, following only stroke and ischaemic heart disease [1, WHO surveillance [13]) or is very likely to have (as evidenced
2]. The highest mortality rates are found in low- and middle- by surrounding countries or evidence from other non-GLASS
income countries (LMICs) [1, 3]. Across the world, infection rates literature [14]) [3], selection of countries to provide geographic
are expected to continue to rise, and by 2050, 4.1 and 4.7 million diversity and representation. A greater number of interviews were
annual infection-related deaths are predicted in Africa and Asia, conducted and survey responses collected for seven countries
respectively [4]. (South Africa, India, Mexico, Brazil, Jordan, Egypt and Kenya),
and fewer interviews conducted and survey responses collected
Several global initiatives have been launched to combat the for seven other countries (Georgia, Pakistan, Guatemala, Nigeria,
growing burden of AMR. In 2017, the WHO launched the AWaRe Colombia, Panama and Serbia) (Table 1). The same topics were
Classification of Antibiotics. The AWaRe classification catego- covered for all countries.
rizes antibiotics into three groups – Access, Watch and Reserve
– and aims to optimize the quantity and quality of antibiotic
prescribing [5]. Reserve antibiotics are last-resort antibiotics
that should only be used to treat severe infections caused by 2.1.1 Data Collection
multidrug-resistant pathogens [5, 6].
2.1.1.1 In-Depth Interviews. The research employed in-
In geographic areas and populations where antibiotic resistance depth qualitative semi-structured interviews of 60-min duration.
is growing, it is important to improve appropriate access to diag- Participants considered were physicians and public health experts
nostics and Reserve antibiotics to address the morbidity, mortality (PHEs). The consulting firm L.E.K. was contracted to conduct,
and healthcare costs associated with AMR. Although LMICs transcribe and summarize the expert interviews.
face disproportionate burden of resistant bacterial pathogens,
including those on the WHO Priority Pathogen List [6], these The selection of study participants was a mix of targeted and
same countries often have limited access to novel antibiotics opportunistic and focused on selecting individuals on the basis
that target resistant infections [7]. Although a number of studies of evidence of participation in initiatives related to AMR (e.g.
have summarized current work on AMR National Action Plans sponsors or stewards of NAPs or national antimicrobial stew-
or stewardship programmes, there is not information in the ardship programmes [ASPs]) or participation in conferences
literature about the process to introduce novel antibiotics in or events related to AMR, authorship of AMR-related peer-
LMICs [8, 9]. The lack of literature on this topic is in contrast to reviewed publications or guidelines. Once solicited, experts had
other disease areas, such as HIV or tuberculosis, where significant to fulfil the following criteria: (1) work at a tertiary, private or
literature on introduction of novel medications exists [10, 11]. university hospital, or a research centre or centre for public
For novel Reserve antibiotics to be introduced appropriately in health; (2) score 3 or more (out of 5) in comfortability dis-
LMICs, the AMR landscape into which they are being introduced cussing antibiotic introduction and AMR burden; (3) be active in
must be better understood, and the introductory pathway built initiatives related to AMR (e.g. involvement in clinical trials, con-
with the leadership of local experts and the government. This ferences, guidelines development or stewardship programmes).
article aims to characterize the local AMR landscape across 14 Finally, experts who were practicing physicians needed to
LMICs, including access to diagnostics and antibiotics, focussing treat 50 or more patients with AMR bacterial infections per
on Reserve antibiotics and map potential introductory pathways month.
for novel Reserve antibiotics.
2.1.1.2 Survey. This research also employed an anonymous
cross-sectional survey of 209 physicians. The online question-
2 Methods naire was informed by findings from the qualitative interviews
and assessment of secondary materials. The questionnaire was
2.1 Study Design and Setting developed in English and translated into Arabic, Portuguese,
Spanish, Georgian and Serbian, then edited for accuracy and
This is mixed-method study, completed in 14 LMICs in Africa, local appropriateness. It was piloted in each of the 14 LMICs
the Americas, Asia and Europe. Countries were selected on and took 20 min to complete. Experts were screened and
the basis of [1] whether the country has identified AMR as selected according to the same criteria as those involved in the
a priority and has some governance structure and/or a plan qualitative research. The recruitment spanned 3 months, from
to address AMR (as evidenced by having an AMR National June to August 2022. The consulting firm L.E.K. was contracted

2 of 13 Public Health Challenges, 2024

TABLE 1 Study participants and characteristics – qualitative research.

Qualitative research
Public health
Physicians experts
Total 54 17

By country and Detailed assessment South Africa 14 2

profession India 5 1
Mexico 5 2
Brazil 4 —
Jordan 2 1
Egypt 4 —
Kenya 2 4
Higher level assessment Georgia 2 2
Pakistan 3 1
Guatemala 3 —
Nigeria 4 2
Colombia 3 1
Panama 1 1
Serbia 2 —
By sector (%) Public 76% n/a
Private 24% n/a
By professional Infectious disease specialist 70% n/a
experience (%) Non-specialist consultant (general hospital-based 15% n/a
physicians, surgeons, neonatologists, paediatricians
etc.)
Medical microbiologist 7% n/a
Critical care specialist 8% n/a
Internal medicine n/a n/a
By primary Primary and secondary centres n/a n/a
treatment setting (%) Tertiary centres n/a n/a

to develop and distribute the questionnaire and analyse the 2.1.1.3 Document Analysis. In parallel, secondary mate-
results. rials relating to antibiotic introduction and AMR burden were
assessed. Key international websites and resources, such as
The survey collected information on participant demographics, GLASS, WHO and Organization for Economic Co-operation and
access to microbiologic and antibiotic sensitivity testing, avail- Development (OECD), were reviewed for information on AMR.
ability or treatment guidelines, presence and implementation of Additionally, national sources, such as the ‘AMR Research and
ASPs, drivers of antibiotic selection and availability and barriers Surveillance Network’ annual report, published by the Indian
to access to prescribed antibiotics. The survey also asked respon- Council of Medical Research in 2021 were also reviewed [15]. This
dents to rate key unmet needs for patients with carbapenem was coupled with other national website for the latest available
resistant infections on a Likert scale, with 1 corresponding to ‘low’, information on antibiotic treatment guidelines, AMR National
2 to ‘medium’ and 3 to ‘high’. Action Plans and national ASPs.

Survey participants were also asked which diagnostic testing

methods were currently available in their centres. This study 2.1.1.4 Review. A semi-structured literature search on
focused on availability and did not examine practices of use of PubMed from 2010–2022 was completed to collate papers related
diagnostic/sensitivity tests or barriers to use (such as patient out- to AMR epidemiology, antibiotic usage and procurement in target
of-pocket payment) for such tests. The study also did not specify countries. Key search terms included: ‘antimicrobial resistance’;
whether the diagnostics were available on site or by sample or ‘AMR’; ‘local resistance patterns’; ‘LMICs’; ‘low- and middle-
patient referral. income countries’; ‘antibiotics’; ‘Reserve’; ‘Access’.

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2.1.1.5 Data Analysis. A thematic analysis of the inter- 4.1 Unmet Needs
view data in English was conducted using the framework
method [16]. Two analysts independently reviewed all tran- The top three unmet needs for patients with CR infections were
scripts, then met to discuss any differences in their reviews, the same across public and private settings and included access
come to consensus and identify key themes that emerged from to new antibiotics to better manage drug-resistant infections
the data. Key themes were reviewed and agreed upon by the (public, average 2.4 [n = 99], private 2.1 [n = 101]), better
interviewer. affordability (public 2.3 [n = 99], private 2.1 [n = 101]) and
improved safety/toxicity profile (public 2.1 [n = 99], private 2.0
The survey data were cleaned to remove any errors, inconsisten- [n = 101]) of these antibiotics (Table 3). Public sector experts
cies or incomplete responses and then analysed descriptively in reported higher overall levels of unmet need versus private sector
Excel and Qualtrics. Data from each of the research methods were experts across all countries included in this study (Table 3).
analysed separately and then integrated, using the qualitative Physicians in Pakistan reported the highest levels of unmet need
findings and assessment of secondary materials to explain the (Table 3). Other high-ranking unmet needs included quality
quantitative survey results. assurance of treatment options, more rapid and accurate diagnos-
tics, better testing for CR specifically, better infection control and
2.1.1.6 Ethical Considerations. This investigation did not improved efficacy and response to currently available treatment
meet the criteria for human subjects research as information options.
collected from key informants was limited to enquiries around
health system functioning and not personal information. How-
ever, informed consent was obtained from all persons interviewed 4.2 Diagnostic and Susceptibility Testing
and surveyed.
The most widely available standard diagnostic tests reported by
experts included Gram staining: average: 98% in private (range:
88%–100%, [n = 95]), 96% in public (67%–100%, [n = 96]); and
3 Results polymerase chain reaction (PCR): 94% in private (78%–100%,
[n = 95]), 84% in public (56%–100%, [n = 96]). Access and
3.1 Profile of Participants use of more complex diagnostic tests were more variable, with
experts from 9 of 14 (64%) countries reporting the availability
3.1.1 Qualitative Study Participants of nanoparticle probe technology, and peptide nucleic acid
fluorescence in situ hybridization (PNA-FISH), and 6 countries
One hundred and sixty-six experts were invited to participate reporting the availability of isothermal nucleic acid amplification
in the qualitative research, and 71 experts accepted. Of the 71 technology (INAAT). The least widely available diagnostic tests
experts interviewed, 76% were healthcare professionals (HCP) reported by experts included PNA-FISH: 15% in private (0%–
and 24% PHEs, defined as non-clinical experts with experience 50%, [n = 95]), 18% in public (0%–50%, [n = 96]); and INAAT:
in AMR. Of the HCPs, 63% worked in public facilities and 8% in private (0%–38%, [n = 95]), 15% in public (0%–56%,
the remainder in the private sector (Table 1). In these, 70% [n = 96]).
of the HCPs were ID specialists, and others included critical
care specialists (8%), general hospital-based physicians – for Clinical laboratories currently use several identification and
example surgeons, neonatologists and paediatricians – (15%) and antimicrobial sensitivity testing (AST) methods. Conventional
medical microbiologists (7%). Among these, 93% of the HCPs AST methods include culture-dependent methods (e.g. a disk
focused on adult patients, whereas 7% had a paediatric focus diffusion test and broth microdilution), molecular-based methods
(Table 1). (e.g. PCR) and more advanced technologies such as whole
genome sequencing, matrix-assisted laser desorption ionization-
time of flight (MALDI-TOF) and INAAT [17]. Access and uptake
3.1.2 Quantitative Study Participants of AST are variable across the countries assessed. Thirteen
of the 14 countries reported access to standard AST methods
Of the 209 experts surveyed, 53% worked in primary and sec- such as broth microdilution, disk diffusion and PCR. The most
ondary centres and 47% in tertiary centres; 51% in private centres widely available AST methods reported by experts included
and 49% in public; 49% of experts were non-specialist consultants broth microdilution: 84% in private (0%–100%, [n = 95]), 73%
or general hospital-based physicians – for example surgeons, in public (33%–100%, [n = 96]); disk diffusion: 85% in private
neonatologists and paediatricians; 25% ID specialists, 11% critical (0%–100%, [n = 95]), 77% in public (44%–100%, [n = 96]); and
care specialists and 13% internal medicine (Table 2). PCR: 82% in private (0%–100%, [n = 95]), 77% in public (40%–
100%, [n = 96]). Access and use of more complex AST methods
were more variable, with 43% (6 of 14) of countries reporting
access to complex tests such as INAAT. The least commonly
4 AMR Management Landscape Assessment available AST methods reported included mass spectrometry
(e.g. MALDI-TOF): 36% in private (0%–56%, [n = 95]), 30% in
The AMR landscape was reviewed for each country, including the public (0%–60%, [n = 96]); whole genome sequencing: 26% in
level of unmet need, access to microbiologic and antibiotic sensi- private (0%–100%, [n = 95]), 16% in public (0%–75%, [n = 96]);
tivity testing, presence and implementation of ASPs, availability and INAAT: 11% in private (0%–38%, [n = 95]), 18% (0%–44%,
and barriers to access to prescribed antibiotics. [n = 96]).

4 of 13 Public Health Challenges, 2024

TABLE 2 Study participants and characteristics – quantitative survey research.

Quantitative research
Physicians
Total 209

By country and Detailed assessment South Africa 20

profession India 20
Mexico 20
Brazil 20
Jordan 20
Egypt 20
Kenya 20
Higher level assessment Georgia 10
Pakistan 10
Guatemala 9
Nigeria 10
Colombia 10
Panama 10
Serbia 10
By sector (%) Public 49%
Private 51%
By professional Infectious disease specialist 25%
experience (%) Non-specialist consultant (general hospital-based 49%
physicians, surgeons, neonatologists, paediatricians etc.)
Medical microbiologist 1%
Critical care specialist 11%
Internal medicine 13%
By primary Primary and secondary centres 53%
treatment setting (%) Tertiary centres 47%

Experts in South Africa, Jordan, Egypt and India reported is national ASPs available in principle but not implemented
the most advanced testing landscapes (i.e. reported the most (Brazil, Jordan, Kenya, Serbia, Georgia, Nigeria, Colombia and
availability of diagnostic and sensitivity tests). Overall, large Panama), and two had no presence of national ASPs (Mexico
tertiary centres (where 47% of sample respondents worked) and Guatemala). Limitations to the successful implementation of
and most private facilities had better access to diagnostic and ASPs were driven by limited funding, a lack of ID physicians, lack
sensitivity testing, including better access to more complex of AMR education and lack of restrictions to limit antibiotic use.
tests or automated equipment (e.g. MALDI-TOF). Experts also In countries where ASPs were not available or only available par-
noted that aside from access to the tools themselves, availability tially, some major tertiary centres did have simplified (e.g. limited
of some materials to support diagnostic and AST is a major to formulary restrictions) ‘in-house’ ASPs developed locally.
issue in LMICs – for example low availability of discs used for
susceptibility testing for sulfamethoxazole in Pakistan. Further to Survey respondents assessed the level of success of their ASPs,
laboratory capacity and capability constraints, many laboratories which were largely similar across private and public settings.
in LMICs, especially in the public sector, lack quality assurance Factors linked to more successful ASPs include better AMR
and accreditation. awareness among the practicing physicians, better and closer
monitoring of AMR (e.g. presence of electronic health records,
which allow accurate tracking of antibiotics usage) and imple-
4.3 Antibiotic Stewardship Programmes mentation of key initiatives, such as formulary restrictions and
pre-authorization requirements for antimicrobials, ID specialist
Four countries had national ASPs available (South Africa, India, and hospital stewardship rounds, dose optimization and nursing
Egypt and Pakistan), eight had ASPs partially available, that practices audits.

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6 of 13
TABLE 3 Unmet needs for patients with carbapenem-resistant infections (1 – low unmet need; 3 – high unmet need).

By sector By country
South
Unmet need Private Public Africa India Mexico Brazil Jordan Egypt Kenya Georgia Pakistan Serbia Guatemala Nigeria Colombia Panama

Stable supply of 1.6 1.7 1.8 1.6 1.2 2.0 1.7 1.4 1.4 2.6 2.5 1.6 2.3 1.8 1.4 1.7
essential antibiotics
Infection control 1.8 1.9 1.9 1.7 1.8 2.1 2.0 1.9 2.0 2.0 2.2 1.9 1.8 1.9 1.6 1.8
New products that 2.1 2.4 2.4 2.0 2.1 2.1 2.2 2.5 2.4 2.5 2.7 2.1 2.6 3.0 2.3 2.7
better manage
carbapenem-
resistant
infections
Improved efficacy 1.8 1.9 2.0 1.6 2.0 1.9 2.0 1.9 1.9 2.2 1.9 1.8 2.0 1.9 1.8 1.9
and response to
currently available
treatments
Convenient 1.7 1.8 1.8 1.8 1.5 1.9 1.7 1.4 1.6 1.9 2.9 1.7 1.8 1.6 1.4 2.0
frequency of
administration (i.e.
improved dosing
schedule due to
longer in vivo
half-lives)
Better 2.1 2.3 2.0 1.6 2.3 2.3 2.5 2.3 2.5 1.9 2.0 2.4 2.8 2.4 2.3 2.4
price/affordability
Improved safety and 2.0 2.1 2.2 2.1 1.9 2.0 2.3 2.1 2.3 1.9 2.3 1.9 2.2 2.1 1.9 2.1
toxicity (e.g. fewer
incidences of
diarrhoea,
constipation, rash,
cough, headache
and nausea)
(Continues)

Public Health Challenges, 2024

 4.4 Availability of and Barriers to Access for Key

Private Public Africa India Mexico Brazil Jordan Egypt Kenya Georgia Pakistan Serbia Guatemala Nigeria Colombia Panama
Antibiotics

2.0
1.8

1.8
Once approved, antibiotic access is impacted by two main drivers.
First, ASP restrictions can limit access to antibiotics deliberately
to promote appropriate use (e.g. vancomycin through ASP audits

1.8

1.7
1.5
or colistin through pre-authorization requirements). Second,
antibiotic access can be limited by other factors such as restric-
tions unrelated to appropriate use (e.g. limitation of antibiotics
included on the Essential Medicines List [EML], cost sensitivity,
1.7

1.7

1.7
stock outs and supply chain issues). These antibiotic access
limitations and restrictions vary according to the sector (e.g.
public vs. private), type of centre (e.g. tertiary vs. quaternary) and
location and strength of individual state procurement systems
2.3

2.1

1.3
(e.g. urban vs. rural). An analysis of Reserve antibiotics included
in the WHO EML shows that very few of these Reserve antibiotics
1.9 are included in national EMLs or are registered in countries

1.9
1.5

(Table 4).

Antibiotics that are commonly included in guidelines to treat

frequent infections (e.g. pneumonia, blood-stream infection,
2.6

2.7

2.7
intra-abdominal infection and urinary tract infection) encoun-
By country

tered in health facilities (primarily inpatient) were identified by

respondents (Table 4), and availability assessed. Across the 14
LMICs, access challenges were most frequent amongst antibiotics
1.9

1.9

1.9

in the Reserve category (Table 5). However, access issues were also
identified for antibiotics under Access and Watch categories (e.g.
Access – penicillin G, cloxacillin and Watch – carbapenems like
2.0
1.9
1.8

meropenem and piperacillin–tazobactam) (Table 5).

Experts from 12 of the 14 countries included in this study (South

1.6

1.6

1.9

Africa, Kenya, Jordan, Brazil, Mexico, Guatemala, Colombia,

Pakistan, Nigeria, Panama, Georgia and Serbia) highlighted
1.8

1.8

1.8

antibiotic access varied according to the sector of the hospital (e.g.

public or private). Across countries, private sector facilities had
better availability of antibiotics and fewer access restrictions. This
2.0
1.9

1.9

is in part because they procure directly from manufacturers or

distributors, whereas in the public sector, antibiotics are typically
procured through periodic tenders. Antibiotic access can be
2.0
1.8

1.7

further limited in public hospitals by which drugs are included

in the EML. Restricted access or lack of EML inclusion due to
high price is a barrier, particularly in the case of drugs such
1.9
1.7

1.7

as ceftazidime–avibactam, daptomycin and tigecycline. However,

access to last-line antibiotics (e.g. colistin) was also often highly
controlled in public hospitals as part of ASPs.
South

2.0
2.1
1.8

Experts from 7 of 14 countries (India, Egypt, Kenya, Serbia,

Pakistan, Georgia and Panama) highlighted antibiotic access also
2.0

2.0
1.8

varied according to the level of care (e.g. secondary or tertiary)

By sector

and associated experience of physicians in those settings. Some

antibiotics are only available in secondary or tertiary hospitals
1.8
1.7

1.7

due to high cost (e.g. vancomycin) or because they are restricted

to use in centres that meet certain requirements as part of ASPs
(Continued)

(e.g. piperacillin–tazobactam requires pre-authorization of ID

diagnosis of bacterial

Quality assurance of
infection (including
cost and availability

accurately interpret

specialists in Serbia).
treatment options
receiving results;
of tests; speed of
Accurate early
Unmet need

carbapenem

Finally, experts from 8 out of 14 countries (South Africa, Mex-

test results)
expertise to

Testing for

resistance

ico, Brazil, Egypt, Kenya, Pakistan, Guatemala and Colombia)

TABLE 3

highlighted that supply chain issues impacted access to cer-

tain antibiotics (e.g. ceftazidime–avibactam, IV fosfomycin and
cefepime). These issues were particularly prominent during the

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8 of 13
TABLE 4 Reserve antibiotics on countries’ Essential Medicines List (EML) versus those approved by national regulatory authorities.

EML Imported/registered
Colistin Polymyxin Ceftazidime– Fosfomycin Colistin Polymyxin Ceftazidime– Fosfomycin
Country Injection B Aztreonam avibactam injection injection B Aztreonam avibactam injection

Brazil N Y N N N Y Y Y Y N
Colombia N N N N N Y Y Y Y Y
Egypt N N N Y N Y N Y Y N
Georgia
Guatemala N N N N N N N N N N
India N N N N N Y Y Y Y Y
Jordan Y N N N N Y N N N N
Kenya Y Y N N N N N N N N
Mexico N N N Y N Y N N Y Y
Nigeria N N N N N Y N N Y Y
Pakistan Y N N Y Y Y N N Y Y
Panama Y Y N N Y
Serbia
South Africa N N N N N N N N Y N
Note: Green – included in lists or registered; amber – not included in lists or not registered; grey – data not available.

Public Health Challenges, 2024

 TABLE 5 Antibiotic availability reported by physicians in the public sector.

Availability of antibiotics that are commonly included in guidelines to treat frequent infections in public facilities

Aminoglycoside Amikacin Gentamycin Plazomicin Tobramycin

Beta-lactam/ Amoxicillin– Ampicillin– Ceftazidime– Ceftolozane– Piperacillin– Cefixime– Cefoperazone– Amoxicillin–
beta-lactamase inhibitors clavulanate sulbactam avibactam tazobactam tazobactam clavulanic acid sulbactam clavulanate
Carbapenem Doripenem Ertapenem Imipenem– Meropenem
cilastatin
Cephalosporin Cefazolin Cefepime Cefiderocol Ceftriaxone Cefotaxime Cephalexin Cefuroxime Cephalexin
Fluoroquinolone Ciprofloxacin Moxifloxacin Levofloxacin Ofloxacin Norfloxacin Gemifloxacin Nalidixic acid
Glycopeptide Teicoplanin Vancomycin
Macrolide Azithromycin Erythromycin Clarithromycin
Penicillin Amoxicillin Cloxacillin Flucloxacillin Penicillin G Ampicillin Dicloxacillin
Phosphonic Fosfomycin (IV) Fosfomycin
(oral)
Polymyxins Colistin Polymyxin B
Tetracycline Doxycycline Tigecycline Minocycline Eravacycline
Other Nitrofurantoin Linezolid Daptomycin Metronidazole Rifamycin Fluconazole Aztreonam
Clindamycin
Trimethoprim- Meropenem–
sulfamethoxazole polymyxin-B
Note: Green – good access and no supply issues noted; amber – no or limited access.

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FIGURE 1 Introductory pathway for novel Reserve antibiotics. AMR, antimicrobial resistance; EML, Essential Medicines List.

COVID-19 pandemic. Concern over the quality of antibiotics (e.g. area and degree of unmet need, formulation, quality, efficacy,
sub-standard or falsified medicines) also limits availability in safety and cost effectiveness for inclusion on the EML (Figure 1).
some countries (e.g. Georgia, Nigeria and Colombia). Price is an EMLs can be updated as regularly as twice a year (e.g. Colombia)
important factor for access, particularly in the public sector. or once every 2 years (e.g. Jordan, Kenya and Nigeria). The
importance of EML inclusion and the downstream impact this
has on access to essential antibiotics is variable by country.
5 Discussion
For example, in some countries, a newly approved drug is
5.1 Introductory Pathways for Novel Reserve automatically included in the EML (e.g. Georgia). Others, for
Antibiotics example, have multiple EMLs, one at the national level and
others specifically for tertiary or quaternary centres (e.g. South
Based on commonalities across 14 LMICs, review of national Africa), public hospitals (e.g. the Cuadro Básico in Mexico) or
policies or guidance and interviewee input, new Reserve antibi- even hospital-specific EMLs (e.g. Panama). In other countries,
otics in general may follow a six-step introductory pathway physicians are not limited to prescribing drugs listed on the
(Figure 1). Although several steps in this pathway are common national EML (e.g. Serbia and India).
across medications, there are some that are specific to Reserve
antibiotics.
5.2.1 Reimbursement

5.1.1 Regulatory Approval Across countries in this study, there are a range of reimbursement
models (Figure 1). For example, in Serbia, around 80% of patients
The introductory pathway for novel Reserve antibiotics starts with are publicly covered and drugs are directly reimbursed by the
regulatory approval at a national level (Figure 1). This process Republic Health Insurance Fund (RFZO), whereas most South
typically takes 6–24 months depending on the country. Across Africans using the public sector are covered by the National
all target countries, prior US FDA and EMA approval accelerates Health Insurance scheme, which uses public funds to provide
timelines. Some countries also have additional data requests as access to drugs on the EML to all citizens.
part of the regulatory approval process. For example, the Central
Drugs Standard Control Organization (CDSCO) in India accepts Public insurance schemes typically cover all drugs on the
Phases I and II trial data generated in high-income countries, EML and procure through tenders with manufacturers. Patients
but the Phase III data needs to be conducted in India or include accessing treatment through private insurance or co-payments
Indians (if multinational) for approval, unless a specific waiver is typically have access to a wider range of antibiotics, as they are
granted. not limited to those included on the EML.

5.2 EML Inclusion 5.2.2 Treatment Guidelines Inclusion

A multidisciplinary panel (e.g. ID specialists from key hos- The inclusion of novel Reserve antibiotics in treatment guidelines
pitals/universities, pharmacist boards) then examines newly is an important step in the introductory pathway to ensure
approved drugs across metrics such as the relevance of the disease appropriate incorporation into clinical practice and longer term

10 of 13 Public Health Challenges, 2024

use (Figure 1). Among the 14 countries included in this study, particularly those with activity against CR infections, some newer
10 published national treatment guidelines related to antibiotic medicines being priced out of reach and lack of diagnostics
usage. In some cases, the national guidelines refer to the US to support both surveillance and cumulative local antibiograms
or European guidelines, which, although useful, may not be and clinical management. In addition, antibiotic supply chains
optimized for local epidemiology. National guideline updates were often noted to be weak, potentially due to several reasons,
occur every 2 years on average and involve collaboration with including lack of information to inform forecasting or long
physicians from leading tertiary hospitals, alongside other experts procurement cycles. Across all countries included in this study,
(e.g. epidemiologists). Additionally, in some countries like South there is a need noted for government involvement to fund, lead
Africa and Colombia, tertiary hospitals often develop hospital- and implement initiatives to tackle AMR. Access barriers may
specific guidelines based on local cumulative antibiograms. In the also be addressed by non-governmental actors.
absence of or, in some instances, instead of national guidelines,
physicians refer to international guidelines (e.g. EU, WHO, Affordability was noted to be a barrier to equitable access for
CDC, IDSA, PAHO and ReLAVRA) to support their clinical many Reserve antibiotics. To improve affordability, originators
decision-making. may engage in public-health oriented licensing with appropriate
controls to support stewardship and to enable a more affordable
supply and registration in LMICs [19]. Low and fragmented
demand may also hamper price negotiations. More focused
5.2.3 Supporting Activities
antibiotic formularies in public hospitals can help consolidate
markets, leading to better buying power and easier forecasting,
Once a novel Reserve antibiotic gains approval, EML inclusion
so long as there are antibiotics of sufficient spectrum to cover
and features in national treatment guidelines, stakeholders,
the resistance patterns encountered and some flexibility to access
including MOH, experts and suppliers, can assist educational
particular antibiotics in special cases through other mechanisms
and data generation activities to support appropriate use and
[20]. In addition, pooled procurement, at the national, regional or
uptake in clinical practice (Figure 1). Targeting large academic
international level, may be employed to help improve negotiating
hospitals before other facilities is beneficial, as they are likely
power.
to have better resources, improved ability to conduct AST in
microbiology labs, and more active stewardship plans, with good
There are opportunities to strengthen the identified introduc-
compliance. The provision of prescribers’ training on how best to
tion pathway for antibiotics. Countries may identify antibiotics
use novel Reserve antibiotics is also important to support long-
that address priority public health needs or priority pathogens
term availability and use. Disseminating key information, either
and support more rapid registration or facilitate special import
directly through medical science liaisons or through conferences
ahead of national regulatory approval to expedite access [21].
or educational events, to raise awareness of novel Reserve antibi-
Recognizing the need for additional data to optimize antibiotic
otics and their appropriate use is important. Stakeholders can
use, countries may develop a network of sentinel sites to help
also support hospitals to generate evidence around local AMR
improve quality data collection in parallel with antibiotic intro-
patterns (including regularly updated cumulative antibiograms)
duction. Countries may also choose to help expand equitable
and antibiotic use, highlighting the need for improved access to
access to Reserve antibiotics, especially in the public sector, by
novel Reserve antibiotics. Lastly, introduction of apps to LMICs,
supporting public reimbursement of these medicines through
similar to the Sanford Guide [18], with minimal or no subscription
including them on the EML or developing a limited-use EML for
fees for better outreach and accessibility may support appropriate
reimbursement only for higher level health facilities, for example
use.
the South Africa National EML for Tertiary and Quaternary Level
Health Facilities [22].

5.2.4 Phase IV/Post-Marketing Surveillance The introduction pathway may depend on baseline country
criteria. Across the countries included in this study, variability
The relevant government body across countries (e.g. the National was observed in the degree of national-level support and guidance
Agency for Food & Drug Administration Control in Nigeria) (e.g. guidelines and national ASPs), access to diagnostic and
monitors and collects Phase IV/post-marketing surveillance data sensitivity testing, antibiotic access and availability, as well as
on registered products (e.g. data related to trial results, side effects other factors like level of awareness of AMR. Different archetypes
and dosing requirements) (Figure 1). Although this is a helpful were identified, ranging from countries with advanced AMR
tool to facilitate launch and appropriate use of novel Reserve landscapes to those facing significant infrastructural or regulatory
antibiotics, their effectiveness can be variable (e.g. if only top challenges; countries at different levels of preparedness can
centres are included in the study, this may not be a representative support different introductory pathways and invest in different
sample and could provide an inaccurate picture of real-world ways to improve access. For example, in countries with national
use). guidelines, national ASPs and access to advanced diagnostic and
sensitivity testing, efforts could focus on initial introduction of
This article characterizes the AMR landscape and an introductory Reserve antibiotics in top tertiary centres to build confidence and
pathway for novel Reserve antibiotics across 14 LMICs, including knowledge of appropriate use and then leverage local key opinion
clinicians’ and PHEs’ perspectives of the availability and barriers leader networks to support wider roll-out.
to access for key antibiotics. There are common barriers to
accessing and appropriately using Reserve antibiotics faced across This mixed-method study was completed in 14 LMICs in Africa,
countries, including lack of availability of newer antibiotics, the Americas, Asia and Europe through a combination of

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in-depth qualitative interviews with 54 physicians and 17 PHEs, Acknowledgements
and a quantitative survey of 209 physicians. The study has impor- GARDP is supported by the governments of Canada, Germany, Japan,
tant limitations which may limit its generalizability. Although Monaco, the Netherlands, South Africa, Switzerland, the United King-
efforts were made to avoid introducing bias into the sample, dom, the Canton of Geneva, the European Union, as well as Global Health
experts were recruited on the basis of their affiliation, evidence EDCTP3, the RIGHT Foundation, Wellcome Trust and other private
foundations. GARDP was created by the World Health Organization and
of participation in initiatives related to AMR (e.g. sponsors
the Drugs for Neglected Diseases initiative (DNDi) in 2016 and legally
or stewards of NAPs or national ASPs) or participation in registered as the GARDP Foundation in Geneva, Switzerland in 2018.
conferences or events related to AMR, authorship of AMR- The content of this publication is solely the responsibility of the authors
related peer-reviewed publications or guidelines. As such, those and does not necessarily represent the official views of any GARDP
included in this study were leading experts in their field and may funders.
have access to more resources than other clinicians and PHEs.
Thus, their views may be biased and suggest better access to Conflicts of Interest
antibiotics, AMR diagnostics and antibiotic susceptibility testing F.M. has received honoraria for Pfizer for speaking engagement. M.V.V.
in their countries versus their colleagues. For example, in Mexico, has received educational grants and honoraria for speaking engagements
most public hospital laboratories have difficulties accessing basic from Pfizer, M.S.D., Biomerieux and West. All other authors have no
consumables for antibiograms, and, although those that have conflicts of interest to declare.
in-house research departments do have some state-of-the-art
equipment, it is rarely used for diagnostic purposes; as a result, Data Availability Statement
most studies describing resistance prevalence in Mexico are based The data that support the findings of this study are available from the
on more basic microbiological methods such as disk diffusion for corresponding author, J.C., upon reasonable request.
AST [23–25].
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