There is a desperate need for improved access to new antibiotics to treat infections caused by drug-resistant organisms, to be able to limit side effects and improve patient outcomes of the currently available drugs. Writing in the SA Medical Journal, experts propose the responsible introduction of new antibiotics to “preserve the longevity of these precious antibiotics”.
Antimicrobial resistance (AMR) is increasing worldwide, particularly in low- and middle-income countries (LMIC), being associated with 4.95m deaths in 2019 – 10m in Africa – and with the WHO identifying “the silent epidemic” as one of the top 10 global healthcare threats.
The highest AMR burden is in respiratory, followed by bloodstream infections. Neonatal deaths associated with AMR exceeded older age groups in most African countries. Six pathogens are associated with almost 1m deaths: Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Acinetobacter baumannii and Pseudomonas aeruginosa.
K. pneumoniae is a more prevalent organism in LMICs compared with high-income countries (HICs), where E.coli contributes more significantly to AMR and associated deaths.
The rate at which AMR develops has been linked to antibiotic-overuse, however, there are several other contributory factors, especially in LMICs, including environmental contamination, healthcare transmission and suboptimal diagnostics. While consumption of antibiotics in HICs is higher than in LMICs, there has been minimal increase over the past five years, contrasting with LMICs, where consumption of antibiotics continues to rise.
The magnitude of AMR in LMICs results from numerous factors, with poor hygiene, malnutrition, shortage of clean water and sanitation and poor healthcare systems all contributing.
Additionally, poor laboratory infrastructure in many African countries, and a paucity of population-based AMR surveillance data and the use of empiric v targeted antimicrobial treatment, would also contribute, as would inadequate infection prevention capacity due to limited resources, and lack of access to antimicrobials for treatable infections.
South Africa has not been spared the burden of AMR, with associated deaths at 17%, almost double those of higher income countries.
SA is part of the Global Antimicrobial Resistance and Use Surveillance system (GLASS) and reports on Enterococcus spp, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa and Enterobacter spp (ESKAPE) pathogens. These common healthcare-associated pathogens contribute to the AMR burden. While these data collected by the SA Society of Clinical Microbiologists (SASCM) provide a good understanding of AMR in healthcare-associated infections, data from the community setting are lacking.
As with other LMICs, the greatest mortality from AMR is associated with K. pneumoniae infections. Additionally, the number of bloodstream infections caused by A. baumannii is increasing, and now ranks third after K. pneumoniae and S. aureus in the public sector, surpassing E. coli.
A. baumannii easily develops resistance to antimicrobials and has been linked to several outbreaks in SA, especially in the neonatal setting.
In the private sector, E. coli remains a significant pathogen, ranking second after K. pneumoniae, while A. baumannii is less frequent and ranks sixth.
Recent data from academic hospitals in SA showed a 36% crude mortality rate for carbapenem-resistant Enterobacterales (CRE) bacteraemia, with K. pneumoniae the most frequently isolated pathogen (80%).
The most common carbapenemase gene associated with resistance was oxacillinase-48 (blaOXA-48-like), accounting for 73%. The metallo-β-lactamases, New Delhi metallo-β-lactamase (blaNDM) and Verona integron-encoded metallo-β-lactamase (blaVIM) contributed 21% and 1%, respectively.
SA’s antimicrobial use
Antimicrobial usage (AMU) data in LMICs are poorly reported and typically rely on import data or bulk dispensing from central medical stores. This is a crude measure, and direct prescription and dispensing data from doctor to patient would be more reliable.
The 2023 SA Report on AMU and AMR gives an annual growth of 50% for antibiotic consumption between 2020 and 2022, with private sector use increasing by 64%. Public data exclude non-tender items, buyouts and section 21 data. Private data exclude primary care prescribing and retail dispensing, and represent only two-thirds of private hospitals, as not all groups shared their data.
In 2017, the WHO introduced the AWaRe categorisation for antibiotics as a tool to support antibiotic stewardship at a local to global level.
A country-level target of at least 60% use of access antibiotics by 2023 was proposed. SA antibiotic consumption, according to the WHO AWaRe categories, was estimated at 75.6% access, 23.5% watch and ~1% reserve antibiotics in 2019.
This contrasts with the SA Report on AMU and AMR, which showed use of 48% access, 52% watch and ~0.03% reserve antibiotics for the period 2020 – 2022.
This report should be interpreted with caution, as reserve drugs like tigecycline, ceftazidime-avibactam (CA) and ceftolozone-tazobactam are not on tender, and colistin is only available by SAHPRA section 21 approval; therefore reserve antibiotic use may be underestimated. Also, global and national shortages of access antibiotics like parenteral penicillin and cloxacillin, may drive use towards watch antibiotics.
This highlights the need for reliable supply chain management for all antibiotics.
While consumption of reserve antibiotics between 2020 and 2022 increased in the public sector by 40%, there was a 20% decrease in reserve antibiotic use in the private sector. However, data from a single private site showed an increase in use of CA, from an average of 51 DDDs per quarter for 2022 to 101 DDDs per quarter for 2023 (personal communication, Warren Lowman).
Antibiotic access
Most of the reserve antibiotics available and registered in SA are not part of the essential medicines list (EML), and not on tender, resulting in higher costs and less predictable access.
The most commonly used are for drug-resistant Gram-negative infections, the highest burden of AMR.
These include Colistin, the side effects of which, especially renal toxicity, require frequent dose adjustment, especially in ICU patients with comorbid conditions, including renal impairment.
These and several other factors, including the availability of new antibiotics with improved outcomes, have resulted in colistin being largely discarded as a first-line recommendation in treatment guidelines for difficult-to-treat resistant Gram-negative bacteria.
However, it remains an important option due to lack of alternatives.
Tigecycline
Tigecycline is useful for drug-resistant intra-abdominal and skin and soft tissue infections, although it is considered unreliable in HAI pneumonias. It has a high volume of distribution and poor serum concentrations, making it less effective in primary bloodstream infections, and limiting its clinical utility, especially as monotherapy.
More recent meta-analyses have shown that high-dose tigecycline is associated with superior clinical and microbiological cure rates, reduced mortality and comparable adverse effects, compared with standard doses. Use in children aged <8 years remains problematic owing to the tooth and bone side-effects of tetracyclines and lack of dosing guidelines, especially in neonates.
Tigecycline isnt a counterintuitive targeted treatment option for monomicrobial infections from the perspective of antimicrobial stewardship.
New beta-lactam beta-lactamase inhibitors (BLBLIs)
In 2022, CA and ceftolazone-tazobactam were registered in SA. Recommendations for their use were published shortly afterwards, aimed at helping to steward the use of these two important antibiotics.
CA has particular use in treating CREs associated with blaOXA-48-like genes prevalent in K. pneumoniae in SA. There has been increasing experience across both the public and private healthcare system with this antibiotic, which is readily available in the private sector; however, in the public sector it’s limited to hospitals with access to carbapenemase testing as well as antibiotic susceptibility testing to CA.
CA has been shown to have both higher clinical cure rates (71% v. 51%, p=0.004) and lower occurrence of acute kidney injury (15% v. 33%, p=0.002) when compared with colistin.
In children, only two randomised controlled clinical trials describing safety and efficacy of CA have been published. These include children ≥3 months of age with complicated urinary tract infection (UTI) and intra-abdominal infection in well-resourced settings.
The use of CA outside these age and clinical indications, including in neonates, is based on pharmacokinetic modelling studies, extrapolation of clinical trial data and case reports. It is expected that the same improved outcomes with CA will be seen in SA, as evidenced by anecdotal reports of favourable outcomes.
However, with its increasing use, there is need for published CA usage and outcome data for the SA setting.
CA has recently been approved for use in the adult EML for targeted therapy for bloodstream infections in the ICU setting. With its addition to the EML, we expect improved access and decreased cost via the tender process.
Current stewardship practices in SA
In many SA institutions, public and private, there are robust antimicrobial stewardship programmes. Most of the private groups have clinical or ward pharmacists assisting with stewardship activities. Within the public sector, many provinces have stewardship committees and are training champions within these hospitals to drive these activities.
Many public sector hospitals, especially tertiary institutions, have authorisation policies for the prescription of precious broad-spectrum antibiotics such as the carbapenems.
With the recent launch of the new BLBLI agents, similar strict measures have been instituted to ensure their judicious use, including motivations to the pharmacy and therapeutics committee and restricted access under microbiological or infectious diseases approval.
This attention to antimicrobial stewardship is not always available at district and regional public sector hospitals, with some staff reporting limited educational activities surrounding antimicrobial stewardship, and only 50% reporting successful local antimicrobial stewardship programmes.
Within the private sector groups, these activities include completion of BLBLI checklists requiring both microbiological or infectious disease input, and then being signed off by regional clinical pharmacists, and clinical pharmacists within other groups monitoring the appropriate use of these new agents and instituting interventions when they are inappropriately used.
Funders request letters of motivation as well as submission of culture and blood results to ensure appropriate use before agreeing to fund new agents.
However, mostly clinicians in private hospitals work independently with no regulation of antibiotic prescribing. These current governance policies should act as a framework for introduction of new antibiotics into the SA market.
Antimicrobial stewardship requires the same governmental backing – human and financial resources – to guide the introduction of new clinically relevant drugs into SA. This can be accomplished by a new One Health antimicrobial resistance directorate with dedicated human and financial resources to lead policy implementation around antimicrobial resistance.
Built on the already developed framework of the MAC on antimicrobial resistance, it should include representation from strategic stakeholders, including the Department of Health, private institutions, lab providers and public health authorities, as well as representation from One Health colleagues, public communications, information technology and data support.
Antimicrobial resistance requires both clinical and administrative expertise and drive.
Urgent need
Antimicrobial resistance is increasing in SA, shifting AMU towards broader-spectrum watch antibiotics. Reserve antibiotic use is still low, thanks to lack of equitable access countrywide, but use is increasing, and major gaps exist in our antibiotic armoury.
Newer reserve antibiotics appropriate to the evolving AMR landscape must be introduced urgently, responsibly, to provide appropriate and effective treatment options while retaining effectiveness in the future.
Study details
The changing landscape of antimicrobial resistance and use in South Africa: The need for access to new antibiotics: A position paper
H Finlayson, V Chibabhai, P Jeena, S Kolman, W Lowman, T C Manzini, T Nana, J Nuttall, A Parker, P Skosana, V Ueckermann, A Wise.
Published in the SA Medical Journal in October 2024
Antibiotic resistance is a global threat, with a disproportionate burden of mortality in low- and middle-income countries. It is increasing in both the public and private healthcare sectors within South Africa, especially in Gram-negative organisms, and is associated with increased use of World Health Organization watch and reserve antibiotics. There is a need for improved access to new antibiotics to treat infections caused by drug-resistant organisms in order to limit side-effects and improve patient outcomes of currently available antibiotics. We propose the responsible introduction of these new antibiotics with both administrative and clinical oversight in order to preserve the longevity of these precious antibiotics.
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