Tackling Antibiotic Resistance

In Aotearoa, the spread of antibiotic resistance follows patterns observed worldwide. Examples include mupirocin resistance in Staphylococcus aureus, which increased from less than 5% to more than 20% in strains tested by laboratories in Tāmaki Makau Rau within just 8 years. Similarly, ciprofloxacin resistance in Neisseria gonorrhoeae jumped from less than 2% to more than 40% between 2000 and 2012.

Extended-spectrum beta-lactamase producing (ESBL+ve) bacteria illustrate the rapid acceleration of resistance: seven such bacteria were isolated from patients in Aotearoa in 1998, but by 2012, over 5,000 ESBL+ve bacteria were isolated annually. These bacteria require treatment with meropenem or related carbapenem antibiotics administered intravenously. Yet resistance to meropenem is also increasing, with cases of patients with meropenem-resistant E. coli, K. pneumoniae or related bacteria rising from just one person in 2009 to 223 people in 2023.

The Global Burden of Disease (GBD) 2019 study revealed the true scope of this crisis. An estimated 1.27 million global deaths were attributed to drug-resistant bacterial infections in 2019, affecting all age groups in all regions, with low and middle-income countries bearing the heaviest burden. Five pathogens - Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae and Pseudomonas aeruginosa - were responsible for 55% of deaths.

In Aotearoa, community antibiotic dispensing rates are notably high compared to other nations. The national rate of community dispensing of beta-lactam antibiotics in 2018 was 12.9 defined daily doses (DDDs) per 1,000 population per day, more than four times the rate in Hōrana (the Netherlands) and more than twice the rates in Nōwei (Norway) and Huītene (Sweden). These high rates have led to higher prevalence of resistance, with methicillin-resistant S. aureus (MRSA) comprising 12.7% of all S. aureus isolates in Aotearoa, much higher than in Hōrana (1.2%), Huītene (1.9%) or Nōwei (0.9%).

A key driver of resistance is inappropriate antibiotic prescribing. In Aotearoa, there is substantial evidence that a large proportion of antibiotic use provides minimal or no benefit. A 2014 study reported that antibiotics were dispensed following 61% of consultations for acute respiratory tract infections at general practices in Aotearoa, a very high rate compared to many other countries.

Increases in antibiotic dispensing in takurua (winter in Māori) provide another measure of inappropriate prescribing. Total per capita antibiotic dispensing was 26% higher in takurua months than matiti months in Aotearoa during 2014-2015, with similar increases across all ethnic groups: 35% in Asian people, 31% in Middle Eastern, Latin American and African people, 29% in Pacific people, 28% in Māori people and 25% in European people. Countries with more appropriate prescribing, such as Tenemāka (Denmark) and Peretānia, show much lower increases in takurua.

Studies suggest that reducing antibiotic use can be accomplished safely. A study of 45 million person-years of observation in Peretānia found that a 10% reduction in antibiotic prescribing for respiratory tract infections would result in one more case of pneumonia per year for a practice with 7,000, and one more case of peritonsillar abscess each decade. A subsequent larger study of 66 million person-years found no association between rates of antibiotic prescribing and risk of serious bacterial infections.

Aotearoa experienced a natural experiment during the COVID-19 pandemic. There was a 36% reduction in community antibiotic prescriptions during weeks 15-20 in 2020 compared to the same periods in previous years. These reductions were not associated with any increase in hospital admissions for pneumonia, peritonsillar abscess, or rheumatic fever.

The World Health Organization has outlined strategic priorities to address drug-resistant bacterial infections in the human health sector for 2025-2035. These include:
• Prevention of infections that lead to antibiotic use through improved hygiene, infection control, and vaccination.
• Universal access to quality diagnosis and appropriate treatment of infections
• Strategic information and innovation, including surveillance of resistance and consumption, research, and development of new treatments

Implementation requires a people-centered approach with four programmatic pillars plus strategic information and governance foundations. The core interventions include universal access to water, sanitation and hygiene; implementation of infection prevention and control; expanded immunization; accessible and affordable diagnosis and management services; quality laboratory systems; evidence-based treatment guidelines; antibiotic stewardship programs; and regulation of non-prescription antimicrobials.

Countries with successful reduction strategies include Wīwī (France), which launched a nationwide campaign to decrease total antibiotic use by 25% and achieved a 26.5% reduction over five years. Ingarangi (England) implemented financial rewards for clinical commissioning groups that reduced antibiotic prescriptions, resulting in an 8.2% decrease in total antibiotic prescriptions and an 18.9% decrease in broad-spectrum antibiotic prescriptions. Huītene set a national target of fewer than 250 antibiotic prescriptions per 1,000 inhabitants per year, which was achieved in 19 out of 21 regions by 2020.

While reducing inappropriate use is clearly pressing, new antibiotics are also needed. Several promising approaches are emerging: Exploring "Unculturable" Bacteria Researchers have identified novel antibiotics by developing methods to access the 99% of soil bacteria that cannot be cultured using standard laboratory techniques. Examples include teixobactin and clovibactin, which bind to lipid II, a precursor of peptidoglycan, and form fibrils that sequester this essential building block and damage bacterial cell membranes.

Since penetrating bacterial membranes is challenging, some researchers are developing antibiotics that target components on the bacterial surface. Murepavadin targets the LPS translocon LptD, while other peptidomimetic antibiotics inhibit the BamA insertase that facilitates the folding and insertion of outer membrane proteins. Darobactin, a natural compound from a nematode symbiont, also targets BamA.

Researchers are using genomic analysis to identify novel antibiotic candidates. By screening bacterial genomes for biosynthetic gene clusters and creating phylogenetic trees, scientists have identified candidates like macolacin, which remains effective against bacteria resistant to colistin, and cilagicin, which sequestors two distinct, indispensable undecaprenyl phosphates used in cell wall biosynthesis.

Now Deep learning approaches are accelerating antibiotic discovery. One team established a training set of approved drugs and natural products, then used a neural network model to screen millions of compounds. This identified Halicin, a compound that dissipates the membrane proton motive force and is active against carbapenem-resistant Enterobacteriaceae and other resistant bacteria.

The development of antibiotic resistance remains a significant public health challenge in Aotearoa and globally. While research indicates that reducing inappropriate antibiotic use can be done safely and effectively, addressing this crisis requires a multifaceted approach including stewardship programs, investment in new technologies, and international cooperation.

As translators, we follow these developments closely as we work with health systems across Pacific Island nations, where accessible information about appropriate antibiotic use in local languages is essential for community engagement.