Antimicrobial stewardship: Primary care can build on recent gains

Antimicrobial resistance (AMR) is largely driven by the use of antimicrobial drugs in humans, and also in animals, plants and the environment. The volume of antimicrobial use in human health is high in Aotearoa New Zealand compared with many other countries.^1,3 Encouragingly, in recent years, there have been positive trends that show our antimicrobial use does not need to be so high.

During COVID-19 lockdown it decreased by a significant 36 per cent with no evidence of harm⁴ (much of this reduction would be due to less use of antibiotics for viral respiratory tract infections in general). Prior to that, a modest 14 per cent decrease in use was recorded across 2015 to 2018 (an average reduction of 3.5 per cent per year), mainly due to reductions in antimicrobial use in under five-year-olds.⁵

It has been suggested that the reductions seen between 2015 and 2018 may reflect changing attitudes due to sustained clinician-led efforts to discourage inappropriate antimicrobial use,⁶ and it is hoped there is greater public awareness of viral illnesses not being helped by antibiotic use through our collective experience with COVID-19.

The task is to build on these gains, and particularly in primary healthcare. What limited resource there is to support appropriate antimicrobial use focuses on public hospitals rather than community healthcare.⁶ Ironically, 95 per cent of our antimicrobial use is in the community⁷ and up to half of this may be inappropriate.⁸

The purpose of this article is to provide an overview of the ongoing high-level initiatives for improving antimicrobial stewardship (AMS), the New Zealand antimicrobial prescribing landscape as it stands, and actions in areas that can immediately improve AMS in primary healthcare, by:

• ensuring good antimicrobial handling and prescribing practice, including the addition of a meaningful indication on every antimicrobial prescription
• addressing penicillin allergy.

The healthcare system, government and population of New Zealand has received praise internationally for its collective response to the COVID-19 pandemic. An equally commendable strategy must also urgently be implemented to counter the gradually developing – but also likely as catastrophic – pandemic of antimicrobial resistance.

“AMR is the developed resistance of a microorganism (bacterium, virus, fungus or parasite) to an antimicrobial agent that it was originally susceptible to. AMR occurs naturally, but is facilitated by antimicrobial use, and inadequate infection prevention and control.”⁶

The core required strategy of antimicrobial stewardship is an established concept, implemented with greater success in many other countries, including Australia. “AMS aims to optimise the use of antimicrobial agents in the prevention and treatment of infections, and minimise the potential harms that may result from their use including AMR, adverse drug reactions and excessive healthcare costs. An AMS programme includes governance, surveillance of the quantity and quality of antimicrobial use, education and training, and implementation of quality improvement initiatives.”⁶

In New Zealand, the development of AMS as a “joined-up” strategy to be implemented across the health sector can be described as slow, siloed, often conflicting and, in areas of primary care, lacking. The new Ngā Paerewa Health and Disability Services Standard sets minimum AMS requirements that some service providers (eg, residential care, public hospitals) must meet to be certified under the Health and Disability Services (Safety) Act 2001.⁹ The inability to include all of primary care within this standard could be rectified by developing a separate clinical care standard for antimicrobial stewardship that applies to all who prescribe, dispense or administer antimicrobials.⁶

AMS and infection prevention and control (IPC) are two human health components within a wider New Zealand AMR Action Plan, which sets out a One Health approach to addressing AMR that acknowledges relationships between human health, animal health, agriculture and the environment.² Nearing the end of this five-year action plan, progress in human health has been poor.⁶ Despite the science and solutions being clear (New Zealand being a member of the Global Health Assembly and having aligned with The Tripartite Global Action Plan on Antimicrobial Resistance 2015)¹⁰ implementation has fallen short. Almost none of the recommendations in the 2017 action plan have been put into place, even though the “bar was set low” to see what could be achieved without additional investment.¹

Opinion leaders – Te Whatu Ora Health New Zealand AMS pharmacists, infectious disease physicians, clinical microbiologists and other experts – continue to push for national leadership and co-ordinated efforts on AMS, most recently in a 2021 New Zealand Medical Journal viewpoint.⁶ A key stakeholder group, the New Zealand Antimicrobial Stewardship and Infection Pharmacist Expert Group (NAMSIPEG), has also led promotion of good AMS practices and activities for World Antimicrobial Awareness Week (WAAW).¹¹ For 2020, it led a national initiative to improve indication documentation on antimicrobial prescriptions, and for 2021 it led a national initiative focusing on penicillin allergy.^12–14

These are component parts to AMS and are applicable in primary care. For WAAW 2022 (18–24 November), NAMSIPEG is promoting best practice for the disposal of antimicrobials.

The implications of AMR for New Zealanders and the imminent threat it represents have been made plain by the Royal Society Te Apārangi in 2017¹⁵ and the Office of the Prime Minister’s Chief Science Advisor in 2021.¹ Estimates suggest, without urgent action, infections due to resistant microorganisms could kill 10 million people globally each year by 2050.¹⁶ A systematic analysis published in The Lancet in 2022 has already estimated global mortality in 2019 attributable to bacterial AMR to be approximately 1.3 million, with almost 5 million deaths associated with bacterial AMR, according to the predictive model used.¹⁷

The consequences of increases in AMR for New Zealand will be enormous given the reliance we have on effective antimicrobial therapy throughout medicine. What is certain is that AMR will disproportionately impact the most socioeconomically disadvantaged New Zealanders.¹ Rates of some infections, including sepsis, in Māori and Pacific peoples are about twice those in people of European descent and other ethnic groups, and rates are significantly above average in the youngest, oldest and most deprived population groups.¹⁸

One of the biggest drivers for AMR is antimicrobial use. Antimicrobial use in New Zealand human populations is high compared with many developed countries^7,19 as indicated by having:

• the fourth highest level of antibiotic prescribing (measured in defined daily dose per 1000 people) in 2017, surpassed only by Greece, Italy, and Korea^1,3
• a community antibacterial consumption rate that increased 49 per cent between 2006 and 2014¹⁹
• near-universal (97 per cent) antibiotic exposure by school age²⁰
• 95 per cent of human antibiotic use being in the community.⁷

Small positive trends can be found. Over three years (2015 to 2018) community antibiotic use reduced by 14 per cent, mainly due to reductions in children under five years old.⁵ And during lockdown (2020), antimicrobial use decreased considerably, by 36 per cent, without evidence of harm.⁴ Thus, much of the previous “usual” antibiotic use may have been for viral respiratory tract infections, and unnecessary.

The consequence of antimicrobial use is that it produces selection pressure on the microbial environment and promotes a proliferation of resistant strains with the potential for harm.² Multi-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and ciprofloxacin-resistant Neisseria gonorrhoeae already challenge clinical care in this country. However, the steadily increasing incidence of infections caused by multi-resistant Enterobacterales, such as Escherichia coli and Klebsiella pneumoniae, in hospitalised and community patients, are of greatest concern.^20–22

• Extended spectrum β-lactamase-producing Enterobacterales (ESBL-E) are resistant to most penicillins and cephalosporins, and often also to other unrelated agents like trimethoprim and ciprofloxacin.
• Carbapenemase-producing Enterobacterales (CPE) are resistant to almost all antimicrobial agents, including “ultra-broad-spectrum” carbapenems (a sub family of β-lactams mainly used in hospital settings), and have 30 to 50 per cent mortality when they cause invasive infections.²³ The Institute of Environmental Science and Research (ESR) recorded a greater than 10-fold increase in identified CPE isolates during 2010–2019.²²

At the patient–clinician level, the impact of an infection due to a multi-resistant pathogen means:

• reduced, and in some cases no, effective funded oral antimicrobials (this is increasingly seen with cystitis due to ESBL-E in the community)
• reduced efficacy when using second-line antimicrobials
• higher toxicity and rates of adverse effects from the use of second-line agents
• patient cost/inconvenience with hospital visits for antimicrobial therapy (affecting rural/low socioeconomic groups disproportionately)
• longer hospital stays
• poorer outcomes from surgery (eg, joint replacement), cancer care and other interventions
• increased mortality
• elevated healthcare costs.⁶

In addition to the selection pressure for AMR caused by antimicrobial use, adverse drug events (ADE) are also common when antimicrobials are used. A 2017 study found 20 per cent of hospitalised patients in the US receiving at least 24 hours of antibiotic therapy developed an antibiotic-associated ADE. Moreover, 20 per cent of ADEs were attributable to antibiotics prescribed for conditions for which antibiotics were not indicated.²⁴

The overarching goal of AMS is wider than counteracting AMR alone – it is to improve patient outcomes as well. Prescribing a first-line antibiotic choice, where one is indicated and appropriate, helps to achieve improved patient outcomes, partly by reducing the risk of ADEs. Non-β-lactam antibiotics are commonly used as second-choice agents, but they carry a raised ADE risk, eg, hyperkalaemia with trimethoprim + sulfamethoxazole. Adverse effects with quinolone antibiotic use are numerous and they have led to US Food and Drug Administration²⁵ and European Medicines Agency²⁶ warnings regarding their use. First-line antibiotic prescribing helps to avoid this risk.

Patient outcome is also impacted by the effect of antibiotic use on the microbiome, which can result in greater risk for infection associated with Clostridioides difficile (formerly named Clostridium difficile) or candida.

Antimicrobials are the only class of medicine where the treatment decisions made for an individual have broader ramifications for their whānau and the wider community. This means that decisions around treating infections affects the outcomes for patients in general, not just the one sitting in front of you.

Antimicrobial stewardship involves co-ordinated strategies designed to measure and support appropriate antimicrobial use. The overarching aims are to improve patient outcomes by managing infections optimally while minimising antimicrobial-related harms, including AMR, toxicity and cost.

Among the strategies for AMS lies a central principle – one that can be applied as well by all prescribers in primary healthcare as it can in the hospital setting. That is, understanding the indication for antimicrobial use underpins all assessments of the quality (appropriateness) of antimicrobial prescribing, including guidelines compliance.

Inclusion of a meaningful indication for antimicrobial use on the prescription is a key quality indicator for AMS as it promotes good practice and outcomes (see panel). There is no nationally set target for this indicator, but NAMSIPEG recommends aiming for ≥95 per cent of prescriptions being annotated with a meaningful indication (this aligns with the equivalent quality indicator used in Australia).¹³

A meaningful indication for antimicrobial use included on the prescription means being specific. It does not mean writing a very general term like “infection” but, for a urinary tract infection for example, terms like “cystitis”, “lower UTI”, or “pyelonephritis” are meaningful.

Once the prescriber has arrived at an understanding of the indication for a proposed use of an antimicrobial, the following further considerations can help make sure both the antimicrobial and the patient are “handled with care”:

• Only use the antimicrobial if the benefits outweigh the harms – never “just in case” or to alleviate “worry”.
• If the antimicrobial is warranted, use it optimally – the “right” agent, dose, route and duration.
• Use the prescription to justify antimicrobial use – document a meaningful indication (see above).
• Determine and document the treatment duration or a review date – most courses should be short and sharp (check local guidelines and engage with speciality services if needed).
• If the patient has a documented “penicillin allergy”, consider a review of how this was determined (see the following section on penicillin allergy to decide whether a challenge to its veracity is appropriate).

Penicillin allergy is the most common adverse drug reaction to be reported. However, our understanding of this has evolved in recent years – what you learned in training may no longer be current, and it may be challenging to unlearn. While approximately 10 per cent of adults believe they are allergic to penicillin, about 90 per cent of these people do not have a true immune-mediated allergy. Reactions such as nausea, diarrhoea or thrush often occur with antibiotics but are side effects not allergies.

A further point to consider is that antibiotic allergies will often resolve over time – approximately 50 per cent of skin prick test-positive penicillin allergies are lost over five years, and about 85 per cent over 10 years.¹⁴ Consequently, a reaction to penicillin during a childhood infection is unlikely to be a true allergy in adulthood. However, with any history of presumed immune-mediated reaction (eg, a delayed non-severe reaction or mild rash), an oral rechallenge with low-dose penicillin (usually amoxicillin) is possible to confirm safety before prescribing a therapeutic course. This is usually done in a hospital environment.²⁷

Incorrect “penicillin allergy” labels cause harm as they often lead to the use of second-line antibiotics that are less effective, broader spectrum and/or more toxic.¹⁴

Having a penicillin allergy label has been associated with:

• an increased risk of Clostridioides difficile, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci infections and colonisation
• increased use of broad-spectrum antibiotics, contributing to AMR
• lengthier hospital stays
• higher hospital readmission rates
• surgical site infections
• admissions to intensive care units.²⁷

A study of 2.3 million general practice adult patients in the UK found penicillin allergy labels are associated with a significantly increased risk of death in the following year (relative risk 1.08), re-prescription of a new antibiotic class within 28 days (RR 1.32), and MRSA infection or colonisation (RR 1.90), when compared with patients with no penicillin allergy label.²⁷

Based on the numbers, most patient penicillin allergy labels can be removed, but the heart of the matter for primary healthcare is which ones can be safely removed with a patient interview and notes review alone? Formal referral pathways for oral challenges are not yet established for primary care. Thus, a focus on patients in the “negligible risk” category is needed; they may be de-labelled following interview and notes review alone (with no need for oral amoxicillin challenge or engagement with speciality services). Check, however, for local policies or guidelines.

The medical records for patients at “negligible risk” for penicillin allergy label removal will reflect the penicillin having caused one or more of the following:

• expected gastrointestinal side effects (eg, nausea, vomiting, diarrhoea)
• thrush (any kind)
• mild, reversible kidney, liver or neurological dysfunction
• allergy reported but the same antibiotic tolerated subsequently
• family history of penicillin allergy only.

Penicillins are a group of antibiotics that are often a first-choice treatment for infection because they tend to be more effective and cause fewer problems such as side effects. Patients can be reminded of this, and many other helpful patient messages can be found in the Challenge your penicillin allgergy resource produced by NAMSIPEG.²⁸

Where a true immune-mediated penicillin allergy is reasonably considered to exist, this does not mean other β-lactam antibiotics cannot be used – sometimes, they can be. Cross-reactivity is less than 2 per cent with cephalosporins and less than 1 per cent with carbapenems but this varies with chemical structure. Advice from infectious diseases and/or immunology specialists should be sought. It is also worth noting that microbiology can sometimes offer additional antibiotic choices for a patient with severe penicillin allergy as they may not release all susceptibility results initially. NPS Medicinewise provides a practical approach to assessment and prescribing with penicillin allergy.²⁹