The widespread use of antibiotics has extended the average life expectancy of humans by an estimated two decades. However, over the past few decades, antimicrobial resistance (AMR) has increased dramatically and the World Health Organization (WHO) warns that it is rising to dangerously high levels in all parts of the world.Inappropriate use of antibiotics is the primary driver of the alarming rate at which AMR is increasing.1,2

Inappropriate use of antibiotics is the primary driver of the alarming rate at which antimicrobial resistance is increasing.

The Covid-19 pandemic is an excellent example of the inappropriate use of antibiotics. Although antibiotics are not effective against viral infections, the outbreak of the Covid-19 pandemic at the end of 2019 saw a huge spike in the prescribing of these agents worldwide – especially at the start of the pandemic.3

Antibiotic use tracked with the number of Covid-19 patients hospitalised. Hospitals in the highest quartiles of Covid-19 cases showed greater increases in antibiotic use as well as subsequent increases in AMR.4  

Nosocomial pathogens identified in hospitalised patients with Covid-19 demonstrated a 42% increase in methicillin-resistant Staphylococcus aureus and a 134% increase in extended-spectrum β-lactamase–producing gram-negative bacteria.4

According to Henig et al several studies and meta-analyses have shown that around 70% of hospitalised patients with Covid-19 were treated with antibiotics. This may have been as a result of concerns about bacterial co-infections and because the clinical manifestations of severe Covid-19 are often indistinguishable from those of bacterial infection (eg acute onset, fever, increased inflammatory markers, and organ failure).3

In their review, Lansbury et al showed that bacterial co-infection in hospitalised patients with Covid-19 were low (7%) compared to for example patients hospitalised for influenza (30%). Bacterial co-infections were however higher in patients (14%) treated in the intensive care units (ICUs). In these patients, the commonest bacteria were Mycoplasma pneumonia, Pseudomonas aeruginosa and Haemophilus influenzae.5

Calderón-Parra et al showed that 34.2% of antibiotic prescriptions in Covid-19 patients were inappropriate and ultimately led to avoidable complications, including increased AMR, Clostridioides difficile infections, renal impairment, pharmacological hypertransaminasemia, drug-induced diarrhoea, rash/allergy caused by antibiotics, diarrhoea, invasive and non-invasive candidiasis, QT prolongation, drug-induced neutropenia, and drug-induced thrombocytopenia.6

Younger age, less comorbidity, and the presence of dry cough, flu-like symptoms, fever, bilateral interstitial infiltrates, and increased C-reactive protein levels were independently associated with inappropriate prescribing. The occurrence of complications potentially resulting from pharmacologic prescription was more frequent in patients with antibiotics (19.6% vs 10.5%).6

The authors stress that by inappropriately prescribing antibiotics, patients with Covid-19 were exposed to pharmacological toxicity and increased risk of morbidity despite the fact that no benefits have been proven, even in critical patients.6

Although clinicians learned from experience as the pandemic progressed, and numerous studies reported that bacterial or fungal infections at presentation were relatively infrequent, inappropriate antibiotic use remained a significant issue.4

As a result, several groups have sounded the alarm and requested the intervention of antimicrobial stewardship (AMS) programmes in these patients.6

Why antimicrobial stewardship programmes are crucial

Antibiotic stewardship can be defined as a ‘coordinated set of actions aimed at promoting prudent use of antimicrobials, with the ultimate goal of optimising clinical outcomes while minimising the unfavourable consequences including resistance as well as adverse drug reaction’.7

According to the American Centres of Disease Control and Prevention (CDC), effective AMS programmes can help clinicians improve clinical outcomes and minimise harms by improving antibiotic prescribing.8

A 2017 Cochrane review based on more than 200 studies from diverse settings, found that AMS programmes reduced the duration of antibiotic treatment by 1.95 days. The risk of mortality, however, was similar between intervention and control groups (11% in both arms), indicating that antibiotic use can likely be reduced without adversely affecting mortality. AMS programmes also reduced hospital stay by 1.12 days.9

Karanika et al compared the economic impact of AMS programmes pre- and post-implementation (six months to three years). They found that the pooled percentage change of total antimicrobial consumption after the implementation of AMS programmes was 19.1%, and the use of restricted antimicrobial agents decreased by 26.6%. In intensive care units, the decrease in antimicrobial consumption was 39.5%.10

The use of broad-spectrum antibiotics (18.5% for carbapenems and 14.7% for glycopeptides), the overall antimicrobial cost (33.9%), and the hospital length of stay (8.9%) decreased.10

Among hospital pathogens, the implementation of an AMS programme was associated with a decrease in infections due to methicillin-resistant Staphylococcus aureus (risk difference [RD] 0.017), imipenem-resistant Pseudomonas aeruginosa (RD 0.079), and extended-spectrum beta-lactamase Klebsiella spp (RD 0.104).10

Baur et al evaluated the evidence of the effect of AMS programmes on the incidence of infections and colonisation with antibiotic-resistant bacteria. They found that AMS programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria (51%), extended-spectrum β-lactamase-producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%), as well as the incidence of C difficile infections (32%).11

AMS programmes were more effective when implemented with infection control measures, especially hand-hygiene interventions than when implemented alone.11

Schuts et al found that the implementation of AMS programmes improved clinician adherence to guideline recommendation, de-escalation of therapy, switch from intravenous to oral treatment, therapeutic drug monitoring, use of a list of restricted antibiotics, and bedside consultation. Guideline-adherent empirical therapy was associated with a relative risk reduction for mortality of 35% and for de-escalation of 56%.12 

In the United States, implementation of AMS programmes in hospitals are mandatory. According to Barlam, the value of AMS programmes was reinforced during the Covid-19 pandemic because these programmes were instrumental in monitoring antibiotic use, assessing emerging Covid-19 therapies, and coordinating implementation of monoclonal antibody infusions and vaccinations.4

Core components of an effective AMS programme

The CDC identified seven core components of an effective AMS programme:8

  1. Hospital leadership commitment:Dedicate necessary human, financial and information technology resources 
  2. Accountability:Appoint a leader or co-leaders, such as a physician and pharmacist, responsible for programme management and outcomes.
  3. Pharmacy expertise:Appoint a pharmacist, ideally as the co-leader of the stewardship programme, to lead implementation efforts to improve antibiotic use.
  4. Action:Implement interventions, such as prospective audit and feedback or pre-authorisation, to improve antibiotic use.
  5. Tracking:Monitor antibiotic prescribing, impact of interventions, and other important outcomes like  difficile infection and resistance patterns.
  6. Reporting:Regularly report information on antibiotic use and resistance to prescribers, pharmacists, nurses, and hospital leadership.
  7. Education:Educate prescribers, pharmacists, and nurses about adverse reactions from antibiotics, ABR and optimal prescribing.

Barriers to the successful implementation of ASM programmes in resource-poor settings

Kakkar et al investigated the barriers that need to be overcome to successfully implement AMS programmes in resource-poor settings. They identified the following stumbling blocks complicating the successful implementation of AMS programmes:7

  • A lack of clear political commitment
  • Inadequate funding
  • Overcrowded healthcare systems
  • Lax legal and regulatory frameworks
  • Non-uniform access to diagnostics
  • Absence of electronic health record systems,
  • Limited knowledge, and awareness especially with existence of multiple systems of medicines
  • Issues with access to quality assured medicines
  • Shortage of trained manpower.

The South African government has shown commitment to limit ABR in the country with the development of a National ABR Strategy Framework in 2014. Chetty et al reviewed the extend to which AMR programmes have been implemented in the public and private healthcare systems in South Africa.  According to the authors, AMR programmes have been implemented in some public and private healthcare facilities in the country, ranging from small quality-improvement projects to fully set-up AMR programmes. The team identified some challenges that hinder the successful implementation of AMR programmes in South Africa:13

  • A study across eight primary healthcare facilities demonstrated that adherence to treatment guidelines were poor, with less than 50% of the prescriptions adhering to treatment guidelines.
  • The Prevalence of Infection in South African ICUs study showed that there were inappropriate prescribing practices across intensive care units in both the public and private sectors.
  • Medical students are ill-prepared for antimicrobial prescribing. A study assessing the knowledge and attitudes of final-year South African medical students towards AMS found that only 33% felt confident in prescribing antibiotics whilst 95% felt they needed more education on the appropriate use of antibiotics. A similar outcome was obtained from a study on final-year pharmacy students. Although 83.5% of the respondents claimed that they knew what AMS was, 90% would like more education and training on AMS concepts.
  • There is a lack of a coordinated standardised training programme for AMS in South Africa. Standardisation of education within the undergraduate curriculum for all healthcare professionals could have a beneficial effect on reduction of AMR.
  • There is a lack of knowledge-sharing between the public and private sectors as well as standardisation of prescribing guidelines.

Can these barriers be overcome?

Kakkar and team from India developed a model for the effective implementation of an ARM programme in their resource-poor settings, which took them about six years to implement. This is what they did:7

  1. Implement an effective prospective audit and feedback system

A typical prospective audit and feedback activity requires a cross functional team comprising a physician (usually an infectious diseases specialist), a microbiologist, and clinical pharmacists. Several studies have shown that these roles are not sacrosanct and various healthcare professionals with adequate expertise and motivation can be trained optimally to perform AMS activities. They utilised nurses and pharmacy students.

  1. Develop an effective educational programmes

Kakkar and team introduced several educational initiatives including for example routine and special case discussions, AMS rounds with bite-sized information sessions given bedside, focussed didactic sessions, disseminating antimicrobial snippets through staff/work mobile phones, dedicated nurse demonstrations, day-long continuing medical education and training programmes for healthcare professionals.

  1. Optimise surgical antibiotic prophylaxis

The team carried out an initial audit aimed to understand the pattern of surgical prophylaxis practices across the healthcare facility. They observed wide variations in prescription practices not only among different departments but also within the same department among various units. Further, the antimicrobials were being continued for durations much longer than recommended and the choice of antibiotics was also not in consonance with guidelines. The clinicians made these choices based on their apprehension of inadequate sterilisation techniques, environmental contaminants, and lack of availability of antimicrobial sensitivity data to support the recommended practices. The susceptibility data, although, being circulated periodically remained underutilised in policy formulation. With this background, the AMS team decided to start the stewardship within a single surgery unit, where it was proposed that suggested modifications of the prophylaxis regimen will be followed. The patients were followed for the development of surgical site infections as well as hospital-acquired infections. Though surgical prophylaxis is not directed against hospital-acquired infections, the team included it as a part of confidence-building measure. The data obtained was discussed with the faculty members of the unit. It was then suggested that they develop a consensus guideline with all the consultants participating in the process.Following the development and implementation of the guidelines, a system for conducting regular audits was simultaneously initiated. These audits not only help in assessing the extent of adherence but also analysing and subsequently addressing the reasons behind any future deviations.

  1. Develop evidence-based guidelines

ICUs are major areas where high end and often multiple antimicrobials are used for prolonged durations in critically ill patients. The team felt that it was crucial to have a guidance document to enable the residents and consultants to have a guidance document on which to base their antibiotic prescribing decisions. Since the profiles of patients presenting to individual ICUs are not homogenous, it was thought that the best way to go about it would be to have ICUs internally discuss and formulate a policy suited best for themselves. They were encouraged to seek advice from AMS programme teams during the process. In follow up of this, the ICU representatives made a presentation of the policies developed by internal consensus. The comments and suggestions made during the meeting were communicated to the ICU in-charge and the nodal persons. These were appropriately addressed and a revised policy was submitted for finalisation. In this meeting, the representatives of various ICUs put forth the idea that mechanisms should be set in place for wide dissemination of these guidelines and audit and feedback procedures. It was clarified that the guidelines were not intended to replace the critical evaluation and judgement that underpin the formulation of appropriate treatment plan in an individual case. Additionally, individual ICUs were advised to revise these guidelines at a period of not more than two years on the basis of their own antibiograms.

Kakkar et al recommend implementing an AMR programme using a plan-do-check-act (PDCA) model to improve the efficiency as well as the likelihood of success of the programme. As in other situations where applied, this iterative PDCA cycle (see Figure 1) results in quicker troubleshooting and continuous improvements in the system.7

Conclusion

The dangers of a post-antibiotic era have prompted policymakers to acknowledge this threat to human health. The world urgently needs to change the way it prescribes and uses antibiotics. Even if new medicines are developed, without behaviour change, AMR will remain a major threat. Without urgent action, states the WHO, we are heading for a post-antibiotic era, in which common infections and minor injuries can once again kill.2

REFERENCES:
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  3. Henig O, Kehat O, Meijer SE, et al. Antibiotic Use during the COVID-19 Pandemic in a Tertiary Hospital with an Ongoing Antibiotic Stewardship Program. Antibiotics (Basel), 2021.
  4. Barlam TF. The state of antibiotic stewardship programs in 2021: The perspective of an experienced steward. Antimicrobial Stewardship & Healthcare Epidemiology, 2021.
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  8. Core Elements of Hospital Antibiotic Stewardship Programs. https://www.cdc.gov/antibiotic-use/core-elements/hospital.html
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