|Year : 2019 | Volume
| Issue : 2 | Page : 60-65
Clinical and cost-effectiveness of antimicrobial stewardship programmes
Pooja Shivananda Siddhi1, Mitul Patel2
1 Department of Microbiology, Birmingham Women's and Children's Hospital; Department of Paediatric, Birmingham City and Sandwell Hospital Trust, Birmingham, England
2 Department of Microbiology, Birmingham Women's and Children's Hospital, Birmingham, England
|Date of Submission||02-Apr-2019|
|Date of Decision||21-May-2019|
|Date of Acceptance||26-Oct-2019|
|Date of Web Publication||17-Jan-2020|
Dr. Pooja Shivananda Siddhi
Siddhi, Birmingham City and Sandwell Hospital Trust, Dudley Road, Birmingham B18 7QH
Source of Support: None, Conflict of Interest: None
Antimicrobial resistance is on an increasing trend worldwide. The WHO has declared it to be a 'Global Threat' in the year 2015. Due to this growing concern, antimicrobial stewardship (AMS) programmes have been implemented all over the world in the last few decades. The main challenge in AMS programme is the long-term sustenance, and hence, there is no worldwide agreed consensus on the 'best' AMS strategies. This review article provides an overview of the evolution of AMS strategies through the years and highlights the clinical effectiveness and cost-effectiveness of the strategies implemented till date.
Keywords: Antimicrobial stewardship, clinical effectiveness, cost-effectiveness
|How to cite this article:|
Siddhi PS, Patel M. Clinical and cost-effectiveness of antimicrobial stewardship programmes. J Acad Clin Microbiol 2019;21:60-5
| Introduction|| |
The First World War marked the very beginnings of infection control and the evolution of antibiotics. There were soldiers dying of wound infections, and the antiseptic measures and treatment available were unavailing. By 1915, infection was the major cause of death. Tremendous research was done during four years of the First World War, where management of infections evolved in many aspects such as sanitation, hygiene measures, use of antiseptics and vaccine introduction. Just before World War II, antibiotics were produced on a substantial scale in industrial countries. Introduction of antibiotics was like 'White Magic' that saved millions of lives around the world.
It has been more than three decades since a newer class antibiotic was brought into the market. Antimicrobial resistance (AMR) is a natural process and can be described as a basic survival instinct of a microorganism when exposed to antimicrobials; however, this process is expedited by persistent use of large volumes of antimicrobials over time. Injudicious use of antibiotics has led to AMR that is taking us to an era called 'post-antibiotic era', where it is predicted to see more deaths related to infections. This crisis is even worse than 'pre-antibiotic era', as the current infections are due to multiresistant super bugs! Pharmaceutical companies are lacking incentives to invest in finding newer antibiotics as microbes are developing resistance to them quicker. It has been predicted that there will be as many as 10 million deaths a year and over $100 trillion losses to global economy by 2050 due to AMR.
| Global Antimicrobial Resistance Burden|| |
In 1945, during the Nobel Prize ceremony, Sir Alexander Fleming warned of the times when the effect of antibiotics would be less due to its overuse. It is predicted that 85% of antibiotics have non-human use in the United States. In hospitals, up to 50% of antibiotics are used inappropriately.
The WHO conducted surveillance on AMR of all member states. Among bacteria-causing infections in hospitals and community, five of six regions in the world had Escherichia More Details coli infections that had more than 50% resistance to third-generation Cephalosporins and Fluoroquinolones. This implies that simple urinary tract infections would be a challenge to treat with oral antibiotics and may need the use of second-generation or third-generation antibiotics that are more expensive and have higher side effects. Interestingly, two of the six regions reported Klebsiella pneumonia infections having more than 50% resistance to Carbapenems. Carbapenems are the strongest antimicrobial options available for the treatment of resistant bacteria. This would mean that we have no further options for treatment. Similarly, all the six regions reported Streptococcal pneumoniae infections having more than 25% resistance to Penicillin. Methicillin resistance in Staphylococcus aureus was reported in five of the six regions. Common skin and wound infections would need costlier second-line antibiotics. Other endemic infections such as multi-drug resistant tuberculosis (MDR-TB) and malaria are trending up too. In Central Asia and Eastern Europe, the newer TB cases (3.6%) and previously treated TB cases (20.2%) are reported to be resistant to conventional antibiotics. A major concern with MDR-TB is that treatment failure is higher with the available options. On similar grounds, recent success of the WHO Global Strategy against malaria could be threatened due to the spread of malaria resistant to Artemisinin in South-East Asia.
| Antimicrobial Stewardship Programme and Its Strategies|| |
The National Institute for Health and Care Excellence (NICE) defines antimicrobial stewardship (AMS) as 'an organisational or healthcare system wide approach to promote and monitor judicious use of antimicrobials to preserve their future effectiveness'.
Ultimate goals of antimicrobial stewardship
- Improve patient safety and care
- Reduce AMR
- Improve healthcare costs.
Centre for Disease Control and Prevention published core elements of AMS, complementing the pre-existing AMS guidelines outlaid by the Infectious Diseases Society of America (IDSA) [Table 1]. These strategies provide a good framework for any institution which can be potentially adapted locally having identified the areas of concerns.
AMS strategies could be categorised into the following three broad categories:
- Pharmacy driven
- Infection and syndrome specific.
Implementing many strategies at a time can be detrimental, and hence, a tailored approach based on the institutional needs is crucial. [Table 2] outlines the AMS strategies based on the three categories mentioned above. 'Antibiotic Stewardship Driver Diagram and Change Package' is an excellent reference document that provides insight into the implementation of strategies and monitoring.
|Table 2: Antimicrobial stewardship strategies based on the three categories|
Click here to view
| Antimicrobial Stewardship Success Stories|| |
One of the earliest AMS studies published was based on battles against AMR in Iceland in 1999. This was the period before pneumococcal conjugate vaccine was introduced into the immunisation schedule. There was a steady rise in Penicillin-resistant strains of S. pneumoniae, a microbe commonly causing upper respiratory tract infections and meningitis in children. The incidence rose by 20% over a period of five years. Among the risk factors for carriage of resistant strain, the use of antibiotics in children was most common followed by younger age of the children (< two years). Iceland government decided to address this by introducing AMS intervention in 1992. The main intervention used was education for medical professionals and the entire nation through television and radios. Mass education for the public concentrated on the adverse effects of unnecessary antimicrobial use, whereas for medical professionals, the prudent use of antibiotics was advocated in conferences and meetings. With this intervention, the use of antibiotics in children was noted to drop by 35% from 1992 to 1997. The incidence of Penicillin-resistant S. pneumoniae was noted to be on a downwards trend. This was an excellent example of the power of mass media and education as physicians noted a change in the approach of parents/patients accessing medical care. However, outcomes such as fall in the incidence of resistant bacteria could not be quantitatively attributed to interventions targeting prescriber's behaviour, as there was no direct measure. It would be interesting to study how long the effect of media could be sustained on the public.
Another national campaign against AMR that was launched during the same time was STRAMA (Swedish Strategic Program Against Antibiotic Resistance) in Sweden in the year 1995, and it has been acclaimed to be one of the most successful national programmes. This is one of the longest running national programmes (>20 years). This was introduced in response to the growing Penicillin-resistant S. pneumoniae. The main objective of this campaign was to evaluate the use of antibiotics and AMR across all sectors (including animals) and improving prescribing practice. This campaign included:
- Monitoring of AMR and antimicrobial use
- Updating and implementing guidelines
- Education campaigns.
This campaign introduced the concept of 'bacteria had no borders', and hence, the thought of containment of resistance beyond the nation was equally important. Since the introduction of this campaign in 1995, there was a significant drop in antibiotic prescriptions for children by 2004, and there was a reduction in hospital admissions for children with infections such as mastoiditis, quinsy and rhinosinusitis. More significant outcome of note was reduction in Fluoroquinolone prescriptions to treat lower urinary tract infections for ages 18–79 years that was tracked by sales of antibiotics between 2000 and 2003.
Similar AMS campaign was launched in Belgium in 1999, Belgian Antibiotic Policy Coordination Committee. Its objective was to promote the judicious use of antibiotics in humans and animals and to promote infection control and hospital hygiene with an overall aim to reduce AMR. This campaign had a holistic approach and created five professional working groups targeting community, hospital, public awareness, infection control and veterinary medicine. A huge success was attributed to mass media campaign that saw 36% reductions in prescriptions pre- and post-campaign. There was a huge drop in the incidences of resistant Streptococcus pneumoniae infections between 1985 and 2007. Following on this campaign, it has been reported that 90% of hospitals in Belgium have established AMS programmes for effective antibiotic management.
A hospital-based study, published by Shorr et al., aimed to measure the impact of using appropriate antibiotics on patients managed in intensive care and non-intensive care settings. This was an interesting comparative study that estimated mortality between a cohort of patients with appropriate antibiotic use (36.4%) and cohort of patients with inappropriate antibiotic use (51.7%). The results favoured the cohort with appropriate use of antibiotics. Patients with appropriate antibiotics had a shorter hospital stay in comparison with patients who had inappropriate antibiotics. This study proved that appropriate use of antibiotics is advantageous. Being a retrospective study, decision on the appropriateness of antibiotic use does not come without any bias. Hence, results need to be taken with some prejudice.
The lead in launching AMS programmes was taken by the economically stronger nations. Economically stronger or industrialised nations that form the Organisation of Economic Cooperation and Development (OECD) monitor AMR among member nations. OECD is an intergovernmental organisation supporting member countries in achieving economic progress and facilitating world trade. The OECD provides platform for economically rich countries to support and share AMS policies in tackling AMR among member nations. The average AMR among member nations in 2014 has been estimated to be 15%. Among them, Sweden (5%) and Belgium (12%) are the countries reported to have lower AMR rates.
An international cross-sectional review of AMS programmes was conducted in 2012. It was an Internet-based survey posing 43 questions that was shared with all nations that volunteered. Questions were based on AMS strategies and measured outcomes. Europe and America had AMS implemented in majority of hospitals, but there was a lag in low- or resource-poor countries. There were huge inconsistencies in strategies and outcomes measured amongst all nations, and hence, it was difficult to draw out any conclusions on the effectiveness of AMS from this study worldwide.
Analysing antimicrobial use in resource-poor nations, a review article published by WHO reported high levels of antibiotic use in countries such as Tanzania (42%), Kenya (46%) and India (54%). This information clearly demonstrates discrepancies in healthcare setup and failure of implementation of AMS programmes in developing economies.
Chinese government implemented a comprehensive campaign to promote rational antibiotic use in 2011. This campaign used clear strategies such as auditing and inspection of hospitals, formulary restriction and setting clear targets for antibiotic use. Within one year, there was 10% drop in antibiotic prescriptions both in inpatient and outpatient settings. It was an impressive attempt, and changes were seen within one year of implementation.
Africa is known to have the highest use of antibiotics and the least number of AMS programmes implemented in hospitals in comparison to rest of the world. In South Africa, private sectors introduced AMS programme targeting Carbapenemase-producing E. coli. As a part of the programme, clinical guidelines were developed, and workshops and surveillance were set-up. An initial drop in defined daily dose of antibiotic/100 patients/days (12.1%) was seen, but, overall, antibiotic use continued to be high. As this programme concentrated on private sector alone, effectiveness observed was not tremendous.
A systematic review and meta-analysis of AMS programmes in Asia indicated that that AMS programme had a positive impact on reducing antimicrobial use with no reported adverse effects on clinical outcomes. Interestingly, there were 6588 articles initially identified; only 77 studies were included. Strategies recommended by the IDSA were used as a framework to measure outcomes. Workload was tremendous, but there were many unclear issues such as inclusion criteria and unmeasured variables that could influence outcomes. This study included mostly hospital- and clinic-based studies and not community-based set-ups. Most of the studies were based on pre- and post-AMS period in hospitals that could corroborate to bias.
| Antimicrobial Stewardship Cost-Effectiveness|| |
As a part of health economic analysis, cost-effectiveness analysis gives us essential information on the costs of different actions and its outcomes. It is expressed as a ratio, with numerator indicating the gain in health and denominator indicating costs per gain in health. Analysis of cost-effectiveness of a programme provides vital information for stakeholders or managers to judiciously invest money to maximise health benefits.
The OECD countries conducted cost-effectiveness analyses of AMS programmes in 36 countries. This was a hospital-based study that recruited adults in their study group. The AMS strategy that was used was Prospective Audit with Intervention and Feedback and rapid diagnostics for all bloodstream infections. As expected, pharmacy expenditures reduced, indicating decrease in antimicrobial prescriptions. Interestingly, due to inconsistencies in the calculation of cost outcomes, the comparison was difficult to ascertain if AMS programmes were truly cost-effective. Apart from pharmacy expenditures, cost-effectiveness should reflect the financial impact of resources used, employments and implementations costs and laboratory expenditures to sustain programme in the long term.
A cost-effectiveness review article on AMS was published from Malaysia (2017). Study conducted analysis from a hospital and payer perspective. Although 313 articles were initially screened, only five articles were included following a stringent quality check. This study attempted to be comprehensive and included warded, procedural, personal and medical costs. Due to the small number of studies that were included, results were not statistically significant, and hence, a further prospective health economic analysis was recommended to ensure credibility.
In a recently published article by Pliakos et al., molecular rapid diagnostic testing (mRDT) for bloodstream infections was used with or without AMS. A decision-analytic model was used to assess the cost-effectiveness of five strategies namely (1) mRDT with or without AMS, (2) mRDT with AMS, (3) mRDT without AMS, (4) conventional methods without AMS and (5) conventional methods with AMS. The cost-effectiveness was determined as number of bloodstream infection deaths averted, number of quality-adjusted life years gained and incremental cost-effectiveness ratios (ICERs). The results were impressive – mRDT with an AMS had an 80% chance of being cost-effective, whereas mRDT without AMS had only 41.1% chance. This was a good study that was able to quantify the outcomes taking into consideration all variables.
In a Brazilian study (2016), comparison of conventional AMS programme to a more proactive bundled AMS programme in a single institute was performed. The conventional AMS involved a clinical pharmacist screening for antimicrobial drug-related problem, case discussions with infectious disease physicians and telephone-based interventions. The bundled AMS involved prospective auditing, local education/feedback about antimicrobial therapy prescription; microbiological data discussion with laboratory personnel to guide empirical or pre-emptive therapy and face-to-face interventions to improve antimicrobial drug therapy. Expenditures included were length of stay, antimicrobial consumption, laboratory resources and costs of workload per day. Although the bundled AMS programme was more expensive in terms of costs per workload per day (92.79 US$) versus conventional AMS programme (45.33US$), it proved to be more efficient. Probability sensitivity analysis showed that despite critical variables, the ICER was unaltered.
| Future Challenges|| |
Research and evidences have shown that AMS programmes are advantageous; however, some finer but crucial aspects still need attention. Resistant infections are reported to be acquired and spread within communities, but mortalities are recorded in hospital or institutes. Keeping this in mind, most of the AMS programmes published are hospital based, and very little data are available on community-based programmes.
Implementing AMS programme is a huge challenge, and obstacles in sustaining the programme on a long run are even higher. Designing a financially self-sustainable AMS programme would be desirable. This is obvious as most of the AMS studies proclaimed to be successful were launched and implemented in economically rich nations. Irony is that the burden of AMR is more in resource-poor nations.
The main strategy of AMS programme is tailored in reducing antimicrobial use with the idea that this would bring down the prevalence of AMR; however, the English Surveillance Program for Antimicrobial Utilisation and Resistance in 2017 reported that the use of antimicrobials and prescriptions decreased with the implementation of NICE AMS programme, but an increasing trend was noted in the prevalence of AMR over five years. This unexpected result raises the question – 'Are we missing an important link?'
Since many decades, non-therapeutic use of antimicrobials in animal farming has persisted. This use in animal farming is to promote growth and productivity. Nearly 80% of antimicrobials used in the United States (2012) were for non-therapeutic animal use, and of them, 60% of antimicrobials were relevant to human use. In this complex ecosystem, AMR microbes can easily transmit from animals to human beings and vice versa. Due to the increasing demand for animal products, it has been predicted that antimicrobial use in animal farming would increase to 67% worldwide by 2030 and double in Brazil, Russia, India, China and South Africa, ensuring that there is food security. The Chief of the Food and Agriculture Association (2018) has advocated responsible use of antimicrobials in animals and to phase out antimicrobials as growth promoters.
Following situational analysis (2010) by the Global Antimicrobial Resistance Partnership, South-East Asia saw the highest AMR. This was attributed to the high population density and dysfunctional health systems. The Viet Nam Resistance Project (2012) is a collaborative project between Vietnam health sector, Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme in Vietnam and Linkoping University, Sweden. This aims to establish an effective AMS programme for Vietnam and bridge the 'know-do' gap in commencing health initiatives in emerging economies. An extensive well-equipped laboratory set-up was a part of the initiative to study the AMR pattern in these parts of the world that would aid in providing critical information on the mechanism of resistance and develop newer antimicrobials to counteract them. On similar grounds, as a part of the global AMR innovation funds, finances have been raised among economically rich nations to establish AMS projects in resource-poor nations to tackle this global burden.
Dr M. Chan, Director General of the WHO, coined AMR as 'tsunami in slow motion' and regarded it as needing the utmost prominence in this current state of matters. Keeping the comparison of AMR to natural disasters, geoscientists have proposed Acoustic Gravity Waves that creates higher magnitude sound waves in ocean that could counteract the effect of tsunami. A similar high-magnitude synchronised global approach against AMR is needed at this crucial time.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]