Background
Methods
Conceptual framework
Rapid methodological review
Results of rapid methodological review
Descriptive results
Hospital-based studies
- A matched cohort design, where patients with antibiotic-resistant and antibiotic-susceptible infections (or no infection at all) are matched and their cost outcomes compared. Matching is based on patient characteristics and differs widely across studies; some have matched only on patient age and gender, while others have used diagnostic codes, severity-of-illness scores or length of stay from admission to infection onset. However, such studies rarely explore whether the matching characteristics are good indicators of the risk of acquiring an antibiotic-resistant infection [22].
- Regression on a patient cohort to link the presence of an antibiotic-resistant infection with cost-related explanatory variables. In both cases, the outcome variable is treatment costs (calculated using hospital charges and/or standard reimbursement tariffs) or an intermediate outcome such as length of stay, which is then used to calculate costs. The latter approach may underestimate costs by ignoring other cost elements that may be greater for antibiotic-resistant infections such as testing and prescription costs, management of complications, and isolation ward and intensive care stays [18].
Conceptual framework
Extension in time: from the present to the long term
Extension in perspective: from the healthcare payer to society
Extension in scope: from the individual patient to the community
Extension in space: from one hospital to national/global estimates
Study | Geography | Pathogens | Costs in original currency | Costs in 2018 I$ | Costs considered |
---|---|---|---|---|---|
Studies in the grey literature | |||||
ECDC and EMEA [6] | EU, Iceland, Norway | S. aureus, Enterococcus spp., S. pneumoniae, E. coli, Klebsiella spp., P. aeruginosa | 1.5 bn/year EUR (2007) | 2.1 bn/year | Increased treatment costs, reduced productivity and labour supply due to morbidity and premature mortality |
KPMG [19] | EU, Iceland, Norway Global | E. coli, K. pneumoniae, S. aureus, HIV, TB, malaria | 1.6 bn/year EUR (2012) 1.66–6.08% of global GDP in 2050 | 2.3 bn/year | Increased treatment costs, reduced productivity and labour supply due to morbidity and premature mortality |
RAND Europe [20] | Global | E. coli, K. pneumoniae, S. aureus, HIV, TB, malaria | 0.5–6.0 tn USD (2011) per year in 40 years (0.14–1.9% of global GDP) | 0.6–6.8 tn per year in 40 years | Reduced labour supply and productivity due to increased morbidity, mortality and caregiving Reduced inter-sectoral transactions and trade |
World Bank [7] | Global | Any | 1.0–3.4 tn USD (2017) per year in 2030 (1.1–3.8% of global GDP) | 1.0–3.5 tn I$ per year in 2030 | Reduced labour supply due to premature mortality |
Studies in the rapid review of published literature | |||||
Chen et al. [45] | Ethiopia | S. pneumoniae | 15.8 m/year USD (2017) | 16.2 m/year | Increased treatment costs and productivity losses due to morbidity and premature mortality |
Chesson et al. [46] | USA | N. gonorrhoeae | 378 m/year USD (2016) | 395 m/year | Increased treatment costs |
de Kraker et al. [32] | 31 European countries | Bloodstream infections caused by MRSA and G3CREC | 62 m/year EUR (2007) | 87 m/year | Increased length of hospital stay |
Elbasha [47] | USA | Any | 0.4–19 bn/year USD (1996) | 0.6–29 bn/year | “Deadweight loss”: reduced antibiotic effectiveness leading to poorer treatment outcomes due to overprescribing antibiotics |
Johnston et al. [48] | United States | Multi-drug resistant organism | 2.39–3.38 bn/year USD (2017) | 2.45–3.46 bn/year | Increased treatment costs |
Lee et al. [49] | USA | Community-associated MRSA | Healthcare: 478 m/year USD (2011) Society: 2.2 bn/year USD (2011) | Healthcare: 539 m/year Society: 2.5 bn/year | Increased treatment costs and productivity loss due to morbidity and premature mortality |
Michaelidis et al. [50] | USA | Any | 4.4 bn/year USD (2013) | 4.8 bn/year | Cost of antibiotic use and stewardship |
Naylor et al. [29] | England | E. coli | Third-generation cephalosporin: 366,600/year GBP (2012) Piperacillin/tazobactam: 275,4000/year GBP (2012) | Third-generation cephalosporin: 578,000/year Piperacillin/tazobactam: 434,000 | Increased treatment costs |
Phelps [37] | USA | Any | 0.15–3 bn/year USD (1984) | 0.3–6.3 bn/year | Treatment costs, mortality |
Phodha et al. [51] | Thailand | Nosocomial infections due to five bacterial species | Healthcare: 2.3 bn/year USD (2012) Society: 4.2 bn/year USD (2012) | Healthcare: 2.5 bn/year Society: 4.6 bn/year | Increased treatment costs Increased societal costs (components not reported) |
Shrestha et al. [52] | USA and Thailand | Any | USA: 2.9 bn/year USD (2016) Thailand: 0.5 bn/year USD (2016) | USA: 3.0 bn/year Thailand:0.5 bn/year | Increased treatment costs and productivity loss due to morbidity and premature mortality |
Smith et al. [39] | UK | MRSA | 0.4–1.6% of national GDP, equivalent to 3–11 bn GBP (1995) | 6.5–24.0 bn | Reduced labour supply and productivity, leading to less capital investment and lowered productivity |
Thorpe et al. [53] | USA | Any | 2.2 bn/year USD (2016) | 2.3 bn/year I$ | Increased treatment costs due to morbidity |
Tillekeratne et al. [54] | Sri Lanka | Any | 229 m/year USD (2017) | 235 m/year | Not specified – costs extrapolated from US and Thai studies |
Touat et al. [55] | France | Gram-negative bacteria | 287 m/year EUR (2015) | 397 m/year | Increased treatment costs |
US Congress, Office of Technology Assessment [56] | USA | Nosocomial infections due to six bacterial species | 1.3 bn/year USD (1992) | 2.1 bn/year | Hospital treatment costs |
Zhen et al. [57] | China | Intra-abdominal bacterial infections | Healthcare: 37 bn/year CNY (2015) Society: 111 bn/year CNY (2015) | Healthcare: 12 bn/year Society: 35 bn/year | Increased treatment costs, 3x multiplier for societal costs |
The impact of interventions
- Some models assume that resistance against a particular antibiotic is only affected by the use of antibiotics of the same class. In practice, antibiotic use can affect ABR against an antibiotic of a different class. For instance, amoxicillin, which is typically prescribed for respiratory tract infections, is associated with increased trimethoprim and ciprofloxacin resistance in Escherichia coli causing urinary tract infections [69, 70]. Conversely, higher nitrofurantoin use was found to be associated with lower levels of trimethoprim and amoxicillin resistance, potentially due to collateral sensitivity or a negative correlation between resistance genes [69].
- Models relating (human) antibiotic consumption to ABR assume that the relationship is not confounded by between-country differences such as in infection prevention and control measures and agricultural antibiotics use. Reverse causality could play a role in cross-sectional data since physicians may avoid a particular antibiotic if ABR to that antibiotic is known to be high in that population [71]. In some cases, the potential role of reverse causality could be assessed using structural equation models or instrumental variables.
- Some models assume that the relationship is instantaneous, i.e. that a given level of antibiotic use will immediately result in some level of ABR. In practice, bacteria take time to acquire resistant genes and reach a new equilibrium prevalence in a population. Indeed, high levels of ABR may be the cumulative effect of years of antibiotic use, i.e. present antibiotic use may be depleting the health and wellbeing of future generations [72]. Furthermore, future changes in ABR can be unpredictable. While the emergence of mutations conferring ABR to certain antibiotics is predictable to some extent, the timing and impact of the introduction of new ABR genes into mobile genetic elements or widespread bacterial strains is not [10, 73].
- Models often assume that the relationship between antibiotic use and ABR is linear (or can be described with a simple function); this has some basis in ecological observations at the national level [74]. However, investigators using non-linear models suggest that the relationship is more complex and dynamic [3, 75, 76].
Discussion
Current evidence base
Conceptual framework
Recommendations for primary data collection | |
• Capture all economic costs related to ABR in hospital patients, not just the directly observed outcomes such as increased length of stay | |
• Explore use of g-methods to correct for both time-dependent biases and time-dependent confounders in studies evaluating time-varying exposures in hospital-based studies | |
• Exhaustively investigate potential confounders that need to be collected and investigated in ABR cost studies, ideally using formal causal inference methods such as causal diagrams | |
• Collect data on lost earnings and out-of-pocket expenses of patients and caregivers so that the wider household and societal costs of prolonged hospital stay and premature mortality can be captured; this is especially important in settings with high out-of-pocket medical expenses | |
• Consider reporting measures of the psychosocial burden of suffering to patients and caregivers associated with illness, either by monetising the value of avoided suffering or by reporting this separately in units such as quality- or disability-adjusted life years | |
• Consider both quality (internal validity) and broader representativeness (external validity) of data collected before extrapolating from study sites to wider regions such as the national or international level; if possible, data from multiple sites should be synthesised using meta-analysis or meta-regression (including geospatial variables, if appropriate) | |
• Implications of ABR outside the hospital setting should be considered unless they are known to be negligible | |
Recommendations for further methodological development | |
• Investigate how levels of ABR may lead to increased costs for everyone, including patients with susceptible infections, those receiving antibiotics prophylactically and patients who are unable to access hospital beds because they are occupied by patients whose hospital stay has been extended by having a resistant infection | |
• Explore the use of longitudinal data from prospective cohorts or large linked patient databases to understand the relationships between antibiotic use, ABR and costs of ABR | |
• Ecological methods, such as regression, may allow extrapolation of site- or region-specific costs to a national or global level, adjusting for levels of ABR as well as other variables; however, further research is needed to investigate the implications of model simplifications, such as assuming linear and static relationships between antibiotic use and ABR, and the use of alternative modelling methods | |
• Insights from transmission dynamic models of bacterial ecology and from economic models of antibiotic market dynamics need to be combined in order to inform optimal policies | |
• Explore ways that long-term projections and macro-economic modelling can be incorporated into economic evaluations of ABR-related interventions |