We estimated that more than one-third of pneumococcal pneumonia cases involved resistance to penicillin, erythromycin or fluoroquinolones. While antibiotic-resistant strains accounted for a substantial portion of inpatient and outpatient pneumococcal pneumonia cases, resistance itself was responsible for a far lower percentage of total pneumococcal pneumonia medical costs (4%) and total costs (5%). This finding is due in part to the fact that discordant therapy and the resulting treatment failure were assumed to only occur in the outpatient setting. Because empiric therapy recommended by national guidelines address resistant infections, we assumed that inpatient treatment would cover resistant organisms for community-acquired pneumococcal pneumonia [22, 23]. Nevertheless, costs attributable to resistance amount to over $90 million in direct medical and $230 million in total costs. Nearly all costs associated with antibiotic resistance resulted from outpatient discordant therapy that led to delays in cure, ultimately requiring additional courses of antibiotics, additional outpatient visits or hospitalization for resolution.
While resistance to penicillin was the most common, the majority of associated costs were due to erythromycin resistance. In particular, macrolide resistant pneumonia in children comprised 39% of total associated costs due to resistance, primarily resulting from hospitalization of cases initially treated in the outpatient setting. From expert opinion, we estimated that 32% of pediatric outpatient pneumococcal pneumonia cases treated with erythromycin were discordant, resulting in an additional 9700 hospitalizations annually due to delayed resolution. To address the threat of macrolide failure, recent guidelines on community-acquired pneumonia from the Pediatric Infectious Disease Society recommend amoxicillin as first line therapy, with macrolides recommended only if there is suggestion of infection with atypical organisms .
Based upon our projections of increased costs due to rising levels of antibiotic resistance, increases in erythromycin resistance are most likely to result in significant increases in cost. This is in agreement with our finding that delayed cure after treatment with erythromycin, predominantly in the pediatric population, is responsible for the majority of costs currently associated with antibiotic resistant pneumococcal infections. Projected increases in resistance are simply reasonable guesses based on current levels of resistance; more dramatic increases in resistance are certainly possible, and would be associated with greater increases in cost.
This study has several limitations. We estimated the impact of antibiotic resistance using an existing decision tree model of pneumococcal disease burden from 2004. The burden of antibiotic resistant cases of pneumococcal pneumonia may have changed substantially since then. We also assumed that antibiotic resistance among non-bacteremic cases was similar to bacteremic cases. In addition, the effects of the 2010 PCV13 introduction on disease burden are not reflected in these estimates. For example, emerging antibiotic resistance in replacement non-vaccine serotypes are difficult to predict and are not addressed in this pre-PCV13 model. Our model benefits from incorporation of extensive data from administrative data sources and an expert panel; however the results are highly sensitive to assumptions about the frequency of discordant therapy for which we did not directly collect data. Our model also assumed that the costs of antibiotic resistance were exclusively due to additional treatment failure for cases initially treated in the outpatient setting; this assumption does not account for the possibility of additional delayed cure among inpatients. However, we believe that the use of broad-spectrum antibiotics for inpatient treatment renders delayed cure much less likely in this setting. In our sensitivity analyses, we assumed that rising resistance would have no effect on virulence; however it has been shown that serotypes differ in their ability to cause disease and thus we likely under-estimated the projected cost associated with increased levels of antibiotic resistant strains . Lastly, we assumed that further increases in resistant strains would not result in changes in empirical prescribing practices, although this is likely if levels of resistance substantially rise.
Despite the introduction of pneumococcal vaccines, the burden of pneumococcal pneumonia remains high. While we estimated that antibiotic resistance was only associated with 4% of total pneumococcal healthcare costs, the absolute cost attributed to antibiotic resistance and treatment failure was considerable. Strategies to reduce antibiotic resistance or improve antibiotic selection may prevent a significant number of hospitalizations and outpatient visits and lead to a substantial savings.