Discussion

In this study, we have demonstrated that a nasopharyngeal RDT to guide management of AOM could be cost-effective compared to usual care if the cost of the RDT is <$212. RDT could also substantially reduce overall antibiotic use (57%) and broad-spectrum antibiotic use (68%). This approach has the potential to individualize care for AOM and to reduce antibiotic-associated morbidity and the development of antibiotic resistance among otopathogens, while assuring that children most likely to benefit from an antibiotic receive the appropriate agent.

Historically, a single first-line agent (amoxicillin) has been recommended for treatment of most children with AOM. ^{Reference Lieberthal, Carroll and Chonmaitree21} The increase in β-lactamase–producing organisms associated with AOM has prompted some to call for a change in the firstline agent to a broader-spectrum antibiotic (ie, amoxicillin-clavulanate) for most children. ^{Reference Wald and DeMuri48} Most children are currently prescribed an immediate antibiotic and 40% are prescribed a broad-spectrum antibiotic. ^{Reference McGrath, Frost and Newland40} A change in guidelines that recommends first-line use of a broad-spectrum antibiotic would likely result in increased resistance, ADEs, and cost. ^{8,Reference Gerber, Ross and Bryan9,Reference Butler, Brown and Durkin49} Fortunately, scientific advancement has rendered it feasible to identify the presence of organisms and resistance-associated genes quickly and reliably. A shift to an evidence-based RDT-guided therapy could reduce ambiguity around which bacterial pathogens are present, if treatment with immediate antibiotics is necessary, and reduce unnecessary costs and ADEs.

Previous studies have demonstrated that individualization of care based on otopathogens improved outcomes in pediatric AOM. ^{Reference Pichichero, Casey and Almudevar50} Unfortunately, these studies have relied on tympanocentesis, which has limited their generalizability and scalability because most clinicians are no longer trained in tympanocentesis and time constraints reduce its utility in routine practice. Although tympanocentesis more reliably detects otopathogens than nasopharyngeal testing, nasopharyngeal testing is likely to be more feasible in most care settings. In particular, nasopharyngeal testing can effectively exclude the presence of otopathogens in the middle-ear fluid >92% of the time. ^{Reference Kaur, Czup, Casey and Pichichero26} In the minority of cases in which nasopharyngeal testing may not accurately detect pathogens that are present in the middle-ear fluid, the risk of complications from delayed antibiotic treatment is exceedingly low. ^{Reference Shaikh, Dando and Dunleavy42} Approaches have been further limited using culture rather than PCR, which is expensive, time-consuming, and may yield less accurate results than PCR, particularly for fastidious organisms such as S. pneumoniae.

We previously demonstrated that the sensitivity of nasopharyngeal PCR for otopathogens compared to culture is >99%. ^{Reference Frost, Sebastian and Keith51} In addition, serum biomarkers have been suggested as a potential option for pathogen-directed therapy for AOM. ^{Reference Pichichero, Morris and Almudevar52} However, this would likely require capital investments from health systems, and it is not clear how antimicrobial resistance would be determined, though it is necessary to choose the appropriate agent, particularly for H. influenzae.

Finally, management of AOM should logically progress over time as AOM pathogens and resistance evolve. The use of an algorithm associated with an RDT would automatically help tailor management to local pathogen epidemiology and resistance patterns.

Although initial observation and complete adherence to the AAP guidelines are the most cost-effective approaches, they do not manifest in routine practice. Management guided by RDTs has improved care for other infections. For example, the use of RDTs, including molecular-based RDTs, to direct treatment of group A β-hemolytic streptococci (GAS) pharyngitis improved care by reducing unnecessary antibiotic use while assuring that patients likely to benefit were prescribed an antibiotic. ^{Reference Luo, Sickler, Vahidnia, Lee, Frogner and Thompson24,Reference Maltezou, Tsagris and Antoniadou25} Similar to AOM, signs and symptoms of pharyngitis can be nonspecific, and accurately establishing the causative organism to appropriately direct antibiotic therapy using clinical criteria alone is difficult. ^{Reference Shaikh, Swaminathan and Hooper53} The use of an RDT could similarly guide management of AOM, albeit more complex than pharyngitis because multiple organisms are associated with AOM and antibiotic resistance is more prevalent among otopathogens than GAS.

Additional parallels exist between AOM and pharyngitis. Both conditions exhibit high carriage rates (eg, high carriage of M. catarrhalis in the nasopharynx). ^{Reference Kaur, Czup, Casey and Pichichero26,Reference Shaikh, Leonard and Martin54} In both scenarios, diagnostic testing is most effective at excluding the presence of organisms rather than predicting that organisms are causing disease. Thus, like pharyngitis, testing would still result in some overtreatment. Additionally, clinicians would similarly need to be able to select appropriate children for testing; thus, AOM diagnostic accuracy would remain important. Despite these challenges, the use of RDTs for GAS profoundly reduced unnecessary antibiotic use for pharyngitis. An AOM RDT has the potential to be a valuable stewardship tool that could be coupled with other stewardship interventions to reduce overall and/or broad-spectrum antibiotic use.

Several important practical aspects of a AOM RDT need to be addressed prior to implementation. First, at an estimated cost of $274, which aligns with commercially available respiratory viral molecular based tests, RDT is unlikely to be cost-effective using the current willingness-to-pay threshold. However, a modest reduction in price (23%, $212) meets the currently established threshold. Notably, this price is comparable to currently used molecular-based tests for GAS. The test would also need to have a quick turnaround time (optimally <30 minutes) to be useful in most outpatient settings. This turnaround time may be a challenge for smaller practices that typically send out samples for PCR testing. Given the complexity of AOM pathogenesis, clinicians would need to have an easy-to-use support tool to interpret RDT results to guide management. Finally, the test would ideally be used on currently available RDT platforms, such as those already used for SARS-CoV-2, influenza, or GAS testing to reduce the need for capital investment.

The strengths of this study include the creation of an iterative model for AOM that can easily be modified as epidemiology and resistance patterns change. We were able to address the polymicrobial nature of AOM by using an algorithm. We also included costs associated with antimicrobial resistance. In addition to evaluating the cost-effectiveness of RDT guided care, we determined the potential reduction in antibiotic use, which is important from antimicrobial stewardship and public health perspectives. We focused on a highly pragmatic aspect of care that included an estimated cost needed for an RDT to be cost-effective. To our knowledge, no prior research has evaluated the potential cost-effectiveness or reduction in antibiotic use with an RDT for AOM. We hope that this analysis will stimulate future studies and discussion on how we can potentially use an RDT to better guide appropriate management of AOM.

Our study also had several limitations. As with all cost-effectiveness evaluations, the results are subject to underlying assumptions. We assumed complete uptake of the algorithm and that all clinicians followed the algorithm. A formative study evaluating parent and clinician acceptability of potential RDT use for AOM would help to inform expected test uptake and antibiotic use with an RDT. We presumed no need for additional capital investment for testing given the widespread implementation of PCR-based platforms. Clinical settings without ready access to PCR-based RDTs, such as rural clinics or private practices, may not be able to adopt this strategy to guide management. We based antibiotic use with each prescribing strategy (ie, immediate antibiotic, delayed antibiotic, and observation) on pragmatic studies of fill rates with these strategies rather than calculating the likelihood of success of treatment by organism. Thus, we may have overestimated actual antibiotic use and costs. A call-in rather than in-person care strategy was assumed for all patients managed with observation whose treatment failed, which might not be appropriate for some patients. Additionally, we estimated a full day of lost productivity for patients whose clinical treatment with observation failed, which may have been an overestimate. Some variables were from single studies, and other variables had a wide range of values. Given the variation in variables, we completed sensitivity analyses to vary values throughout the range of estimates. Given the paucity of evidence on the risks of chronic medical conditions (eg, inflammatory bowel disease) associated with a single antibiotic course, we did not include costs and disutilities associated with chronic medical conditions. Finally, this study was designed to be exploratory to begin the discussion on how we move the field of AOM management forward. It was not designed to be a definitive study on best strategies for AOM management.

In conclusion, RDT could be a feasible mechanism to individualize care for AOM. In the era of increasing antimicrobial resistance, RDT should be explored as a potential patient-centered mechanism to improve care and reduce unnecessary antibiotic use.