DISCUSSION

In this study, we evaluated the clinical factors associated with ASP recommendations and identified important factors associated with ASP recommendation disagreement. Our PAF ASP performs approximately 8 reviews daily. Sixteen percent of those reviews resulted in a recommendation regarding antimicrobial use prescribed in our pediatric hospital. Frequently reviewed antimicrobials were associated with a high probability of a recommendation (eg, ASP drug plus clindamycin, third-generation cephalosporins) and common diagnoses such as CAP and ENT infections had the highest predictive probability of an ASP recommendation. The types of recommendations (eg, stop therapy, consult ID) also varied by specific antimicrobials and/or diagnosis class. Finally we found that there was disagreement with a minority of our ASP recommendations. Disagreement by the primary medical service was more likely to occur when addressing broader-spectrum antimicrobial agents (eg, linezolid, meropenem) or certain commonly encountered diagnoses (eg, sepsis evaluation, CAP).

When assessing the probability of an ASP recommendation based on drug or diagnosis, several findings were striking. Overall, broader-spectrum antimicrobials had a relatively low probability of an ASP recommendation. This finding likely partially stems from having a prior authorization process for certain agents including linezolid and levofloxacin. Thus, prior authorization can minimize PAF ASP workload, supporting the value of combined PAF and prior authorization strategies as an effective approach for stewardship.Reference Di Pentima, Chan and Hossain ^{2 ,} Reference Dellit, Owens and McGowan ¹⁰ There is no prior approval required for cefepime, but it also had a low likelihood of triggering an ASP recommendation. Cefepime is the drug of choice for empirical therapy for fever in the setting of neutropenia hospital-wide per our local guideline. Successful implementation of hospital guidelines to standardize care in specific clinical settings can likely further decrease the frequency of ASP recommendations.

On the basis of national surveys of pediatric ASP programs, third-generation cephalosporins, aminoglycosides, ampicillin-sulbactam, and clindamycin are less likely to be monitored compared with the extended-spectrum antimicrobials such as vancomycin, linezolid, and carbapenemsReference Hersh, Beekmann, Polgreen, Zaoutis and Newland ^{11 ,} Reference Newland, Gerber and Weissman ¹² ; however, these commonly prescribed antimicrobials were associated with frequent ASP recommendations at our hospital with 1 recommendation occurring per 5 reviews for ceftriaxone/cefotaxime. Although reviewing these commonly prescribed antimicrobials requires more stewardship resources, these reviews represented a high proportion of necessary recommendations. Interestingly, clindamycin and gentamicin, antimicrobials that are not actively monitored by our stewardship program, were both strongly associated with a recommendation to either stop therapy or obtain ID consultation, when used in combination with an ASP-monitored drug. This may reflect that combination therapy is indicated in a limited number of clinical situations.

CAP was the diagnosis with the highest probability of a stewardship recommendation, despite existence of both national and local hospital clinical practice guidelines.Reference Bradley, Byington and Shah ^{15 ,} Reference Newman, Hedican, Herigon, Williams, Williams and Newland ¹⁶ Determining illness severity and differentiating viral from bacterial pneumonia remains challenging for the clinician. Useful biomarkers predicting CAP severity are lacking and even among pediatric ID specialists, variability in treatment is common.Reference Bradley, Byington and Shah ^{15 ,} Reference Toikka, Irjala and Juven ^{17 ,} Reference Hersh, Shapiro, Newland, Polgreen, Beekmann and Shah ¹⁸ Not only were ASP recommendations frequent with a CAP diagnosis, but also recommendations to consult ID were more likely to occur with CAP compared with other diagnoses, suggesting that the ASP potentially identified the clinical cases that were more severe or atypical and helped facilitate ID involvement in those circumstances. Fortunately, a clinical practice guideline for the treatment of CAP was implemented 4 months following ASP initiation at our hospital. Combined, these approaches resulted in a significant decrease in the use of ceftriaxone with a concomitant increase in ampicillin for the empirical treatment of CAP, confirming that a combined approach of stewardship activities can be very effective in changing clinical practice.Reference Newman, Hedican, Herigon, Williams, Williams and Newland ¹⁶

Stop therapy accounted for the highest proportion of overall recommendations, raising the question about whether prior authorization or PAF might be more effective for certain antimicrobials. There are advantages to both prior authorization and the PAF approaches. Prior authorization offers an opportunity to prevent the initiation of unnecessary antimicrobials, determine the indication and planned duration of therapy, or recommend an ID consultation at the point of antimicrobial initiation.Reference Metjian, Prasad, Kogon, Coffin and Zaoutis ^{6 ,} Reference Sick, Lehmann, Tamma, Lee and Agwu ^{19 –} Reference Mehta, Haynes and Wileyto ²¹ Many of the diagnoses associated with a recommendation in our evaluation were those where diagnostic or therapeutic uncertainty exists and therefore allowing 48 hours to gather clinical information before review may be beneficial. However, because some broad-spectrum antimicrobials such as carbapenems (which were associated with a high likelihood of recommendation to stop therapy) should be used only in select clinical circumstances, our findings suggest that expanding use of prior authorization should be considered. Also, the majority of combination antibiotic therapy was frequently associated with the recommendation to stop, suggesting that combination therapy in general is a high-yield area for stewardship interventions.

Evaluation of both process and outcome measures is a critical part of stewardship.Reference Dellit, Owens and McGowan ¹⁰ Our approach to evaluating the predictive probability of a review as well as the likelihood of agreement with the recommendation by the prescribing clinician is generalizable to other programs. Evaluation can provide key information on the distribution and utilization of ASP resources, as well as on potential areas for additional stewardship strategies. Our analysis revealed that review of commonly prescribed antimicrobials is critical in our program because these reviews result in a high number of recommendations. Further collaborations with physicians and allocation of pediatric stewardship resources that will address the most highly predictive antimicrobials and diagnoses identified in this study will likely result in a further reduction of inappropriate antimicrobial use and better use of available resources. Currently, we monitor only antibacterials. To expand the program to other anti-infectives such as antifungals and antivirals, we could consider eliminating reviews that infrequently result in an ASP recommendation.

This study has limitations. We evaluated a single institution’s PAF ASP. Therefore the findings may not be generalizable to other institutions where prescribing practices differ. Specific ASP recommendations were excluded for 2.7% of the original sample, although this is unlikely to have influenced our findings. We did not look at the clinical outcomes associated with these recommendations. Stewardship has been shown to improve clinical outcomes.Reference Di Pentima, Chan and Hossain ^{2 ,} Reference DiazGranados ^{4 –} Reference Morgan, Brennan and Fishman ^{9 ,} Reference Davey, Brown and Charani ^{22 ,} Reference Nowak, Nelson, Breidenbach, Thompson and Carson ²³ It is possible that reviews that had a low probability of a recommendation may have had a higher likelihood of clinical impact. Further evaluation of the clinical impact of stewardship recommendations is warranted. Classification of diagnoses was performed by the ASP reviewer and therefore misclassification could occur. Diagnoses are extracted from the medical chart and clarified by the medical team when unclear, making misclassification less likely. Finally, because the program does not currently review all prescribed antimicrobials, it is possible that opportunities for important stewardship recommendations may go unrecognized.

In summary, evaluation of both the types and distribution of ASP recommendations provides essential feedback to better understand our stewardship program. Continued evaluation of an ASP is critical so that strategies can be tailored to enhance stewardship efforts.Reference MacDougall and Polk ²⁴ Although each hospital is unique in terms of clinical practice, our results provide an understanding of potentially high-yield targets for ASP recommendations. This approach can be adopted by other institutions that are initiating and continually evaluating their respective programs.