Discussion
The pharmacist-driven ASP group interventions in febrile neutropenic patients showed a favorable effect on antibiotic appropriateness in our study. We found higher antibiotic appropriateness in the pharmacist intervention group than the control group (88.9% versus 51.1%,P <0.001). When providing empirical therapy, the pharmacist-driven ASP group was more appropriate than the control group which was different from a previous study.16 We believe that main reason for this discrepancy was that the previous study evaluated only prescribed antibiotic appropriateness based on the hospital guideline and described only antibiotics indicated for febrile neutropenia but did not assess the appropriateness of dosage regimens which was included in our assessment of appropriateness of prescribed antibiotics.16,22 Moreover, our ASP implementation provided daily review and feedback while the Madran et al study implemented a hospital guideline and had only a weekly discussion with the ASP team.16 Likely our study which provided more frequent feedback improved the primary physicians’ compliance as noted in a recent study.10 Furthermore, our result showed that appropriate dosage regimens was more frequently found in the pharmacist-driven ASP group than the control group (97.8% versus 88.7%, P =0.049). Our finding was similar to previous studies that appropriateness was 6.5-fold higher in the pharmacist intervention group then the control group.23 On the other hand, appropriateness of antibiotic indication in the pharmacist-driven ASP group resembled the control group as described in Madran et al study.16 However, we also used current standard guidelines and all of our patients had a high risk of febrile neutropenia similar to the previous study.16
In documented infection evaluations, the pharmacist-driven ASP group had greater appropriateness of prescribed antibiotics than the control group (88.9% versus 64.4%, P =0.004). Our result was similar to previous study in which more appropriateness was found in the intervention group.16 Moreover, appropriate duration of therapy was higher in the pharmacist-driven ASP group (P =0.039). Our result was concordant with a previous study that pharmacist-driven ASP could reduce the duration of antibiotic therapy.24 However, appropriateness of antibiotic indication was similar in both groups because our study divided the category of appropriateness into microbial susceptibilities and penetration of antibiotic to target site. If pathogens were identified and antibiotics susceptibilities were reported, it could help physicians to choose proper antibiotics. Since most pathogens in the control group were ESBL-producing organisms, this might affect antibiotic appropriateness because carbapenems are drugs of choice for ESBL-producing organisms and choice of antibiotics was controlled by an infectious diseases physician.25 In addition, overall antibiotic appropriateness and proper duration of therapy in the pharmacist-driven ASP group were also greater than the control group when the source of infection was unknown (P = 0.039 and 0.066, respectively) (supplementary data, Table 3S). However, total antibiotic duration between two groups did not difference. The reasons for prolonging antibiotic duration in intervention group were fungal infection (e.g., invasive pulmonary aspergillosis and mucormycosis), superinfection with MDR organisms, uncontrolled source of infection. Although the result did not show any difference of antibiotic appropriateness in case of known causative pathogens and source of infection between the two groups, the pharmacist-driven ASP group tended to use more proper antibiotics than the control group in terms of indication, dose and duration (P =0.384, 0.833, and 0.872, respectively) (supplementary data, Table 4S).
Nevertheless, our study did not show a difference in the 30-day infectious diseases-related mortality between the two study groups. Our patients tended to have longer neutropenia durations and higher CRE infection rates in the intervention group which differed from a previous study (16). As a result of rising CRE incidence in Thailand, our patients were more likely to be infected with CRE than reported in a previous study which might have affected the mortality rate in our study.16,26-27 However, other ASP studies in febrile neutropenic patients also showed no difference in mortality between two groups as well.10, 28-31 Based on our multivariate analysis, pharmacists should collaborate with other medical personnel such as infectious diseases physicians to improve the 30-day infectious diseases-related mortality in febrile neutropenic patients caused by cytotoxic chemotherapy. This study supports the IDSA Guideline that ASP team should be done by a multidisciplinary team to achieve successful ASP implementation.5 On-site infectious diseases specialist, including ID physician and pharmacist, can improve ASP effectiveness in recent study.32 Hence, multidisciplinary team would be beneficial for ASP implementation in these specific population which data are limited such as febrile neutropenic patient. Notably, although most of the febrile neutropenic patients in our study were caused by cytotoxic chemotherapy, there are some patients caused by hematologic abnormalities during diagnosis in our study which also mentioned in previous study.33Furthermore, our study did not find any difference in length of stay in both groups as has been noted in a previous study.10
Although our target antibiotics utilization in the pharmacist-driven ASP group increased during study period which was similar to a previous study, it might have affected inappropriate prescriptions in the control group.10 For instance, there were some antibiotics improperly used in empirical therapy in the control group such as ceftriaxone which were not included in our target antibiotics and antibiotics might have been prescribes at an improper low dose. Therefore, DDD of target antibiotics in the control group might be lower than expected. Moreover, we implemented a high dose of target antibiotics according to previous pharmacokinetic studies this might have contributed to higher DDD of target antibiotic in the pharmacist-driven ASP group.2-3 Besides, overall intravenous antibiotics in the pharmacist-driven ASP group demonstrated a lower trend than the control group.
Our study had several limitations. First, ward physician rotation could have affected the result. However, the result of this study also showed that the pharmacist intervention group had more appropriateness than the control group. Second, the study was implemented only in medical wards since TUH did not have a hematology-oncology ward during the study period and we could not fully perform interventions in the other wards such as the emergency department and intensive care unit. Ideally, the ASP implementations in febrile neutropenic patients should be done in all wards. Third, we calculated our sample size to demonstrate antibiotic appropriateness rather than 30-day infectious diseases-related mortality. A larger sample size is needed to assess the effect of pharmacist-driven ASP on 30-day infectious diseases-related mortality. Fourth, we could not evaluate the effect of pharmacist-driven ASP on antibiotic resistance since the study site did not have an isolation ward for febrile neutropenia patient with multidrug-resistant pathogens. Thus, acquisition of antibiotic resistance organisms from other patients might have affected our results. Finally, the role of pharmacists in Thailand may be different from western countries. Pharmacists cannot change antibiotic dosage regimen or discontinue antibiotics by themselves, a physician’s signature is needed. Thus, pharmacist cooperation with physician was also an important aspect to implement a successful pharmacist-driven ASP in Thailand.