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Article

Pharmacist-Driven Antibiotic Stewardship Program in Febrile Neutropenic Patients: A Single Site Prospective Study in Thailand

by
Kittiya Jantarathaneewat
1,2,
Anucha Apisarnthanarak
3,
Wasithep Limvorapitak
4,
David J. Weber
5 and
Preecha Montakantikul
1,*
1
Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
2
Department of Pharmaceutical care, Faculty of Pharmacy, Thammasat University, Pathum Thani 12120, Thailand
3
Division of Infectious Diseases, Faculty of Medicine, Thammasat University, Pathum Thani 12120, Thailand
4
Division of Hematology, Faculty of Medicine, Thammasat University, Pathum Thani 12120, Thailand
5
School of Global Public Health, University of North Carolina, Gillings, Chapel Hill, NC 27599-7400, USA
*
Author to whom correspondence should be addressed.
Antibiotics 2021, 10(4), 456; https://doi.org/10.3390/antibiotics10040456
Submission received: 23 March 2021 / Revised: 11 April 2021 / Accepted: 15 April 2021 / Published: 17 April 2021
(This article belongs to the Special Issue Antimicrobial Prescribing and Stewardship, 2nd Volume)
Review Reports Versions Notes

Abstract

The antibiotic stewardship program (ASP) is a necessary part of febrile neutropenia (FN) treatment. Pharmacist-driven ASP is one of the meaningful approaches to improve the appropriateness of antibiotic usage. Our study aimed to determine role of the pharmacist in ASPs for FN patients. We prospectively studied at Thammasat University Hospital between August 2019 and April 2020. Our primary outcome was to compare the appropriate use of target antibiotics between the pharmacist-driven ASP group and the control group. The results showed 90 FN events in 66 patients. The choice of an appropriate antibiotic was significantly higher in the pharmacist-driven ASP group than the control group (88.9% vs. 51.1%, p < 0.001). Furthermore, there was greater appropriateness of the dosage regimen chosen as empirical therapy in the pharmacist-driven ASP group than in the control group (97.8% vs. 88.7%, p = 0.049) and proper duration of target antibiotics in documentation therapy (91.1% vs. 75.6%, p = 0.039). The multivariate analysis showed a pharmacist-driven ASP and infectious diseases consultation had a favorable impact on 30-day infectious diseases-related mortality in chemotherapy-induced FN patients (OR 0.058, 95%CI:0.005–0.655, p = 0.021). Our study demonstrated that pharmacist-driven ASPs could be a great opportunity to improve antibiotic appropriateness in FN patients.

1. Introduction

Febrile neutropenia (FN) is a life-threatening complication of cancer therapy which can increase morbidity and mortality [1]. Broad spectrum antimicrobial agent administration is an essential part of the treatment of febrile neutropenia to cover hospital-acquired pathogens. Pharmacokinetic alterations of several antibiotics (e.g., piperacillin/tazobactam) were found in febrile neutropenic patients [2,3]. Prescribing antibiotics with common dosage regimens might be inadequate for these patients. Furthermore, incorrect antibiotic dosing was found as the most common non-compliant antibiotic prescription practice in febrile neutropenic patients [4]. Antibiotic optimization would be a challenging method among febrile neutropenic patients. An antibiotic stewardship program (ASP) in immunocompromised patients is suggested by the Infectious Diseases Society of America (IDSA) 2010 guidelines [5]. Recent evidence supports that adherence to an ASP is associated with a lower mortality rate [6]. Although several studies have shown the effectiveness of ASP implementation in febrile neutropenic patients, there is limited evidence of the effectiveness of ASP implementation led by a pharmacist [7,8,9,10,11]. Pharmacist-driven ASPs have been reported to increase antibiotic appropriateness in several studies [12,13,14]. We believe this is the first study to demonstrate that a pharmacist-driven ASP can be beneficial among febrile neutropenic patients. Our study compared antibiotic appropriateness between a pharmacist-driven ASP and a control group.

2. Results

Ninety febrile neutropenic events occurred in 66 patients. The proportion of men in the control group was higher than the intervention group (57.8% vs. 35.6%, p = 0.035). The mean age of all patients was 51.6 ± 15.6 years. Most patients were diagnosed with cytotoxic chemotherapy-induced febrile neutropenia (74.4%) while twenty patients were identified as a febrile neutropenia during the period of initial hematologic abnormalities diagnosis (22.2%) and only three patients were diagnosed as a febrile neutropenia from other causes such as vitamin B12 deficiency, severe infection, and zidovudine-induced pancytopenia. The majority of our patients had hematologic malignancy (80%) and 8.9% had solid cancer. The Multinational Association for Supportive Care in Cancer (MASCC) risk index median score was 20 (interquartile range (IQR) 17–21). The median absolute neutrophil count was 153.9 cells/mm3 (IQR 19–520). Fifty-one percent of patients had a history of febrile neutropenia and 55.6% of patients had been exposed to antibiotics within the past 3 months. The median duration of neutropenia was 7 days. The frequency of infectious diseases consultation was similar in both groups. The baseline characteristics are displayed in Table 1.
The major causative organisms were Gram-negative bacteria (43.3%), followed by Gram-positive bacteria (13.3%) and fungi (3.3%). The most common causative Gram-negative bacteria were Escherichia coli (33.3%), Klebsiella pneumoniae (25.6%), and Pseudomonas aeruginosa (10.3%). Most Gram-negative bacteria exhibited multiple-drug resistance (MDR) (69%). More carbapenem-resistant Gram-negative bacteria were often found in the pharmacist-driven ASP group compared to the control group (8.9% vs. 2.2%, p = 0.167) while extended spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria were lower than the control group (6.7% vs. 20%, p = 0.063). The most common causative Gram-positive bacteria were Enterococci spp. (41.7%), Staphylococcus aureus (33.3%), and Corynebacterium spp. (16.7%). Ampicillin-resistant Enterococci spp. was isolated from only in one patient and only one patient had methicillin-resistant Staphylococcus aureus (MRSA). Most of the causative organisms were isolated from blood, urine, or sputum (27.8%, 12.2%, and 8.9%, respectively). The most common sources of infection were primary bacteremia, urinary tract infection, and pneumonia (23.3%, 13.3%, and 10%, respectively). However, the causative organisms were not isolated in nearly half of patients.
Overall, antibiotic appropriateness in the pharmacist-driven ASP group was significantly higher than the control group (88.9% vs. 51.1%, p < 0.001) (Table 2). In providing empirical therapy, the pharmacist-driven ASP group was more appropriate than the control group (97.8% vs. 77.8%, p = 0.007). The appropriate dosage regimen in the pharmacist-driven ASP group was significantly higher than the control group (97.8% vs. 88.7%, p = 0.049) as well as appropriate antibiotic coverage (100% vs. 91.1%, p = 0.041), while appropriate indications were similar in both groups. When providing therapy for definitive infections, the overall appropriateness was greater in the pharmacist-driven ASP group than in the control group (88.9% vs. 64.4%, p = 0.004), as was the duration of therapy (91.1% vs. 75.6%, p = 0.039). For therapy if the source of infection was unknown, the overall appropriateness in the pharmacist-driven ASP group also significantly greater than the control group (90% vs. 54.4%, p = 0.011). Furthermore, the appropriateness of duration of therapy in the pharmacist-driven group was significantly greater than in the control group (93.2% vs. 75.6%, p = 0.022). However, the antibiotic appropriateness in cases of known causative pathogens were not significantly greater than the control group, but there was a trend of improved appropriateness in the pharmacist-driven ASP group. The total antibiotic duration between two groups were similar (p = 0.948) (Table 2). The compliance rate to the pharmacist suggestion was 93.8% in the pharmacist-driven ASP group. The most common pharmacist interventions were de-escalation (31.3%), adding additional antimicrobials (18.8%), and avoiding serious drug interaction (18.1%).
Overall, the antibiotic appropriateness in the pharmacist-driven ASP group was significantly higher than control group (88.9% vs. 51.1%, p < 0.001) (Table 2). In providing empirical therapy, the pharmacist-driven ASP group was more appropriate than the control group (97.8% vs. 77.8%, p = 0.007). The appropriate dosage regimen in the pharmacist-driven ASP group was significantly higher than the control group (97.8% vs. 88.7%, p = 0.049) as well as the appropriate antibiotic coverage (100% vs. 91.1%, p = 0.041) while the appropriate indications were similar in both groups. When providing therapy for definitive infections, the overall appropriateness was greater in the pharmacist-driven ASP group than in the control group (88.9% vs. 64.4%, p = 0.004) as was the duration of therapy (91.1% vs. 75.6%, p = 0.039). For therapy if the source of infection was unknown, the overall appropriateness in the pharmacist-driven ASP group was also significantly greater than the control group (90% vs. 54.4%, p = 0.011). Furthermore, the appropriateness of duration of therapy in the pharmacist-driven group was significantly greater than in control group (93.2% vs. 75.6%, p = 0.022). However, the antibiotic appropriateness in cases of known causative pathogens were not significantly greater than the control group, but there was a trend of improved appropriateness in the pharmacist-driven ASP group. The total antibiotic duration between two groups were similar (p = 0.948) (Table 2). The compliance rate to the pharmacist suggestion was 93.8% in the pharmacist-driven ASP group. The most common pharmacist interventions when compared with the control group were de-escalation (22.2% vs. 20%, p = 0.796), adding additional antimicrobials (17.8% vs. 8.9%, p = 0.215), and avoiding serious drug interaction (6.7% vs. 0%, p = 0.078).
The 30-day infectious diseases-related mortality and length of stay were similar in both groups (Table 2). In univariate analysis, neither the pharmacist-driven ASP nor ID consultation showed a significant impact on 30-day infectious diseases-related mortality (p = 0.810 and 0.267, respectively). However, in multivariate analysis, the pharmacist-driven ASP group and infectious diseases consultation significantly reduced the 30-day infectious diseases mortality in patients with cytotoxic chemotherapy-induced febrile neutropenia (OR 0.058, 95% CI: 0.005–0.655, p = 0.021). A history of febrile neutropenia was associated with an increased 30-day infectious diseases mortality, as described in Table 3. The utilization rate of target antibiotics in the pharmacist-driven ASP group tended to be higher than control group (882 Defined Daily Dose (DDD)/1000 patient-day vs. 705.1 DDD/1000 patient-day). The trend of the overall target antibiotic seemed to be higher in both groups (supplementary data, Table S1). The trend of ceftazidime, cefepime, and meropenem utilization was lower in the pharmacist-driven ASP group while piperacillin/tazobactam utilization was higher. In the control group, ceftazidime utilization tended to be decreased, but other target antibiotics’ utilization including cefepime, piperacillin/tazobactam, and meropenem were increased. Overall intravenous antibiotic utilization in the pharmacist-driven ASP group declined while amount of utilization in the control group increased.

3. 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% vs. 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 [15]. We believe that main reason for this discrepancy was that the previous study evaluated only the prescribed antibiotic appropriateness based on the hospital guidelines and described only the antibiotics indicated for febrile neutropenia, but did not assess the appropriateness of dosage regimens which was included in our assessment of the appropriateness of prescribed antibiotics [15,16]. 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 [15]. Likely our study, which provided more frequent feedback, improved the primary physicians’ compliance, as noted in a recent study [10]. Furthermore, our results showed that the appropriate dosage regimens were more frequently found in the pharmacist-driven ASP group than the control group (97.8% vs. 88.7%, p = 0.049). Our finding was similar to previous studies that the appropriateness was 6.5-fold higher in the pharmacist intervention group then the control group [17]. On the other hand, the appropriateness of antibiotic indication in the pharmacist-driven ASP group resembled the control group, as described in Madran et al. study [15]. However, we also used current standard guidelines and all of our patients had a high risk of febrile neutropenia, similar to the previous study [15].
In documented infection evaluations, the pharmacist-driven ASP group had a greater appropriateness of prescribed antibiotics than the control group (88.9% vs. 64.4%, p = 0.004). Our result was similar to previous study in which more appropriateness was found in the intervention group [15]. Moreover, the 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 ASPs could reduce the duration of antibiotic therapy [18]. However, the appropriateness of antibiotic indication was similar in both groups because our study divided the category of appropriateness into microbial susceptibilities and the penetration of antibiotics to the 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 [19]. In addition, the 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 S2). However, the total antibiotic duration between two groups did not differ. The reasons for prolonging antibiotic duration in the intervention group were fungal infection (e.g., invasive pulmonary aspergillosis and mucormycosis), superinfection with MDR organisms, and an uncontrolled source of infection. Although the result did not show any difference of antibiotic appropriateness in the 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 S3).
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 carbapenem resistance Enterobacteriaceae (CRE) infection rates in the intervention group which differed from a previous study [15]. 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 [15,20,21]. However, other ASP studies in febrile neutropenic patients also showed no difference in mortality between two groups as well [10,22,23,24,25]. 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 Guidelines that ASP team should be made up of a multidisciplinary team to achieve successful ASP implementation [5]. On-site infectious diseases specialists, including an ID physician and pharmacist, can improve the ASP effectiveness in recent study [26]. Hence, a multidisciplinary team would be beneficial for ASP implementation in these specific populations where data are limited, such as febrile neutropenic patients. 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 was also mentioned in previous study [27]. Furthermore, our study did not find any difference in the 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 the 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 prescribed at an improper low dose. Therefore, the 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 a higher DDD of target antibiotic in the pharmacist-driven ASP group [2,3]. Besides, the 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 Thammasat University Hospital 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 carried out 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 a pharmacist-driven ASP on 30-day infectious diseases-related mortality. Fourth, we could not evaluate the effect of pharmacist-driven ASPs on antibiotic resistance since the study site did not have an isolation ward for febrile neutropenia patients with multidrug-resistant pathogens. Thus, the 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 the antibiotic dosage regimen or discontinue antibiotics by themselves; a physician’s signature is needed. Thus, pharmacist cooperation with a physician was also an important aspect to implement a successful pharmacist-driven ASP in Thailand.
In conclusion, our study showed that a pharmacist-driven ASP in febrile neutropenic patients could improve the antibiotic appropriateness in both empirical and documentation therapy. However, 30-day infectious diseases-related mortality and the length of stay were not different between the groups. Although the target antibiotic utilization in the intervention group increased, we found a reduction in the total antibiotic utilization in the pharmacist-driven ASP group.

4. Materials and Methods

This prospective study was conducted at Thammasat University Hospital in Thailand, a tertiary care and teaching hospital, between 1 August 2019 and 30 April 2020. Two medical wards were pre-designated as the pharmacist-driven ASP group and two other similar medical wards were pre-designated as the control group. Febrile neutropenia in our study was defined as fever (single temperature equivalent to ≥38.3 °C orally or equivalent to ≥38.0 °C orally over a 1 h period) with neutropenic condition (patient who had ≤500 neutrophils per microliter or ≤500 neutrophils per microliter and a predicted declined to ≤500 neutrophils per microliter over the next 48 h). High risk of febrile neutropenia was identified by the MASCC risk index score less than 21 [28]. Inclusion criteria included adult patients (i.e., age >18 years); patient diagnosed with febrile neutropenia; and patient received antibiotics for treatment of febrile neutropenia. Exclusion criteria included the receipt of antibiotics for febrile neutropenia <24 h, pregnancy, or lactation. This study was approved by the human research ethics committee, Thammasat University (protocol no. MTU-EC-OO-0-078/62).
Our ASP team consisted of an infectious diseases-trained clinical pharmacist, infectious diseases physicians and hematologists. We developed TUH’s recommended antibiotic and dosage regimen for empirical therapy in febrile neutropenia, which, adapted from the IDSA 2010 and National Comprehensive Cancer Network (NCCN) 2020 guidelines and distributed to primary physicians prior to the pharmacist-driven ASP, was implemented in two medical wards groups [5,28]. In the intervention group, a clinical pharmacist performed the daily prospective audit and feedback to the primary physician. The pharmacist suggested a suitable antibiotic for each patient, calculated an appropriate dose and recommended the treatment duration for both empirical therapy and documented infection. The antibiotic appropriateness and antibiotic utilization in the intervention group was reported monthly by the clinical pharmacist. Medical personnel practicing in the intervention group were provided education via lectures and posters by the clinical pharmacists during monthly ward conferences. No ASP interventions were performed in the control group. The criteria to evaluate antibiotic appropriateness was adapted from previous studies (supplementary data, Figure S1) [29,30,31]. In empirical therapy evaluations, a clinical pharmacist evaluated an appropriateness of indications, antibiotic coverage, and dosage regimen of the antibiotics. Therapeutic evaluations for documented infection were divided into 2 groups—unknown source of infection and known causative pathogens and source of infection. Both groups were also evaluated for antibiotic indication, dosage regimen, and duration of antibiotic therapy by pharmacist.
The primary outcome of this study was to compare antibiotic appropriateness between pharmacist-ASP driven group and the control group. Secondary outcomes were to compare antibiotic utilization, patient length of stay, 30-day infectious diseases-related mortality between the intervention and control groups. Target antibiotics in this study were ceftazidime, cefepime, piperacillin/tazobactam, meropenem and imipenem which are recommended as an empirical therapy for febrile neutropenia in current guidelines [28,32,33]. All intravenous antibiotics classes commonly used in these patients were evaluated in this study.
To have an 80% power and 95% confidence interval, the minimum sample size required in each arm, calculated based on a previous study, was 33 subjects [15]. Each outcome was defined as a febrile neutropenic event. All statistical analyses were performed using STATA version 16 (College Station, TX). Chi-square test (two-tailed) was used to compare proportion for categorical variables while t-test was used to compare means for continuous variables. Antibiotic utilization was reported as the defined daily dose per 1000 patient-days. The trend of antibiotic utilization was analyzed by linear regression and reported as the coefficient and p-value. Univariate and multivariate analyses of variables influencing on 30-day infectious diseases-related mortality were performed. All comparisons were 2-sided and a p value < 0.05 was consider statistically significant.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/antibiotics10040456/s1, Figure S1: criteria of antibiotic appropriateness evaluation, Table S1: antibiotics utilization, Table S2: antibiotic appropriateness in documentation therapy: unknown source of infection, Table S3: antibiotic appropriateness in documentation therapy: known causative pathogens and source of infection.

Author Contributions

Conceptualization, methodology and formal analysis, P.M., A.A., W.L. and K.J.; investigation, K.J.; writing—original draft preparation, W.L. and D.J.W.; writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Thammasat University (protocol no. MTU-EC-OO-0-078/62).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Acknowledgments

We thank the primary physicians who practiced in the medical wards during the study period at Thammasat University Hospital.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Talcott, J.A.; Finberg, R.; Mayer, R.J.; Goldman, L. The medical course of cancer patients with fever and neutropenia. Clinical identification of a low-risk subgroup at presentation. Arch. Intern. Med. 1988, 148, 2561–2568. [Google Scholar] [CrossRef] [PubMed]
  2. Lortholary, O.; Lefort, A.; Tod, M.; Chomat, A.M.; Darras-Joly, C.; Cordonnier, C. Pharmacodynamics and pharmacokinetics of antibacterial drugs in the management of febrile neutropenia. Lancet Infect. Dis. 2008, 8, 612–620. [Google Scholar] [CrossRef]
  3. Sime, F.B.; Roberts, M.S.; Warner, M.S.; Hahn, U.; Robertson, T.A.; Yeend, S.; Phay, A.; Lehman, S.; Lipman, J.; Peake, S.L.; et al. Altered pharmacokinetics of piperacillin in febrile neutropenic patients with hematological malignancy. Antimicrob. Agents. Chemother. 2014, 58, 3533–3537. [Google Scholar] [CrossRef][Green Version]
  4. Naeem, D.; Alshamrani, M.A.; Aseeri, M.A.; Khan, M.A. Prescribing Empiric Antibiotics for Febrile Neutropenia: Compliance with Institutional Febrile Neutropenia Guidelines. Pharmacy 2018, 6, 83. [Google Scholar] [CrossRef]
  5. Barlam, T.F.; Cosgrove, S.E.; Abbo, L.M.; MacDougall, C.; Schuetz, A.N.; Septimus, E.J.; Srinivasan, A.; Dellit, T.H.; Falck-Ytter, Y.T.; Fishman, N.O.; et al. Implementing an Antibiotic Stewardship Program: Guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin. Infect. Dis. 2016, 62, 51–77. [Google Scholar] [CrossRef] [PubMed]
  6. Rosa, R.G.; Goldani, L.Z.; dos Santos, R.P. Association between adherence to an antimicrobial stewardship program and mortality among hospitalised cancer patients with febrile neutropaenia: A prospective cohort study. BMC Infect. Dis. 2014, 14, 286. [Google Scholar] [CrossRef] [PubMed]
  7. Paskovaty, A.; Pflomm, J.M.; Myke, N.; Seo, S.K. A multidisciplinary approach to antimicrobial stewardship: Evolution into the 21st century. Int. J. Antimicrob. Agents. 2005, 25, 1–10. [Google Scholar] [CrossRef]
  8. Cheng, V.C.; To, K.K.; Li, I.W.; Tang, B.S.; Chan, J.F.; Kwan, S.; Mak, R.; Tai, J.; Ching, P.; Ho, P.L.; et al. Antimicrobial stewardship program directed at broad-spectrum intravenous antibiotics prescription in a tertiary hospital. Eur. J. Clin. Microbiol. Infect. Dis. 2009, 28, 1447–1456. [Google Scholar] [CrossRef]
  9. Yeo, C.L.; Chan, D.S.; Earnest, A.; Wu, T.S.; Yeoh, S.F.; Lim, R.; Jureen, R.; Fisher, D.; Hsu, L.Y. Prospective audit and feedback on antibiotic prescription in an adult hematology-oncology unit in Singapore. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 583–590. [Google Scholar] [CrossRef]
  10. So, M.; Mamdani, M.M.; Morris, A.M.; Lau, T.T.Y.; Broady, R.; Deotare, U.; Grant, J.; Kim, D.; Schimmer, A.D.; Schuh, A.C.; et al. Effect of an antimicrobial stewardship programme on antimicrobial utilisation and costs in patients with leukaemia: A retrospective controlled study. Clin. Microbiol. Infect. 2018, 24, 882–888. [Google Scholar] [CrossRef]
  11. Ruiz-Ramos, J.; Frasquet, J.; Poveda-Andrés, J.L.; Romá, E.; Salavert-Lleti, M.; Castellanos, Á.; Ramirez, P. Impact of an antimicrobial stewardship program on critical haematological patients. Farm. Hosp. 2017, 41, 479–487. [Google Scholar]
  12. Storey, D.F.; Pate, P.G.; Nguyen, A.T.; Chang, F. Implementation of an antimicrobial stewardship program on the medical-surgical service of a 100-bed community hospital. Antimicrob. Resist. Infect. Control 2012, 1, 32. [Google Scholar] [CrossRef]
  13. Rattanaumpawan, P.; Thamlikitkul, V.; Upapan, P. 239A Cluster-Randomized Controlled Trial of Trained Pharmacists and Infectious Disease Clinical Fellows for Approval of Restricted Antibiotics in Hospitalized Medical Patients at Siriraj Hospital. Open Forum Infect. Dis. 2014, 1, 103. [Google Scholar] [CrossRef]
  14. Apisarnthanarak, A.; Lapcharoen, P.; Vanichkul, P.; Srisaeng-Ngoen, T.; Mundy, L.M. Design and analysis of a pharmacist-enhanced antimicrobial stewardship program in Thailand. Am. J. Infect. Control 2015, 43, 956–959. [Google Scholar] [CrossRef]
  15. Madran, B.; Keske, Ş.; Tokça, G.; Dönmez, E.; Ferhanoğlu, B.; Çetiner, M.; Mandel, N.M.; Ergönül, Ö. Implementation of an antimicrobial stewardship program for patients with febrile neutropenia. Am. J. Infect. Control 2018, 46, 420–424. [Google Scholar] [CrossRef] [PubMed]
  16. Van den Bosch, C.M.; Geerlings, S.E.; Natsch, S.; Prins, J.M.; Hulscher, M.E. Quality indicators to measure appropriate antibiotic use in hospitalized adults. Clin. Infect. Dis. 2015, 60, 281–291. [Google Scholar] [CrossRef]
  17. DeWitt, K.M.; Weiss, S.J.; Rankin, S.; Ernst, A.; Sarangarm, P. Impact of an emergency medicine pharmacist on antibiotic dosing adjustment. Am. J. Emerg. Med. 2016, 34, 980–984. [Google Scholar] [CrossRef] [PubMed]
  18. Ohashi, K.; Matsuoka, T.; Shinoda, Y.; Mori, T.; Yoshida, S.; Yoshimura, T.; Sugiyama, T. Clinical outcome of pharmacist-led prospective audit with intervention and feedback after expansion from patients using specific antibiotics to those using whole injectable antibiotics. Eur. J. Clin. Microbiol. Infect. Dis. 2019, 38, 593–600. [Google Scholar] [CrossRef]
  19. Harris, P.N.A.; Tambyah, P.A.; Lye, D.C.; Mo, Y.; Lee, T.H.; Yilmaz, M.; Alenazi, T.H.; Arabi, Y.; Falcone, M.; Bassetti, M.; et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With, E. coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA 2018, 320, 984–994. [Google Scholar] [CrossRef] [PubMed]
  20. Chotiprasitsakul, D.; Srichatrapimuk, S.; Kirdlarp, S.; Pyden, A.D.; Santanirand, P. Epidemiology of carbapenem-resistant Enterobacteriaceae: A 5-year experience at a tertiary care hospital. Infect. Drug Resist. 2019, 12, 461–468. [Google Scholar] [CrossRef]
  21. Righi, E.; Peri, A.M.; Harris, P.N.; Wailan, A.M.; Liborio, M.; Lane, S.W.; Paterson, D.L. Global prevalence of carbapenem resistance in neutropenic patients and association with mortality and carbapenem use: Systematic review and meta-analysis. J. Antimicrob. Chemother. 2017, 72, 668–677. [Google Scholar] [CrossRef] [PubMed]
  22. Ko, J.H.; Kim, S.H.; Kang, C.I.; Cho, S.Y.; Lee, N.Y.; Chung, D.R.; Peck, K.R.; Song, J.H. Evaluation of a Carbapenem-Saving Strategy Using Empirical Combination Regimen of Piperacillin-Tazobactam and Amikacin in Hemato-Oncology Patients. J. Korean Med. Sci. 2019, 34, 17. [Google Scholar] [CrossRef] [PubMed]
  23. Kirk, A.; Pierce, J.; Doll, M.; Lee, K.; Pakyz, A.; Kim, J.; Markley, D.; De la Cruz, O.; Bearman, G.; Stevens, M.P. Effect of carbapenem restriction on prescribing trends for immunocompromised wards at an academic medical center. Am. J. Infect. Control 2019, 47, 1035–1037. [Google Scholar] [CrossRef] [PubMed]
  24. Snyder, M.; Pasikhova, Y.; Baluch, A. Early Antimicrobial De-escalation and Stewardship in Adult Hematopoietic Stem Cell Transplantation Recipients: Retrospective Review. Open Forum Infect. Dis. 2017, 4, 226. [Google Scholar] [CrossRef]
  25. Paskovaty, A.; Pastores, S.M.; Gedrimaite, Z.; Kostelecky, N.; Riedel, E.R.; Seo, S.K. Antimicrobial de-escalation in septic cancer patients: Is it safe to back down? Intensive Care Med. 2015, 41, 2022–2023. [Google Scholar] [CrossRef]
  26. Livorsi, D.J.; Nair, R.; Lund, B.C.; Alexander, B.; Beck, B.F.; Goto, M.; Ohl, M.; Vaughan Sarrazin, M.S.; Goetz, M.B.; Perencevich, E.N. Antibiotic stewardship implementation and patient-level antibiotic use at hospitals with and without on-site Infectious Disease specialists. Clin. Infect. Dis. 2020, 388. [Google Scholar] [CrossRef]
  27. Keng, M.K.; Sekeres, M.A. Febrile neutropenia in hematologic malignancies. Curr. Hematol. Malig. Rep. 2013, 8, 370–378. [Google Scholar] [CrossRef]
  28. NCCN; Clinical Practice Guidelines in Oncology. Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections Version 2.2020 June 5, 2020. Available online: https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf (accessed on 27 December 2020).
  29. Kollef, M.H. Inadequate antimicrobial treatment: An important determinant of outcome for hospitalized patients. Clin. Infect. Dis. 2000, 31, 131–138. [Google Scholar] [CrossRef]
  30. Kollef, M.H. Rebuttal from Dr Kollef. Chest 2017, 151, 744–745. [Google Scholar] [CrossRef][Green Version]
  31. Kollef, M.H. The importance of appropriate initial antibiotic therapy for hospital-acquired infections. Am. J. Med. 2003, 115, 582–584. [Google Scholar] [CrossRef]
  32. Freifeld, A.G.; Bow, E.J.; Sepkowitz, K.A.; Boeckh, M.J.; Ito, J.I.; Mullen, C.A.; Raad, I.I.; Rolston, K.V.; Young, J.A.; Wingard, J.R. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2011, 52, 427–431. [Google Scholar] [CrossRef] [PubMed]
  33. Klastersky, J.; de Naurois, J.; Rolston, K.; Rapoport, B.; Maschmeyer, G.; Aapro, M.; Herrstedt, J. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann. Oncol. 2016, 27, 111–118. [Google Scholar] [CrossRef] [PubMed]
Table 1. Baseline characteristics.
Table 1. Baseline characteristics.
Baseline CharacteristicTotal
(90 FN Episodes),
No. (%)		Intervention
(45 FN Episodes),
No. (%)		Control
(45 FN Episodes),
No. (%)		p Value
Age, mean years ± SD 51.6 ± 15.615.6 ± 14.652.0 ± 16.70.894
Male 42 (46.7)16 (35.6)26 (57.8)0.035
Weight, mean kg ± SD57.76 ± 1.5058.94 ± 1.9460.57 ± 2.300.590
Cause of febrile neutropenia
   Cytotoxic chemotherapy67 (74.4)34 (75.6)33 (73.3)1.000
   During period of initial hematologic abnormalities diagnosis20 (22.2)10 (22.2)10 (22.2)1.000
Other causes a3 (3.33)1 (2.22)2 (4.44)1.000
Active hematologic cancer 72 (80)34 (75.6)38 (84.4)0.496
Active solid cancer8 (8.9)4 (8.9)4 (8.9)0.496
MASCC score, median (IQR) 20 (17–21)19 (13–21)21 (19–21)0.129
High risk of febrile neutropenia (MASCC < 21)45 (50)25 (55.6)20 (44.4)0.292
Absolute neutrophil count, median cells/mm3 (IQR)153.9 (19–520)184 (40–645)77 (13–368)0.198
Had history of febrile neutropenia46 (51.1)20 (44.4)26 (57.8)0.206
Recent exposed to antibiotic within past 3 months50 (55.6)25 (55.6)25 (55.6)1.000
Neutropenia duration, median days (IQR)7 (4–14)8 (4–14)6 (4–10)0.435
Infectious diseases specialist consultation50 (55.6)27 (60)23 (51.1)0.396
Time to administer antibiotic, median hours (IQR)1 (0–4)1.5 (0–4)1 (0–4)0.497
Causative organism identified49 (54.4)26 (57.8)23 (51.1)0.525
   Gram-positive bacteria12 (13.3)7 (15.6)5 (11.1)0.774
   Gram-negative bacteria39 (43.3)20 (44.4)19 (42.2)0.761
     ESBL-producing organisms12 (13.3)3 (6.7)9 (20)0.118
     Carbapenem resistance organisms5 (5.6)4 (8.9)1 (2.2)0.361
ESBL, extended spectrum beta-lactamase; FN, febrile neutropenia; IQR, interquartile range; MASCC, Multinational Association for Supportive Care in Cancer risk index score; SD, standard deviation. a Other causes of febrile neutropenia were from vitamin B12 deficiency, zidovudine-induce pancytopenia and severe infection.
Table 2. Study outcomes.
Table 2. Study outcomes.
OutcomesIntervention
(45 FN Episodes),
No. (%)		Control
(45 FN Episodes),
No. (%) 		p Value
Overall appropriateness40 (88.9)23 (51.1)<0.001
Step 1 Empirical therapy44 (97.8)35 (77.8)0.007
Appropriate Indication45 (100)45 (100)-
Appropriate coverage45 (100)41 (91.1)0.041
Appropriate dosage regimen44 (97.8)39 (88.7)0.049
Step 2 Documentation therapy40 (88.9) b29 (64.4)0.004
Appropriate indication43 (95.6)41 (91.1)0.361
Appropriate dosage regimen 44 (97.8)43 (93.3)0.242
Appropriate duration41 (91.1)34 (75.6)0.039
Length of stay, median days (IQR)28 (19–42)23 (16–35)0.689
30-day infectious diseases related mortality6 (13.6)5 (11.1)1.000
Total antibiotic duration, median days (IQR)14 (10–23)15 (10–21)0.948
   antibiotic duration in de-escalation 21 (14–28) 17.5 (15.5–29.5)0.666
   antibiotic duration in escalation19 (13–34.5)15 (11–25.5)0.309
FN, febrile neutropenia; IQR, interquartile range. b Total 44 FN episodes since one death occurred before culture was reported.
Table 3. Multivariate analysis of 30-day infectious diseases-related mortality.
Table 3. Multivariate analysis of 30-day infectious diseases-related mortality.
VariablesUnivariate AnalysisMultivariate Analysis
OR95%CIp ValueOR95%CIp Value
Pharmacist-driven ASP group and infectious diseases consultation in chemotherapy-induced febrile neutropenic patient0.1840.037–0.9110.0380.0580.005–0.6550.021
Male0.6530.176–2.4190.5240.7440.133–4.1480.736
High risk of febrile neutropenia5.4261.098–26.8290.0385.1550.762–34.8900.093
Had history of febrile neutropenia5.1431.040–25.4200.0459.3801.311–67.1000.026
Carbapenem resistance organisms8.1111.015–64.8390.04818.7710.560–628.8480.102
ESBL producing Gram negative bacteria2.750.614–12.3070.1867.4170.787–69.9060.080
ASP, antibiotic stewardship program; CI, confidence interval; ESBL, extended spectrum beta-lactamase; MASCC, Multinational Association for Supportive Care in Cancer risk index score; OR, odds ratio.
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Jantarathaneewat, K.; Apisarnthanarak, A.; Limvorapitak, W.; Weber, D.J.; Montakantikul, P. Pharmacist-Driven Antibiotic Stewardship Program in Febrile Neutropenic Patients: A Single Site Prospective Study in Thailand. Antibiotics 2021, 10, 456. https://doi.org/10.3390/antibiotics10040456

AMA Style

Jantarathaneewat K, Apisarnthanarak A, Limvorapitak W, Weber DJ, Montakantikul P. Pharmacist-Driven Antibiotic Stewardship Program in Febrile Neutropenic Patients: A Single Site Prospective Study in Thailand. Antibiotics. 2021; 10(4):456. https://doi.org/10.3390/antibiotics10040456

Chicago/Turabian Style

Jantarathaneewat, Kittiya, Anucha Apisarnthanarak, Wasithep Limvorapitak, David J. Weber, and Preecha Montakantikul. 2021. "Pharmacist-Driven Antibiotic Stewardship Program in Febrile Neutropenic Patients: A Single Site Prospective Study in Thailand" Antibiotics 10, no. 4: 456. https://doi.org/10.3390/antibiotics10040456

APA Style

Jantarathaneewat, K., Apisarnthanarak, A., Limvorapitak, W., Weber, D. J., & Montakantikul, P. (2021). Pharmacist-Driven Antibiotic Stewardship Program in Febrile Neutropenic Patients: A Single Site Prospective Study in Thailand. Antibiotics, 10(4), 456. https://doi.org/10.3390/antibiotics10040456

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