Assessment of Caspofungin use at a Tertiary Teaching Hospital and compliance with IDSA guidelines and FDA labelings

Objective The aim of this study is to evaluate the utilization pattern of Caspofungin in an academic tertiary care hospital in Riyadh, Saudi Arabia. Methods This is a retrospective study, conducted at King Saud University Medical City, Riyadh, Saudi Arabia. Adult patients who received Caspofungin from January 2015 to December 2018 were included. The appropriate use of Caspofungin was evaluated according to the international guidelines and approved recommendations. Caspofungin doses were assessed according to the FDA-approved loading and maintenance doses as well as dose-adjustment per hepatic function for cirrhotic patients and drug-drug interactions. Cultures and laboratory tests were used to evaluate the appropriate duration of Caspofungin therapy. Results 388 patients were included. Caspofungin was inappropriately used in 253 (64%) patients. This included 78 (20%) due to inappropriate indication, 165 (42%) due to wrong dosage, and 10 (2%) patients who had a wrong duration of therapy. Conclusion The rate of inappropriate use of Caspofungin was high. Hence, developing antifungal stewardship and drug restriction program is highly recommended.


Introduction
Caspofungin is a member of a class of antifungals termed echinocandins which are approved by the US Food and Drug Administration (FDA) in adult and pediatric patients (3 months of age and older) as empiric therapy for presumed fungal infections in febrile neutropenia and for treatment of invasive aspergillosis (IA) in cases that are refractory or intolerant to azole antifungal agents (''Cancidas (Caspofungin Acetate) Injection," 2001; Patterson et al., 2016), as well as for treatment of severe Candida (C.) infections including candidemia, intra-abdominal abscesses, peritonitis, pleural space infections, and esophageal candidiasis (''Cancidas (Caspofungin Acetate) Injection," 2001; Pappas et al., 2016). In addition, Caspofungin has been used off-label to treat oropharyngeal candidiasis, candida osteomyelitis, septic arthritis, endocarditis, suppurative thrombophlebitis, and as empirical therapy in septic shock (Pappas et al., 2016).

Study design and variables
Patients who received at least one dose of Caspofungin from January 2015 to December 2018 at King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia, were identified from the medical records and their charts were retrospectively reviewed. Pregnant women and children were excluded from the study. The research was approved by the Institutional Review Board at KSUMC (E-19-3872). The primary objective was to assess Caspofungin use and compliance to international guidelines and approved recommendations (see A.1).
A data collection sheet was created to collect demographic information, medical and medication histories, lab tests, and microbiological cultures. The child-Pugh score was calculated for cirrhotic patients to determine dose adjustment based on the severity of chronic liver diseases.
Drug interactions and dose appropriateness were assessed using a comprehensive drug interaction checker and reliable databases (e.g., Lexi-comp and Micromedex).

Statistical analysis
Descriptive statistics were used to summarize the data. Variables were presented in numbers and percentages. Mean and standard deviation (SD) were used to describe age, height, and weight. Statistical analyses were performed using STATA 15.1 (StataCorp LP, College Station, Texas, USA).

Results
Three hundred and eighty-eight adult patients were identified. The mean age was 54 ± 18, and 51% were male. Around 133 (34%) patients weighed > 80 kg, among which 104 had BMI 30 kg/m 2 . The mean level of albumin was lower than the normal range (22.7 ± 6.7), while the mean level of total bilirubin and the mean level of prothrombin time (PT) were higher than the normal range (50.3, ± 124.9) and (19.4 ± 10.9), respectively. (Table 1) Caspofungin was initiated as empiric therapy for septic shock in 184 patients (48%) and documented fungal infections in 131 patients (34%) ( Table 1).
Cultures were positive in 50 patients (12.8%) and Candida albicans was the most frequently isolated pathogen. More details about the sources of infections and etiologic pathogens are listed in Table 2.

Discussion
To our knowledge, this is the first study to evaluate the utilization pattern of Caspofungin in terms of indication, dose, and duration. This study showed an overall inappropriate utilization of caspfungin and lack of compliance to international guidelines and approved recommendations at a tertiary teaching hospital, mainly, in terms of dosing and indication.
Noteworthy, in our study, we had 21 patients with severe liver disease who received at least one dose of Caspofungin. Despite the absence of recommended dose for this population by the manufacturer, we categorized this dosing as appropriate according to a pharmacokinetic study which concluded that severe liver impairment does not necessitate further dose reduction compared to moderate liver impairment (Gustot et al., 2018).
Interestingly, few patients received Caspofungin with inappropriate dose adjustment due to the acute changes in liver parameters accompanied with their critical condition which later normalized after admission. Hence, the acuity of the patient status and the abnormality of lab parameters upon admission should be considered before dosing Caspofungin.
Moreover, 60% of the patients included in our study were categorized as overweight or obese who have received sub-therapeutic dosing of Caspfungin per the 2004 EMA recommendations (Cancidas (previously Caspofungin MSD), 2009). Nevertheless, this recommendation was based on two pharmacokinetic studies with small number of patients reported a decrease in serum trough concentrations (C 24 ) in overweight individuals (Mistry et al., 2007;Stone et al., 2004). On the other hand, subsequent studies assessed Caspofungin concentrations in overweight individuals showed contradicting results (Hall et al., 2013;Muilwijk et al., 2014;Nguyen et al., 2007;Ryan et al., 2011;Würthwein et al., 2013).
Caspofungin was found to be used in 2 patients with candiduria, and 15 patients with urinary sepsis, in spite of the insufficient data to support the use of Caspofungin in Candida renal parenchymal infections, nor long-term follow-up to assess recurrence of Candida cystitis (Fisher, 2011).
Implementation of antifungal stewardship (AFS) program showed significant improvement in Caspofungin dosing; however, no significant improvement was reported in terms of indication and duration (Lachenmayr et al., 2019). Further, AFS programs showed improvment in antifungal use, cost saving and patients' survival (López-Medrano et al., 2013;Micallef et al., 2015;Ramos et al., 2015;Valerio et al., 2015). López-Medrano, et al showed that the dispensed defined daily doses (DDD) and expenditure of Caspofungin was reduced by 20% after implementing AFS program (López-Medrano et al., 2013). Additionally, the in-hospital mortality decreased after the implementation of AFS program compared with the previous period (López-Medrano et al., 2013;Ramos et al., 2015;Valerio et al., 2015).
Our study is not free from limitations such as being conducted retrospectively at a single tertiary care center, the difficulty in evaluating the duration of Caspofungin regimens, the de-escalation of Caspofungin to oral antifungal options, and the difficulty in assessing patients' clinical improvements. Lastly, the causes behind Caspofungin misuse were not investigated.

Conclusion
As a conclusion, Caspofungin is highly likely to be inappropriately prescribed in terms of dosing and indication. Implementation of AFS program is of high necessity to improve Caspofungin utilization.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement
This research project is the graduation project of Abrar Alshehri to obtain Master's Degree in Clinical Pharmacy Program, King Saud University, Saudi Arabia. The authors would like to thank King Saud University, Riyadh, Saudi Arabia for supporting this research project (RSP-2021/74). The authors would also like to thank the Deanship of Scientific Research at Umm Al-Qura University for supporting this work by Grant Code:19-MED-1-03-0006.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.   (Freifeld et al., 2011) d As single agent or as first choice in treating invasive aspergillosis (IA) without any contraindication to other antifungal agents d Reported Caspofungin hypersensitivity d First choice to treat Candida infections: (Pappas et al., 2016) d Reported Caspofungin resistance (e.g., Caspofungin-resistant C. parapsilosis, or Caspofungin-resistant C. glabrata) (Pappas et al., 2016) d Candida urinary tract infections (unless complicated by disseminated candidiasis) (Freifeld et al., 2011;Kalra & Raizada, 2009) -Severe Candida infection (e.g., hemodynamically unstable or with organ involvement). Mild Candida infection, with recent azole exposure or contraindication d Empirical use in septic shock (without the criteria mentioned in the appropriate use) I. Documented culture with C. krusei, or fluconazole-resistant C. glabrata II. Prolonged QT or drug interaction (Patterson et al., 2016) d Alternative choice for esophageal candidiasis and unable to tolerate oral agent (Pappas et al., 2016) d Alternative choice (salvage therapy) to treat invasive aspergillosis (IA) in combination with other antifungal in patients who are refractory or intolerant of other antifungal agents (e.g., amphotericin B and azole) (Patterson et al., 2016) d Empirical therapy in septic shock with risk factors for candidemia such as: (Pappas et al., 2016) - a. Continue for 14 days after the last negative culture b. Consider de-escalation after 5-7 days for patients who are clinically stable and have negative repeated blood culture II. Endocarditis: as initial treatment, followed by de-escalation (total duration 6 weeks) III. Osteomyelitis & osteoarticular infections: 2 weeks, followed by de-escalation (total duration 6-12 months). IV. Intra-abdominal: guided by clinical response and the adequacy of source control. V. Esophageal candidiasis: 14-21 days, de-escalation if tolerate oral.