Correlation between antifungal clinical practices and a new clinical decision support system ANTIFON-CLIC® for the treatment of invasive candidiasis: a retrospective multicentre study.

BACKGROUND: Invasive candidiasis is still recognized as a major cause of morbidity and mortality. To support clinicians in the optimal use of antifungals for the treatment of invasive candidiasis, a computerized decision support system (CDSS) was developed based on institutional guidelines. OBJECTIVES: To evaluate the correlation of this newly developed CDSS with clinical practices, we set-up a retrospective multicentre cohort study with the aim of providing the concordance rate between the CDSS recommendation and the medical prescription (NCT05656157). PATIENTS AND METHODS: Adult patients who received caspofungin or fluconazole for the treatment of an invasive candidiasis were included. The analysis of factors associated with concordance was performed using mixed logistic regression models with department as a random effect. RESULTS: From March to November 2022, 190 patients were included from three centres and eight departments: 70 patients from centre A, 84 from centre B and 36 from centre C. Overall, 100 patients received caspofungin and 90 received fluconazole, mostly (59%; 112/190) for empirical/pre-emptive treatment. The overall percentage of concordance between the CDSS and medical prescriptions was 91% (173/190) (confidence interval 95%: 82%-96%). No significant difference in concordance was observed considering the centres (P > 0.99), the department of inclusion (P = 0.968), the antifungal treatment (P = 0.656) or the indication of treatment (P = 0.997). In most cases of discordance (n = 13/17, 76%), the CDSS recommended fluconazole whereas caspofungin was prescribed. The clinical usability evaluated by five clinicians was satisfactory. CONCLUSIONS: Our results demonstrated the high correlation between current antifungal clinical practice and this user-friendly and institutional guidelines-based CDSS.

Impact of an electronic alert on prescription patterns of meropenem, voriconazole and caspofungin.

BACKGROUND: Antimicrobial stewardship programs promote the appropriate use of antimicrobial substances through the implementation of evidence-based, active and passive interventions. We analyzed the effect of a computer-assisted intervention on antimicrobial use in a tertiary care hospital. METHODS: Between 2011 and 2016 we introduced an electronic alert for patients being prescribed meropenem, voriconazole and caspofungin. At prescription and at day 3 of treatment, physicians were informed about the risk related to these antimicrobial substances by an electronic alert in the medical records. Physicians were invited to revoke or confirm the prescription and to contact the infectious disease (ID) team. Using interrupted time series regression, the days of therapy (DOTs) and the number of prescriptions before and after the intervention were compared. RESULTS: We counted 64,281 DOTs for 5549 prescriptions during 4100 hospital stays. Overall, the DOTs decreased continuously over time. An additional benefit of the alert could not be observed. Similarly, the number of prescriptions decreased over time, without significant effect of the intervention. When considering the three drugs separately, the alert impacted the duration (change in slope of DOTs/1000 bed days; P = 0.0017) as well as the number of prescriptions (change in slope of prescriptions/1000 bed days; P < 0.001) of voriconazole only. CONCLUSIONS: The introduction of the alert lowered prescriptions of voriconazole only. Thus, self-stewardship alone seems to have a limited impact on electronic prescriptions of anti-infective substances. Additional measures such as face-to-face prompting with ID physicians or audit and feedback are indispensable to optimize antimicrobial use.

Candida Bloodstream Infection, a Dire Complication in Hospitalized COVID-19 Patients: Three Cases from a Single Center in Northern Israel.

BACKGROUND: Patients with severe coronavirus disease-2019 (COVID-19) are susceptible to superimposed infections. OBJECTIVES: To describe COVID-19 patients who presented with complications due to Candida bloodstream co-infection (candidemia) and their outcome in a single center in northern Israel (Emek Medical Center) during the second outbreak of COVID-19 in Israel (15 June 2020 to 20 September 2020). METHODS: A retrospective study of COVID-19 patients presenting with candidemia was conducted, including clinical and laboratory data. The incidence of candidemia among hospitalized COVID-19 patients was compared to a historical cohort of non-COVID-19 controls. RESULTS: Three COVID-19 patients complicated with candidemia were documented. All three patients died shortly after the detection of candidemia. Three different Candida sp. were isolated from the blood cultures: C. albicans, C. parapsilosis, and C. glabrata. The incidence of candidemia among COVID-19 patients was 0.679 episodes per 1000 hospital days. CONCLUSIONS: Our small sample suggests a much higher incidence of candidemia among COVID-19 patients compared to a historical cohort of non-COVID-19 controls. All clinicians treating COVID-19 patients in GICU should be aware of this complication.

Mangiferin enhances the antifungal activities of caspofungin by destroying polyamine accumulation.

The incidence of fungal infections has increased continuously in recent years. Caspofungin (CAS) is one of the first-line drugs for the treatment of systemic fungal infection. However, the emerging CAS-resistant clinical isolates and high economic cost for CAS administration hamper the wide application of this drug. Thus, the combined administration of CAS with other compounds that can enhance the antifungal activity and reduce the dose of CAS has gained more and more attention. In this study, we investigated the effect of mangiferin (MG) on the antifungal activities of CAS. Our results showed that MG acted synergistically with CAS against various Candida spp., including CAS-resistant C. albicans. Moreover, MG could enhance the activity of CAS against biofilm. The in vivo synergism of MG and CAS was further confirmed in a mouse model of disseminated candidiasis. To explore the mechanisms, we found that SPE1-mediated polyamine biosynthesis pathway was involved in the fungal cell stress to caspofungin. Treatment of CAS alone could stimulate SPE1 expression and accumulation of polyamines, while combined treatment of MG and CAS inhibited SPE1 expression and destroyed polyamine accumulation, which might contribute to increased oxidative damage and cell death. These results provided a promising strategy for high efficient antifungal therapies and revealed novel mechanisms for CAS resistance.

Fungal endocarditis with heart valve replacement and atrial fibrillation posing a treatment challenge: A case report.

RATIONALE: Fungal endocarditis (FE) is a rare disease, in which antifungal treatment is necessary. When FE is complicated with prosthetic heart valve and/or atrial fibrillation, the coadministration of antifungal agents and warfarin is inevitable. We report a case of rheumatic heart disease with atrial fibrillation who developed FE following prosthetic heart valve replacement. The international normalized ratio (INR) increased significantly during the antifungal treatment with fluconazole. A discussion of the antifungal strategy in FE patients with prosthetic heart valves and/or atrial fibrillation and the interaction between antifungal agents and warfarin was performed. PATIENT CONCERNS: A 54-year-old Chinese woman experienced intermittent fevers, aphemia, and weakness in her right extremities. Her temperature was 38.7°C, and there was atrial fibrillation with heart rate 110 times/min. Neurological examination revealed that she had drowsiness, Broca aphasia, right central facial paralysis, and hemiplegia (Medical Research Council scale, upper limb grade 0, lower limb grade II). DIAGNOSES: Multiple infarction on magnetic resonance imaging and the occlusion of left middle cerebral artery suggested the occurrence of cerebral embolism. The presence of Candida parapsilosis in the results of 4 blood cultures and the existence of valve vegetation in the reexamination of echocardiogram supported the diagnosis of FE. INTERVENTIONS: The patient was given antifungal therapy with fluconazol. The INR increased dramatically on the 9th day of antifungal treatment, and subcutaneous bruising occurred at the intravenous infusion site. The antagonist of vitamin K1 was used and warfarin was reduced to a smaller dosage. The antifungal agent was replaced with caspofungin. OUTCOMES: Her speech improved significantly, and the muscle strength of her paralyzed side reached the Medical Research Council scale of grade IV. She continued to receive caspofungin for antifungal treatment with relatively stable INR and waited for heart valve surgery. LESSONS: The choice of antifungal agents is often a big challenge for FE patients, especially when they need warfarin for anticoagulation. It is better to administer a low dose of warfarin while carefully monitoring the INR or choose the antifungal drugs with little or no effect on warfarin.

Pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Anidulafungin, caspofungin and micafungin are three widely used echinocandin drugs licensed for the treatment of invasive fungal infections, and their clinical use is widespread. To evaluate pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients by comparing the differences in pharmacokinetic parameters between critically ill patients and healthy volunteers or general patients. METHODS: MEDLINE, EMBASE, The Cochrane Library and Pubmed were searched from inception until 6 September 2018. Studies investigating the pharmacokinetic parameters of echinocandins in critically ill patients, healthy volunteers or general patients were included. Our primary outcomes included AUC0-24 h , Cmax and Cmin (24 hours). Two reviewers independently reviewed all titles, abstracts and text, and extracted data. We applied R software (R 2017) to conduct meta-analysis. RESULTS AND DISCUSSION: Of 3235 articles screened, 17 studies were included in the data synthesis. Descriptive data from single-arm studies show that critically ill patients who received caspofungin had more stable AUC0-24 h than those who received anidulafungin and micafungin. The Cmax of critically ill patients who received caspofungin and micafungin was similar to healthy volunteers. However, the Cmax in critically ill patients who received anidulafungin was lower than in healthy volunteers. The Cmin and T1/2 of critically ill patients who received caspofungin were larger than in healthy volunteers. The Vd and CL of critically ill patients receiving anidulafungin and micafungin were larger than in healthy volunteers. WHAT IS NEW AND CONCLUSION: This systematic review provides an analysis of the pharmacokinetic/pharmacodynamics variability of echinocandins in critically ill patients. Based on the limited data available, caspofungin has less pharmacokinetic/pharmacodynamics variability than anidulafungin and micafungin.

Caspofungin: a review of its characteristics, activity, and use in intensive care units.

INTRODUCTION: Candidemia is the fourth frequent reason of healthcare-related bloodstream infections in critically ill patients. For initial management of (suspected) invasive candidiasis in critically ill patients, usage of an echinocandin, e.g. caspofungin, has been recommended. AREAS COVERED: In this study, characteristics of caspofungin and its use in intensive care unit (ICU) patients are reviewed based on an electronic search using PubMed and Google scholar. EXPERT OPINION: Caspofungin is a semisynthetic derivative from pneumocandin B and the first member of the echinocandins that was approved by the U.S. Food and Drug Administration (FDA) to fight fungal infection. Caspofungin inhibits the enzyme ß(1,3)-D-glucan synthase of the fungal cell wall resulted in inhibition of the synthesis of ß(1,3)-D-glucan. For critically ill patients, inter- and intraindividual variations affect the caspofungin concentration. The incidence rates and densities of candidemia in surgical ICUs may be higher than medical ICUs resulting in a higher burden of candidemia in surgical ICUs. However, the mortality rate in surgical ICU patients with candidemia is higher than that medical ICU patients due to differences in their underlying conditions.

Pulsed echinocandin therapy in azole intolerant or multiresistant chronic pulmonary aspergillosis: A retrospective review at a UK tertiary centre.

INTRODUCTION: Chronic pulmonary aspergillosis (CPA) is a fungal disease with high mortality and morbidity. Guidelines suggest treatment with azoles as first-line therapy. However, patients often develop treatment intolerance or increasingly azole resistance. OBJECTIVES: This retrospective review assesses outcomes in azole resistant or intolerant patients with CPA treated with cyclical echinocandin therapy. METHODS: We retrospectively examined records of 25 patients with CPA treated with cyclical caspofungin, 6 of whom were either azole-resistant or azole intolerant. Baseline characteristics, high-resolution computed tomography severity scores, forced expiratory volume after 1 minute (FEV1), forced vital capacity (FVC), body mass index and serology (Aspergillus fumigatus-specific IgG, Aspergillus fumigatus-specific IgE, total IgE and CRP) were assessed before and after caspofungin. RESULTS: Of the six patients, four (66%) started caspofungin due to intolerance and two (33%) due to pan-azole resistance. On treatment, there was stability in FEV1 with an overall mortality of 33% during the follow-up period with a median survival of 875.5 days (IQR 529-1024). No significant change in serology (A. fumigatus-specific IgG and CRP was seen. CONCLUSIONS: With pulsed echinocandin therapy, azole-intolerant or pan-resistant CPA patients have similar mortality rates to azole-naïve CPA patients. Pulsed echinocandin therapy may present a strategy to stabilize CPA in patients with pan resistance or intolerance to, azole therapy.

Factors influencing caspofungin plasma concentrations in kidney transplant patients with high incidence of invasive fungal infections.

WHAT IS KNOWN AND OBJECTIVE: Caspofungin is commonly used in kidney transplant patients for prophylaxis or treatment of invasive fungal infections (IFIs) caused by Candida spp. and Aspergillus spp. Factors such as concomitant medications, co-morbidity and rejection often cause caspofungin pharmacokinetic parameters alterations in kidney transplant patients. Here, we aimed to investigate factors influencing caspofungin plasma concentrations and evaluate its prophylaxis and treatment efficiency for IFIs in kidney transplant patients. METHODS: The prophylaxis and treatment efficiency of caspofungin for IFIs were assessed in 164 kidney transplant patients in the study. Six hundred and fifty-two caspofungin trough concentrations (Cmin ) from the 164 patients were monitored by the liquid chromatography-tandem mass spectrometry method. Basic demographic variables, baseline disease, surgery, rejection, indwelling catheter, coinfection, concomitant medication and other caspofungin-related factors were collected. Univariate and multivariate analyses were used to assess factors influencing caspofungin plasma concentrations. RESULTS AND DISCUSSION: The success rates were 94.96% (132/139) for caspofungin prevention and 80% (20/25) for caspofungin for IFIs. Caspofungin Cmin in the kidney recipients varied largely compared with healthy volunteers (0.10-12.25 mg/L vs. 1.12-1.78 mg/L). Caspofungin Cmin significantly increased in patients with continuous renal replacement therapy before transplantation (P = .001), concomitant medication of cyclosporine A (CsA, P = .009), ALB concentration of > 30 g/L (P = .019). WHAT IS NEW AND CONCLUSION: This is an uncontrolled observational study of caspofungin as prophylaxis or treatment for IFIs in kidney transplant patients. Caspofungin could be an effective and well-tolerated option for antifungal prophylaxis and treatment in kidney transplant patients, and a number of factors could influence caspofungin Cmin in these patients.

Saccharomyces cerevisiae Sepsis Following Probiotic Therapy in an Infant.

A 3.5-month-old infant with undiagnosed underlying combined immunodeficiency presented with S. ceravisiae fungemia following treatment with S. boulardii containing probiotic preparation. This case highlights that the use of probiotics in sick patients may be fraught with danger.

High initial (1, 3) Beta-d-Glucan concentration may be a predictor of satisfactory response of c aspofungin combined with TMP/SMZ for HIV-negative patients with moderate to severe Pneumocystis jirovecii pneumonia.

OBJECTIVES: The aim of this study was to investigate the efficacy of combination therapy of caspofungin and TMP/SMZ (trimethoprim/sulfamethoxazole) in moderate to severe pneumocystis jirovecii pneumonia (PJP) in patients without human immunodeficiency virus infection (HIV) and the relationship between therapeutic effect and plasma (1, 3) Beta-d-Glucan (BDG) levels. METHODS: We retrospectively reviewed HIV-negative patients with PJP diagnosed in our department, who were treated with combination therapy of caspofungin and TMP/SMZ or monotherapy of TMP/SMZ during a six and a half year period. RESULTS: A total of 126 moderate to severe PJP patients were enrolled in the study. In the multivariate analysis, low lymphocyte counts, high serum lactate dehydrogenase levels at the diagnosis of PJP and progression to shock were significant risk factors for death. In all patients, there was no significant difference in risk of death at 3 months. In the group of BDG≥800pg/m, patients receiving combination therapy was associated with a significantly decreased risk of death at 3 months, whereas in the group of BDG<800pg/ml, there were no statistically significant difference in survival rate between the two treatment regimens. CONCLUSION: High initial plasma (1, 3) Beta-d-Glucan concentration may be a predictor of satisfactory caspofungin response to HIV-negative patients with PJP. Based on our findings, we suggest the choice of combination therapy with caspofungin and TMP/SMZ as the initial treatment when BDG≥800pg/ml in moderate to severe HIV-negative patients with PJP.

Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model.

OBJECTIVES: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model. DESIGN: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole). SETTING: University research laboratory. PATIENTS: None. INTERVENTIONS: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug. MEASUREMENTS AND MAIN RESULTS: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates. CONCLUSIONS: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.

Successful treatment of a Candida auris intra-articular infection.

A 78-year-old woman with a long-term ankle spacer with antibacterials developed an intra-articular Candida auris infection. Treatment with systemic antifungal therapy plus an amphotericin B moulded cement spacer was successful.

Comparison of the effectiveness of caspofungin and liposomal amphotericin-B for the treatment of C. tropicalis-induced peritonitis in mice.

In order to compare the effectiveness of liposomal amphotericin B (LAB) and caspofungin monotherapy in Candida tropicalis-induced peritonitis in an experimental mice model 56 healthy male BALB/c mice (10-12 weeks; 20-25 g) were divided into groups and C. tropicalis strains were intraperitoneally (IP) inoculated into mice groups except the control group. After the injection, three doses of LAB (0.5, 1.0, 2.0 mg/kg/day) and caspofungin (1.0, 2.0, 5.0 mg/kg/day) were administered to groups for five consecutive days, starting 48-h post-infection. The mice were then followed up for 14 days and killed by cervical dislocation. When their peritoneal fluid was examined, the difference in fungal growth between the treatment group and control group was significant (p <0.05). Evaluation of the treatment groups revealed that fungal growth decreased with increasing dose of the antifungal agent (p >0.05). There was no dose-related difference from mice which received LAB or those which received caspofungin in our experimental model. During our study, no death was detected despite the similar injection doses compared with other studies using Candida species. The results of this study suggest that C. tropicalis could have lower virulence, perhaps limited by natural immunity, and causes mortality at much higher doses.

A retrospective study of patients with systemic lupus erythematosus combined with Pneumocystis jiroveci pneumonia treated with caspofungin and trimethoprim/sulfamethoxazole.

Systemic lupus erythematosus (SLE) complicated with Pneumocystis jiroveci pneumonia (PCP) is a clinical complex with unsatisfying treatment efficacy and poor prognosis which is difficult to be diagnosed at early stage. The present study aimed to investigate the clinical features of SLE with PCP, recognize the early onset indicating factors, and evaluate the treatment efficacy of combined caspofungin and trimethoprim/sulfamethoxazole (coSMZ).We reviewed data of 9 patients admitted with SLE-PCP and treated with caspofungin combined with coSMZ at Tangshan Gongren Hospital from January 2013 to December 2017. Patients' clinical manifestation and laboratory data [leucocyte, lymphocyte, cluster of differentiation 4 (CD4)T cell, lactate dehydrogenase (LDH), blood gas, etc] were compared before and after treatments. And the early onset factors of SLE-PCP, treatment efficacy of combined caspofungin and CoSMZ were analyzed.Among these 9 patients, 8 patients suffered renal impairment, and all of them had been taking prednisone in the past 3 months at an average dose of 29.4 ±â€Š13.6 mg/day. In addition, they had taken at least one kind of immunosuppressants. Laboratory data (leucocyte, lymphocyte, CD4T cell, PaO2, LDH) were remarkably abnormal at hospital admission, but they were improved significantly after 2 weeks of treatment, which is also statistically significant (P < .05), except that leukocyte had no significance change to the value at admission (P = .973). In addition, none of the studied patients died.The results of the study indicated that long-term use of glucocorticoids and immunosuppressants, low CD4T cell count, and renal impairment are the early-onset factors for SLE-PCP, caspofungin, when combined with CoSMZ, it could be a promising and effective strategy to treat SLE with PCP.

Body Surface Area-Based Dosing Regimen of Caspofungin in Children: a Population Pharmacokinetics Confirmatory Study.

We evaluated the population pharmacokinetics of caspofungin in children (2 to 12 years of age). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics, compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin dosage based on body surface area is most appropriate for pediatric use.

Isavuconazole in a Successful Combination Treatment of Disseminated Mucormycosis in a Child with Acute Lymphoblastic Leukaemia and Generalized Haemochromatosis: A Case Report and Review of the Literature.

Invasive mucormycosis in immunocompromised children is a life-threatening fungal infection. We report a case of a 7-year-old girl treated for acute lymphoblastic leukaemia complicated by disseminated mucormycosis during induction therapy. Microscopic examination of surgically removed lung tissue revealed wide, pauci-septate hyphae suggesting a Mucorales infection. This diagnosis was confirmed immunohistochemically and by PCR analysis followed by a final identification of Cunninghamella sp. The patient was treated successfully with surgical debridement and antifungal combination therapy with amphotericin B, caspofungin and isavuconazole. The use of isavuconazole in a child was not previously reported. Additionally, case reports concerning pulmonary mucormycoses in paediatric population published after 2010 were reviewed. Nineteen out of 26 identified patients suffered from haematological diseases. Reported mortality reached 38.5%. By the fact of rising morbidity, unsatisfactory results of treatment and remaining high mortality of mucormycoses in immunocompromised patients, new therapeutic options are warrant. Isavuconazole, with its broad-spectrum activity, good safety profile and favourable pharmacokinetics, is a promising drug. However, further studies are necessary to confirm positive impact of isavuconazole on mucormycosis treatment in children.

Caspofungin dosage adjustments are not required for patients with Child-Pugh B or C cirrhosis.

Background: Controversies remain over caspofungin dosage adjustments in cirrhosis, particularly Child-Pugh (CP) B or C. The product information for of caspofungin recommends a maintenance dose reduction from 50 to 35 mg for patients with CP-B cirrhosis. Objectives: To quantify the impact of cirrhosis and the severity of hepatic impairment on the pharmacokinetics (PK) of caspofungin. Patients and methods: We performed PK studies of a single 70 mg dose of caspofungin in patients with decompensated CP-B (n = 10) or CP-C (n = 10) cirrhosis and of multiple doses in 21 non-cirrhotic ICU patients with hypoalbuminaemia. A Monte Carlo simulation was performed to investigate the impact of a maintenance dose reduction from 50 to 35 mg on the steady-state area under the 24 h concentration-time curve. Results: We observed a marginal reduction of caspofungin clearance in a PK study in patients with decompensated CP-B or CP-C cirrhosis. Dose reduction to 35 mg in cirrhotic patients resulted in lower drug exposure than with the approved dose in non-cirrhotic patients. Conclusions: In contrast to the product information, we recommend giving the full dose of caspofungin regardless of the presence and severity of cirrhosis to avoid a subtherapeutic exposure.

Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients.

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.