Prophylaxis Of Invasive Fungal Infections Research Articles

Efficacy and safety of fluconazole in prophylaxis of invasive fungal infections in very low birth weight infants: a Meta analysis

To assess the efficacy and safety of fluconazole in the prophylaxis of invasive fungal infection in very low birth weight (VLBW) infants. Databases including PubMed, Embase, the Cochrane Library, Wanfang Data, Weipu, and CNKI were searched for randomized controlled trials (RCTs) of prophylactic fluconazole in VLBW infants. Review Manager 5.3 software was used to perform a Meta analysis of the included studies. A total of 12 RCTs were included, involving 1 679 VLBW infants. The Meta analysis showed that prophylactic fluconazole significantly reduced the incidence of invasive fungal infection (RR=0.44, 95%CI: 0.27-0.71, P<0.001), the incidence of fungal colonization (RR=0.31, 95%CI: 0.24-0.40, P<0.001), and the mortality during hospitalization (RR=0.74, 95%CI: 0.58-0.94, P=0.01) compared with the control group. There were no significant differences between VLBW infants using different doses of fluconazole in the incidence of invasive fungal infection and fungal colonization (P>0.05). No significant differences were found in the incidence of fluconazole resistance and complications between the fluconazole and control groups (P>0.05). Prophylactic fluconazole can effectively and safely prevent invasive fungal infection in VLBW infants, even at a small dose.

Efficacy of Posaconazole Prophylaxis for Fungal Disease in Hematology Patients Treated With Chemotherapy and Transplantation: An Open-Label, Prospective, Observational Study.

BackgroundPosaconazole (PCZ) is used prophylactically to prevent invasive fungal infections (IFIs) in patients with hematological malignancies.ObjectiveTo evaluate the cut-off serum concentration of PCZ for successful IFI prophylaxis in Chinese subjects.Patients and MethodsA total of 74 patients treated with induction chemotherapy (n = 10) and allogeneic hematopoietic stem cell transplantation (HSCT) (n = 64), who received PCZ prophylactically as an oral suspension for >7 days, were included in the study. Clinical, radiological, microbiological culture results, and treatment responses were analyzed and drug concentration assays performed.ResultsThe overall incidence of possible, probable, and proven IFIs was 13.5% (10/74), with five patients in the chemotherapy group and five in the HSCT group. The PCZ serum concentration in most patients (54/63) was in the range of 0.25–1.0 μg/ml, and this concentration range was significantly associated with the success rate of PCZ prophylaxis. A cut-off value of 0.47 μg/ml can be considered as an evaluation index for PCZ prophylaxis. Taking a proton pump inhibitor (PPI) would reduce the PCZ blood concentration, but not affect the IFD breakthrough point. PCZ treatment for hematopoietic malignancy or HSCT patients with a serum concentration of PCZ < 0.47 μg/ml were risk factors for PCZ prophylaxis of IFIs, determined by univariable and multivariable regression analyses.ConclusionThe serum concentration of PCZ was related to the incidence of IFIs and a serum concentration of >0.47 μg/ml is highly recommended to avoid IFIs after chemotherapy or HSCT.Clinical Trial RegistrationChinese Clinical Trial Registry: ChiCTR1900026294.

The current place of echinocandins in the treatment and prophylaxis of invasive fungal infections

Invasive fungal infections continue to show steady growth among various patient populations, accompanied by high rates of both morbidity and attributive mortality. For the treatment of invasive mycoses, a few number of drugs are currently available, which include polyenes, azoles, echinocandins, allylamines and flucytosine. Among these groups, echinocandins – anidulafungin, caspofungin and mycafungin – represent a key class of antifungal drugs, primarily for the treatment of the most common form of systemic fungal infections – Invasive candidiasis. Possessing a unique mechanism of action that determines fungicidal activity against yeast pathogens, a predictable pharmacokinetics profile, and good safety profile, echinocandins have firmly taken the lead in the treatment of infections caused by Candida species. In addition, they are used in the treatment of refractory cases of invasive aspergillosis and for the prevention of invasive mycoses in selected patient populations. In this brief review, the main clinical and pharmacological characteristics of echinocandins and their positioning within the current versions of practical recommendations will be presented.

Isavuconazole Prophylaxis during Early Phases of Allogeneic HSC Transplantation Is Not Associated to an Increase Need of Cyclosporin-a Dose Modification

Background: Isavuconazole is an effective treatment of invasive fungal infections (IFI). Since its broad spectrum of activity and favorable toxicity, it could also be used as a prophylaxis. Experience in use of isavuconazole as prophylaxis of IFI is, however, limited. In allogeneic transplant setting, its feasibility should also be assessed in regard of changes of Cyclosporine (CYA) metabolism. Aim: To evaluate feasibility of the administration of Isavuconazole as short term prophylaxis during early phase of allogeneic transplantation and to study its influence on CYA trough blood levels and CYA dosing. Methods: In a prospective study from July 2017 to April 2019, we treated 34 HSC transplantation using Isavuconazole (ISA) prophylaxis, ISA was administered at dosage of 200 mg /day i.v. (with a loading-dose of 200 mg x 3 /days for the first 48 hours) from day + 2 after HSCT infusion and until day + 30. The patients were selected using the criteria: any underlying diagnosis; age 18-70; any type of allogeneic donor; GVHD prophylaxis including CYA i.v.. Blood trough levels of CYA were measured bi-weekly by ELISA. Blood CYA level was maintained between 100 - 300 mcg/ml by dose adjustment. The need for CYA dose modification, IFI rate and patient outcome (TRM, OS) was studied and compared to an historical control group who received prophylaxis using Fluconazole during day +2 to day +30 (n 29). Results: Groups receiving Isavuconazole or Fluconazole were not significanly different in diagnosis, age, sex, disease status at transplant, donor type, stem cell-source, GVHD-prophylaxis and conditioning regimen. No patients in the Fluco-group had a previous invasive fungal infection (IFI), while 2 patients had a previously IFI in the Isa-group. All patients reached engraftment, neutrophils engraftment was reached in a mean of 19 days and 18 days in the Isa and Fluco-group, respectively. No IFI occurred in the fluco-group, while 1 proven IFI (Blastoschyzomyces Capitatus blood-stream infection) occurred in the Isa-group. Mucositis occurred in 56 patients (88%). Mucositis grade III-IV grade of was registered in 62% and 61%, in the Isa- and Fluco-Group respectively. Isavuconazole was well tolerated, without significant toxicity, no patient needed dose-reduction or suspension. Mean values of trough CyA blood-levels were compared at for 1st, 2nd, 3rd and 4th week and no difference was found between the two groups (Mann Whitney U test p value: 0.2, 0.5, 0.8, 0.9 respectively for 1st, 2nd, 3rd and 4th week), Fig 1. Mean number of CYA-dose adjustments was 1.3 /patient in Isa-group and 1.2/patient in Fluco-group. Difference was not significant (p = 0.6, Mann-Whitney U-test). Overall survival (OS) at 1 year was 64 % in Fluco-group (95% CI: 44-79%) and 66% in Isa-group (95% CI: 44-81%) (log-rank, p value: 0.9). Non-relapse mortality (NRM) at 1 year was 16.3% (95% CI: 5.7-31%) in Isa-group and 14.2% (95% CI:4.3-29%) in Fluco-group (Gray test, p: 0.61). Conclusions: In this prospective study, short term prophylaxis using Isavuconazole, after allogeneic HSC transplant, was found to be feasible. No significant difference with standard fluconazole prophylaxis was found in trough CYA blood levels and in the need of cyclosporin dose modification. Further studies are needed extending the lenght of Isavuconazole prophylaxis. Figure 1 Disclosures No relevant conflicts of interest to declare.

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

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. 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. 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 (0.10-12.25mg/L vs. 1.12-1.78mg/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>30g/L (P=.019). 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.

Use of Micafungin for the Prevention and Treatment of Invasive Fungal Infections in Everyday Pediatric Care in France: Results of the MYRIADE Study.

Invasive fungal infections are responsible for significant morbidity and mortality. Safety and effectiveness of antifungal agents is a particular concern in pediatric populations, where data are often limited. Micafungin is an echinocandin with demonstrated antifungal activity against a wide spectrum of Candida spp.; this subanalysis of data from the MYRIADE study describes the use of micafungin and its therapeutic outcomes in pediatric patients, in normal clinical practice. MYRIADE was an observational, multicenter, national, prospective, longitudinal study conducted from January 2010 to December 2012, in patients treated with micafungin using a prophylactic or curative strategy, across 17 sites [oncohematology (n = 8), neonatal intensive care units (ICUs) (n = 5) and pediatric ICUs (n = 4)]. The treatment regimen, the achievement of the therapeutic objective and the tolerance were reported. The study population consisted of 110 pediatric patients (31 neonates, 24 children <2 years old and 55 children ≥2 to <16 years old). The therapeutic objective was achieved in 49/64 (76.6%) oncohematology patients, 28/29 (96.6%) neonatal ICU patients and 12/14 (85.7%) pediatric ICU patients. Twenty-four (21.8%) children developed an adverse event (AE); more AEs were observed in oncohematology patients compared with ICU patients [17 (26.1%) vs. 7 (15.6%)]. Only one serious AE, reported in an oncohematology patient, was considered related to micafungin. In the first large observational study of micafungin treatment or prophylaxis conducted under real-world conditions in France, micafungin was effective and well tolerated for prophylaxis of invasive fungal infections in pediatric oncohematology patients and for curative purposes in pediatric and neonatal ICU patients.

PS1272 A SURVEY OF PRACTICE RELATING TO THE PREVENTION AND TREATMENT OF INVASIVE FUNGAL INFECTIONS IN UK HAEMATOLOGY CENTRES

Background:Invasive fungal infections (IFIs), particularly due to Aspergillus species, are an important cause of morbidity and mortality in patients with haematological malignancies. In 2017 and 2018 the European Conference on Infections in Leukaemia (ECIL) published guidelines for both prophylaxis and treatment of IFIs in haematology patients. A previous survey of UK practice undertaken in 2010 demonstrated marked variability in practice in relation to the prevention and treatment of IFIs in this patient group, similar to what had been reported in earlier Europe‐wide surveys.Aims:The aim of the current study was to investigate whether variability in practice still exists in the UK or whether recently published guidelines have helped to standardise practice.Methods:A questionnaire was sent electronically to all members of the UKBMT pharmacists’ group. The majority of questions focused on prophylaxis and treatment of fungal infection in four clinical areas – AML induction, ALL induction, autologous stem cell transplantation (SCT) and allogeneic SCT. Further questions related to uptake of the newer azole, isavuconazole, and the use of therapeutic drug monitoring (TDM) for azoles.Results:Responses were received from 29 centres. All centres treated autologous SCT and AML/ALL patients and 25 treated allogeneic SCT patients. Seventeen centres treated adult patients only, seven were paediatric centres and five treated both adults and children. The most commonly recommended prophylactic antifungals for the four indications were:Autograft – fluconazole (59% of centres); Allograft – posaconazole (44%); AML induction – posaconazole (45%); ALL induction – lipid amphotericin (69%). There was marked variability in dosing schedules for fluconazole (50mg‐400 mg/day) and lipid amphotericin (12 different schedules ranging from 50 mg thrice weekly (TTW) to 3 mg/kg TTW) and only 69% of centres gave prophylaxis routinely to all 4 patient groups. Compared with the previous survey, itraconazole use had fallen sharply and was only used prophylactically by 38% of centres (previously 76%). Empirical therapy was recommended by 79% of centres. The criteria for starting an antifungal empirically (i.e. duration of fever unresponsive to broad spectrum antibiotics) varied from 48–120 hours. As in the previous survey, Ambisome® (at doses ranging from 1–3 mg/kg/day) was the most common empirical antifungal agent, followed by caspofungin. However, voriconazole had replaced Ambisome® as the most widely recommended first line drug for the management of invasive aspergillosis. Caspofungin, micafungin, posaconazole and IV itraconazole were only recommended in a minority of policies. Ambisome® was the most popular second line agent, being recommended in 62% of policies, followed by caspofungin (24%) and isavuconazole (17%). Twenty one centres (72%) would consider giving dual therapy. In terms of uptake of new agents, Isavuconazole was included in the antifungal policy in 34% of centres, had been used on an adhoc basis in a further 28% but had not yet been used in 38% of centres. For those centres that included the following azoles in their antifungal policies, the use of TDM was inconsistent – 76% of centres undertook TDM for voriconazole, 71% for itraconazole and 55% for posaconazole.Summary/Conclusion:Similar to the previous 2010 survey, this study showed significant variations in practice between UK haematology centres with respect to both preventing and treating invasive fungal infections. Recent guidelines in this area do not appear to have resulted in a noticeable standardisation of practice.

A Multicenter, Randomized, Open-Label Study to Compare Micafungin with Fluconazole in the Prophylaxis of Invasive Fungal Infections in Living-Donor Liver Transplant Recipients

BackgroundAlthough invasive fungal infections (IFIs) contribute to substantial morbidity and mortality in liver transplant recipients, only a few randomized studies analyzed the results of antifungal prophylaxis with echinocandins. The aim of this open-label, non-inferiority study was to evaluate the efficacy and safety of micafungin in the prophylaxis of IFIs in living-donor liver transplantation recipients (LDLTRs), with fluconazole as the comparator. MethodsLDLTRs (N = 172) from five centers were randomized 1:1 to receive intravenous micafungin 100 mg/day or fluconazole 100~200 mg/day (intravenous or oral). A non-inferiority of micafungin was tested against fluconazole. ResultsThe per-protocol set included 144 patients without major clinical trial protocol violations: 69 from the micafungin group and 75 from the fluconazole group. Mean age of the study patients was 54.2 years and mean model for end-stage liver disease (MELD) score amounted to 16.5. Clinical success rates in the micafungin and fluconazole groups were 95.65% and 96.10%, respectively (difference: − 0.45%; 90% confidence interval [CI]: − 6.93%, 5.59%), which demonstrated micafungin’s non-inferiority (the lower bound for the 90% CI exceeded − 10%). The study groups did not differ significantly in terms of the secondary efficacy endpoints: absence of IFIs at the end of the prophylaxis and the end of the study, time to proven IFI, fungal-free survival, and adverse reactions. A total of 17 drug-related adverse events were observed in both groups; none of them was serious and all resolved. ConclusionMicafungin can be used as an alternative to fluconazole in the prevention of IFIs in LDLTRs. Clinical Trials RegistrationNCT01974375.

Risk-Adapted Anti-Mould Prophylaxis Improves Supportive Care in Childhood Leukemia Patients

BACKGROUND: Prophylaxis of invasive fungal infections in children treated for malignant hematologic disease has traditionally been based on the widespread use of fluconazole. With the awareness of increasing rates of invasive mould infections, new agents have been developed and offered to patients at highest risk.METHODS: We compared the tolerance and outcome of different antifungal prophylaxis in 198 childhood patients treated for acute myeloid and lymphoblastic leukemia in a pediatric cancer center. Until 2011 antifungal prophylaxis with fluconazole was offered to all patients, resulting in 15.2-19.4% of invasive mould infections. As the burden of fungal infections was restricted to high risk patients only (i.e. acute myeloid leukemia, leukemia relapse, high risk acute lymphoblastic leukemia and patients after stem cell transplant) and no infection with candida was registered, antifungal prophylaxis was replaced with liposomal amphotericin and offered to this particular patient group.RESULTS: Liposomal amphotericin was well tolerated; there was no occurrence of infusion-related reaction and/or glomerular-associated nephrotoxicity. The development of vincristine-induced neurotoxicity was significantly reduced, as stool frequency was increased up to 38% in patients treated with liposomal amphotericin (p = 0.024). Importantly, there was a marked shift in the percentage of patients with severe constipation (15.5% versus 4.2%, fluconazole versus liposomal amphotericin respectively, p = 0.010). Notably, with limitation of prophylactic treatment to high risk patients a major group of patients did not receive any antifungal prophylaxis (48.81%) and most importantly, the occurrence of invasive fungal infection was completely prevented (p = 0.021). In comparison, 10 patients in the fluconazole group developed proven invasive pulmonary infections. Of these, 6 patients developed disseminated disease, and 4 patients died. Aspergillus was isolated in 40% and rhizopus in 30% of biopsy specimens.CONCLUSION: Polyene prophylaxis offers effective antifungal activity with improved tolerability compared to older agents. The potential impact of this treatment should be included in current prophylaxis guidelines of antileukemic treatment. DisclosuresNo relevant conflicts of interest to declare.

Pharmacokinetic-Pharmacodynamic Analyses to Provide Rezafungin Prophylaxis Dose Selection for Prevention of Invasive Fungal Infections for Bone Marrow Transplant Patients

Background: Rezafungin is a novel antifungal of the echinocandin class being developed as a single agent for prevention of invasive fungal infections (IFIs) caused by Candida, Aspergillus, and Pneumocystis spp. in patients at high risk of infection. Rezafungin exhibits an exceptionally long half-life (~133 h) which enables the administration of once-weekly dosing regimens. Treatment efficacy in a mouse Pneumocystis model is achieved at a human equivalent dose of <50 mg once-weekly [EHA. 2017. Abstr 9645]. A dose of 400 mg, followed by 200 mg once-weekly achieved >90% target attainment for treatment of Candida [AAC. 2018. 62:e02614-17]. Although lower doses of rezafungin might be useful for prevention of Pneumocystis and Candida infections, prevention of invasive aspergillosis in immunosuppressed populations is often considered more challenging. Pharmacokinetic-pharmacodynamic simulations were performed, at the dosing regimen for treatment of Candida, to evaluate the appropriateness of rezafungin for prophylaxis against A. fumigatus among bone marrow transplant (BMT) patients.Methods: A previously developed rezafungin population pharmacokinetic (PK) model [AAC. 2018. 62:e02603-17] was refined in NONMEM Version 7.2 using intravenous (IV) data from additional Phase 1 and Phase 2 studies. The ability of covariates such as body size, age, sex, albumin, markers of liver and renal function, and infection status to explain a portion of the interindividual variability on select PK parameters was explored using stepwise forward selection (α = 0.01) and backward elimination (α = 0.001). The final model was validated by comparing model-based predictions to observed data.Baseline demographic data were available from 100 patients who underwent a BMT at Stanford Medical Center. Using this dataset and the developed population PK model, a Monte Carlo simulation (n=2,000) was conducted to simulate expected rezafungin concentration-time profiles in BMT patients following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11. Using a human protein-binding value of 97.4%, free-drug concentration-time profiles were evaluated relative to the maximum observed A. fumigatus minimal effective concentration to inhibit 100% of isolates tested (MEC100) from surveillance data collected in 2016 [ASM Microbe 2018. Abstr Friday-485].Results: The final population PK model was a linear, 4-compartment model with zero order IV input. Albumin was an important predictor of the interindividual variability in rezafungin PK, as significant relationships were found between serum albumin concentration and clearance and volume of peripheral compartment 1. Additional relationships were found between PK parameters and sex, body surface area, presence of cirrhosis, and infection status. The model provided precise and unbiased fits to the observed data (r2=0.993 observed vs individual-predicted concentrations).The demographic dataset utilized for the simulations contained 100 BMT patients, of which 39 were female. Median (range) baseline body surface area and albumin were 1.84 m2 (1.27 - 2.61) and 3.35 g/dL (1.8 - 4.43), respectively. None of the patients had a baseline infection nor did any of the patients have cirrhosis. Following administration of rezafungin 400 mg IV on Week 1 then 200 mg IV weekly x11, free-drug plasma concentration-time profiles for Weeks 1, 2, and 12 relative to the A. fumigatus MEC100 (0.03 mg/L) are displayed in Figure 1. On Weeks 1, 2, and 12, 98.4%, 93.3%, and 91.9% of simulated patients, respectively, had rezafungin free-drug concentrations above the MEC100 value for the entire dosing interval (one week). This result was ≥99.9% for all 12 weeks when based on the MEC90 (0.015 mg/L).Conclusions: These data provide support for a once-weekly rezafungin dosing regimen for prevention of A. fumigatus infections among BMT patients. The effectiveness of current antifungal prophylactic regimens is frequently limited by safety, tolerability, drug interactions, adherence, pill burden and patient factors such as mucositis or background chemotherapeutic regimens. In addition to the excellent safety, tolerability, and lack of drug interactions exhibited by echinocandin agents, the favorable PK profile of rezafungin presents the opportunity to mitigate the typical challenges faced when administering IFI prophylaxis in BMT and other immunocompromised patients. [Display omitted] DisclosuresLakota:Cidara Therapeutics: Research Funding. Flanagan:Cidara Therapeutics: Employment, Equity Ownership. Sandison:Cidara Therapeutics: Employment, Equity Ownership. Brown:Cidara Therapeutics: Consultancy. Rubino:Cidara Therapeutics: Research Funding.

2389. Effect of Rezafungin on QT Interval in Healthy Subjects

BackgroundRezafungin (RZF), a novel, once-weekly echinocandin for treatment and prophylaxis of invasive fungal infections, successfully met safety and efficacy endpoints in Phase 2 and is advancing to Phase 3 studies. RZF is the first echinocandin to undergo a definitive QT evaluation.MethodsThis Phase 1, single-center, randomized, double-blind, comparative study evaluated the effects of RZF on the QTcF (corrected using Fridericia’s formula) interval), heart rate, and other cardiac parameters. There were three dose groups, RZF (600 mg or 1,400 mg IV), IV placebo, and oral moxifloxacin (positive control). The 600 mg (therapeutic) and 1400 mg (supratherapeutic) doses were selected to achieve exposures approximating those after multiple doses of the highest dosage regimen assessed in the Phase 2 study (400 mg once weekly) and exposures ~2.5-fold higher, respectively. The primary endpoint was based on an analysis of change of QTcF from Baseline (ΔQTcF) as a function of RZF plasma concentration, to derive the estimated mean placebo-adjusted change of QTcF from Baseline (ΔΔQTcF) for the RZF dose groups at the geometric mean Cmax for each dose level. The outcome was defined by a comparison of the upper bounds of the 2-sided 90% CIs within 10 ms.Results60 subjects were enrolled and completed the study. Demographics included: sex (43.3% male) and age (median age 34.0 years; ranging from 20 to 51 years) approximately evenly distributed by treatment. A linear regression model best fit the data, as shown in Figure 1. From this model, the estimated mean ΔΔQTcF at the Cmax for both of the RZF doses had upper bounds <10 ms. The mean ΔΔQTcF at each time point by dose, showed all 1-sided 95% upper bounds to be <10 ms, thus supporting the conclusion of the primary analysis. Assay sensitivity was established for moxifloxacin. No clinically significant effects on any of the cardiac parameters tested (RR, QRS, HR) were observed. RZF was generally well tolerated. All adverse events (AE) were mild to moderate in severity with no discontinuations due to AEs.ConclusionRezafungin, in single IV doses up to 1,400 mg, does not prolong the QT interval. This finding supports the clinical safety and continued development of RZF. Disclosures S. Flanagan, Cidara Therapeutics: Employee and Shareholder, Salary and stock options. A. Jandourek, Cidara Therapeutics: Consultant, Consulting fee. T. Sandison, Cidara Therapeutics: Employee, Salary.

Aspergilosis invasora en el receptor de trasplante de órgano sólido

Solid organ transplant (SOT) recipients have a high risk for developing invasive fungal infections (IFI). Treatment is difficult due to the interaction between the antifungal and immunosuppressant drugs, as well as the risk of hepatotoxicity and kidney failure associated with voriconazole and amphotericinB, respectively. Isavuconazole is a new antifungal triazole agent with excellent oral bioavailability, predictable and linear pharmacokinetics, good tolerance and low adverse effects. It has been approved for the treatment of invasive aspergillosis and mucormycosis.A review is presented of the reported experience in the use of isavuconazole in SOT. According to the published studies, isavuconazole has a significantly lower risk of interaction with tacrolimus, and is less hepatotoxic than voriconazole. Nevertheless, there is a significant variability between patients, and between each type of SOT.Isavuconazole reduces the side effects associated with the treatment of IFI in SOT. It would be of great interest the implementation of future clinical trials with isavuconazole for the treatment and/or prophylaxis of IFI in these patients.

Clinical Outcomes of Oral Suspension versus Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections.

Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared the incidence of breakthrough IFIs and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1 January 2010 and 30 June 2016. We defined probable or proven breakthrough IFIs using the European Organization for Research and Treatment of Cancer (EORTC) criteria. Overall, 547 patients received 860 courses of posaconazole (53% received the oral suspension and 48% received the tablet); primary indications for prophylaxis were acute myeloid leukemia (69%), graft-versus-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indications between patients receiving the different formulations. The incidence and incidence rate of probable or proven IFIs were 1.6% and 3.2 per 10,000 posaconazole days, respectively. There was no significant difference in the rate of IFIs between suspension courses (2.8 per 10,000 posaconazole days) and tablet courses (3.7 per 10,000 posaconazole days) (rate ratio = 0.8, 95% confidence interval [CI] = 0.3 to 2.3). Of the 14 proven or probable cases of IFI, 8/14 had posaconazole serum concentrations measured, and the concentrations in 7/8 were above 0.7 μg/ml. Posaconazole was discontinued early in 15.5% of courses; however, the frequency of discontinuation was also not significantly different between the tablet (16.5%) and oral suspension (14.6%) formulations (95% CI for difference = -0.13 to 0.06). In conclusion, the incidence of breakthrough IFIs was low among patients receiving posaconazole prophylaxis and not significantly different between patients receiving the tablet formulation and those receiving the oral suspension formulation.

In vitro and in vivo evaluation of a posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex.

Posaconazole (PCZ) is a triazole antifungal agent with an extended spectrum of antifungal activity. It is approved for the prophylaxis of invasive fungal infections in patients with neutropenia or in hematopoietic stem cell transplant recipients undergoing high-dose immunosuppressive therapy for graft-vs-host disease, and for the treatment of fungal infections. However, its pharmacological effects are severely limited owing to its poor solubility and low bioavailability. In order to solve these problems, a sulfobutyl ether-β-cyclodextrin compound was used to prepare an intramuscular injection to improve the bioavailability of posaconazole. The extracorporeal dissolution rate of posaconazole was markedly improved by this inclusion complex with >90% being released within 5 min, and the in vivo pharmacokinetics were studied using a HPLC/MS/MS method for quantifying posaconazole and the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex in rat blood. Posaconazole and an internal standard, itraconazole, were extracted by protein precipitation using acetonitrile. The concentration range of posaconazole was 0.05-4.0 μg/mL with good linearity (r = 0.9980), the peak concentrations of pure posaconazole and the inclusion complex were 0.565 ± 0.102 μg/mL and 1.12 ± 0.091 μg/mL, the values for AUC0-t were 12.2 ± 2.5 and 19.9 ± 2.5 μg h/mL, and the values for AUC0-∞ were 16.4 ± 3.2 and 25.0 ± 3.5 μg h/mL, respectively. The main pharmacokinetics parameters showed significant differences (P<0.01). Compared with pure posaconazole, the posaconazole-sulfobutyl ether-β-cyclodextrin inclusion complex markedly improved the bioavailability of posaconazole.

Cost-effectiveness analysis of voriconazole, fluconazole, and amphotericin B for invasive fungal infections following allogeneic hematopoietic stem cell transplantation in Mexico.

BackgroundPatients receiving allogeneic hematopoietic stem cell transplantation (alloHSCT) are at high risk of invasive fungal infections (IFIs), which are associated with high mortality and economic burden. The cost-effectiveness of prophylaxis for the prevention of IFIs in alloHSCT recipients in Mexico has not yet been assessed.MethodsThis analysis modeled a hypothetical cohort of 1,000 patients to estimate costs and outcomes for patients receiving prophylaxis for IFIs following alloHSCT, from the perspective of institutional payers in Mexico. The main prophylaxis agents currently used in Mexican clinical practice are voriconazole, fluconazole, and amphotericin B (AmB). The model accounted for event rates of IFIs during each treatment, assuming IFI causality due to invasive aspergillosis, invasive candidiasis, or other IFIs, and that the outcome for patients during follow-up was IFI-related death, death from other causes, or survival. Clinical efficacies were obtained from published literature; costs were based on local sources. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs). Univariate (assessing the impact of varying each model parameter) and probabilistic sensitivity analyses were performed.ResultsVoriconazole was associated with the lowest number of breakthrough IFIs, IFI-related deaths, and total number of deaths. Total costs were lower for fluconazole (Mexican pesos [MXN] 72,944; US $4,079) than voriconazole (MXN 101,413; US $5,671) or AmB (MXN 110,529; US $6,180). Voriconazole had better clinical outcomes and lower costs than AmB and could be considered cost-effective compared with fluconazole in line with the local ICER threshold. Drug costs, monitoring costs, and duration of prophylaxis were most sensitive to variation from univariate sensitivity analysis. Findings from the probabilistic sensitivity analysis were consistent with the base-case results.ConclusionVoriconazole had the most favorable clinical outcomes, but overall prophylaxis costs were higher than with fluconazole. Overall, based on local ICER thresholds (MXN 184,665; US $10,326), voriconazole was considered a cost-effective option for prophylaxis of IFI in Mexico.

Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies.

The aim of this study was to determine clinical variables associated with posaconazole exposure among adult patients with haematological malignancies who received posaconazole tablets for prophylaxis of invasive fungal infections (IFIs). The study population included adult patients with haematological malignancies who received posaconazole delayed-release tablets for prophylaxis of IFIs after induction chemotherapy for acute leukaemia or graft-versus-host-disease (GVHD) complicating hematopoietic stem cell transplantation (HSCT) in the period January 2016-December 2017. Sixty-six consecutive patients with 176 posaconazole Cmin were included for evaluation in the study. Subtherapeutic posaconazole concentrations (< 0.7mgl-1 ) were observed at least once in 33.3% of patients (22/66), and overall in 17.0% of therapeutic drug monitoring (TDM) episodes (30/176). At multilevel linear regression, use of PPIs (P=0.008), use of intermediate or high dose steroids (>0.7mgkg-1 daily) (P=0.022) and male gender (P=0.025) were significantly associated with decreased Cmin , whereas time from starting therapy (P=0.032) was associated with increased Cmin in our patient population. Posaconazole exposure during treatment with delayed-released tablet formulation may be affected by the use of PPIs and/or of intermediate or high dose steroids.

Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis

BackgroundPosaconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of posaconazole TDM and the target of posaconazole plasma concentration for clinical successful prophylaxis remain uncertain and controversial. The aim of this study was to evaluate posaconazole exposure-response relationship and determine an optimum posaconazole concentration for prophylaxis against invasive fungal infections (IFIs).MethodsBibliographic databases were searched (from inception to September 2017) to select studies including the clinical outcomes below and above concentration cut-off value of 0.5 mg/L and 0.7 mg/L. The reliability of the results were evaluated with trial sequential analysis (TSA).ResultsTwenty-eight studies with 1930 patients included were analyzed. The results of our pooled analysis demonstrated that patients with posaconazole plasma concentrations over 0.5 mg/L were twice more likely to achieve successful responses compared with those with lower concentrations (odds ratio, OR = 1.98, 95% confidence interval, CI 1.09–3.58, P = 0.02) while the threshold, 0.7 mg/L showed no significant difference (OR = 1.84, 95% CI 0.94–3.63, P = 0.08). The TSA results showed that there was sufficient information to support these findings.ConclusionsAn optimal posaconazole concentration target of 0.5 mg/L is suggested to ensure the clinical prophylactic efficacy and may help reduce the dosage and dose-dependent toxicity comparing with the target of 0.7 mg/L.

Timing Determination of Invasive Fungal Infection Prophylaxis According to Immune Function in HSCT Patients.

Patients who receive a hematopoietic stem cell transplantation (HSCT) exhibit an immune defect after recovering from neutropenia. The current guidelines do not recommend fungal prophylaxis in these patients, except for grades III to IV GVHD in HSCT. Thus, the timing for the initiation and cessation of IFI prophylaxis in immune-compromised patients remains a challenging endeavor. We retrospectively analyzed patients who received auto or allo-HSCT and monitored their immune function after recovering from neutropenia by measuring the levels of IgG, IgA, IgM, as well as the number of T, B, NK cells. We found that the level of IgG and NK cell count exhibited a significant difference with the incidence of IFI by logistic regression (p = 0.000 vs. 0.000, respectively) and conditional logistic regression (p = 0.009 vs. p = 0.002). The initiation of IFI prophylaxis was determined to be IgG < 7 mg/mL and NK cell count < 6.5 × 104/mL by an receiver operating characteristic curve separately. Tests in parallel increased the test sensitivity and specificity. Thus, the optimal timing for initiating prophylaxis in patients after HSCT could be IgG < 7 mg/mL or NK cell count < 6.5 × 104/mL. Future large-scale prospective clinical trials are required to verify these findings. Patients who are immuno-compromised after auto or allo-HSCT may benefit from a lower fungi infection incidence with immune surveillance and proper fungal prophylaxis.

Prevention of Invasive Aspergillus Fungal Infections with the Suspension and Delayed-Release Tablet Formulations of Posaconazole in Patients with Haematologic Malignancies

Posaconazole is a triazole antifungal used to prevent invasive fungal infections (IFIs) in patients receiving chemotherapy or haemotopoietic stem cell transplantation. Due to highly variable bioavailability of the oral suspension formulation, a delayed-release tablet was developed which showed improved bioavailability. A minimal target posaconazole plasma concentration of 0.7 mg/L is recommended for prophylaxis of IFIs. However, the relationship between plasma concentration of posaconazole and its efficacy against IFIs remains unclear. We analysed trough posaconazole concentrations and response against IFIs in 50 and 104 patients with haematologic malignancies receiving prophylactic posaconazole as the tablet or suspension formulation, respectively. Mean plasma concentration of posaconazole was 1.91 ± 1.06 mg/L and 0.82 ± 0.57 mg/L in the tablet and the oral suspension group, respectively (p < 0.0001). The percentage of patients reaching the minimal target concentration of 0.7 mg/L was 92.0% and 47.1% in the tablet and oral suspension groups, respectively (p < 0.0001). Emergent aspergillosis occurred in 9 (8.7%) patients in the suspension group and in none of the patients taking the tablet formulation (p = 0.032). Our results show a relationship between plasma concentrations of posaconazole and its prophylactic efficacy in patients with haematologic malignancies. Target posaconazole concentrations are reached more efficiently with the tablet than with the suspension formulation.

Meta-analysis of the safety of voriconazole in definitive, empirical, and prophylactic therapies for invasive fungal infections

BackgroundVoriconazole has been used in the treatment and prophylaxis of invasive fungal infections (IFIs) while its wide use was limited by some frequent adverse events, especially neurotoxicity, hepatotoxicity and even renal disruption. The aim of this study was to comprehensively compare voriconazole-induced toxicity, including tolerability, neurotoxicity, visual toxicity, hepatotoxicity and nephrotoxicity with the composite of other antifungals commonly used in clinic.MethodsBibliography databases were searched to select randomized controlled trials providing information about the incidence of toxicity referred above. A total of 4122 patients from 16 studies were included in the meta-analysis.ResultsAnalysis of individual types of toxicity showed that there was a significant difference between voriconazole and the composite of other antifungal agents. The primary outcome, the tolerability of voriconazole was slightly inferior (OR = 1.71, 95% CI = 1.21–2.40, P = 0.002) and it is noteworthy that the probabilities of neurotoxicity and visual toxicity were around twice higher and six-fold for voriconazole compared with the counterpart (OR = 1.99, 95% CI = 1.05–3.75, P = 0.03 and OR = 6.50, 95% CI = 2.93–14.41, P < 0.00001, respectively). Hepatotoxicity was more common in voriconazole group (OR = 1.60, 95% CI = 1.17–2.19, P = 0.003) whereas its pooled risk of nephrotoxicity was about half of the composite of other five antifungal agents (OR = 0.46, 95% CI = 0.26–0.84, P = 0.01).ConclusionOur analysis has revealed differences in multiple types of toxicity induced by VRC versus other antifungals and quantified the corresponding pooled risks, which could provide an alternative for patients with a certain antifungal intolerance and help the clinician to select the optimal intervention.