Treatment Of Serious Fungal Infections Research Articles

601. Characterizing Modifiable Risk Factors for Liposomal Amphotericin B (L-AMB) Nephrotoxicity

Abstract Background Liposomal amphotericin B (L-AMB) is a broad spectrum anti-fungal utilized in the treatment of serious fungal infections. Despite its liposomal formulation aimed at reducing toxicity, it is still associated with relatively high rates of nephrotoxicity. Few studies have attempted to assess the effectiveness of mitigation strategies to lower the risk of L-AMB-associated nephrotoxicity. Methods The purpose of this study is to characterize the time course of nephrotoxicity secondary to L-AMB, evaluate modifiable risk factors for L-AMB-related nephrotoxicity, and identify potential interventions to minimize nephrotoxicity. A retrospective chart review of inpatients who received L-AMB: Oct 1, 2020 through Jan 31, 2022 at the University of Washington Medical Center (UWMC) and Seattle Cancer Care Alliance (SCCA). The primary objective was to identify the incidence and onset of L-AMB related nephrotoxicity. Eligible patients ≥18 years old with a history of hematologic malignancy, solid organ transplant, or bone marrow transplant were included. Univariable associations were evaluated with either Chi-square or T-test. Results A total of 132 patients were reviewed with 77 patient courses included. The baseline characteristics are depicted in TABLE 1. The mean dose of L-AMB was 4.9 mg/kg with an average treatment duration of 8.2 days. Nephrotoxicity occurred in 33.8 % of patients with median onset of 3 days. IV hydration occurred in 88.5 and 68% of patients pre and post, respectively. Patients had at least one concomitant nephrotoxin (87 %) with an average of 2. Comparing those patients with nephrotoxicity and those without, age and L-AMB duration, were associated with nephrotoxicity. Table 1- Baseline CharacteristicsTable 2- Nephrotoxicity Risk Factors Conclusion L-AMB nephrotoxicity occurred at a relatively high rate in this patient population despite high utilization of toxicity mitigating strategies such as IV hydration. Nephrotoxicity was associated with longer durations of therapy. Further investigation is necessary to determine alternative strategies for nephrotoxicity prevention. Disclosures All Authors: No reported disclosures.

Biguanides enhance antifungal activity against Candida glabrata

ABSTRACT Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC50 of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC50 in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.

Pharmacokinetics, Safety, and Target Attainment of Single and Multiple Doses of CD101 IV

Introduction: CD101 is a novel, long-acting echinocandin with activity against Candida and Aspergillus spp. in development for prevention and treatment of serious fungal infections. CD101 has shown robust efficacy in neutropenic mouse infection models of disseminated candidiasis as well as aspergillosis and an excellent nonclinical safety/toxicology profile. Two randomized, double-blind, placebo-controlled, phase 1, dose-escalation trials were conducted to establish the safety and pharmacokinetics (PK) of single and multiple weekly dosing of CD101 administered intravenously. PK-pharmacodynamic (PD) analyses of these data were conducted to evaluate the probability of achieving therapeutic targets against Candida.Methods: Sequential cohorts of 8 healthy subjects (n=6, CD101; n=2, placebo) received a single dose of CD101 (50, 100, 200, 400 mg) or multiple weekly doses (100 mg x2, 200 mg x2, 400 mg x3) infused intravenously over 1 hour. PK was assessed using plasma and urine samples collected over 21 days. Safety and tolerability were assessed by adverse events (AEs), vital signs, physical exams, electrocardiograms, and safety laboratory values up to 21 days after dosing. Data from these clinical trials were used to develop a population PK model and perform Monte Carlo simulation (n=2000) evaluating a single dose of 400 mg and multiple weekly doses (400 mg x3 or 400 mg x1 followed by 200 mg x2) chosen for an upcoming Phase 2, dose-ranging trial in candidemia. For each dosing regimen, percent probabilities of PK-PD target attainment against Candida albicans (R303, human blood isolate) were calculated.Results: CD101 and placebo groups had similar incidences of AEs. The majority were mild, and all resolved completely. Slightly higher incidences of AEs and mild transient infusion reactions were seen in the group that received CD101 400 mg x 3 weekly doses. There were no clinically significant safety issues in observed or laboratory assessments, and no deaths, serious AEs, severe AEs, or withdrawals due to an AE. CD101 IV demonstrated dose-proportional plasma exposures, low apparent clearance (<0.3 L/h), long half-life (t1/2 >80 h), minimal urinary excretion (<1%), and minor accumulation (30% to 55%, multiple-dose study). The percent probability of therapeutic target attainment against C. albicans was 100% for both weekly dosing regimens of CD101 (Figure) and >99% for the single dose of CD101 400 mg.Conclusion: CD101 IV was safe and well tolerated as single and multiple doses up to 400 mg once weekly for up to 3 weeks. Target attainment analyses support the dosing regimens evaluated and suggest these regimens will effectively cover the vast majority of Candida likely to be encountered clinically. The high plasma exposures achieved with CD101 IV may improve treatment outcomes compared to other echinocandins, and its long t1/2 enables weekly dosing. These findings support the continued development of CD101 IV dosed once-weekly as treatment or prophylaxis for invasive fungal infections, delivering PK-PD optimized drug exposures while reducing the resources required for therapeutic drug monitoring. [Display omitted] DisclosuresSandison:Cidara Therapeutics, Inc.: Employment, Equity Ownership. Ong:Cidara Therapeutics, Inc.: Employment. Thye:Cidara Therapeutics, Inc.: Employment, Equity Ownership.

Efficacy of CD101, a Novel Echinocandin, in Mouse Models of Aspergillosis and Azole-Resistant Disseminated Candidiasis

Background: CD101 is a novel echinocandin with long-acting pharmacokinetics and exceptional stability in development for prevention and treatment of serious fungal infections. The in vivo efficacy of CD101 was evaluated using neutropenic mouse models of azole-resistant candidiasis and aspergillosis.Methods: An azole-resistant strain of Candida albicans (R357; resistant to fluconazole [Flu], voriconazole, and posaconazole but susceptible to amphotericin B [AmB] and echinocandins) isolated from human blood was used for the mouse candidiasis model. A test strain of Aspergillus fumigatus (ATCC 13073) was used for the mouse aspergillosis model. Mice were rendered neutropenic by cyclophosphamide and then infected by injections of C. albicans (105 CFU/mouse) or A. fumigatus (104 CFU/mouse) into the tail vein. Test articles were administered starting 2 hours after infection. In the mouse candidiasis model, groups of 5 mice each received one dose of AmB (3 mg/kg IV), Flu (20 mg/kg orally), or CD101 (3, 10 or 30 mg/kg by intraperitoneal administration [IP]). After 72 hours post-infection, mice were euthanized and C. albicans counts in kidney tissue (CFU/g) were measured. In the mouse aspergillosis model, groups of 10 mice each received one dose ofAmB (2 mg/kg IP) or CD101 (2 mg/kg IV and IP). Survival was monitored daily for 10 days. Differences between vehicle and test article groups were assessed for significance by one-way ANOVA followed byDunnett's test and Fisher's Exact test in the candidiasis and aspergillosis models, respectively.Results: One dose of CD101 3 mg/kg produced a >99.9% (or > 3-log; P<0.001) reduction in C. albicans CFU compared with vehicle through at least 72hours post-dose following a single IP dose.AmB showed similar, albeit less robust, efficacy (>99% or >2-log reduction in CFU; P<0.05), whereas fluconazole was less efficacious (83.9% or <2-log reduction in CFU). In the aspergillosis model, CD101 administered 2 mg/kg IV or IP showed similar efficacy to that ofAmB 2 mg/kg IP, both with significantly longer survival than vehicle (P<0.05; Figure).Conclusions: A single dose of CD101 3 mg/kg produced significant reduction in C. albicans burden compared with vehicle (P<0.001) in the neutropenic mouse model of azole-resistant candidiasis, demonstrating efficacy comparable, if not better, to that of AmB at the same dose. One dose of CD101 also demonstrated efficacy in the mouse model of aspergillosis. These data support the continued development of CD101 for treatment of serious infections caused by Candida, including azole-resistant strains, and Aspergillus spp. [Display omitted] DisclosuresOng:Cidara Therapeutics, Inc.: Employment. Bartizal:Cidara Therapeutics, Inc.: Employment, Other: Stockholder. Miesel:Eurofins Panlabs: Employment; Cidara Therapeutics, Inc: Research Funding.

Voriconazole and Non-Melanoma Skin Cancer after Allogeneic HSCT: Results of a Prospective Dedicated Follow-up Program in 302 Patients

IntroductionVoriconazoleis a second-generationtriazolebroad-spectrum antifungal agent indicated in adults and children aged 2 years and above as treatment of invasive aspergillosis, treatment ofcandidaemiain non-neutropenic patients (pts), treatment of fluconazole-resistant serious invasive Candida infections, treatment of serious fungal infections caused byScedosporiumspp. and Fusarium spp.Voriconazoleis associated with a broad spectrum of dermatologically adverse reactions: it seems to be responsible for a multistep process beginning with acute and chronicphototoxicity, followed by actinic keratosis (AK), and finally skin squamous cell carcinoma (SCC), especially if therapy is maintained. Strictphotoprotectionis mandatory; drug replacement by anothertriazolemust be discussed in case of acutephototoxicity.Voriconazolemust be stopped in pts with chronicphototoxicity, and a long-term dermatologic follow-up of skin lesions is required even after withdrawal.It is now established thatvoriconazoleis an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. Recently, a retrospective study from the Mayo Clinic (WojenskiDJ et al, Transplant Infectious Disease 2015, 17, 250-58) confirmed the association betweenvoriconazoleand SCC also after allo-HSCT (allogeneic hematopoietic stem cell transplantation) and identified cumulative days ofvoriconazoleas a risk factor for SCC.MethodsThe current study seeks to analyze the correlation betweenvoriconazoleexposure and non-melanoma skin cancer (NMSC) in our Center, where it is available an intensive dedicated follow-up after allo-HSCT to prevent and early detect second solid tumors.ResultsWe analyze data prospectively collected at our Long-Term Follow-Up clinic between 2011 and 2016 including 302 adult pts with a minimum follow-up of 24 months. A written consent was given by pts allowing the use of medical records for research in accordance with the Declaration of Helsinki.Baseline characteristics of the 302 pts are outlined in table 1. In total, 25 pts developed NMSC - median time from allo-HSCT 42 months (range, 9 months - 20 years) - median follow-up after NMSC diagnosis 2 years (range, 2 months - 12 years). The estimated cumulative incidence of NMSC at 3 years was 3.2% and at 5 years 6.2%.At the dermatological annual evaluation 3 pts were presenting AK, only one progress to basal cell carcinoma (BCC), the 2 pts with AK are under dermatological follow-up. All pts were treated withvoriconazolefor more than 180 days.In total 19 pts were diagnosed with BCC and 6 pts with SCC. Five pts with SCC and 17 with BCC were treated withvoriconazole, overall 16/22 (4 SCC) for more than 180 days. All pts were treated according to standard practice for NMSC, unfortunately 1 pts deceased due to SCC progression.Only 2 pts were diagnosed and treated for NMSC before transplantation. Six pts had antecedent acute GvHD and 8 pts had antecedent moderate to severe chronic GvHD.History ofvoriconazoleexposure, cumulative days ofvoriconazoleuse, gender, age at transplant, TBI based conditioning regimen, acute/chronic GvHD and skin cancer pre-transplant were considered for analysis. Age at transplant above 48 years (p <0.0001),voriconazoleexposure (p 0.0088) and cumulative days ofvoriconazoleexposure greater than 180 days (p 0.0038) were associated with higher risk of NMSC.ConclusionsOur experience confirms the correlation betweenvoriconazoleand occurrence of NMSC after allo-HSCT. Incidence of NMSC is higher than previously reported in registry reports, and the occurrence of NMSC in pts exposed tovoriconazoleseems to be precocious. This observation confirms the relevance of counseling and prevention of NMSC in patients benefiting fromvoriconazoleas a crucialmold-active antifungal prophylaxis and treatment. [Display omitted] DisclosuresBonini:Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.

Risk of Non-Melanoma Skin Cancer Following Hematopoietic Cell Transplantation and Voriconazole-Associated Risk

Introduction: Recipients of hematopoietic cell transplant (HCT) are at increased risk for secondary malignancy, most commonly non-melanoma skin cancer (NMSC) including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) (Leisenring et al J Clin Oncol 2006).While both SCC and BCC are generally associated with low mortality, HCT recipients are more likely to develop clinically aggressive forms of disease associated with poorer prognosis and requiringchemoradiotherapy(Lott et al Transplantation 2010).Voriconazolehas been available since 2002 for the treatment of serious fungal infections, and has contributed to improved clinical outcomes in patients who undergo HCT. However,voriconazoleis associated with several known cutaneous toxicities including photosensitivity, and along with its metabolite,voriconazoleN-oxide, sensitizes keratinocytes to UVA light and may cause DNA damage and inhibition of repair mechanisms (Onaet alBr J Dermatol 2015). While the association betweenvoriconazoleuse and NMSC has been established in the solid organ transplant population (Singer et al J Heart Lung Transplant 2012), less is known about HCT patients. Therefore, we sought to determine the post-HCT risk of NMSC related tovoriconazoleuse.Methods: We performed a retrospective cohort study by exposure tovoriconazolefor allogeneic (n = 1370) and autologous (n = 1538) HCT recipients at Stanford University Medical Center between January 2003 and March 2015. Post-HCT incidence rates (IR) and hazard ratios (HR) were calculated based on first diagnosed NMSC after HCT. Multivariate analysis includedvoriconazoleexposure and known risk factors for NMSC including history of chronic graft-versus-host disease, age at transplant, sex, race, and history of NMSC.Results: The 10-year IR for NMSC in the overall HCT population was 14.1 (95% CI = 11.7 - 16.8) and time to incident NMSC ranged from 0.1 to 10.9 years post-transplant.Among allogeneic HCT recipients, 90 patients developed NMSC with a 10-year IR of 25.6 (95% CI = 20.6 - 31.5) (Table 1). The median time from HCT to first diagnosis of NMSC was 1.9 years (range 0.1 - 9.9 years). The 10-year IR for SCC was 19.7 (95% CI = 15.3 - 24.9) and 6.8 (95% CI = 4.4 - 10.2) for BCC (Table 1). NMSC occurred more often on the head and neck in the exposed cohort compared to the unexposed cohort (p = 0.020). In multivariate analyses, among allogeneic HCT recipients,voriconazoleuse was associated with an increased overall risk for NMSC (HR = 1.86, 95% CI = 1.18 - 2.92, p = 0.008) (Table 2). The association withvoriconazoleexposure was largely for SCC (HR = 2.12, 95% CI = 1.26 - 3.57, p = 0.005). Exposure tovoriconazoledid not appear to affect the risk for BCC (HR = 1.03, 95% CI = 0.43 - 2.46, p = 0.954).Among autologous HCT recipients, 34 developed NMSC with a 10-year IR of 6.3 (95% CI = 4.4 - 8.9) and a median time from HCT to diagnosis of 1.6 years (range 0.2 -10.9 years) (Table 1). The 10-year IRs among autologous HCT recipients for SCC and BCC respectively were 3.6 (95% CI = 2.2 - 5.9) and 2.1 (95% CI = 1.1 - 3.8) (Table 1). In the multivariate analysis, we found no relationship betweenvoriconazoleuse and risk for NMSC (HR = 0.93, 95% CI = 0.33 - 2.64, p = 0.887) (Table 3).Conclusion: There is a high rate of incident NMSC in the post-HCT setting with a wide range of times to diagnoses, and voriconazoleuse represents a novel factor that may contribute to increased risk for SCC in the allogeneic HCT population. Our data indicate that any history of exposure to voriconazolemay increase the risk of SCC, but not BCC, in allogeneic but not autologous HCT recipients. While other factors have greater impacts on HCT recipientsÕ risk of NMSC, the widely accepted use of voriconzaoleas either a prophylactic or therapeutic anti-fungal agent in HCT recipients makes it an important consideration in overall risk assessment.Regardless ofvoriconazole exposure, NMSC is prevalent in the post-HCT setting and there is a critical need for patient education and regular, vigilant surveillance by an experienced dermatologist to screen for and treat early skin cancer or precursor lesions. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Activity of a Long-Acting Echinocandin (CD101) and Comparator Antifungal Agents Tested Against Contemporary Worldwide Invasive Fungal Isolates

Activity of a Long-Acting Echinocandin (CD101) and Comparator Antifungal Agents Tested Against Contemporary Worldwide Invasive Fungal Isolates

Is fungal disease in Sri Lanka underestimated? A comparison of reported fungal infections with estimated disease burden using global data

Introduction With an increase in the elderly population and developments in medical care, increased numbers of patients with fungal diseases are expected. This necessitates a new vision for fungal diseases in Sri Lanka, a tropical country with a population of 20 million. The objective of this study was to estimate national fungal infection caseloads using global and national epidemiological datasets. Methods We searched national data and surveillance studies published by us and other authors for relevant disease terms. Locally collected incidence data were available for candidaemia, fungal keratitis, cryptococcosis, allergic broncho-pulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). Global disease estimation was done using international data. Generally, disease estimates were conservative as they assumed the lowest incidence rates reported in the literature and focused only on well-defined risk populations. Results Among the 1,317 HIV/AIDS patients (in 2010), there were 639 estimated oral candidiasis cases, 100 oesophageal candidiasis cases and only 13 cases of cryptococcal meningitis. The estimated prevalence of chronic pulmonary aspergillosis (CPA) post TB is estimated to be 1,443 and all forms of chronic pulmonary aspergillosis (including aspergilloma) 2,886 patients. We estimated 229 cases of invasive aspergillosis and 41 cases of mucormycosis. The projected annual incidence of candidaemia is 507 and an estimated 76 candida peritonitis cases post-surgery. According to our estimates 10,344 patients were suffering from ABPA and 13,654 were suffering from SAFS. The projected annual incidence of fungal keratitis would be 1,277 and tinea infections would affect 50 children. Pneumocystis incidence could not be estimated. Conclusions Our estimates suggest that candidaemia and invasive aspergillosis could be the leading causes of fungal-associated deaths in Sri Lanka whereas globally it is due to SAFS, ABPA and CPA. More precise data from the whole country is needed to validate these estimates. Such data would be very useful for developing healthcare policies for prevention, diagnosis and treatment of serious fungal infections.

Rola flucytozyny w leczeniu ciężkich zakażeń grzybiczych w oddziale intensywnej terapii

Rola flucytozyny w leczeniu ciężkich zakażeń grzybiczych w oddziale intensywnej terapii

Fungal infections of the hand

Fungal infections of the hand can range from simple cosmetic infection of the nails to life and limb-threatening deep space infections. Deep fungal infections are rare and mostly confined to immunocompromised patients. However, the practicing surgeon must have a high degree of suspicion to diagnose and treat these types of infection in an expeditious manner. This article reviews the recent relevant literature on fungal infections of the hand. Treatment typically includes early radical debridement and systemic antifungal therapy. This review highlights the principle that timely diagnosis and appropriate treatment of serious fungal infections of the upper extremity can result in limb salvage and prevention of mortality.

Pharmacokinetics, antifungal activity and clinical efficacy of anidulafungin in the treatment of fungal infections

Importance of the field: Anidulafungin is one of three available intravenous echinocandins that plays an important role in the treatment of serious fungal infections. Currently, anidulafungin is approved for the treatment of esophageal candidiasis, candidemia and other invasive Candida infections including intra-abdominal abscesses and peritonitis.Areas covered in this review: This paper covers a comprehensive review of anidulafungin.What the reader will gain: The reader will be provided the most recent data available regarding the pharmacology, pharmacokinetics, in vitro activity and clinical utility of anidulafungin for the treatment of serious fungal infections.Take home message: Echinocandin antifungals, such as anidulafungin, are now considered first line for the treatment of candidemia and invasive candidiasis, particularly in critically ill patients or those who have previously received azole therapy. Anidulafungin has potent in vitro activity against Candida and Aspergillus species, predictable pharmacokinetics that does not require dosage adjustment, few drug interactions and is well tolerated. Because of these favorable characteristics, anidulafungin is an important addition to our antifungal armamentarium.

Voriconazole, Chronic Photosensitivity, and Melanoma

The antifungal agent voriconazole is indicated for the treatment of serious fungal infections. One of its complications is chronic photosensitivity. We recently covered a report describing the development of aggressive squamous cell carcinomas (SCCs) in immunosuppressed recipients of long-term voriconazole therapy. The same researchers now describe the occurrence of five melanomas in two patients treated with voriconazole for fungal infections. The first patient was a 39-year-old woman with Fitzpatrick skin type III who was …

Clinical Practice: Combination Antifungal Therapy for Mold Infections: Much Ado about Nothing?

In general, mortality rates associated with systemic fungal infections have not improved much in more than a decade, although the number of antifungal agents available for the treatment of serious fungal infections has increased in the past few years. A possible approach to decreasing mortality rates associated with fungal infections may be to treat patients with combinations of different classes of antifungals. Recently, in vitro and animal studies evaluating different combinations of antifungal agents have demonstrated important synergistic and/or additive activity against many genera of fungi. However, prudence is required, because some antifungal combinations have demonstrated antagonistic activity. Well-controlled clinical trials are still necessary to define the most efficacious antifungal combination. In addition, these clinical trials should evaluate the adverse event profile of the combination regimens, as well as their pharmacoeconomic impact.

Combination Antifungal Therapy: The New Frontier

The past decade has seen a significant increase in the incidence of invasive fungal infections. The antifungal armamentarium for the treatment of serious fungal infections remains limited. A possible approach to overcoming antifungal drug resistance and high mortality rates seen in severe fungal infections is to combine two or three classes of antifungals, especially if the drugs have different mechanisms of action. Combinations of new agents along with more traditional antifungals have now been shown to possess some synergistic or at least additive activity against many fungi in in vitro and animal studies. On the other hand, caution is still needed since some antifungal combinations have also demonstrated antagonistic activity. Well-controlled clinical trials are still required to define the most efficacious antifungal regimen. Furthermore, these trials should also evaluate the side-effect potential of combination regimens and the pharmacoeconomic impact these regimens may have.

Combination of caspofungin and an azole or an amphotericin B formulation in invasive fungal infections

Combination of caspofungin and another anti-fungal agent raise expectation of improved efficacy in severe fungal infections including failures to first line therapy. We assessed the efficacy and safety of a combination therapy including caspofungin in 17 immunosuppressed or postoperative patients progressive despite standard anti-fungal therapy. The infections included aspergillosis (6), invasive candidiasis (9), mucormycosis (1) and Scedosporium pneumonia (1). Infections had failed one to four prior lines of treatment. The anti-fungal agent combined to caspofungin was either an amphotericin B formulation or an azole. There were 12 favourable responses (71%) and five failures. The survival rate at 3 months was 47%. Eleven patients died within 2-533 days. The causes of death included the initial fungal infection (4), relapse of the infection after switching to oral monotherapy (2), breakthrough aspergillosis (1), and the underlying condition (4). Clinical and renal tolerance were good. Significant hepatic abnormalities were recorded in eight (50%) of the 16 patients evaluable for biological tolerance. Caspofungin combined with an azole or with amphotericin B may be of interest in the treatment of serious fungal infections after failure of conventional therapy. Close monitoring of hepatic function is required. These approach should be evaluated in prospective trials.

Posaconazole: a potent, extended-spectrum triazole anti-fungal for the treatment of serious fungal infections.

Posaconazole is a potent, extended-spectrum, investigational triazole anti-fungal that is highly active in pre-clinical in vitro and in vivo models against a wide array of yeasts and moulds, including Aspergillus, Fusarium and Zygomycetes, which are often refractory to polyenes and older azoles. In humans, orally administered posaconazole is absorbed under fed or fasted conditions; however, absorption is significantly improved when it is coadministered with food or liquid nutritional supplements and when the daily dose is divided (into two or four daily doses). Unlike newer azoles, posaconazole is not extensively metabolised by cytochrome P450 (CYP) enzymes and is primarily excreted as parent compound in the faeces. Posaconazole is a CYP3A4 inhibitor, but it does not inhibit the activity of other CYP enzymes. Therefore, in comparison with other azole anti-fungal drugs, posaconazole may have the potential for fewer drug interactions. The pharmacokinetics of posaconazole are not influenced by age, gender or race. Dose adjustments for renal or hepatic impairment do not appear to be indicated based on results from single-dose studies. Preliminary efficacy data from clinical trials are promising. As salvage therapy, posaconazole elicited complete or partial responses in 44 to 75% of patients (N = 97) with invasive fungal infections who were intolerant of, or who had disease refractory to, amphotericin B or itraconazole. In an analysis of patients with aspergillosis, a 42% success rate was observed in the posaconazole arm (n = 107) compared with a 26% success rate in the control arm (n = 86). Importantly, Kaplan-Meier analysis demonstrated a survival benefit in posaconazole-treated patients. Moreover, posaconazole yielded complete or partial responses in 71% of patients with zygomycosis (N = 24). Posaconazole appears to be well tolerated over long-term administration (>1 year) and may represent an important addition to the anti-fungal armamentarium.

Combination antifungal therapy against Candida species: the new frontier--are we there yet?

In the past decade, we have seen a significant increase in the incidence of invasive fungal infections. In addition, opportunistic fungal infections resistant to antifungal agents have become increasingly common and their frequency will more than likely continue to increase. The antifungal armamentarium for the treatment of serious fungal infections remains limited. A possible approach to overcoming antifungal drug resistance and high mortality rates seen in severe fungal infections is to combine two or three classes of antifungals, especially if the drugs have different mechanisms of action. The unique properties of newer antifungals now provide us with the opportunity to investigate antifungal combinations that may become the standard of care for serious fungal infections. Combinations of new agents along with more traditional antifungals have now been shown to possess some synergistic or at least additive activity against Candida in clinical trials. On the other hand, caution is still needed since other antifungal combinations have demonstrated antagonistic activity in vitro. Well-controlled clinical trials are needed to define the most efficacious antifungal regimen. Furthermore, these trials should also evaluate the side effect potential of combination regimens and the pharmacoeconomic impact these regimens may have. Thus, while much optimism exists for combination therapy, there is much yet to be done.

Liquid Chromatographic Determination of Amphotericin B in Different Pharmaceuticals

Amphotericin B (AmB) is one of the most potent antifungal agents and the drug of choice in the treatment of serious fungal infections. A liquid chromatographic (LC) method was developed to determine AmB in pharmaceutical formulations for injection, tissue culture, cream, and lotion. pBondapak C18 reversed-phase column and a simple mobile phase consisting of acetonitrile-water-acetic acid (40 + 54 + 6, v/v) was used. The flow rate was 1.8 mL/min and the effluent was monitored at 405 nm. The developed LC method uses piroxicam as an internal standard and has a limit of detection of 10 ng/mL, a limit of quantitation of 30 ng/mL, and the assay is linear from 0.01 to 100 microg/mL. AmB and piroxicam elute with retention times of 12.4 and 4.0 min, respectively, and the resolution between AmB and piroxicam was 10.6. In comparison with the official United States Pharmacopeia microbial assay for AmB, this LC method is more rapid, selective, sensitive, and offers positive identification.

Fluconazole for Life-Threatening Fungal Infections in Patients Who Cannot Be Treated with Conventional Antifungal Agents

Fluconazole therapy was evaluated prospectively in patients with serious fungal infections who failed to respond to or could not tolerate conventional antifungal therapy. Patients were enrolled if they had a life-threatening fungal infection and conventional therapy had failed to eradicate the infection, had caused serious toxic reactions, or was contraindicated. Patients were treated with 200 mg/day, a dosage that could be increased to 400 mg/d if the initial response was not satisfactory. AIDS was the underlying risk factor in 65% of 232 patients evaluated in the study and in 85% of 151 patients with cryptococcal infection. Fifty-eight patients had active cryptococcal infection; 74% had a satisfactory clinical response, and 75% of 44 patients became culture-negative. Patients with inactive infection had a relapse rate of 4.5/1,000 patient-weeks. Twenty-three of 30 patients with coccidioidal infection and 10 of 14 patients with candidiasis or another mycosis were clinically improved. Five patients (2%) discontinued fluconazole therapy because of adverse effects possibly attributable to therapy. Fluconazole may be effective in the treatment of serious fungal infections in patients who cannot continue conventional antifungal therapy.