amphotericin-b and Candidiasis--Invasive

Regardless of the available antifungals, intraabdominal candidiasis (IAC) mortality continues to be high and represents a challenge for clinicians.. This opinion paper discusses alternative antifungal options for treating IAC. This clinical entity should be addressed separately from candidemia due to the peculiarity of the required penetration of antifungals into the peritoneal cavity. Intraabdominal concentrations may be further restricted in critically ill patients where pathophysiological facts alter normal drug distribution. Echinocandins are recommended as first-line treatment in guidelines for invasive candidiasis. However, considering published data, our pharmacodynamic analysis suggests the required increase of doses, postulated by some authors, to attain adequate pharmacokinetic (PK) levels in peritoneal fluid. Given the limited evidence in the literature on PK/PD-based treatments of IAC, an algorithm is proposed to guide antifungal treatment. Liposomal amphotericin B is advocated as first-line therapy in patients with sepsis/septic shock presenting candidemia or endophthalmitis, or with prior exposure to echinocandins and/or fluconazole, or with infections by Candida glabrata. Other situations and alternatives, such as new compounds or combination therapy, are also analysed.. There is a critical need for more robust clinical trials, studies examining patient heterogeneity and surveillance of antifungal resistance to enhance patient care and optimise treatment outcomes. Such evidence will help refine the existing guidelines and contribute to a more personalised and effective approach to treating this serious medical condition. Meanwhile, it is suggested to broaden the consideration of other options, such as liposomal amphotericin B, as first-line treatment until the results of the fungogram are available and antifungal stewardship could be implemented to prevent the development of resistance.

Topics: Antifungal Agents; Candidemia; Candidiasis, Invasive; Echinocandins; Humans

Invasive fungal infections in liver transplant recipients are associated with elevated morbidity and mortality and pose a challenge to the treating physicians. Despite of lacking clinical data, the use of antifungal combination therapy is often considered to improve response rates in an immunocompromised patient population. We herein report a case of refractory invasive candidiasis in a liver transplant recipient treated successfully with a combination of isavuconazole und high-dose liposomal amphotericin B. The antimycotic combination treatment was able to clear a bloodstream infection with C. glabrata and led to regression of bilomas among tolerable side effects. The use of the above-mentioned antifungal combination therapy in a liver transplant recipient has not been reported previously. This case highlights the efficacy and safety of antifungal combination therapy in immunocompromised patients with refractory invasive candidiasis.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Humans; Liver Transplantation; Nitriles; Pyridines; Triazoles

BACKGROUND + OBJECTIVES: The echinocandins, amphotericin B preparations, voriconazole and fluconazole are approved for the treatment of invasive candidiasis, though it remains unclear which agent is most effective. In order to answer this question, we performed a systematic review and network meta-analysis of the randomised controlled trials (RCTs) which evaluated these agents in comparison.. Four electronic databases were searched from database inception to 8 October 2020. RCTs comparing triazoles, echinocandins or amphotericin B for the treatment of invasive candidiasis or candidemia were included. Random effect Bayesian network meta-analysis methods were used to compare treatment outcomes.. Thirteen RCTs met inclusion criteria. Of the 3528 patients included from these trials, 1531 were randomised to receive an echinocandin, 944 to amphotericin B and 1053 to a triazole. For all forms of invasive candidiasis, echinocandins were associated with the highest rate of treatment success when compared to amphotericin B (OR 1.41, 95% CI 1.04-1.92) and the triazoles (OR 1.82, 95% CI 1.35-2.51). Rank probability analysis favoured echinocandins as the most effective choice 98% of the time. Overall survival did not significantly differ between groups.. Among patients with invasive candidiasis, echinocandins had the best clinical outcomes and should remain the first-line agents in the treatment of invasive candidiasis.

Topics: Amphotericin B; Antifungal Agents; Candidemia; Candidiasis; Candidiasis, Invasive; Echinocandins; Humans; Network Meta-Analysis; Randomized Controlled Trials as Topic; Triazoles

The aim of this perspective is to give an overlook on the utility of pharmacokinetics/pharmacodynamics (PK/PD) in predicting the efficacy of antifungals in invasive candidiasis. Overall, from the available literature it appears that bridging data of PK/PD of antifungals from the laboratory to the clinic for the treatment of invasive candidiasis are feasible only partially. Fluconazole is the only antifungal agent having the pharmacodynamic threshold of efficacy identified in experimental animal models convincingly validated in the clinical setting of invasive candidiasis as well. Conversely, for voriconazole and posaconazole data on this topic are very limited. For the echinocandins, robust PK/PD identified in the laboratory represented the rationale for defining differential clinical breakpoints of echinocandins against different species of Candida by the regulatory agencies. However, translation of the findings in the clinical setting provided conflicting results. Data on PK/PD of amphotericin B and flucytosine in models of invasive candidiasis are quite limited, and clinical studies assessing the role of drug exposure on efficacy are currently lacking. The expectation is that prospective studies could test more and more frequently the validity of experimental PK/PD data of antifungals in the clinical setting of invasive candidiasis. The findings could represent a step forward in addressing adequate antifungal stewardship programmes.

Topics: Amphotericin B; Animals; Antifungal Agents; Antimicrobial Stewardship; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candida tropicalis; Candidiasis, Invasive; Echinocandins; Fluconazole; Flucytosine; Humans; Species Specificity; Triazoles; Voriconazole

Echinocandins are recommended for the treatment of suspected or confirmed invasive candidiasis (IC) in adults. Less is known about the use of echinocandins for the management of IC in children. The aim of this study was to investigate the overall efficacy and safety of echinocandin class in neonatal and pediatric patients with IC.. PubMed, Cochrane Central, Scopus and Clinical trial registries were searched up to July 27, 2017. Eligible studies were randomized controlled trials that evaluated the efficacy and safety of any echinocandin versus agents of other antifungal classes for the treatment of IC in pediatric patients. The primary outcome was treatment success with resolution of symptoms and signs, and absence of IC. In the meta-analysis a random effects model was used, and the odds ratio (OR) and 95% confidence intervals (CIs) were calculated.. Four randomized clinical trials (324 patients), 2 confirmed IC (micafungin vs. liposomal amphotericin B (L-AmB) and caspofungin vs. L-AmB) and 2 empirical therapy trials (caspofungin vs. deoxycholate amphotericin B and caspofungin vs. L-AmB) were included. There was no significant difference between echinocandins and comparator in terms of treatment success (OR = 1.61, 95% CI: 0.74-3.50) and incidence of treatment-related adverse events (OR = 0.70, 95% CI: 0.39-1.26). However, fewer children treated with echinocandins discontinued treatment because of adverse events than amphotericin B formulations (OR = 0.26, 95% CI: 0.08-0.82, P = 0.02).. In the treatment of IC in children, echinocandins show non-inferior efficacy compared with amphotericin B formulations with fewer discontinuations than in comparator arm.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Child; Child, Preschool; Deoxycholic Acid; Drug Combinations; Echinocandins; Female; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Randomized Controlled Trials as Topic; Treatment Outcome

The aim of this meta-analysis was to assess the efficacy and safety of treatment with echinocandins compared with amphotericin B in paediatric patients with invasive candidiasis.. PubMed, Embase and Cochrane databases were searched up to August 2018. Only randomized controlled trials (RCTs) evaluating echinocandins and amphotericin B in the treatment of paediatric patients with invasive candidiasis were included. The outcomes were clinical responses and adverse effects.. There were no differences in efficacy between the echinocandins group and the amphotericin B group in the treatment of invasive candidiasis in paediatric patients. However, the echinocandins group had a significantly lower risk of discontinuing treatment than the amphotericin B group.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Echinocandins; Female; Humans; Infant; Infant, Newborn; Male; Randomized Controlled Trials as Topic; Treatment Outcome; Withholding Treatment

Invasive candidiasis is the most common fungal infection affecting critically ill adults. International guidelines provide differing recommendations for first-line antifungal therapy, with echinocandins considered first-line in the majority. Amphotericin B has broad activity and low minimum inhibitory concentration resistance patterns across most Candida species and guidance away from its use should be supported by the available evidence. Areas Covered: A systematic literature review was conducted from August to September 2017 to determine whether treatment with echinocandins or other available drugs, namely voriconazole, confers a therapeutic or survival benefit over amphotericin B in critically ill adults with invasive candidiasis. Inclusion criteria were: (1) studies describing critically ill adults with invasive candidiasis, (2) studies describing therapeutic benefit or survival as an outcome, and (3) studies comparing amphotericin B, deoxycholate or lipid preparations, with any newer antifungal agent. Eight studies were included in the final review, incorporating 2352 unique patients. No difference in treatment efficacy or mortality outcomes in critically ill patients with invasive candidiasis receiving an amphotericin B formulation compared with those receiving an echinocandin or voriconazole was shown. Expert Commentary: We conclude that in the existing literature, there is no evidence that choice between echinocandins, voriconazole, or amphotericin B formulations as first-line therapy for critically ill adults with invasive candidiasis is associated with a therapeutic or survival benefit. Clinicians must therefore consider other factors in the selection of first-line therapy.

Topics: Adult; Amphotericin B; Antifungal Agents; Candida; Candidemia; Candidiasis, Invasive; Critical Illness; Humans; Microbial Sensitivity Tests; Practice Guidelines as Topic

Obesity is a worldwide epidemic associated with multiple comorbidities that increase the risk of hospitalization. Very little pharmacokinetic data are available for antifungal agents in obesity, as this population is often excluded from drug development studies and these agents are less commonly used than other antimicrobials. Systemic antifungal therapy for invasive candidiasis continues to have a high failure rate, and dose optimization in obesity provides an opportunity for improvement. Based on currently available data, some antifungals should be dosed based on total body weight (i.e. fluconazole), while others should not be adjusted for increased body weight (i.e. posaconazole). More studies are needed to determine if and when dosing changes are needed for many of the antifungal agents. Therefore, drug therapy regimens should be individually evaluated for dose optimization due to body weight.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Echinocandins; Fluconazole; Humans; Lipopeptides; Micafungin; Mycoses; Nitriles; Obesity; Pyridines; Triazoles

Invasive fungal sinusitis (IFS) represents an often fatal condition within the pediatric population. In an effort to characterize demographics, treatment modalities, and prognostic factors, we performed a systematic review.. We systematically reviewed EMBASE, Medline, TRIPdatabase, SCOPUS and the Cochrane database for invasive fungal nasal and sinus infections limited to individuals <18 years of age. Case series including 3 or more patients were included. Demographics, treatment and outcomes were analyzed using R Gui statistical software.. Twelve studies met inclusion criteria (103 patients). There was male preponderance of 48.5% with median age of 11 years old. Majority of patients had underlying leukemia (44.6%). Aspergillus was the predominant organism (47%). Isolated nasal findings occurred in 14% of patients and nasal findings occurred in 49% overall. Absolute neutrophil count (ANC) of immunocompromised patients was below 600 in most patients (99%). Average and median length of neutropenia was 2 weeks. All patients were prescribed amphoterocin with 50% as single medicinal therapy. Surgery occurred in 82.8% of cases. The mortality rate was 46%. Univariate analysis identified presenting with facial pain as a negative predictor of overall mortality (OR 0.296, 95% CI: 0.104-0.843, p < 0.05).. Mortality remains high in pediatric patients with IFS. An ANC of <600 occurred in the majority of immunocompromised patients at a duration of 2 weeks. Presenting with facial pain was a negative predictor of mortality. Many studies label this condition as invasive fungal sinusitis; however, approximately one seventh presented with only nasal findings and half overall had nasal involvement.

Topics: Amphotericin B; Anemia, Aplastic; Antifungal Agents; Aspergillosis; Burkitt Lymphoma; Candidiasis, Invasive; Child; Facial Pain; Female; Fusariosis; Humans; Immunocompromised Host; Leukemia; Male; Mucormycosis; Mycoses; Neutropenia; Otorhinolaryngologic Surgical Procedures; Prognosis; Retrospective Studies; Sinusitis

Neonatal fungal and viral infections are associated with mortality and neurologic impairment among survivors. Advances in pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial medications have led to improved dosing guidance for neonates. This article discusses the basic PK/PD properties and dosing of the most common antifungal and antiviral medications used in neonates.

Topics: Acyclovir; Amphotericin B; Antifungal Agents; Antiviral Agents; Candidiasis, Invasive; Cytomegalovirus Infections; Deoxycholic Acid; Drug Combinations; Fluconazole; Ganciclovir; Herpes Simplex; Humans; Infant; Infant, Newborn; Mycoses; Practice Guidelines as Topic; Pregnancy Complications, Infectious; Valganciclovir; Virus Diseases

Invasive candidiasis is responsible for ∼ 10% of nosocomial sepsis in very-low-birth-weight infants and is associated with substantial morbidity and mortality. Over the last two decades, the antifungal armamentarium against Candida spp. has increased; however, efficacy and safety studies in this population are lacking.. We reviewed the medical literature and extracted information on clinical and observational studies evaluating the use of antifungal agents in neonates with invasive candidiasis.. Efficacy and safety data for antifungals in neonates are lacking, and the majority of studies conducted to date have concentrated on pharmacokinetic/pharmacodynamic evaluations. Unlike other anti-infective agents, efficacy data in the setting of neonatal candidiasis cannot be extrapolated from adult studies due to differences in the pathophysiology of the disease in this population relative to older children and adults. Data for amphotericin B deoxycholate, fluconazole, and micafungin suggest that these are the current agents of choice for this disease in neonates until data for newer antifungal agents become available. For prophylaxis, data from fluconazole randomized controlled trials will be submitted to the regulatory agencies for labeling. Ultimately, the field of therapeutics for neonatal candidiasis will require multidisciplinary collaboration given the numerous challenges associated with conducting clinical trials in neonates.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Deoxycholic Acid; Drug Combinations; Echinocandins; Humans; Infant, Newborn; Lipopeptides; Micafungin; Triazoles

Invasive fungal infections due to Candida are the third most common late-onset infection in infants born with birth weight <1500 g. Invasive candidiasis in infants born with birth weight <1000 g is associated with a 30% mortality and with neurodevelopmental impairment in more than half the survivors. A high degree of suspicion and a thorough multisystem evaluation is necessary for diagnosis of invasive fungal infections and to detect complications or sequalae. Amphotericin B deoxycholate is the mainstay in the treatment of invasive fungal infections in newborns. Early initiation of enteral feeds with human milk, decreasing dependence on catheters and avoidance of antacids, steroids and broad-spectrum antibiotics are the recommended preventive measures. Fluconazole prophylaxis should be targeted towards neonates born with <1000 g in neonatal units where baseline rates of invasive candidiasis are more than 5%.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Deoxycholic Acid; Drug Combinations; Drug Therapy, Combination; Echinocandins; Humans; Infant, Low Birth Weight; Infant, Newborn; Nucleosides; Risk Factors; Triazoles

Candidemia and invasive candidiasis (CIC) is associated with considerable morbidity and mortality, with a paucity of controlled data in neutropenic patients. A systematic review was conducted of available data for the treatment of CIC during neutropenia. A structured OVID search of multiple databases was performed. Data from randomized controlled trials of CIC and of empirical antifungal therapy in febrile neutropenic patients was included. A total of 17 trials randomizing 342 neutropenic patients were included. Eight of the studies compared amphotericin B (AmB) to other non-polyene antifungal agents. Pooling of results favored use of comparator compounds (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.42-1.29). To strengthen our analysis, a pre-planned sensitivity analysis was also conducted. Overall, there was a non-significant benefit in favor of non-polyene compounds. Across studies, echinocandins provided the benefit of favorable outcomes with fewest side effects and toxicity.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Echinocandins; Humans; Neutropenia; Odds Ratio; Randomized Controlled Trials as Topic

Invasive fungal infections (IFIs) are important causes of morbidity and mortality in immunocompromised children. The increased incidence and high mortality rates associated with IFIs has led to development of novel antifungal agents to expand the breadth and effectiveness of treatment options available to clinicians. Since its initial approval in 1958, conventional amphotericin B deoxycholate had been considered the standard in treatment for IFIs. However, because of the dose-limiting toxicity of conventional amphotericin B deoxycholate, lipid formulations of amphotericin have been developed to potentially improve outcomes and mitigate the adverse effects associated with antifungal therapy. While less frequently employed today as prophylaxis (given the expanded availability of safer alternatives), amphotericin B is still considered a treatment option in select cases of severe or life-threatening IFIs. This article reviews the clinical use of amphotericin B for the prevention and treatment of IFIs.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis, Invasive; Chemistry, Pharmaceutical; Child; Cryptococcosis; Humans; Lipids; Zygomycosis

Candida tropicalis is one of the more common Candida causing human disease in tropical countries; the frequency of invasive disease varies by geography causing 3--66% of candidaemia. C. tropicalis is taxonomically close to C. albicans and shares many pathogenic traits. C. tropicalis is particularly virulent in neutropenic hosts commonly with hematogenous seeding to peripheral organs. For candidaemia and invasive candidiasis amphotericin B or an echinocandin are recommended as first-line treatment, with extended-spectrum triazoles acceptable alternatives. Primary fluconazole resistance is uncommon but may be induced on exposure. Physicians in regions where C. tropicalis is common need to be mindful of this lesser-described pathogen.

Topics: Amphotericin B; Antifungal Agents; Candida tropicalis; Candidiasis, Invasive; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Microbial Sensitivity Tests

Investigate the efficacy of caspofungin in participants <3 months of age with invasive Candida infection (ICI).. This multicentre, randomized, double-blind, comparator-controlled, Phase 2 study (protocol MK0991-064; NCT01945281) enrolled participants <3 months of age with culture-confirmed ICI within 96 h of study entry. Participants were randomly assigned 2:1 to once-daily intravenous 2 mg/kg caspofungin or intravenous 1 mg/kg amphotericin B deoxycholate (dAMB). The primary endpoint was fungal-free survival (FFS) 2 weeks after treatment in the full-analysis-set (FAS) population, defined as participants with culture-confirmed ICI who received ≥1 dose of therapy. Planned enrolment was 90 participants.. Fifty-one participants were enrolled; 49 received treatment (caspofungin, n=33; dAMB, n=16); 2 additional participants did not have confirmed infections at study entry. The study was terminated after ∼ 3.5 years because of low enrolment. Forty-seven participants were included in the FAS population (caspofungin, n=31; dAMB, n=16). FFS rate at 2 weeks after treatment was 71.0% (22/31) in the caspofungin arm and 68.8% (11/16) in the dAMB arm [difference, stratified by weight, - 0.9% (95% CI, - 24.3%-27.7%)]. Adverse events developed in 84.8% (28/33) of participants in the caspofungin arm and 100% (16/16) in the dAMB arm.. Among neonates and infants with confirmed ICI, FFS at 2 weeks was similar in the caspofungin and dAMB treatment arms. A smaller proportion of participants who received caspofungin experienced adverse events.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Deoxycholic Acid; Double-Blind Method; Drug Combinations; Female; Humans; Infant; Infant, Newborn; Male; Treatment Outcome

Amphotericin B deoxycholate (AmB-D) is standard of care treatment for neonatal invasive candidiasis (IC). Micafungin (MCA) has broad-spectrum fungicidal activity against Candida spp. We compared the efficacy and safety of intravenous MCA with intravenous AmB-D and assessed the pharmacokinetics of MCA in infants >2-120 days of age with proven IC in a phase 3, randomized, double-blind, multicenter, parallel-group, noninferiority study (NCT00815516).. Infants were randomized 2:1 to MCA (10 mg/kg/d) or AmB-D (1 mg/kg/d) for ≥21 days. Primary efficacy endpoint was fungal-free survival (FFS) 1 week after last study drug dose. MCA population pharmacokinetics included simulated area under the curve (AUC) at steady state and maximum plasma concentration after 2-hour infusion. AUC pharmacodynamic target exposure was 170 µg·h/mL.. Thirty infants received MCA (n = 20) or AmB-D (n = 10). The trial was terminated early because of slow recruitment. FFS was observed in 12 of 20 [60%; 95% confidence interval (CI): 36%-81%] MCA-group infants and in 7 of 10 (70%; 95% CI: 35%-93%) AmB-D-group infants. The most common treatment-emergent adverse events were anemia [MCA: n = 9 (45%); AmB-D: n = 3 (30%)] and thrombocytopenia [n = 2 (10%) and n = 3 (30%), respectively]. Model-derived mean AUC at steady state for MCA was 399.3 ± 163.9 µg·h/mL (95% prediction interval: 190.3-742.3 µg/mL); steady state and maximum plasma concentration after 2-hour infusion was 31.1 ± 10.5 µg/mL (95% prediction interval: 17.0-49.7 µg/mL). MCA exposures were above the AUC pharmacodynamic target exposure.. Within the study limitations, infants with IC treated with MCA achieved similar FFS compared with AmB-D. Both agents were safe and well tolerated.

Topics: Administration, Intravenous; Amphotericin B; Antifungal Agents; Area Under Curve; Candida; Candidiasis, Invasive; Deoxycholic Acid; Double-Blind Method; Drug Combinations; Female; Hematologic Tests; Humans; Infant; Infant, Newborn; Male; Micafungin; Treatment Outcome

Caspofungin is an echinocandin agent with fungicidal activity against Candida species.. To assess the efficacy, safety and tolerability of caspofungin relative to amphotericin B in neonates with invasive candidiasis.. Thirty-two neonates with invasive candidiasis were randomly assigned to receive either caspofungin (n = 15) or amphotericin B (n = 17). Efficacy was evaluated, with a successful outcome defined as fulfilling all the components of a prespecified five-part composite endpoint. Evaluation of safety was done by monitoring drug-related adverse events.. At the end of intravenous therapy, evaluation showed that caspofungin was superior, with a favorable response in 86.7% of patients as compared with 41.7% of those who received amphotericin B (p = 0.04). There were significantly fewer adverse events in the caspofungin group than in the amphotericin B group.. Caspofungin is more effective, safer and alternative to amphotericin B for the treatment of invasive candidiasis in newborn infants.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Caspofungin; Chi-Square Distribution; Double-Blind Method; Echinocandins; Female; Humans; Infant, Newborn; Lipopeptides; Male; Prospective Studies; Saudi Arabia; Treatment Outcome

Disseminated candidiasis is a life-threatening disease and remains the most common bloodstream infection in hospitalized patients in the United States. Despite the availability of modern antifungal therapy, the crude mortality rate in the last decade has remained unacceptably high. Novel approaches are urgently needed to supplement or replace current antifungal therapies. In our study, we show that human intravenous immunoglobulin (IVIG) can provide protection against Candida auris and Candida albicans disseminated infections in A/J and C57BL/6 mouse models. The protective efficacy of IVIG is evidenced by the prolonged survival of mice with invasive candidiasis that were treated with human IVIG alone or in combination with amphotericin B. Our previous studies have led to the identification of a panel of

Topics: Amphotericin B; Animals; Antifungal Agents; Candida; Candida albicans; Candida auris; Candidiasis, Invasive; Humans; Immunoglobulins, Intravenous; Mice; Mice, Inbred C57BL; Polysaccharides

Candidemia and other forms of invasive candidiasis (C/IC) are serious conditions, especially for immunosuppressed individuals with prolonged hospitalization in intensive care units (ICU). This study analyzed the incremental cost-effectiveness and budgetary impact (BI) of treatment for IC with anidulafungin compared to amphotericin B lipid complex (ABLC) and amphotericin B deoxycholate (ABD) or conventional amphotericin B (CAB), in the Brazilian Unified Health System (SUS). A decision model was conducted with a time horizon of two weeks from the perspective of SUS. The primary effectiveness endpoints were survival and treatment response rate. All patients were followed up until successful therapy or death. BI analysis was performed based on the measured demand method. A five-year time horizon was adopted based on the number of hospitalizations (per 1,000 hospitalizations). For effectiveness measured in the successful response rate (SRR), anidulafungin dominated the ABLC and ABD formulations. In the results of the analysis with the effectiveness measured according to survival, anidulafungin had a better cost-effectiveness ratio (R$988.26/survival) compared to ABD (R$16,359.50/survival). The BI estimate related to the incorporation of anidulafungin suggests savings of approximately 148 million reais in 5 years when comparing it to ABD. The economic evaluation of anidulafungin and its comparators found it to be cost-effective. The consensus of international scientific societies recommends it as a first-line drug for IC, and its incorporation by SUS would be important.

Topics: Anidulafungin; Brazil; Candidemia; Candidiasis, Invasive; Cost-Effectiveness Analysis; Humans

Galleria mellonella is a model that uses adult larvae to assess the prophylactic, therapeutic, and acute toxic potential of substances. Given their benefits, G. mellonella models are being employed in investigations of systemic infections caused by highly resistant microorganisms. Among the multiresistant microorganisms, we highlight Candida auris, a yeast with high mortality potential and resistance. Among the potential drugs, amphotericin B (AmB) stands out; however, microbial resistance episodes and side effects caused by low selectivity have been observed. The incorporation of AmB into a nanoemulsion (NE) can contribute to the control of C. auris infections and resistance as well as decrease the side effects of this drug. This study aimed to develop AmB-loaded NE (NEA) and evaluate its antifungal action against C. auris in G. mellonella. NEs were obtained by using sunflower oil and cholesterol as the oily phase, polyoxyethylene 20 cetyl ether (Brij® 58) and soy phosphatidylcholine as the surfactant system, and PBS buffer as the aqueous phase. An alternative in vivo assay with G. mellonella for acute toxicity and infection was performed using adult stage larvae (200 mg to 400 mg). According to the obtained results, NE and NEA exhibited sizes of 43 and 48 nm, respectively. The PDI was 0.285 and 0.389 for NE and NEA, respectively. The ZP showed electronegativity for both systems, with -3.77 mV and -3.80 mV for NE and NEA, respectively. Acute toxicity showed that free AmB had greater acute toxicity potential than NEA. The survival assay showed high larval viability. NEA had a better antifungal profile against systemic infection in G. mellonella. It is concluded that the alternative model proved to be an efficient in vivo assay to determine the toxicity and evaluate the therapeutic property of free AmB and NEA in systemic infections caused by C. auris.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida auris; Candidiasis, Invasive; Moths

The need for pediatric antifungal stewardship programs has been driven by an increasing consumption of antifungals for prophylactic and empirical use. Drivers and rational of antifungal prescribing need to be identified to optimize prescription behaviors.. A prospective modified weekly Point Prevalence Survey capturing antifungal prescriptions for children (> 90 days to < 18 years of age) in 12 centers in England during 26 consecutive weeks was performed. Demographic, diagnostic and treatment information was collected for each patient. Data were entered into an online REDCap database.. One thousand two hundred fifty-eight prescriptions were included for 656 pediatric patients, 44.9% were girls, with a median age of 6.4 years (interquartile range, 2.5-11.3). Most common underlying condition was malignancy (55.5%). Four hundred nineteen (63.9%) received antifungals for prophylaxis, and 237 (36.1%) for treatment. Among patients receiving antifungal prophylaxis, 40.2% did not belong to a high-risk group. In those receiving antifungal treatment, 45.9%, 29.4%, 5.1% and 19.6% had a diagnosis of suspected, possible, probable of proven invasive fungal disease (IFD), respectively. Proven IFD was diagnosed in 78 patients, 84.6% (n = 66) suffered from invasive candidiasis and 15.4% (n = 12) from an invasive mold infection. Liposomal amphotericin B was the most commonly prescribed antifungal for both prophylaxis (36.6%) and empiric and preemptive treatment (47.9%). Throughout the duration of the study, 72 (11.0%) patients received combination antifungal therapy.. Antifungal use in pediatric patients is dominated by liposomal amphotericin B and often without evidence for the presence of IFD. A significant proportion of prophylactic and empiric antifungal use was seen in pediatric patients not at high-risk for IFD.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Antimicrobial Stewardship; Antiprotozoal Agents; Azoles; Candidiasis; Candidiasis, Invasive; Child; Child, Preschool; England; Female; Humans; Invasive Fungal Infections; Liposomes; Male; Prescriptions; Prospective Studies

The aim of the study was to investigate the Candida species distribution and their antifungal sensitivities, clinical characteristics, and risk factors of the critically ill patients with invasive Candida infections in a tertiary hospital.. Candida strains from critically ill patients were isolated in a tertiary hospital of Anhui Province from June 2019 to June 2020 through fungal cultures and identified with MALDI-TOF MS system. The antifungal susceptibility was measured by ATB Fungus-3 method. Demographic information and laboratory data were retrieved from the computerized hospital data system.. Candida albicans (C. albicans, 41.49%) was the predominant species in sterile body sites of critically ill patients developing invasive candidiasis, followed by C. glabrata (24.47%) and C. tropicalis (20.21%). The specimen sources were mainly urine (47.87%), then bronchoalveolar lavage fluid (18.09%) and blood (14.89%). In vitro, common Candida species were observed to be highly sensitive to amphotericin B and 5-fluorocytosine. All C. albicans exhibited susceptibility to both fluconazole and voriconazole, as did C. glabrata and C. parapsilosis. However, some C. tropicalis identified were frequently resistant to fluconazole, itraconazole, and voriconazole. The rate of Candida infection was positively correlated with certain risk factors including invasive interventions, age, length of stay in hospital, etc. Conclusions: C. albicans was the main species of invasive Candida infections in critically ill patients, followed by C. glabrata and C. tropicalis. Candida spp. showed the highest rate (10.60%) of resistance to fluconazole, followed by itraconazole (5.30%), voriconazole (5.30%), and 5-fluorocytosine (1.10%). All invasive Candida isolates were sensitive to amphotericin B. In addition, several C. tropicalis were tested and exhibited a high-level resistance to azoles. Notably, a variety of specific risk factors for candidiasis were identified in critically ill patients which need to be taken into consideration.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis; Candidiasis, Invasive; Critical Illness; Drug Resistance, Fungal; Fluconazole; Flucytosine; Humans; Itraconazole; Microbial Sensitivity Tests; Risk Factors; Voriconazole

Invasive candidiasis and/or candidemia (IC/C) is a common fungal infection leading to significant health and economic losses worldwide. Caspofungin was shown to be more effective than fluconazole in treating inpatients with IC/C. However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-utility of caspofungin compared to fluconazole-initiated therapies as primary treatment of IC/C in Ethiopia.. A Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-utility ratio (ICUR). These QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia's gross domestic product/capita (i.e.,US$476). Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings.. In the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. At a cost-effectiveness threshold of US$476/QALY, treating IC/C patient with fluconazole-initiated treatment followed by caspofungin was more likely to be cost-effective in 67.2% of simulations.. Our study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment for patients with IC/C in Ethiopia.

Topics: Adult; Antifungal Agents; Candidemia; Candidiasis, Invasive; Caspofungin; Cost-Benefit Analysis; Echinocandins; Ethiopia; Fluconazole; Humans; Lipopeptides

Topics: Amphotericin B; Antifungal Agents; Azoles; Candida; Candidiasis, Invasive; Cross Infection; District of Columbia; Drug Resistance, Multiple, Fungal; Echinocandins; Humans; Texas

This study evaluated the activity of echinocandins, azoles and amphotericin B against Candida spp. isolates and other yeasts and characterised azole resistance mechanisms in Candida parapsilosis and Candida tropicalis. Invasive Candida spp. isolates (n = 2936) collected in 60 hospitals worldwide during 2016-2017 underwent antifungal susceptibility testing by broth microdilution. Azole-resistant C. parapsilosis and C. tropicalis were submitted to qPCR for ERG11, CDR1 and MDR1, and the whole genome sequence was analysed. Results of non-susceptibility to echinocandins ranged from 0.0-2.3%, being highest in Candida glabrata. More than 99.0% of the Candida albicans isolates were susceptible to both fluconazole and voriconazole. Fluconazole resistance in C. glabrata was 6.5% overall, being highest in the USA (13.0%). Resistance to voriconazole in Candida krusei was only noted in the USA (5.0%). Azoles inhibited 89.1-91.6% of C. parapsilosis isolates, with most resistant isolates noted in Europe (15.1%), including 36 isolates from Italy (three hospitals), of which 34 harboured Erg11 Y132F mutations and overexpressed MDR1. Azole non-wild-type C. tropicalis (7/227) were found in five countries: 3 isolates from Thailand had the same Erg11 Y132F alteration. Fluconazole non-wild-type isolates were noted among 3/77 (3.9%) Candida dubliniensis, 4/17 (23.5%) Candida guilliermondii, 4/47 (8.5%) Candida lusitaniae and other less common yeast species. Echinocandin use has been recommended over fluconazole for invasive Candida infections. However, azoles are still active against the most common Candida spp. and resistance appears to be restricted to certain geographic regions and associated with Erg11 Y132 alterations in C. parapsilosis and C. tropicalis.

Topics: Amino Acid Substitution; Amphotericin B; Antifungal Agents; Azoles; Candida albicans; Candida parapsilosis; Candida tropicalis; Candidiasis; Candidiasis, Invasive; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; Microbial Sensitivity Tests; Sterol 14-Demethylase; Voriconazole

Topics: Amphotericin B; Candidiasis, Invasive; Critical Illness; Humans

With improved and prolonged survival of very and extremely low birth weight infants, invasive fungal infection has emerged as an important concern in the neonatal intensive care units. Candidiasis is the third leading cause of late onset sepsis in these neonates and is associated with 20-30% mortality. Extreme prematurity, central venous catheters, prolonged antibiotic exposure, parenteral nutrition are important risk factors. Various forms of cutaneous manifestations of candidiasis have been described ranging from local diaper dermatitis and oral thrush to widespread erosive and ulcerative lesions with extensive crusting in invasive fungal dermatitis. We report a series of four cases with cutaneous hyperpigmentation as manifestation of systemic candidiasis.

Topics: Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Candidemia; Candidiasis, Invasive; Female; Humans; Hyperpigmentation; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Neonatal Sepsis

Topics: Amphotericin B; Candida; Candidiasis, Invasive; Critical Illness; Humans

The aims of the study were to examine the distribution of Candida spp. isolated from sterile body sites, the antifungal susceptibility of the isolates to amphotericin B, and fluconazole, risk factors and clinical outcomes associated with invasive health care-associated Candida infections in neonates and children. Between January 2007 and January 2012, the patients with invasive candidiasis were detected from microbiology laboratary records and medical records were examined retrospectively. Candida spp. were isolated from sterile body sites in 94 patients. The most common underlying diseases were prematurity in neonates and surgery in children. Parenteral nutrition, stay in intensive care unit (ICU), and mechanical ventilation (MV) were major risk factors in neonates. Hospitalization before infection and immunosuppressant therapy were significantly more frequent in children. Of Candida infection episodes, 29.8% was due to C. albicans and 70.2% was due to non-albicans Candida spp. The most common isolated species was C. parapsilosis. Of the Candida species, 90.8% were sensitive, and 9.2% were resistant to fluconazole. The rate of amphotericin B resistant was 1.3%; 23.4% of the patients died in the first 30 days. The main variables associated with mortality were neonates, prematurity, stay in the ICU, parenteral nutrition, MV, length of stay, amphotericin B susceptibility, and high levels of C-reactive protein.

Topics: Amphotericin B; Candida; Candidiasis, Invasive; Child; Child, Preschool; Cross Infection; Drug Resistance, Fungal; Female; Fluconazole; Humans; Infant; Infant, Newborn; Male; Retrospective Studies; Risk Factors

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.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida tropicalis; Candidiasis, Invasive; Caspofungin; Male; Mice; Mice, Inbred BALB C; Peritonitis; Random Allocation

Invasive candidiasis is an important cause of sepsis in extremely low birth weight infants (ELBW, < 1000 g), is often fatal, and frequently results in neurodevelopmental impairment (NDI) among survivors. We sought to assess the antifungal minimum inhibitory concentration (MIC) distribution for Candida in ELBW infants and evaluate the association between antifungal resistance and death or NDI.. This was a secondary analysis of a National Institute of Child Health and Human Development Neonatal Research Network study. MIC values were determined for fluconazole, amphotericin B and micafungin. NDI was assessed at 18-22 months adjusted age using the Bayley Scales of Infant Development. An infant was defined as having a resistant Candida isolate if ≥ 1 positive cultures from normally sterile sites (blood, cerebrospinal fluid, or urine) were resistant to ≥ 1 antifungal agent. In addition to resistance status, we categorized fungal isolates according to MIC values (low and high). The association between death/NDI and MIC level was determined using logistic regression, controlling for gestational age and Bayley Scales of Infant Development (II or III).. Among 137 ELBW infants with IC, MICs were determined for 308 isolates from 110 (80%) infants. Three Candida isolates from 3 infants were resistant to fluconazole. None were resistant to amphotericin B or micafungin. No significant difference in death, NDI, or death/NDI between groups with low and high MICs was observed.. Antifungal resistance was rare among infecting Candida isolates, and MIC level was not associated with increased risk of death or NDI in this cohort of ELBW infants.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis, Invasive; Cohort Studies; Drug Resistance, Fungal; Female; Fluconazole; Gestational Age; Humans; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Newborn, Diseases; Intensive Care Units, Neonatal; Male; Micafungin; Microbial Sensitivity Tests; Neurodevelopmental Disorders; Prospective Studies; Sepsis; Treatment Outcome

Usually, 7-20% of preterm neonates colonized by Candida species present invasive candidiasis. Candida albicans, and several non-albicans species cause invasive infection with C. albicans being the most dominant agent. In the last two decades, infection due to non-albicans have been increased dramatically due to their low sensitivity to antifungal drugs such as fluconazole. The aim of present study was to evaluate Candida colonization pattern and antifungal susceptibility among preterm neonates from Khorramabad, South west of Iran.. Samples were collected from 80 preterm neonates, cultured on CHROMagar Candida and incubated at 37°C. All recovered isolates were primarily screened based on classical methods and identified by PCR-RFLP targeting the ITS-rDNA regions. Antifungal susceptibility testing of all isolates was performed according to the CLSI method against amphotericin B, caspofungin, itraconazole, fluconazole and voriconazole.. Totally 23 isolates of Candida species were recovered from 20 patients (female: male, 50:50) including, C. albicans (18), C. parapsilosis (2) and C. glabrata (1). Furthermore, the blood cultures from two patients were yielded C. albicans and C. parapsilosis so that patient with C. albicans died after five days. Generally, in this study, 9 (39.1%) isolates were resistant to amphotericin B including; 7 (30.4%) C. albicans and 2 (8.7%) C. parapsilosis. In addition, 2 (8.7%) and 4 (17.4%) isolates were also resistant to itraconazole and caspofungin, respectively.. In conclusion, Candida colonization among preterm neonates is still an important issue in hospitals. In addition, in spite of a significant amphotericin B resistant Candida, voriconazole, fluconazole, and itraconazole are valuable antifungals, due to fully sensitivity to Candida.

Topics: Amphotericin B; Antifungal Agents; Candida; Candida albicans; Candida glabrata; Candidiasis, Invasive; Caspofungin; Drug Resistance, Fungal; Female; Fluconazole; Hospitals; Humans; Infant, Newborn; Infant, Premature; Iran; Itraconazole; Male; Microbial Sensitivity Tests; Voriconazole

Invasive candidiasis differs greatly between children and neonates. We aimed to investigate the different therapeutic approaches and their effects on treatment outcomes of these two groups.. Episodes of neonatal invasive candidiasis were compared with non-neonatal pediatric episodes during a 12-year cohort study. Clinical isolates were documented by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and DNA sequencing, and antifungal susceptibility testing was performed.. A total of 342 episodes of invasive candidiasis (113 neonatal and 229 non-neonatal pediatric episodes) in 281 pediatric patients (96 neonates and 185 children) were identified. Candida albicans was the most common pathogen causing invasive candidiasis in neonates and children (47.8% vs. 44.1%). The antifungal susceptibility profiles were not significantly different between neonates and children. More neonates received amphotericin B as therapy, whereas more children received fluconazole or caspofungin. Compared with children, neonates had a significantly longer duration of fungemia, higher rates of septic shock (34.5% vs. 21.8%; P = 0.013), sepsis-attributable mortality (28.3% vs. 17.5%; P = 0.024) and in-hospital mortality (42.7% vs. 25.4%; P = 0.004) than children. Independent risk factors for treatment failure of invasive candidiasis were septic shock (odds ration [OR] 16.01; 95% confidence interval [CI] 7.64-33.56; P <  0.001), delayed removal of intravenous catheter (OR 6.78; 95% CI 2.80-17.41; P <  0.001), renal failure (OR 5.38; 95% CI 1.99-14.57; P = 0.001), and breakthrough invasive candidiasis (OR 2.99; 95% CI 1.04-8.67; P = 0.043).. Neonatal invasive candidiasis has worse outcomes than non-neonatal pediatric candidiasis. Neonatologists and pediatricians must consider age-specific differences when developing treatment and prevention guidelines, or when interpreting studies of other age groups.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Candida albicans; Candidiasis, Invasive; Caspofungin; Child; Child, Preschool; Cohort Studies; Female; Fluconazole; Fungemia; Hospital Mortality; Humans; Incidence; Infant; Infant, Newborn; Male; Risk Factors; Taiwan; Treatment Outcome

Micafungin was reported to be non-inferior to liposomal amphotericin B (LAmB) in treating patients with candidaemia and invasive candidiasis (IC). The current study aimed to evaluate the economic impact of using micafungin versus LAmB for treatment of candidaemia and IC in Turkey. A decision analytic model, which depicted economic consequences upon administration of micafungin or LAmB for treating patients with candidaemia and IC in the Turkish hospitals, was constructed. Patients were switched to an alternative antifungal agent if initial treatment failed due to mycological persistence. All patients were followed up until treatment success or death. Outcome probabilities were obtained from published literature and cost inputs were derived from the latest Turkish resources. Expert panels were used to estimate data that were not available in the literature. Cost per patient treated for each intervention was then calculated. Sensitivity analyses including Monte Carlo simulation were performed. For treatment of candidaemia and IC, micafungin (€4809) was associated with higher total cost than LAmB (€4467), with an additional cost of €341 per treated patient. Cost of initial antifungal treatment was the major cost driver for both comparators. The model outcome was robust over a wide variation in input variables except for drug acquisition cost and duration of initial antifungal treatment with micafungin or LAmB. LAmB is cost-saving relative to micafungin for the treatment of candidaemia and IC from the Turkish hospital perspective, with variation in drug acquisition cost of the critical factor affecting the model outcome.

Topics: Amphotericin B; Antifungal Agents; Candidemia; Candidiasis, Invasive; Cost-Benefit Analysis; Decision Support Techniques; Humans; Micafungin; Treatment Outcome; Turkey

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Candidiasis, Invasive; Cross Infection; Drug Resistance, Fungal; Echinocandins; Female; Fluconazole; Hospitals, Teaching; Humans; Italy; Male; Microbial Sensitivity Tests; Middle Aged; Mycological Typing Techniques; Retrospective Studies; Young Adult

To investigate the species distribution and antifungal susceptibility profiles of yeast isolates causing invasive infections across Beijing.. A total of 1201 yeast isolates recovered from blood and other sterile body fluids were correctly identified by matrix-assisted laser desorption/ionization TOF MS supplemented by DNA sequencing. Antifungal susceptibility testing was performed according to the Clinical and Laboratory Standards Institute broth microdilution method.. Candida (95.5%) remained the most common yeast species isolated; Candida albicans (38.8%) and Candida parapsilosis (22.6%) were the leading species of candidemia. Azole resistances were mainly observed in Candida glabrata and Candida tropicalis isolates.. This study outlined the epidemiologic data of invasive yeast infections and highlighted the need for continuous monitoring of azole resistances among C. glabrata and C. tropicalis isolates in Beijing.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Beijing; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candida tropicalis; Candidemia; Candidiasis, Invasive; Child; Child, Preschool; Drug Resistance, Fungal; Echinocandins; Epidemiological Monitoring; Female; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Middle Aged; Sequence Analysis, DNA; Triazoles; Yeasts; Young Adult

Pulmonary valve infections without the involvement of other valves account for only 1.5- 2% of all infective endocarditis cases. Isolated pulmonary valve endocarditis due to fungus is extremely rare. The case is presented of a 36-year-old male who was found to have isolated pulmonary valve endocarditis caused by a very rare organism, Candida parapsilosis, and that was solely managed with medical therapy. The patient was evaluated for three weeks of lowgrade fever, generalized rash and fatigue, and found to have C. parapsilosis in the blood. Transesophageal echocardiography (TEE) demonstrated a 4.5 cm vegetation on the pulmonary valve, without involvement of other valves. The patient was deemed not to be a surgical candidate and was subsequently started on intravenous liposomal amphotericin B and 5-flucytosine, with excellent clinical outcome. Based on these case details, it must be emphasized that in selective cases and if there are no known complications, fungal endocarditis can be managed successfully using anti-fungal agents.

Topics: Administration, Intravenous; Adult; Amphotericin B; Antifungal Agents; Candida parapsilosis; Candidiasis, Invasive; Echocardiography, Transesophageal; Endocarditis; Flucytosine; Humans; Male; Pulmonary Valve; Treatment Outcome

Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔΕ value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of isavuconazole and micafungin are synergistic against Candida spp., while those of isavuconazole and amphotericin B are indifferent in vitro.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis, Invasive; Drug Synergism; Echinocandins; In Vitro Techniques; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Nitriles; Pyridines; Time Factors; Triazoles

Amphotericin B (AmB) is a polyene antibiotic produced by Streptomyces nodosus and has been used for >50 years in the treatment of acute systemic fungal infections. In the present study, we demonstrated that lysine, an essential amino acid, could enhance the effect of AmB against Candida albicans in vitro, although lysine itself did not exert a fungicidal effect. In addition, the combination of AmB with lysine could provide an enhanced action against Candida parapsilosis and Cryptococcus neoformans compared with AmB alone. Lysine could also enhance the antifungal effect of caspofungin or nystatin. An enhanced effect of the combination of lysine with AmB was observed for the prevention of biofilm and hypha formation. Furthermore, our results demonstrated that lysine-mediated oxidative damage, such as the generation of endogenous reactive oxygen species, may be the mechanism underlying the enhancing effect of lysine on AmB. Our results also showed that CaMCA1 gene plays an important role in increasing the sensitivity of C. albicans cells upon AmB treatment. Using AmB together with lysine may be a promising strategy for the therapy of disseminated candidiasis.

Topics: Amphotericin B; Antifungal Agents; Biofilms; Candida albicans; Candidiasis, Invasive; Drug Resistance, Fungal; Drug Synergism; Genes, Fungal; Humans; Hyphae; In Vitro Techniques; Lysine; Membrane Potential, Mitochondrial; Microbial Sensitivity Tests; Reactive Oxygen Species

Candida kefyr is an emerging pathogen able to cause disseminated infection, especially in immunocompromised patients. Although guidelines for the treatment of invasive candidiasis have been published, no specific recommendations against C. kefyr are available. We determine the in vitro killing activity of amphotericin B (AMB), fluconazole (FLC) and caspofungin (CFG) as well as their efficacy in a murine model of systemic infection by two C. kefyr strains. Time-kill curves of AMB, FLC and CFG were determined in final volumes of 10 ml containing the assayed drugs ranged from 0.03 to 32 μg ml

Topics: Amphotericin B; Animals; Antifungal Agents; beta-Glucans; Candida; Candidiasis, Invasive; Caspofungin; Colony Count, Microbial; Disease Models, Animal; Echinocandins; Fluconazole; Kidney; Lipopeptides; Male; Mice; Microbial Sensitivity Tests; Microbial Viability; Proteoglycans; Survival Analysis; Treatment Outcome

Colonization of patients occurs before development into invasive candidiasis. There is a need to determine the incidences of Candida colonization and infection in SICU patients, and evaluate the usefulness of beta-D-glucan (BDG) assay in diagnosing invasive candidiasis when patients are colonized.. Clinical data and fungal surveillance cultures in 28 patients were recorded from November 2010, and January to February 2011. Susceptibilities of Candida isolates to fluconazole, voriconazole, amphotericin B, micafungin, caspofungin and anidulafungin were tested via Etest. The utilities of BDG, Candida score and colonization index for candidiasis diagnosis were compared via ROC.. 30 BDG assays were performed in 28 patients. Four assay cases had concurrent colonization and infection; 23 had concurrent colonization and no infection; three had no concurrent colonization and infection. Of 136 surveillance swabs, 52 (38.24 %) were positive for Candida spp, with C. albicans being the commonest. Azole resistance was detected in C. albicans (7 %). C. glabrata and C. tropicalis were, respectively, 100 and 7 % SDD to fluconazole. All 3 tests showed high sensitivity of 75-100 % but poor specificity ranging 15.38-38.46 %. BDG performed the best (AUC of 0.89).. Despite that positive BDG is common in surgical patients with Candida spp colonization, BDG performed the best when compared to CI and CS.

Topics: Adult; Aged; Aged, 80 and over; Amphotericin B; Anidulafungin; Antifungal Agents; beta-Glucans; Candida; Candida albicans; Candida glabrata; Candidiasis; Candidiasis, Invasive; Carrier State; Caspofungin; Critical Care; Echinocandins; Female; Fluconazole; Humans; Incidence; Intensive Care Units; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Sensitivity and Specificity; Singapore; Tertiary Care Centers; Voriconazole

The incidence of invasive candidiasis caused by non-albicans Candida (NAC) spp. is increasing. The aim of this analysis was to evaluate the efficacy of micafungin, caspofungin and liposomal amphotericin B in patients with invasive candidiasis and candidaemia caused by different Candida spp. This post hoc analysis used data obtained from two randomised phase III trials was conducted to evaluate the efficacy and safety of micafungin vs. caspofungin and micafungin vs. liposomal amphotericin B. Treatment success, clinical response, mycological response and mortality were evaluated in patients infected with C. albicans and NAC spp. Treatment success rates in patients with either C. albicans or NAC infections were similar. Outcomes were similar for micafungin, caspofungin and liposomal amphotericin B. Candida albicans was the most prevalent pathogen recovered (41.0%), followed by C. tropicalis (17.9%), C. parapsilosis (14.4%), C. glabrata (10.4%), multiple Candida spp. (7.3%) and C. krusei (3.2%). Age, primary diagnosis (i.e. candidaemia or invasive candidiasis), previous corticosteroid therapy and Acute Physiology and Chronic Health Evaluation II score were identified as potential predictors of treatment success and mortality. Micafungin, caspofungin and liposomal amphotericin B exhibit favourable treatment response rates that are comparable for patients infected with different Candida spp.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candida; Candidemia; Candidiasis, Invasive; Caspofungin; Clinical Trials, Phase III as Topic; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Survival Analysis; Treatment Outcome; Young Adult

The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient's risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Catheter-Related Infections; Chemotherapy-Induced Febrile Neutropenia; Clinical Trials as Topic; Combined Modality Therapy; Drug Monitoring; Drug Therapy, Combination; Echinocandins; Fungemia; Humans; Immunocompromised Host; Immunotherapy; Invasive Pulmonary Aspergillosis; Mycoses; Neoplasms; Salvage Therapy; Triazoles

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Candidiasis, Invasive; Chemotherapy-Induced Febrile Neutropenia; Cytarabine; Daunorubicin; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Hepatitis; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Splenic Diseases; Tomography, X-Ray Computed

Micafungin was non-inferior to liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC) in a major clinical trial. The present study investigated the economic impact of micafungin vs. LAmB in treating candidaemia and IC. A decision analytical model was constructed to capture downstream consequences of using micafungin or LAmB as primary definitive therapy. The main outcomes were treatment success and treatment failure due to mycological persistence, or death. Outcome probabilities were derived from key published sources. Resource used was estimated by an expert panel and cost inputs were from the latest Australian resources. The analysis was from an Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. Micafungin (AU$61 426) had a lower total cost than LAmB (AU$72 382), with a total net cost-saving of AU$10 957 per patient. This was primarily due to the lower cost associated with initial antifungal treatment and shorter length of stay for patients in the micafungin arm. Hospitalisation was the main cost driver for both arms. Results were robust over a wide range of variables. The uncertainty analysis demonstrated that micafungin had a 99.9% chance of being cost-saving compared with LAmB. Micafungin was associated with cost-saving relative to LAmB in the treatment of candidaemia and IC in Australia.

Topics: Amphotericin B; Antifungal Agents; Australia; Candidemia; Candidiasis, Invasive; Echinocandins; Health Care Costs; Humans; Lipopeptides; Micafungin; Treatment Outcome

The effect of delayed antifungal therapy in critically ill infants with invasive candidiasis has not been studied. Our objective was to evaluate the effect of time to initiation of antifungal therapy (TIA) on mortality, disseminated disease, and postinfection hospital stay. We conducted a cohort study of critically ill infants with cultures positive for Candida from 1990 to 2008. TIA was defined as the number of hours from the collection of the first positive culture until the start of antifungal therapy. Of 96 infants, 57% were male, the median gestational age was 27 weeks (range, 23 to 41 weeks), and the median birth weight was 956 g (range, 415 to 6,191 g). Most subjects received amphotericin B deoxycholate. TIA was ≤ 24 h for 35% of infants, between 25 and 48 h for 42%, and >48 h for 23%. Eleven subjects died during hospitalization, and 22% had disseminated candidiasis. The median duration of hospital stay postinfection was 53 days (range, 6 to 217 days). Both univariate and multivariate analyses demonstrated that TIA was not associated with mortality, disseminated disease, or hospital stay postinfection. However, ventilator use for >60 days significantly increased the risk of death (odds ratio [OR], 9.5; 95% confidence interval [CI], 2.2 to 66.7; P = 0.002). Prolonged candidemia increased the risk of disseminated disease by 10% per day of positive culture (OR, 1.1; 95% CI, 1.08 to 1.2; P = 0.007), and low gestational age was associated with increased neonatal intensive care unit (NICU) stay after the first positive Candida culture by 0.94 weeks (95% CI, 0.70 to 0.98; P < 0.001). The TIA was not associated with all-cause mortality, disseminated candidiasis, and postinfection length of hospital stay.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis, Invasive; Cohort Studies; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Length of Stay; Male; Time Factors; Time-to-Treatment; Treatment Outcome

There are concerns of a reduced effect of liposomal amphotericin B (L-AmB) given sequentially after mold-active azoles due to a possible antagonism in their antifungal mechanism. To investigate this possible effect in the clinic, we retrospectively studied 182 high risk hematologic patients with invasive fungal infections (IFI) who were treated with L-AmB. Overall, 96 patients (52.7%) had possible, 52 (28.6%) probable and 34 (18.7%) proven IFI according to EORTC classification. Most had suspected or proven invasive aspergillosis. We compared patients with prior exposure to mold-active azoles (n=100) to those having not (n=82). The group with prior mold-active azoles included more patients with poor risk features for IFI as acute myeloid leukemia (p<0.05) and prolonged neutropenia (p<0.05). A favorable response in the IFI, defined as a complete or partial response, was achieved in 75% and 74.4% of patients in the whole cohort, and in 66% and 74.4% of patients with probable or proven IFI in the two groups. None of these differences were significant. Multivariate analysis showed that refractory baseline disease and renal dysfunction were adverse factors for response in the IFI (p<0.05). Survival was poorer for patients with prior broad spectrum azoles (p<0.05), and for those who did not recover from neutropenia (p<0.05). In conclusion, the effectiveness of treatment of breakthrough fungal infection with L-AmB is not likely to be affected by prior exposure to mold-active azoles prophylaxis, but survival largely depends on host and disease factors.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Candidiasis, Invasive; Child; Child, Preschool; Combined Modality Therapy; Cross Infection; Drug Evaluation; Female; Fungemia; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Postoperative Complications; Retrospective Studies; Risk; Transplantation, Homologous; Treatment Outcome; Triazoles; Young Adult

Antifungal prophylaxis with liposomal amphotericin B in high-risk liver transplant recipients is recommended, but experience with amphotericin B lipid complex (ABLC, Abelcet(®)) in this setting is limited. Data from 615 liver transplants performed during 1999-2005 were analyzed retrospectively. High-risk patients (n = 146) received a mean cumulative ABLC dose of 955 ± 609 mg (mean duration of 23.3 ± 11.9 days). Low-risk patients (n = 469) received no prophylaxis. During a mean follow-up of 43.8 ± 29.2 months, fungal infections occurred in 32.2% of ABLC patients versus 43.5% of non-prophylaxis patients (P = 0.015). The overall rate of invasive fungal infection was 12.3% in the ABLC group versus 15.6% in the non-prophylaxis patients (P = 0.34). Any Candida infection (ABLC 29.5%, non-prophylaxis 41.2%, P = 0.011), probable or proven invasive Candida infection requiring systemic antifungal treatment (ABLC 18.5%, non-prophylaxis 32.4%, P = 0.001) and invasive abdominal candidiasis during the first 3 months (ABLC 4.1%, non-prophylaxis 9.2%, P = 0.049) were significantly less frequent in the ABLC group. There was no significant difference between groups in the incidence of Aspergillus infections. The ABLC group showed no evidence of nephrotoxicity. In conclusion, the marked and significant differences in infection rates and requirement for systemic treatment in this large population suggest that targeted use of low-dose ABLC therapy to high-risk patients is a valid prophylactic strategy following liver transplantation.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspergillosis; Candidiasis, Invasive; Cyclosporine; Female; Follow-Up Studies; France; Humans; Immunosuppressive Agents; Kidney; Liposomes; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Retrospective Studies; Safety; Tacrolimus; Treatment Outcome

Invasive candidiasis is a leading cause of mortality and morbidity in neonatal intensive care units. Treatment recommendations are limited by a lack of comparative outcomes data.. We identified all infants ≤ 120 days of age with positive blood, urine, or cerebrospinal fluid cultures for Candida species who received amphotericin B deoxycholate, fluconazole, amphotericin B lipid products, or combination therapy admitted to one of 192 neonatal intensive care units in the United States between 1997 and 2003. Primary outcome measures included overall mortality and therapeutic failure (combined outcome of duration of infection >7 days, need for additional antifungal therapy, or death before discharge). We compared outcomes by antifungal therapy using logistic regression, controlling for gestational age, day of life at start of antifungal therapy, delay in therapy, and site of infection.. Overall, 138 of 730 (19%) infants died. On multivariable logistic regression, we observed higher overall mortality for infants receiving amphotericin B lipid products compared with infants receiving amphotericin B deoxycholate (odds ratio 1.96 [95% confidence intervals: 1.16, 3.33]; P = 0.01) or fluconazole (odds ratio 2.39 [1.18, 4.83]; P = 0.02).. Infants treated with amphotericin B lipid products had higher mortality than infants treated with either amphotericin B deoxycholate or fluconazole. This finding may be related to inadequate penetration of amphotericin B lipid products into the kidneys, inappropriate dosing in premature infants, or unknown differences in acuity of illness in infants treated with amphotericin B lipid products.

Topics: Amphotericin B; Antifungal Agents; Candida; Candidiasis, Invasive; Deoxycholic Acid; Drug Combinations; Female; Fluconazole; Humans; Infant; Infant Mortality; Infant, Newborn; Intensive Care Units, Neonatal; Logistic Models; Male; Treatment Outcome; United States

The objective of this work was to assess the antifungal activity of a tropically stable formulation of amphotericin B (AmB) (iCo-010) over short period of treatment in a rat model of invasive candidiasis. The rats were infected with Candida albicans (ATCC 18804); 48 h later, the animals were assigned either to a control group, AmBisome(®) group (5 mg/kg QD), or iCo-010 groups (0.5, 1, 2.5, 5 and 10 mg/kg TID). The animals were treated for two days and then sacrificed 18 h following the completion of the treatment. The blood, liver, lungs, kidneys and spleen were harvested to assess the colony forming units in the samples. There was no significant difference in the reduction of the fungal burden in the organs between the AmBisome(®) and iCo-010 groups except in the spleen and liver. There was a linear correlation between the antifungal activity in renal tissues and the administered doses of iCo-010. The plasma creatinine levels were not significantly different among the control and all the treatment groups. Oral iCo-010 has high efficacy against invasive candidiasis in renal and pulmonary tissues. Longer treatment period than the two-days regimen should be considered for higher therapeutic efficacy of iCo-010 in all the tissues.

Topics: Administration, Intravenous; Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Candidiasis, Invasive; Creatinine; Kidney; Lipids; Liver; Lung; Male; Rats; Rats, Sprague-Dawley; Spleen

In the present work, we studied the distribution of Candida parapsilosis complex species and the antifungal susceptibility of clinical isolates collected during an Italian surveillance study of yeast invasive fungal infections (IFIs) in intensive care units (ICUs). Minimum inhibitory concentrations (MICs) were determined using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method. BanI digestion patterns of the secondary alcohol dehydrogenase polymerase chain reaction (PCR) products were used to identify C. parapsilosis sensu stricto, C. orthopsilosis, and C. metapsilosis. A total of 138 C. parapsilosis isolates were stored (January 2007-December 2008). The overall frequency of C. parapsilosis complex in IFIs was 22%. Of the 138 tested isolates, 95% were C. parapsilosis sensu stricto, 3.6% were C. orthopsilosis, and 1.4% were C. metapsilosis. The MIC(50) values (expressed as μg/ml) for anidulafungin, caspofungin, and micafungin for C. parapsilosis complex were 2, 1, and 2, respectively, and the MIC(90) values were 4, 2, and 4, respectively. The MIC(50) and MIC(90) values for itraconazole and posaconazole were 0.12 and 0.25, respectively, and for fluconazole, they were 1 and 4, respectively. This study, the most comprehensive study conducted to date to evaluate the frequency and antifungal susceptibility profiles of C. parapsilosis complex isolates from critically ill patients in Italy, highlights the low prevalence of C. orthopsilosis and C. metapsilosis in IFIs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alcohol Dehydrogenase; Amphotericin B; Antifungal Agents; Candida; Candidiasis, Invasive; Child; Child, Preschool; Critical Illness; Echinocandins; Fungal Proteins; Humans; Infant; Infant, Newborn; Intensive Care Units; Italy; Microbial Sensitivity Tests; Middle Aged; Mycological Typing Techniques; Polymerase Chain Reaction; Triazoles; Young Adult

In many instances a report from the clinical laboratory indicating candiduria represents colonization or procurement contamination of the specimen and not invasive candidiasis. Even if infection of the urinary tract by Candida species can be confirmed, antifungal therapy is not always warranted. Further investigation may reveal predisposing factors, which if corrected or treated, result in the resolution of the infection. For those with symptomatic urinary tract infections (UTIs), the choice of antifungal agent will depend upon the clinical status of the patient, the site of infection, and the pharmacokinetics and pharmacodynamics of the agent. Because of its safety, achievement of high concentrations in the urine, and availability in both an oral and intravenous formulation, fluconazole is preferred for the treatment of Candida UTIs. Flucytosine is concentrated in urine and has broad activity against Candida spp, but its use requires caution because of toxicity. Low-dose amphotericin B may be useful for Candida UTIs in selected patients. The role of echinocandins and azoles that do not achieve measurable concentrations in the urine is not clear. Small case series note some success, but failures have also occurred. Irrigation of the bladder with antifungal agents has limited utility. However, with fungus balls, irrigation of the renal pelvis through a nephrostomy tube can be useful in combination with systemic antifungal agents.

Topics: Algorithms; Amphotericin B; Antifungal Agents; Azoles; Candida; Candidiasis; Candidiasis, Invasive; Causality; Echinocandins; Fluconazole; Flucytosine; Humans; Urinary Tract Infections

In the USA, the incidence of invasive candidiasis in neonates is respectively 0.3% of infants over 2500 g and up to 20% of infants less than 1000 g. Their incidence is increasing. Two populations of newborn infants are particularly vulnerable: the premature infants and newborn infants with severe neonatal digestive diseases. Fifty percent of infants hospitalized in NICU are colonized with Candida at the end of the first week of hospitalization; a direct relationship exists between the importance of colonization and the invasive infection risk. C. albicans is the species most often responsible for invasive candidiasis in the newborn. These infections represent the third cause of related-catheter infection in the USA. Mortality rate in neonates linked to this disease is 20 to 50%; morbidity primarily concerns brain and lungs. Neonatal invasive candidiasis risk factors are known and a primary prevention is possible. The diagnosis of neonatal invasive candidiasis is difficult and often delayed because of a polymorphic clinical expression. Empiric and preemptive treatment are based on the use of amphotericin B. Prophylactic treatment using fluconazole of newborns with birth weight ≤ 1000 grams and/or gestational age ≤ 27 weeks gestation is recommended by the American Academy of Paediatrics and the Infectious Diseases Society of America. A better knowledge of French epidemiological data in this area would improve both the diagnosis and therapeutic management of this disease.

Topics: Amphotericin B; Antifungal Agents; Candidiasis, Invasive; Catheters; Fluconazole; France; Humans; Incidence; Infant; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intensive Care Units, Neonatal; Intensive Care, Neonatal; Risk Factors; Treatment Outcome

Invasive candidiasis is rare in children after the neonatal period, but can occur in children with (secondary) immunodeficiency with a damaged gastrointestinal or skin barrier, or when receiving antibiotics. A 10-month-old girl was diagnosed as suffering from cystic fibrosis (CF) when showing failure to thrive, pulmonary symptoms and hypoproteinaemia. At that time, Candida albicans was identified from blood culture and treated intravenously with liposomal amphotericin B for 13 days. Six weeks later, the girl presented with osteoarticular infection of the left knee caused by C. albicans. The infection showed insufficient response to therapy with liposomal amphotericin B, but the patient recovered after therapy with fluconazole and flucytosine. Follow-up over 4 years revealed no sequelae. In conclusion, invasive Candida infections may occur in patients with CF, and preventive measures might be considered in patients at risk. In the case of an invasive infection, prolonged treatment with a combination of antifungal drugs may be required.

Topics: Amphotericin B; Antifungal Agents; Candida albicans; Candidemia; Candidiasis, Invasive; Cystic Fibrosis; Female; Fluconazole; Flucytosine; Humans; Infant; Osteoarthritis; Treatment Outcome

We previously reported that the IgM MAb B6.1, specific for β-1,2-mannotriose on the surface of the cell wall of Candida albicans, prevents mice from disseminated candidiasis. The preventive activity of the antibody is mediated by enhanced phagocytosis that caused killing of the fungus and involvement of the complement system. In the present study, MAb B6.1 was tested if the antibody enhances therapeutic efficacy of amphotericin B (Amp B) in a murine model of disseminated candidiasis due to C. albicans. Determination by the kidneys-cfu (colony forming unit) and survival times was used to assess treatment. Mice treated intraperitoneally with MAb B6.1 at 1h post-infection with C. albicans (5 x 10⁵ yeast cells/mouse) developed fewer 28%cfu and prolonged survival rates than negative controls, whereas administration of B6.1 to mice at 2h post-infection was ineffective. Therapeutic effect of Amp B on mice with the disseminated disease was dose-dependent, but dosage of Amp B (0.5mg/kg body weight of mice) was not effective. A combination of MAb B6.1 given at 1h post-infection plus Amp B (0.5mg dose) enhanced survival times beyond the effect due to only antibody (P<0.05). The MST (mean survival times) value resulted from the combination therapy-received mice was as almost the same as MST value from 2mg dose of Amp B-given animals (P<0.05). In case mice given a combination of Amp B (0.5mg dose) plus MAb B6.1 at 2h post-infection - a condition of developing no therapeutic efficacy, the combination also reduced disease severity. All these data indicate that MAb B6.1 acts in concert with Amp B, the antibody enhances therapeutic efficacy of Amp B, and this combination therapy augments protection which implies a possibility of reducing Amp B dose. The augmentation of the response appeared to be specific because an irrelevant IgM carbohydrate-specific MAb was not protective. In conclusion, these studies show that Amp B combined with MAb B6.1 may be an option of solving the problem of limited antifungal drug choices due to drug-resistant C. albicans.

Topics: Amphotericin B; Animals; Antibodies, Monoclonal; Antifungal Agents; Candida albicans; Candidiasis, Invasive; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Immunoglobulin M; Mice; Mice, Inbred BALB C; Trisaccharides