Global Distribution and Outcomes for<Emphasis Type="Italic"> Candida</Emphasis> Species Causing Invasive Candidiasis: Results from an International Randomized Double-Blind Study of Caspofungin Versus Amphotericin B for the Treatment of Invasive Candidiasis

In a randomized study, caspofungin was compared with amphotericin B for the treatment of invasive candidiasis in a total of 239 adults from 56 sites in 20 countries. This study provided a unique opportunity to assess the frequency and outcome of invasive candidiasis caused by different Candida species worldwide, and the results are presented here. Efficacy was primarily assessed at the end of intravenous therapy using a modified intent-to-treat (MITT) analysis. This analysis was performed on 224 of the 239 patients enrolled in the study. Attempts were made to collect baseline Candida isolates from all patients for species identification at a central laboratory. Yeasts were identified to the species level using two commercial systems and microscopic examination. Viable baseline isolates were recovered from 210 of the 224 (94%) patients included in the MITT analysis. Candida albicans was the most frequently isolated species in all regions and was responsible for 45% of cases overall. Nevertheless, the majority of cases of infection were caused by non-albicans Candida species. In the USA and Canada, Candida glabrata was the second most commonly isolated pathogen (18%). In contrast, Candida parapsilosis and Candida tropicalis accounted for 55% of cases in Latin America. Outcomes were comparable for patients treated with caspofungin (74% overall; 64% and 80% for infections due to Candida albicans and non-albicans species) and amphotericin B (62% overall; 58% and 68% for infections due to Candida albicans and non-albicans species), and were generally similar across continents. The distribution of Candida species isolated from patients enrolled in a clinical trial may not be representative of pathogens causing invasive candidiasis in the general population. Nevertheless, our findings may affect the regional choice of empirical antifungal therapy for seriously ill patients with suspected or documented invasive candidiasis since different Candida species have varying susceptibility to conventional antifungal drugs.     

Neonatal candidiasis: analysis of epidemiology, drug susceptibility, and molecular typing of causative isolates

A prospective observational study of invasive candidiasis was conducted in the neonatal intensive care unit of Aristotle University in Hippokration Hospital between 1994 and 2000. During this period, 59 neonates developed invasive candidiasis (58 cases of candidemia and 1 case of peritonitis), resulting in an overall incidence of 1.28% that showed a decreasing trend over the study period. Eleven (18.6%) cases developed within the first week of life and the others within a mean (±SEM) of 13.4±1.7 days after birth. The three most frequent causative species were Candida albicans (65.5%), Candida parapsilosis (15.5%), and Candida tropicalis (7%). C. albicans was the predominant species between 1994 and 1998, whereas, non-albicans Candida spp., particularly C. parapsilosis, were the most frequent species during the period 1999–2000 (P<0.001). While the overall mortality due to candidemia was 29% (17 of 59 cases), mortality associated with C. albicans and C. parapsilosis was 39.5% and 11.1%, respectively (P=0.032), and that observed in the 1999–2000 period was 0% (P=0.011). Virtually all isolates were susceptible to amphotericin B, flucytosine, fluconazole, and itraconazole, and no increases in minimal inhibitory concentrations were observed during these years. With the exception of a limited cluster of cases due to genotypically identical isolates, no clonal relation of C. albicans isolates was found. Moreover, no clonal persistence of C. albicans and no decrease in antifungal drug susceptibility occurred over the 6-year study period. Non-albicans Candida spp., mostly C. parapsilosis, have emerged as important pathogens in neonatal intensive care units, with infected patients having better outcomes as compared to patients infected with C. albicans.     

A comparison of AmBisome to amphotericin B for treatment of systemic candidiasis in very low birth weight infants

PURPOSE: Amphotericin B is considered the treatment of choice for systemic candidiasis, but adverse effects may limit its use. An alternative option for the treatment of candidiasis includes lipid preparations of amphotericin B. This study investigated the safety and efficacy of AmBisome, a lipid formulation of amphotericin B containing liposomal structures, for the treatment of systemic candidiasis in very low birth weight infants (VLBWI). MATERIALS AND METHODS: Data from 26 VLBWI treated with AmBisome in the study group (AmBisome group) from October 2003 to July 2006 were compared with data from 20 VLBWI treated with amphotericin B as a historical control (Amphotericin group). This study was a prospective, historical control, multi-center trial. RESULTS: Candida spp. was isolated in 73% (19/26) of the cases for the AmBisome group and 90% (18/20) of the cases for the Amphotericin group. The fungal eradication rate and the time to eradication was 84% (16/19) and 9+/-8 days in the AmBisome group, and 89% (16/18) and 10+/-9 days in the Amphotericin group, respectively (p=0.680 vs p=0.712). The major adverse effects were lower in the AmBisome group (renal toxicity, 21% vs 55%, p=0.029; hepatotoxity, 25% vs 65%, p=0.014, AmBisome group vs Amphotericin group, respectively). There was no significant difference in mortality attributed to systemic candidiasis (12% in the AmBisome group, 10% in the Amphotericin group, p=0.868). CONCLUSION: AmBisome is effective and safe for treating systemic fungal infections in VLBWI.     

Candidiasis

Candida spp. are the most common fungal pathogens isolated in immunocompromised hosts, particularly cancer patients. Numerous clinical manifestations of candidiasis have been recognized, including localized infection such as oropharyngeal candidasis or focal hepatic candidiasis, and disseminated infection resulting from hematogenous spread, with or without documented fungemia. Granulocytopenic patients are particularly at risk.Candida albicans is isolated in approximately 40 % of cases of fungemia, otherCandida spp. now also commonly being isolated. The rate of morbidity and mortality secondary to candidiasis is still significant despite numerous attempts to develop better diagnostic techniques, and more effective means of chemoprophylaxis and therapy. Currently, new antifungal agents and galenic preparations of amphotericin B are being evaluated with the aim of improving the prognosis of candidiasis in immunocompromised hosts.     

Mixed oropharyngeal candidiasis due toCandida albicans and non-albicans Candida strains in HIV-infected patients

In order to determine the clinical significance of mixed oropharyngeal candidiasis (Candida albicans plus a non-albicans strain ofCandida) in patients infected with HIV-1, a retrospective chart review was done in 12 HIV-1-infected patients with a clinical episode of oropharyngeal candidiasis, in whom a mixed culture ofCandida albicans (found to be fluconazole-sensitive) plus a non-albicans species ofCandida was obtained from their oral cavities. This group was compared with 26 HIV-positive patients (control group) with oropharyngeal candidiasis due toCandida albicans (found to be fluconazole-sensitive). Antifungal susceptibility testing was performed by a broth microdilution test with RPMI-2% glucose. A fungal strain was considered fluconazole-sensitive if its MIC was < 0.5 g/ml. Both the study and control groups had similar clinical and demographic characteristics. All the patients were severely immunocompromised, with a mean CD4+ lymphocyte count of 63/mm³ (95% Cl 41–84) and 80/mm³ (95% Cl 25–135) in the study and control groups, respectively. In the study group, seven patients hadCandida albicans andCandida krusei in their oral cavity, four hadCandida albicans andCandida glabrata, and one hadCandida albicans andCandida tropicalis. Antifungal therapy consisted of ketoconazole (5 patients in the study group, 14 in the control group) or fluconazole (7 patients in the study group, 12 in the control group); no statistically significant difference in clinical outcome was observed. Fungal strain persistence after therapy was frequently observed in both groups. It is concluded that non-albicans strains ofCandida, less sensitive to azole drugs than theirCandida albicans counterparts, are not clinically relevant in episodes of mixed oropharyngeal candidiasis in HIV-1-infected patients.     

Comparison of the in vitro antifungal activity of free and liposome-encapsulated amphotericin B

One hundred and four pathogenic yeast isolates (32Candida albicans, 20 Candida tropicalis, 20Candida parapsilosis and 32Cryptococcus neoformans) and 21 mould isolates (13Aspergillus spp. and eightFusarium spp.), most of which were isolated from patients with cancer, were tested for susceptibility to free amphotericin B and a small unilamellar liposomal formulation of amphotericin B using a microbroth dilution method. Minimal fungicidal concentrations were also determined forCandida spp. andCryptococcus neoformans. The minimal inhibitory concentrations of liposomal amphotericin B were comparable with those of the free drug; furthermore, the fungicidal activity of these two drugs did not differ significantly.     

Prospective study ofCandida colonization,use of empiric amphotericin B and development of invasive mycosis in neutropenic patients

The association between colonization withCandida spp., subsequent occurrence of invasive candidiasis and empiric use of amphotericin B was investigated prospectively in 139 neutropenic patients with hematologic malignancies. Treatment with amphotericin B was required in 67 % of patients colonized in multiple non-contiguous body sites (multicolonized) versus 31 % of patients colonized in single or contiguous sites (monocolonized) and in 21 % of non-colonized patients (p=0.0037 and p=0.00026, respectively). Invasive candidiasis was documented in 22.2 % of multicolonized versus 4.8 % of monocolonized patients and in none of the non-colonized patients (p=0.035 and p=0.0036, respectively). Analysis of the spectrum of colonizingCandida spp. showed that multicolonized subjects were colonized with increased frequency byCandida albicans compared to monocolonized subjects, and that the association between multicolonization, invasive candidiasis and amphotericin B usage was statistically significant in patients colonized byCandida albicans but not in patients colonized by otherCandida species. The association betweenCandida multicolonization and the occurrence ofCandida infection seems to be confirmed by a double-blind placebo-controlled study performed in a small subgroup of the multicolonized patients treated with fluconazole.     

Voriconazole Salvage Treatment of Invasive Candidiasis

Data on the salvage treatment of invasive candidiasis with voriconazole in 52 patients intolerant of other antifungal agents or with infection refractory to other antifungal agents were analyzed. Patients had received a mean of two previous antifungal agents (range, 1–4 agents), and 83% had received an azole. Manifestations of invasive candidiasis included candidemia (37%), disseminated disease (25%), and infection of other sites (38%). The median duration of voriconazole therapy was 60 days (range, 1–314 days). The overall rate of response was 56% (95%CI, 41–70), with the following response rates observed for individual Candida species: Candida albicans, 44% (20–70); Candida glabrata, 38% (14–68); Candida krusei, 70% (35–93); Candida tropicalis, 67% (30–93); and other Candida spp., 100% (40–100). The response rate in patients who had failed previous azole therapy was 58% (42–73). Common adverse events (~20%) included nausea and emesis, abnormal liver enzymes, and visual disturbances. Serious adverse events occurred in four patients, and nine patients died. Voriconazole has promise as a salvage agent for the treatment of invasive candidiasis, even in the settings of previous azole therapy and infection due to Candida krusei.This work was presented as abstract no. 352 at the 40th Annual Meeting of the Infectious Diseases Society of America, Chicago, 2002. This work was supported by a grant from Pfizer, Inc.     

PCR monitoring of response to liposomal amphotericin B treatment of systemic candidiasis in neutropenic mice.

When a diagnosis of invasive candidiasis has been made, treatment with toxic fungicidal agents is inevitable. The crucial decision of when to stop such treatment is difficult to make, because cultures are often negative despite ongoing invasive candidiasis and can therefore not be used as a reliable parameter of effective therapy. In the present study, the use of PCR in monitoring the therapeutic efficacy of antifungal treatment with liposomal amphotericin B was evaluated by using neutropenic mice with systemic candidiasis. Blood cultures of infected mice treated with different doses of liposomal amphotericin B were only positive at the early onset of the infection process and became sterile within 3 days; this was true even with mice treated with 1 mg of liposomal amphotericin B per kg of body weight that experienced a relapse of infection 14 days later. A significant correlation between presence of Candida albicans in the kidneys and PCR results obtained with blood was demonstrated. Thus, PCR results obtained with blood samples correlated well with the therapeutic efficacy of antifungal treatment.     

Treatment of deep mycoses with liposomal amphotericin B

Amphotericin B is the mainstay of therapy of many deep mycoses, but its use is seriously hampered by dose-limiting nephrotoxicity. In this study a liposomal formulation of amphotericin B was administered to ten patients with proven deep mycoses: invasive aspergillosis (n=4), deep candidiasis (n=4) and zygomycosis (n=2). The mean daily dosage of liposomal amphotericin B was 3.0 mg/kg (range 2.5 to 4 mg/kg), the mean total dosage of liposomal amphotericin B 2,781 mg (range 87 to 5,220 mg) and the mean duration of treatment 17 days (range 3 to 33 days). Treatment with liposomal amphotericin B was associated with little nephrotoxicity and an overall survival rate of 50 %. The median increase of serum creatinine from baseline levels was 0.38 mg/dl (–1.2 to 2.6 mg/dl).     

Contribution of Serological Tests and Blood Culture to the Early Diagnosis of Systemic Candidiasis

The isolation of Candida species from a single blood culture is considered sufficient evidence for the initiation of systemic antifungal therapy. However, blood cultures still lack sensitivity. Previous reports have suggested that the combined serological detection of mannanemia and anti-mannan antibodies may be useful for the diagnosis of systemic candidiasis caused by Candida albicans (specificity and sensitivity 93% and 80%, respectively). In this study, serological tests to detect Candida albicans mannan and Candida albicans antibodies (Platelia Candida Antigen and Antibody tests; Bio-Rad, France) were applied retrospectively to a series of patients with at least one Candida-positive blood culture and from whom at least one serum sample, taken before or on the day of blood culture, was available. Forty-five patients were selected, including 23 infected by Candida albicans, 4 by Candida glabrata, 9 by Candida tropicalis, 5 by Candida parapsilosis, and 4 by Candida krusei. Serological tests were positive in 73% of patients at least 2 days, and in some patients, up to 15 days before blood cultures became positive. These data suggest that serological surveillance of at-risk patients using the Platelia Candida tests could result in earlier initiation of antifungal therapy, especially when used in conjunction with blood cultures. In this way, more efficient management of nosocomial infections caused by Candida species can be achieved. Electronic Publication     

Candida tropicalis in human disease

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.     

Factors related to survival and treatment success in invasive candidiasis or candidemia: a pooled analysis of two large, prospective, micafungin trials

Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remain unacceptably high. It is important to reach a more complete understanding of the risk factors underlying poor outcomes in patients with invasive Candida infections. Micafungin therapy has been assessed in two phase 3 trials compared to either liposomal amphotericin B or caspofungin. The availability of this large dataset allows the analyses of non-drug factors associated with survival and treatment success. A multivariate regression analysis was performed on data from the two trials separately and as a pooled analysis (N = 1,070). Analysis outcomes were survival at 42 days post-initiation of therapy and treatment success. For the pooled analysis, treatment success was significantly more likely for candidemia than invasive candidiasis. Both survival and treatment success were significantly less likely for the non-removal of catheter versus removal, Asian-Indians versus Caucasians, APACHE II score >20 to ≤30 and >30 versus ≤20, age ≥70 years versus <50 years, baseline corticosteroids, and persistent neutropenia. Survival was also significantly less likely for treatment in other regions versus North America and for patients with renal failure at baseline. These findings help to define non-antifungal drug factors that may impact survival and treatment success in invasive candidiasis or candidemia.     

Treatment of oropharyngeal candidiasis in HIV-infected children with oral fluconazole

In an open, noncomparative, multicentre study the efficacy and safety of oral fluconazole was evaluated in the treatment of oropharyngeal candidiasis in children with HIV infection. Fifty-one children with a mean age of five years were enrolled. Oropharyngeal candidiasis was caused byCandida albicans in 28 cases (55 %). Fluconazole was given in a mean dosage of 3.4 mg/kg/d (range 2 to 5.6 mg/kg/d) for a mean duration of 12 days (range 6 to 28 days). By the end of treatment, 90 % of the children were clinically cured, 6 % had improved and 4 % failed to respond.Candida was eradicated in 82 % of the patients. Clinical failure occurred only in children given 3 mg/kg/d or less. Two and four weeks after therapy, clinical cure was confirmed in 88 % and 82 % of the children respectively as well as eradication in 76 % respectively. Six children experienced mild side effects (1 skin rash, 5 mild elevation of liver enzyme levels). The data show that fluconazole is safe and effective in treating oropharyngeal candidiasis in HIV-infected children.     

Granulomatous Inflammation in the Lungs of Mice with Systemic Candidiasis Receiving a Composition of Amphotericin B and Dialdehyde Dextran

A composition of amphotericin B and dialdehyde dextran was used for the therapy of male C57Bl/6 mice with systemic candidiasis. The composition was more effective than free amphotericin B. A decrease in the number and size of candidal granulomas in the lungs was more significant after therapy with the study composition (compared to free amphotericin B). Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Suppl. 1, pp. 80–82, 2008     

Ocular infections caused by Candida species: Type of species,in vitro susceptibility and treatment outcome

Purpose: To report clinical and microbiological profile of patients with ocular candidiasis. Materials and Methods: Patients with ocular candidiasis were retrospectively identified from microbiology records. Significant isolates of Candida species were identified by Vitek 2 compact system. Minimum inhibitory concentration (MIC) of antifungal agents such as amphotericin B, itraconazole, voriconazole, fluconazole and caspofungin was determined by E test and of natamycin by microbroth dilution assay. Data on treatment and outcome were collected from medical records. Results: A total of 42 isolates of Candida were isolated from patients with keratitis-29, endophthalmitis-12 and orbital cellulitis-1. The most common species isolated was Candida albicans (12-keratitis, 4-endophthalmitis, 1-orbital cellulitis). All except one isolate were susceptible to amphotericin B. MIC of caspofungin was in the susceptible range in 28 (96.5%) corneal isolates while 12 out of 29 (41.3%) corneal isolates were sensitive to fluconazole. Resistance to voriconazole was seen in four corneal isolates. All isolates were susceptible to natamycin and all except two isolates were resistant or susceptible dose-dependent to itraconazole. Outcome of healed ulcer was achieved in 12/18 (66.6%) patients treated medically, while surgical intervention was required in 11 patients. Among the isolates from endophthalmitis patients, 11/12 were susceptible to amphotericin B, 6/12 to voriconazole and all to natamycin. Ten out of 11 patients (one patient required evisceration) with endophthalmitis were given intravitreal amphotericin B injection with variable outcome. Conclusions: Ocular candidiasis needs early and specific treatment for optimal results. Candida species continue to be susceptible to most commonly available antifungals including amphotericin B, voriconazole and natamycin.     

Management of <Emphasis Type="Italic">Aspergillus</Emphasis> Osteomyelitis: Report of Failure of Liposomal Amphotericin B and Response to Voriconazole in an Immunocompetent Host and Literature Review

Presented here is a case of Aspergillus osteomyelitis in an immunocompetent patient that progressed despite surgery and prolonged treatment with liposomal amphotericin B; the report is followed by a review of the literature. The review of this case and 41 similar cases found an overall cure rate of 69%. The importance of surgery when amphotericin B is used as first-line therapy is indicated by a 14% cure rate when amphotericin B is used alone compared to 75% when combined with surgery. When therapy is failing or surgery is contraindicated, dose escalation using a lipid formulation was not effective. On review, the addition of another agent, in particular 5-fluorocytosine, appears to be more beneficial. The patient reported here responded rapidly to voriconazole, a promising new antifungal agent for Aspergillus infections. Electronic Publication     

Evaluation of in vitro antifungal activity of LY121019

LY121019 is a new semisynthetic lipoeptide antifungal agent with potent in vitro fungicidal activity against multiple clinical strains ofCandida albicans andCandida tropicalis but is 10–100 fold less active againstTorulopsis glabrata andCandida parapsilosis. Its in vitro activity againstCandida albicans andCandida tropicalis is comparable to that of amphotericin B. The in vitro fungicidal activity of this new agent supports further investigations into its use in treatment ofCandida infections.     

Systemic fungal infections in neonates

Advances in neonatal management have led to considerable improvement in newborn survival. However, early (<72 hours) and late (>72 hours) onset systemic infections, both bacterial and fungal, remain a devastating complication and an important cause of morbidity and mortality in these babies. Most neonatal fungal infections are due to Candida species, particularly Candida albicans. The sources of candidiasis in NICU are often endogenous following colonization of the babies with fungi. About 10% of these babies get colonized in first week of life and up to 64% babies get colonized by 4 weeks of hospital stay. Disseminated candidiasis presents like bacterial sepsis and can involve multiple organs such as the kidneys, brain, eye, liver, spleen, bone, joints, meninges and heart. Confirming the diagnosis by laboratory tests is difficult and a high index of suspicion is required. The diagnosis of fungemia can be made definitely only by recovering the organism from blood or other sterile bodily fluid. Amphotericin B continues to be the mainstay of therapy for systemic fungal infections but its use is limited by the risks of nephrotoxicity and hypokalemia. Newer formulations of amphotericin B, namely the liposomal and the lipid complex forms, have recently become available and have been reported to have lesser toxicity. More recently Indian liposomal Amphotericin B derived from neutral lipids (L-Amp-LRC-1) has shown good response with less toxicity. A clinical trial with this preparation has shown to be safe and efficacious in neonatal fungal infections. Compared to other liposomal preparations, L-Amp-LRC-1 is effective at lower dose and is less expensive drug for the treatment of neonatal candidiasis.     

Antimicrobial effects of liquid anesthetic isoflurane on Candida albicans

Candida albicans is a dimorphic fungus that can grow in yeast morphology or hyphal form depending on the surrounding environment. This ubiquitous fungus is present in skin and mucus membranes as a potential pathogen that under opportunistic conditions causes a series of systemic and superficial infections known as candidiasis, moniliasis or simply candidiasis. There has been a steady increase in the prevalence of candidiasis that is expressed in more virulent forms of infection. Although candidiasis is commonly manifested as mucocutaneous disease, life-threatening systemic invasion by this fungus can occur in every part of the body. The severity of candidal infections is associated with its morphological shift such that the hyphal morphology of the fungus is most invasive. Of importance, aberrant multiplication of Candida yeast is also associated with the pathogenesis of certain mucosal diseases. In this study, we assessed the anti-candidal activity of the volatile anesthetic isoflurane in liquid form in comparison with the anti-fungal agent amphotericin B in an in vitro culture system. Exposure of C. albicans to isoflurane (0.3% volume/volume and above) inhibited multiplication of yeast as well as formation of hyphae. These data suggest development of potential topical application of isoflurane for controlling a series of cutaneous and genital infections associated with this fungus. Elucidiation of the mechanism by which isoflurane effects fungal growth could offer therapeutic potential for certain systemic fungal infections.