A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis

BACKGROUND: Candida esophagitis remains an important cause of morbidity in patients with advanced human immunodeficiency virus (HIV) infection. Fluconazole is widely regarded as the treatment of choice for this condition. METHODS: The efficacy and safety of caspofungin were compared with fluconazole in adult patients with Candida esophagitis in a double-blind randomized trial. Eligible patients had symptoms compatible with esophagitis, endoscopic demonstration of mucosal plaques, and microscopic demonstration of Candida from the esophageal lesions. Patients were randomly assigned to receive caspofungin (50 mg) or fluconazole (200 mg) intravenously once daily for 7 to 21 days. The primary endpoint was the combined response of symptom resolution and significant endoscopic improvement 5 to 7 days after discontinuation of treatment. Data were analyzed with a modified intention-to-treat analysis, which excluded 2 ineligible patients. RESULTS: Most patients (154/177; 87%) had HIV infection, with a median CD4 count of 30 cells/mm(3). Candida albicans was the predominant isolate. Favorable response rates were achieved in 66 (81%) of the 81 patients in the caspofungin arm and in 80 (85%) of the 94 patients in the fluconazole arm (difference = -4%; 95% confidence interval: -15% to +8%). Symptoms had resolved in >50% of patients in both groups by the fifth day of treatment. No patient in the caspofungin group developed a serious drug-related adverse event; therapy was only discontinued in 1 patient (receiving fluconazole) due to a drug-related adverse experience. Four weeks after stopping study drug, symptoms had recurred in 18 (28%) of 64 patients given caspofungin and in 12 (17%) of 72 patients given fluconazole (P = 0.19). CONCLUSIONS: In this study, caspofungin appeared to be as efficacious and generally as well tolerated as fluconazole in patients with advanced HIV infection and documented Candida esophagitis.     

Evolution of antifungal susceptibility among Candida species isolates recovered from human immunodeficiency virus-infected women receiving fluconazole prophylaxis.

The effect of fluconazole on the susceptibility of Candida isolates recovered from women infected with human immunodeficiency virus (HIV) was evaluated in a randomized, double-blind, placebo-controlled trial. Women with CD4(+) cell counts of < or =300 cells/mm(3) received either fluconazole (200 mg/week) or placebo as prophylaxis. The antifungal susceptibility of specimens was evaluated. One patient who received fluconazole and 2 patients assigned to placebo had Candida albicans isolates recovered that were resistant to fluconazole (MIC, > or =64 microg/mL). Eleven patients assigned fluconazole and 4 patients assigned placebo had non-albicans Candida strains (all Candida glabrata) recovered that were resistant to fluconazole. There was significant azole cross-resistance among the non-albicans Candida species isolates. Although the rate of azole resistance did not significantly increase after fluconazole prophylaxis, there was a trend toward more in vitro azole resistance in C. glabrata isolates from patients assigned fluconazole. Moreover, the majority of resistant vaginal isolates of Candida species were recovered after initiation of open-label fluconazole use.     

Conservative management of Candida infection of prosthetic aortic graft by means of caspofungin and fluconazole alone

Candida albicans infections after prosthetic graft implantation due to acute aortic dissection are rare. A combination of surgical resection and lifelong antifungal drug therapy is the gold standard for treatment of aortic graft infection, yet surgical interventions are associated with high mortality rates. Herein, we present the case of a 57-year-old man who presented with peripheral microembolism due to late-onset C. albicans infection of a prosthetic graft of the thoracic aorta, which was diagnosed by positron emission tomographic imaging. Given the high risk of reoperation, the patient was treated with intravenous caspofungin for 4 weeks, followed by oral administration of fluconazole. During a follow-up of 500 days, he remained asymptomatic, with slightly elevated inflammatory markers. This case suggests that in some instances, particularly in patients with high operative risk, Candida prosthetic graft infection can be managed conservatively with antifungal therapy alone. However, such an approach should be applied with caution and necessitates close follow-up on a long-term basis.     

A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis.

Caspofungin is a new broad-spectrum antifungal drug. A multicenter, double-blind, randomized trial was conducted to assess the efficacy, safety, and tolerability of caspofungin relative to amphotericin B in adults with endoscopically documented symptomatic Candida esophagitis. By use of a modified intent-to-treat analysis, endoscopically verified clinical success was achieved in 74% (95% confidence interval [CI], 59%-86%) and 89% (95% CI, 72%-98%) of patients receiving caspofungin at 50 and 70 mg/day, respectively, and in 63% (95% CI, 49%-76%) of patients given amphotericin B at 0.5 mg/kg/day. Therapy was stopped because of drug-related adverse events in 24% of patients in the amphotericin B group and 4% and 7%, respectively, for the caspofungin groups. This report provides the first demonstration of clinical utility for an echinocandin compound. Caspofungin appeared in this study to be as effective as and better tolerated than amphotericin B for the treatment of esophageal candidiasis.     

Evaluation of caspofungin and amphotericin B deoxycholate against Candida albicans biofilms in an experimental intravascular catheter infection model

Candida albicans biofilms complicate the treatment of infected implanted intravascular devices because of decreased antifungal susceptibility. In our investigation, 48 rabbits with experimental central venous catheter C. albicans infection were equally allocated to a control arm or to receive amphotericin B deoxycholate or caspofungin treatment while undergoing systemic and intraluminal lock therapy for 7 days. C. albicans was cultured from catheters from all control rabbits, from 3 that received amphotericin B, and from 0 that received caspofungin. Differences in colony counts were detected between the control and amphotericin (P<.001) and control and caspofungin (P<.001) arms. Caspofungin may be useful in the treatment of C. albicans biofilm-associated intravascular catheter infections, which warrants further study.     

Interleukin-2 treatment for persistent cryptococcal meningitis in a child with idiopathic CD4(+) T lymphocytopenia

We report a 16-year-old male patient who presented with headache, behavior changes, and fever. His cerebral spinal fluid and blood cultures grew Cryptococcus neoformans. His laboratory evaluation was negative for human immunodeficiency virus infection but flow cytometry revealed low CD4(+) count of 39 cells/mm(3) and CD4:CD8 ratio of 0.43. He was initially treated with antifungal agents with only partial clinical improvement, and he was discharged to home on oral fluconazole and prophylactic co-trimoxazole. After discharge, he continued to have persistent headache and recurrent episodes of vomiting. He was readmitted several times because of worsening of meningitis symptoms and received prolonged courses of multiple antifungal therapy, with clearance of infection from the central nervous system. He was subsequently placed on prophylactic therapy with fluconazole. His peripheral CD4(+) cell count remained low after resolution of his meningitis. Eight months after the initial diagnosis, recombinant IL-2 therapy was initiated and within a few months, his CD4(+) cell count started to increase. Treatment with rIL-2 and prophylactic antifungal therapy continued and he has been asymptomatic for almost 20 months so far. This case is the first reported pediatric idiopathic CD4(+) T-lymphocytopenia case with cryptococcal meningitis that was successfully treated by the addition of rIL-2 therapy to antifungal therapy.     

15例真菌败血症的回顾性研究

目的：探讨真菌败血症的治疗及早期诊断,以改善预后。方法：结合文献复习,回顾性研究1992年8月－2000年月间的15例真菌败血症患者的临床特征,治疗效果及预后,结果：15例中,除1例为社区获得性感染外,14例为医院获得性感染,后者首次阳性血培养前的住院时间7d-12个月,中位数为1．5个月。易感危险因素中,以严重基础疾病（10例／15例）使用广谱抗生素（14例／15例）、应用糖皮质激素或化疗药物（11例／15例）的因素最为突出,少数（4例／15例）有中性粒细胞减少。而具有上述两种以上易感危险因素者达11例。主要致病菌为念珠菌属包括白色念珠菌和非白色念珠菌属（如热带念珠菌、近平滑念珠菌等）。病死率为53．3％（8／15）,对抗真菌治疗有效的7例中,合并心内膜炎的2例成功地施行了瓣膜赘生物（直径均＞1cm）清除术,结论：本组败血症多发生在机体防御功能明显降低的患者中,主要致病菌为白色念珠菌和非白色念珠菌属,尽可能及早明确诊断和治疗有助于降低病死率。     

Well diffusion for antifungal susceptibility testing.

INTRODUCTION: The increasing clinical and microbiologic resistance of Candida spp. isolates to several antifungal agents is becoming a serious problem. It is now reasonable to propose the use of antifungal susceptibility testing in Candida spp. isolates from patients who have failed conventional therapy, before the selection of an empirical therapy. METHODS: One hundred and fifty eight isolates of Candida spp. were evaluated simultaneously by broth microdilution (NCCLS standard) and well diffusion testing (WD), a diffusion method similar to disc diffusion. RESULTS: According to the Wilcoxon Signed Ranks test performed, there was no significant difference (p>0.05) between both methodologies for all antifungal agents tested (fluconazole, itraconazole, posaconazole, caspofungin and amphotericin B, with C. tropicalis, C. krusei, C. dubliniensis, C. guillermondii, C. parapsilosis, C. albicans and C. glabrata). A significant difference was observed when comparing well diffusion with NCCLS for fluconazole WD 80% (p=0.008) in C. glabrata, as well as WD 80% (p=0.002) and WD 50% (p=0.002) in C. albicans. CONCLUSIONS: The well diffusion test is simple, easy to reproduce, inexpensive, easy both to read and interpret, and has a good correlation to the reference NCCLS microdilution test and may represent an alternative method for antifungal drug susceptibility testing of Candida spp., mainly in laboratories with few resources.     

The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer

PURPOSE: Candida glabrata is an increasing cause of candidemia, especially at cancer and bone marrow transplant centers where fluconazole is used for antifungal prophylaxis. This yeast is less susceptible to fluconazole in vitro than is Candida albicans. We compared the characteristics of patients who had C. glabrata and C. albicans candidemia at a large cancer center. SUBJECTS AND METHODS: We searched the microbiological laboratory reports and identified 116 cases of C. glabrata candidemia between 1993 and 1999. The 116 cases of C. albicans candidemia that occurred most closely in time (before or after each case of C. glabrata candidemia) served as the control group. Data were collected from patients' medical records. RESULTS: When compared with patients who had C. albicans infection, patients with C. glabrata candidemia more often had an underlying hematologic malignancy (68 [59%] vs. 26 [22%], P = 0.0001), had an Acute Physiology and Chronic Health Evaluation (APACHE) II score > or =16 (55 [48%] vs. 28 [25%], P = 0.0002), and received fluconazole prophylaxis (57 [49%] vs. 8 [7%], P = 0.0001). Patients with C. albicans candidemia more often had concomitant infections (101 [87%] vs. 78 [67%], P = 0.0003) and septic thrombophlebitis (11 [10%] vs. 2 [2%], P = 0.01). Among patients treated with antifungal therapy, those with C. albicans candidemia had a significantly greater overall response to therapy (83/104 [80%] vs. 60/97 [62%], P = 0.005) and to primary therapy (74/104 [71%] vs. 45/97 [46%], P = 0.0003). Amphotericin B preparations were not more effective than fluconazole (19/45 [42%] vs. 20/38 [53%], P = 0.5) in patients with C. glabrata candidemia. Fluconazole was less effective against C. glabrata than against C. albicans (20/38 [53%] vs. 57/74 [77%], P = 0.008). CONCLUSION: C. glabrata has emerged as an important cause of candidemia, especially among neutropenic patients who receive fluconazole prophylaxis.     

Evolution of vaginal Candida species recovered from human immunodeficiency virus-infected women receiving fluconazole prophylaxis: the emergence of Candida glabrata? Terry Beirn Community Programs for Clinical Research in AIDS (CPCRA).

The effect of fluconazole prophylaxis on the vaginal flora of 323 human immunodeficiency virus-infected women was evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. Women with CD4 cell counts of < or = 300/mm3 received either 200 mg of fluconazole per week or placebo. Vaginal surveillance cultures were performed every 3 months. After a follow-up of 29 months, Candida albicans was recovered from 53% of patients receiving fluconazole and 68% of patients assigned placebo. Fluconazole was associated with a 50% reduction in the odds of being colonized with C. albicans but with higher rates for non-albicans Candida species. Candida glabrata was recovered from 40 women assigned fluconazole and 29 assigned placebo (relative odds, 1.96; 95% confidence interval, 0.98-3.94). Fluconazole had an early and persistent effect on the vaginal mycoflora, with the emergence of C. glabrata vaginal colonization within the first 6 months. The effect of fluconazole prophylaxis can be attributed to the reduction in vaginal C. albicans colonization; however, C. glabrata colonization rapidly supervened.     

Effect of prolonged discontinuation of successful antiretroviral therapy on CD4+ T cell decline in human immunodeficiency virus-infected patients: implications for intermittent therapeutic strategies

This study evaluates the change in CD4(+) T cell counts among patients who achieved complete viral suppression and subsequently discontinued highly active antiretroviral therapy (HAART). We included 72 human immunodeficiency virus (HIV)-1-infected patients with plasma HIV RNA loads of <500 copies/mL for at least 3 months who then discontinued therapy for at least 12 weeks. The median CD4(+) T decay while off HAART was 16 cells/mm(3)/month (interquartile range, -6 to -34 cells/month). The mean follow-up after therapy ended was 45 weeks. The slope of the CD4(+) T cell decay was inversely correlated with the increase of CD4(+) T cells while receiving HAART, baseline virus load, CD4(+) T cell count at the time therapy was discontinued, age, and duration HIV RNA levels were undetectable. In a multiple regression analysis model, the increase of CD4(+) T cells while receiving therapy and age were independently associated with the rate of CD4(+) T cell loss.     

Effect of adjunct hydroxyurea on helper T cell immunity in HIV type 1-infected patients with virological suppression

Hydroxyurea (HU) has preferential activity in virus reservoirs not effectively targeted by current antiretroviral drug regimens, but concern for potential toxicity has precluded its routine use. The effect of adjunct HU on T cell proliferative responses and phenotypic markers was examined in a randomized study of 39 chronically HIV-1-infected patients with virological suppression on potent antiretroviral therapy. While patients in the HU arm showed modest declines in the median CD4(+) T cell counts (total, -151 cells/mm(3); naive, -91 cells/mm(3)), no significant differences were noted in the Candida, HIV-1 p24, and HIV-1 gp160 responses between the treatment arms following 24 weeks of therapy. In conclusion, although adjunct HU was associated with modest declines in the CD4(+) T cell counts, there was no significant adverse effect on helper T cell function. Further trials to address the role of HU in HIV-1 treatment may be appropriate after careful selection of HU dose and the adjunct drugs to avoid nonhematological toxicity.     

Severe Candida albicans panophthalmitis treated with all available and potentially effective antifungal drugs: fluconazole, liposomal amphotericin B, caspofungin, and voriconazole

A severe case of Candida albicans panophthalmitis, probably prompted by an underlying diabetes mellitus, is reported. The course was prolonged (more than 16 weeks), although favourable after treatment with several antifungal agents, all with a predictable activity in this ocular complication and with proven susceptibility in the present case: fluconazole, liposomal amphotericin B, caspofungin, and voriconazole.     

Surveillance of triazole susceptibility of colonizing yeasts in patients with haematological malignancies

The species distribution and antifungal susceptibility of yeasts isolated from colonization cultures, and the contribution of previous fluconazole prophylaxis to the emergence of resistance, was prospectively studied in 87 neutropenic patients treated for haematological malignancies. Minimal inhibition concentrations (MICs) to fluconazole, itraconazole and voriconazole for 123 yeast isolates (65 Candida albicans, 22 Candida glabrata, 15 Saccharomyces cerevisiae, 5 Candida krusei, 5 Candida norvegensis, 11 other Candida spp.) were determined by E-test. Fluconazole MICs for Candida species and S. cerevisiae isolated from patients given prophylaxis were > or =2 mg/l in 24 of 40 (60%) isolates compared with 26 of 83 (31%) isolates from patients in the non-prophylaxis group (p =0.002). Among the non-albicans yeast species reduced susceptibility was common against itraconazole but was rarely found against voriconazole. Cross resistance between fluconazole and itraconazole was observed in 14 of all isolates, 4 of them also showing reduced susceptibility to voriconazole (MICs 4-8 mg/l). Fluconazole prophylaxis may contribute to emergence of less susceptible yeast strains also in patients with haematological malignancies not treated with allogeneic bone marrow transplantation.     

Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response

The effects of 1 year of zidovudine, lamivudine, and ritonavir treatment on immune reconstitution were evaluated in 34 human immunodeficiency virus (HIV)-infected individuals. After 48 weeks of therapy, 20 (59%) subjects had <100 copies HIV RNA/mL. CD4+ T cells increased from a median of 192/mm3 at baseline to 362/mm3 at week 48. Lymphocyte proliferative responses to Candida normalized within 12 weeks, but responses to HIV and tetanus remained depressed throughout therapy. Alloantigen responses increased within 12 weeks and then declined to baseline levels. Recovery of delayed-type hypersensitivity responses occurred after 12 weeks for Candida and after 48 weeks for mumps. The magnitude of virologic suppression was correlated with numeric increases in CD4+ T cells, but not with measures of functional immune reconstitution. Plasma virus suppression <100 copies/mL was not significantly correlated with increases in CD4+ T cells or functional immune reconstitution.     

Late cytomegalovirus infection after oral ganciclovir prophylaxis in renal transplant recipients

The purpose of this study was to retrospectively review our experience with a consecutive group of 41 renal transplant recipients (R) who received a kidney from a cytomegalovirus (CMV) seropositive donor (D(+)) and had 3 months of prophylaxis with oral ganciclovir. Patients were prospectively monitored clinically and with determinations of CMV antigenemia for at least 6 months. Patients were followed for a mean period of 247+/-16 days. CMV antigenemia developed in 51% of patients (53% D(+)R(-), 47% D(+)R(+)) after the transplant, but in no case was antigenemia seen during the period of oral ganciclovir therapy. Antigenemia developed at a median of 167 days post transplant (range 99-522 days) and peak antigen counts ranged from <1-3940, and tended to be higher in D(+)R(-) recipients. Infection was symptomatic in 67% of the antigenemic patients and symptoms tended to be more marked in the D(+)/R(-) than in the D(+)/R(+) group. All symptomatic patients were treated with intravenous ganciclovir (21 days) followed by 9 weeks of oral ganciclovir and responded with resolution of symptoms and antigenemia. No evidence of tissue-invasive disease was seen. Recurrence of antigenemia was observed exclusively in the D(+)R(-) group, occurred with less severe manifestations of CMV infection, and invariably responded to retreatment with ganciclovir. Our results suggest that oral ganciclovir prophylaxis is effective in preventing CMV infection during the 3-month period of prophylaxis, that a 3-month period of prophylaxis appears to be sufficient for D(+)R(+) recipients, but a longer period of oral ganciclovir prophylaxis may be needed in D(+)R(-) recipients. Clinicians caring for renal transplant recipients should be vigilant to the possibility of late CMV infection, especially in D(+)R(-) recipients.     

Candidemia before and during the fluconazole era: prevalence, type of species and approach to treatment in a tertiary care community hospital

The characteristics of candidemia before and after the introduction of fluconazole were compared at our institution. In the pre-fluconazole era (1986-89), the incidence of candidemia rose from 0.02% to 13% over the course of 4 y. Candida albicans accounted for 44/66 isolates (67%) and C. glabrata and C. parapsilosis were the predominant non-albicans species (9% each). In one-third of cases antifungal therapy was not given and the overall mortality rate was 55%. During the fluconazole era (1994-97), the incidence of candidemia remained constant between 1994 and 1996 at 0.09-0.11% and dropped to 0.06% in 1997. Bloodstream infection associated with neutropenia increased significantly but only accounted for 13% of cases; antifungal prophylaxis was not employed. The isolation of C. albicans decreased (n = 49; 50%) whereas isolation of both C. parapsilosis (n = 23; 24%) and C. tropicalis (n = 16; 16%) increased. The vast majority of patients received antifungal therapy and the overall mortality rate was 39%. These findings show that the incidence of candidemia rose steadily prior to the fluconazole era and then stabilized in spite of a shift towards non-albicans species. When candidemia was encountered in the fluconazole era, it was rare not to give antifungal treatment.     

Candidaemia in allogeneic stem cell transplant recipients: low risk without fluconazole prophylaxis

Invasive fungal infections (IFI) are common in allogeneic SCT recipients. We have reviewed our experience of IFI with special reference to candidaemia in 685 adult patients transplanted in 1983-2002. The donor was a matched sibling in 505 patients and an unrelated donor in 180 patients. A BM graft was used in 561 patients and a PB graft in 124 patients. Fluconazole prophylaxis was not used during the study period. Definite or probable IFI was observed in 60 patients (8.7%) with a dominance of Aspergillus infections (46 patients, incidence 6.7%). Candidaemia was found only in nine patients (1.3%). The causative agents were Candida albicans (n=8), C. krusei (n=2), and C. glabrata (n=1); in two patients, two causative agents were found. The median time to the diagnosis of candidaemia was 53 days (range 6-249 days) post transplant. Seven patients were neutropaenic at diagnosis, and four patients had experienced acute GVHD. All patients received antifungal therapy, but only one patient was cured. According to this study, candidaemia was a rare event in allogeneic SCT recipients. Thus, systematic prophylaxis against Candida infections might not be indicated. The prognosis of established infections is still poor due to comorbid conditions, notably GVHD.     

Successful discontinuation of fluconazole as secondary prophylaxis for cryptococcosis in AIDS patients responding to highly active antiretroviral therapy

Seven AIDS patients with disseminated cryptococcosis who had had immune reconstitution following highly active antiretroviral therapy (HAART) had discontinued their secondary antifungal prophylaxis to prevent relapse of Cryptococcus neoformans infection. The median CD4+ count was 236 cells/ micro L (range, 117-404 cells/ micro L; mean, 247 cells/ micro L) and the plasma viral loads were undetectable in five patients at discontinuation of antifungal prophylaxis. No relapse of cryptococcosis was detected in these patients after a median observation duration of nine months (range, 5.5-4.1 months, mean, 14.6 months) following discontinuation. Our data and review of the literature suggest that discontinuation of fluconazole prophylaxis is safe in patients with reconstitution of immunity following#10; initiation of HAART.     

Candidemia in cancer patients: a prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organization for Research and Treatment of Cancer (EORTC).

In a surveillance study of candidemia in cancer patients that was conducted by the European Organization for Research and Treatment of Cancer, 249 episodes were noted; Candida albicans was isolated in 70% (63) of the 90 cases involving patients with solid tumors (tumor patients) and in 36% (58) of the 159 involving those with hematologic disease (hematology patients). Neutropenia in tumor patients and acute leukemia and antifungal prophylaxis in hematology patients were significantly associated with non-albicans candidemia in a multivariate analysis. Overall 30-day mortality was 39% (97 of 249). In a univariate analysis, Candida glabrata was associated with the highest mortality rate (odds ratio, 2.66). Two multivariate analyses showed that mortality was associated with older age and severity of the underlying disease. Among hematology patients, additional factors associated with mortality were allogeneic bone marrow transplantation, septic shock, and lack of antifungal prophylaxis.