The association between anatomic site of Candida colonization, invasive candidiasis, and mortality in critically ill surgical patients

We evaluated whether the likelihood of developing invasive candidiasis (IC) differed depending upon the anatomic site of Candida colonization in 182 surgical intensive care unit (SICU) patients who participated in a randomized trial of fluconazole to prevent candidiasis. We also determined the impact of Candida colonization of different anatomic sites on all-cause SICU and hospital mortality. A total of 2851 surveillance fungal cultures collected from 5 anatomic sites were analyzed. There was a statistically significant difference in the frequency of IC comparing patients with and without urinary (13.2% versus 2.8%, P = .02), respiratory (8.0% versus 1.2%, P = .04), and rectum/ostomy (8.4% versus 0%, P = .01) colonization. Patients with negative rectum/ostomy cultures and patients with both negative urine and respiratory tract cultures did not develop IC. Candiduria detected at any time in the SICU was independently associated with SICU mortality (odds ratio, 2.86; 95% confidence interval, 1.05-7.74). Surveillance fungal cultures of particular anatomic sites may help differentiate patients at higher risk of developing IC from those at low risk.     

A bedside scoring system ("Candida score") for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization

OBJECTIVE: To obtain a score for deciding early antifungal treatment when candidal infection is suspected in nonneutropenic critically ill patients. DESIGN: Analysis of data collected from the database of the EPCAN project, an ongoing prospective, cohort, observational, multicenter surveillance study of fungal infection and colonization in intensive care unit (ICU) patients. SETTING: Seventy-three medical-surgical ICUs of 70 teaching hospitals in Spain. PATIENTS: A total of 1,699 ICU patients aged 18 yrs and older admitted for at least 7 days between May 1998 and January 1999 were studied. INTERVENTIONS: Surveillance cultures of urine, tracheal, and gastric samples were obtained weekly. Patients were grouped as follows: neither colonized nor infected (n=719), unifocal or multifocal Candida colonization (n=883), and proven candidal infection (n=97). The odds ratio (OR) for each risk factor associated with colonization vs. proven candidal infection was estimated. A logistic regression model was performed to adjust for possible confounders. The "Candida score" was obtained according to the logit method. The discriminatory power was evaluated by the area under the receiver operating characteristics curve. MEASUREMENTS AND MAIN RESULTS: In the logit model, surgery (OR=2.71, 95% confidence interval [CI], 1.45-5.06); multifocal colonization (OR=3.04, 95% CI, 1.45-6.39); total parenteral nutrition (OR=2.48, 95% CI, 1.16-5.31); and severe sepsis (OR=7.68, 95% CI, 4.14-14.22) were predictors of proven candidal infection. The "Candida score" for a cut-off value of 2.5 (sensitivity 81%, specificity 74%) was as follows: parenteral nutrition, +0.908; surgery, +0.997; multifocal colonization, +1.112; and severe sepsis, +2.038. Central venous catheters were not a significant risk factor for proven candidal infection (p=.292). CONCLUSIONS: In a large cohort of nonneutropenic critically ill patients in whom Candida colonization was prospectively assessed, a "Candida score">2.5 accurately selected patients who would benefit from early antifungal treatment.     

Impact of antifungal treatment on <Emphasis Type="Italic">Candida</Emphasis>–<Emphasis Type="Italic">Pseudomonas</Emphasis> interaction: a preliminary retrospective case–control study

OBJECTIVE: A pathogenic interaction between Candida albicans and Pseudomonas aeruginosa has recently been demonstrated. In addition, experimental and clinical studies identified Candida spp. tracheobronchial colonization as a risk factor for P. aeruginosa pneumonia. The aim of this study was to determine the impact of antifungal treatment on ventilator-associated pneumonia (VAP) or tracheobronchial colonization due to P. aeruginosa. DESIGN AND SETTING: Retrospective observational case-control study conducted in a 30-bed ICU during a 1-year period. PATIENTS AND METHODS: One hundred and two patients intubated and ventilated for longer than 48 h with tracheobronchial colonization by Candida spp. Routine screening for Candida spp. and P. aeruginosa was performed at ICU admission and weekly. Antifungal treatment was based on medical staff decisions. Patients with P. aeruginosa VAP or tracheobronchial colonization were matched (1:2) with patients without P. aeruginosa VAP or tracheobronchial colonization. In case and control patients, risk factors for P. aeruginosa VAP or tracheobronchial colonization were determined using univariate and multivariate analyses. RESULTS: Thirty-six patients (35%) received antifungal treatment. Nineteen patients (18%) developed a P. aeruginosa VAP or tracheobronchial colonization, and all were successfully matched. Antifungal treatment [31% vs 60%; p=0.037, OR (95% CI)=0.67 (0.45-0.90)], and duration of antifungal treatment (7+/-11 vs 14+/-14 days; p=0.045, in case and control patients respectively) were significantly associated with reduced risk for P. aeruginosa VAP or tracheobronchial colonization. Antifungal treatment was the only variable independently associated with P. aeruginosa VAP or tracheobronchial colonization (OR=0.68, 95% CI=0.49-0.90, p=0.046). CONCLUSION: In patients with Candida spp. tracheobronchial colonization, antifungal treatment may be associated with reduced risk for P. aeruginosa VAP or tracheobronchial colonization.     

Prospective Study of Candida Species in Patients at a Comprehensive Cancer Center

Since most nosocomial systemic yeast infections arise from the endogenous flora of the patient, we prospectively evaluated the species stratification and antifungal susceptibility profile of Candida spp. associated with heavy colonization and systemic infection in patients at Memorial Sloan-Kettering Cancer Center in New York. A total of 349 Candida isolates were obtained from 223 patients during the later half of 1998. Cancer was the most common underlying disease, occurring in 91% of the patients, including 61.8% with organ and 23.7% with hematological malignancies; 4.4% of the patients had AIDS. Candida albicans was the predominant species (67.3%); among 114 non-albicans Candida spp., C. glabrata (45.6%) was the most frequent, followed by C. tropicalis (18.4%), C. parapsilosis (16.6%), and C. krusei (9.6%). The overall resistance to triazole-based agents among all yeast isolates was 9.4 and 10.8% for fluconazole and itraconazole, respectively. A total of 5% of C. albicans strains were resistant to triazole antifungals, whereas 30.8 and 46.2% of C. glabrata strains were resistant to fluconazole (MIC > or = 64 microg/ml) and itraconazole (MIC > or = 1 microg/ml), respectively. A significant association was observed between prior treatment with triazole and isolation of fluconazole-resistant C. albicans (P = 0.005, OR 36), although this relationship was not seen in C. glabrata isolates (P = 0.4). This study reinforces the importance of periodic, prospective surveillance of clinical fungal isolates to determine appropriate prophylactic, empiric, and preemptive antifungal therapy for the highly susceptible patient population.     

Point prevalence,microbiology and fluconazole susceptibility patterns of yeast isolates colonizing the oral cavities of HIV-infected patients in the era of highly active antiretroviral therapy

We conducted a prospective study to address the prevalence and microbiological characteristics of yeast isolates colonizing the oral cavities of HIV-infected patients undergoing highly active antiretroviral therapy. Sixty-eight patients (67%) from a total of 102 were found to be colonized with yeasts. Sixty-five patients carried a single species (60 Candida albicans, three Candida glabrata and two Candida krusei) and three patients had mixed colonization of C. albicans and C. krusei. The status of yeast carrier was not associated with the number of CD4 cells or the viral load. Similarly, the type of antiretroviral regimen was not associated with the carriage of Candida spp. The only predictor of Candida colonization was a previous history of oropharyngeal candidiasis (P = 0.009). Although many patients in this series had already been treated with repeated courses of fluconazole therapy for previous episodes of oropharyngeal candidiasis, fluconazole susceptibility patterns showed that 93% of yeasts were susceptible to this triazole in vitro (MIC < or = 8.0 mg/L).     

Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?

Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.     

Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: systematic review and meta-analysis of randomized clinical trials

OBJECTIVES: This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections. METHODS: Systematic review and meta-analysis of randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal or another antifungal agent or regimen in non-neutropenic critically ill adult patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005) and EMBASE (1980 to week 36, 2005). We also hand-searched reference lists, abstracts of conference proceedings and scientific meetings (1998-2004) and contacted authors of included studies and pharmaceutical manufacturers. The primary outcomes assessed were all-cause mortality and proven invasive fungal infections. Two reviewers independently applied selection criteria, performed quality assessment and extracted data using an intention-to-treat approach. Data were synthesized using the random effects model and expressed as relative risk with 95% confidence intervals. RESULTS: Twelve unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a non-absorbable agent) involving 1606 randomized patients were included. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by one-quarter (relative risk 0.76, 95% confidence interval 0.59-0.97) and invasive fungal infections by about one-half (relative risk 0.46, 95% confidence interval 0.31-0.68). No significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or Candida krusei was demonstrated, although the confidence intervals of the summary effect measures were wide. Adverse effects requiring treatment discontinuation were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics. CONCLUSIONS: Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one-half and total mortality by one-quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.     

Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.

OBJECTIVE: To evaluate the efficacy and safety of intravenous fluconazole for the prevention of intra-abdominal Candida infections in high-risk surgical patients. DESIGN: Randomized, prospective, double-blind, placebo-controlled study. SETTING: Two university-affiliated hospitals in Switzerland. PATIENTS: Forty-nine surgical patients with recurrent gastrointestinal perforations or anastomotic leakages. INTERVENTIONS: Prophylaxis with intravenous fluconazole (400 mg per day) or placebo continued until resolution of the underlying surgical condition. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated daily, and specimens for culture were obtained three times per week during prophylaxis. The primary study end points were the frequency of and the time to intra-abdominal Candida infections. Secondary end points were the frequency of candidiasis (intra-abdominal and extra-abdominal) and the emergence or persistence of Candida colonization. Among patients who were not colonized at study entry, Candida was isolated from surveillance cultures during prophylaxis in 15% of the patients in the fluconazole group and in 62% of the patients in the placebo group (relative risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis occurred in one of 23 patients (4%) who received fluconazole and in seven of 20 patients (35%) who received placebo (relative risk, 0.12; 95% confidence interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida albicans sepsis occurred in a fluconazole-treated patient. Thus, overall, candidiasis developed in two fluconazole patients and seven placebo patients (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C. albicans accounted for 87% of the Candida species isolated before or during prophylaxis, and all C. albicans strains were susceptible to fluconazole. Fluconazole was well tolerated, and adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS: Fluconazole prophylaxis prevents colonization and invasive intra-abdominal Candida infections in high-risk surgical patients.     

Urine D-arabinitol/L-arabinitol ratio in diagnosing Candida infection in patients with haematological malignancy and HIV infection

Adult patients with hematologic malignancies along with HIV infected patients were prospectively studied to determine the performance of urine D-arabinitol/L-arabinitol (DA/LA) ratio in diagnosing invasive candidiasis. Ten evaluable febrile neutropenic patients had proven invasive candidiasis and elevated DA/LA ratios were found in 5. Invasive candidiasis with normal DA/LA ratios was most frequently due to Candida krusei infection. This Candida species is a non-producer of arabinitol. Only 4 of 81 febrile neutropenic patients given either antifungal prophylaxis or empiric antifungal treatment had elevated DA/LA ratios. Only 1 of 15 HIV positive patients with either oropharyngeal or esophageal candidiasis had elevated DA/LA ratios. Widespread use of fluconazole prophylaxis in bone marrow transplantation patients at the study hospital has led to an increased prevalence of C. krusei infection. This is the likely reason for the low sensitivity of the test in proven and suspected invasive Candida infections reported here.     

Management of candidiasis in the intensive care unit

In the last two decades, Candida has emerged as an important opportunistic pathogen. Patients admitted to the intensive care unit (ICU) are particularly susceptible to this infection because of the severity of their underlying illness and the excess use of medical and surgical interventions. The frequent use of antibiotics, central venous catheters and other intravascular devices as well as poor gut motility or abdominal surgery place these patients at high risk of infection, which contributes to the morbidity and mortality of the already critically ill patient. Early recognition and appropriate management of invasive candidiasis are therefore important. This article addresses important management issues such as the role of screening for Candida colonization, the use of prophylaxis and the choice of antifungal agents for the treatment of presumed and proven invasive candidiasis in the adult ICU setting.     

Clinical efficacy and safety of intravenous itraconazole in the management of invasive candidiasis in patients of surgery and critical care

Although itraconazole exhibits potent activity against Candida species, there have been few studies examining the use of intravenous itraconazole in the treatment of invasive candidiasis. A nationwide multicenter clinical study was conducted to evaluate the efficacy and safety of intravenous itraconazole in the management of invasive candidiasis, including non-albicans Candida species, in non-neutropenic patients undergoing surgery and critical care. Between September 2007 and August 2009, patients with proven and presumed candidiasis were enrolled at 22 participating institutions. Patients with presumed candidiasis had a deep-body temperature of 37.8°C or higher and were positive for serum β-D: -glucan or two or more colonization sites of Candida species. The main exclusion criterion was severe renal impairment (creatinine clearance <30 ml/min). The primary efficacy analysis was based on clinical and microbiological responses 5-10 days after the end of treatment, assessed by an independent data review committee. Of the 60 patients enrolled, 49 were included in the modified intention-to-treat population; 31 patients received a definitive diagnosis and 18 patients a presumed diagnosis. Intravenous itraconazole was used as first-line therapy to treat 39 patients and as second-line therapy for 10 patients. The isolated species included Candida albicans (25 strains with definitive diagnosis and 17 with presumed diagnosis) and non-albicans species (16 and 10, respectively). Treatment was successful in 61.5% patients (65.5% in first-line and 50.0% in second-line therapy); 60% of proven invasive candidiasis (IC) patients were judged as successful compared with 63.2% of presumed candidiasis patients. Eradication rate was 63.6% for C. albicans and 71.4% for C. glabrata. Adverse effects occurred in 9 of 60 patients (15.0%), commonly impaired liver function. The clinical efficacy and safety of intravenous itraconazole were suggested in the management of proven and presumed candidiasis including C. glabrata in non-neutropenic patients. The status of intravenous itraconazole in the Japanese guideline warrants reconsideration.     

Quantitation of antibody to Candida mannan by enzyme-linked immunosorbent assay

Early clinical diagnosis of invasive candidiasis is difficult. To facilitate rapid diagnosis of Candida infections, we developed an ELISA to quantitate levels of antibody to Candida mannan. The test was standardized by analysis of a nonselected inpatient population to determine a cutoff point defining the upper 5% of such a population as test-positive. Passively acquired sera from patients in intensive care units, patients with neoplastic disease or recent renal allografts, and other patients were analyzed. There was no significant difference between the number of positive tests obtained from patients in whom candidiasis was considered but cultures were negative and from the nonselected inpatient population. Positive tests were obtained from 18.5% of patients with Candida mucocutaneous colonization or infection and 40% and 63.6% of patients with probable and proven invasive candidiasis, respectively. Patients with neoplastic disease had lower test sensitivity than patients in other test categories. These results demonstrate the usefulness of a simple, rapid, standardized test for quantitation of levels of antibody activity to Candida mannan in the serodiagnosis of candidiasis.     

Candidoses en réanimation

Invasive candidiasis is a dread complication in hospitalized patients, characterized by mortality rates comparable to that of septic shock (40 to 60%). Its incidence in hospitalized patients is 0.5/1000 admissions, but about 10 per 1000 admissions in critical care where it represents 5 % to 10 % of all nosocomial bloodstream infections. Although a high proportion of hospitalized patients may become colonized with Candida spp, only a minority subsequently develop an infection. Clinical signs of such infection manifest only late rending them particularly difficult to diagnose. Early empiric antifungal treatment may improve the prognosis. However, for economical and epidemiological reasons, such a treatment can not be applied to all patients at risk. For these patients, empiric antifungal treatment could be started only when the colonization index reaches a threshold value that predicts subsequent infection. A better knowledge of the pathophysiology of Candida infections and the availability of triazoles compounds that are less toxic than amphotericin B, allowed the concept of prophylactic and preemptive therapy. However, antifungal prophylaxis is suspected as a major promoter of the emergence of potentially resistant non-albicans Candida, mostly in cancer centers. For critically ill patients, a strict restriction of prophylaxis to selected groups of patients for whom its efficacy is proven may contribute to limit this epidemiology.     

Candida peritonitis

PURPOSE OF REVIEW: The review highlights current insights in the epidemiology, diagnosis and therapy of Candida peritonitis, focusing on complicated secondary and tertiary peritonitis. RECENT FINDINGS: Candida peritonitis is still associated with poor prognosis. Antifungal prophylaxis is therefore recommended in patients with an overt risk profile for invasive candidiasis (immunodeficiency and prior antibiotic exposure). The clinical and microbiological diagnosis of Candida peritonitis remains problematic. It is still unclear which peritonitis patients may benefit from antifungal treatment. Antifungal therapy can be suggested in critically ill patients with nosocomial peritonitis where Candida is diagnosed based on perioperatively sampled peritoneal fluid. Patients with prior exposure to fluconazole are at risk for Candida nonalbicans spp. involvement with possible reduced susceptibility. SUMMARY: The main challenge in Candida peritonitis remains the interpretation of Candida cultured from the peritoneal cavity. Future research should focus on more conclusive diagnosis and on factors potentially confounding outcome, such as site of the perforation and failure of surgical source control. While awaiting progress to discriminate Candida colonization from invasive infection, antifungal therapy is recommended in high-risk critically ill surgical patients. Rapid detection of Candida might be beneficial in this regard. Besides antifungal therapy, adequate source control is of key importance.     

Decreased susceptibility of Candida albicans to azole antifungals: a complication of long-term treatment in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS1) is an autosomal recessive disease exceptionally common in Finland. Most patients have chronic oral candidiasis from early childhood and this infection has been shown to be carcinogenic. Hence, patients receive repeated treatment and prophylactic courses of antifungals throughout life. In Finland, 92 patients have been diagnosed with APECED and 66 of them are currently alive. Our aim was to study the effect of long-term azole treatment on the candidal colonization of APECED patients and the influence on antifungal susceptibilities. METHODS: We evaluated the culture reports from 1994 to 2004 of 56 APECED patients followed in Helsinki University Central Hospital. Candida albicans strains of all 11 patients initially reported resistant (n = 27) and 12 patients reported susceptible (n = 16) to fluconazole were re-analysed for their susceptibility to fluconazole. Antifungal usage was analysed up to 30 years back. RESULTS: A total of 162 fungal cultures had been performed. Of these, 75% had been reported positive for Candida and 63% for C. albicans. Eleven patients (31.4%) had been reported to harbour at least once a C. albicans strain resistant to fluconazole. Re-analysis of the stored C. albicans strains originally reported to be resistant to fluconazole revealed a mean MIC of 19.5 mg/L. CONCLUSIONS: Multiple courses (>6) of fluconazole annually and low dose prophylaxis are major risk factors for persistent colonization with C. albicans with decreased susceptibility in APECED patients.     

Efficacy of FK463, a (1,3)-beta-D-glucan synthase inhibitor, in disseminated azole-resistant candida albicans infection in mice

The efficacy of FK463, a new (1,3)-beta-D-glucan synthase inhibitor, against azole-resistant Candida albicans strains has been studied. The MIC of FK463 was lower than those of azoles and amphotericin B against CDR1-expressing C26 and CaMDR-expressing C40 strains. All mice treated with FK463 (1 mg/kg) survived disseminated murine candidiasis. The fungal burden in the kidney after 6 days was markedly reduced after therapy with FK463 and amphotericin B sodium deoxycholate, and plasma (1,3)-beta-D-glucan concentration was found to be lower in FK463-treated mice. In our study, FK463 was found to be a potent antifungal agent against disseminated infection with azole-resistant C. albicans.     

Use of antifungal agents in febrile patients nonresponsive to antibacterial treatment: the current status in surgical and critical care patients in Japan

Disseminated candidiasis is difficult to diagnose and treat, and often becomes life-threatening in critically ill patients. However, guidelines or consensus views regarding the management of disseminated candidiasis do not exist in Japan. To develop feasible guidelines in Japan, we studied the current status of antifungal treatment in critically ill patients in Japan. From April 1999 to January 2000, critically ill patients from either surgical wards or critical care/intensive care units of 26 teaching hospitals were studied, using a prospective enrollment protocol. Patient enrollment criteria included persistent fever(≧38°C) for 3 days or more despite antibacterial agent administration. Data were entered at each institution and managed centrally using Clinware software. Of the 200 patients in the study, 68 (34%) received antifungal agents. Factors associated with antifungal treatment in the 68 patients included: central venous or pulmonary artery catheter, re-surgery, carbapenem or cephem administration, prolonged antibacterial agent administration, and high body temperature. Proven or probable disseminated candidiasis was presumed or diagnosed by culture in 34 patients, and by clinical signs and/or serological tests in 34 patients. Fungi isolated from blood included Candida albicans (57%), C. tropicalis (14%), C. parapsilosis (7%), C. glabrata (7%), and others (14%). Treatment patterns were as follows: 65 patients (96%) were treated with fluconazole (60 as monotherapy and 5 with amphotericin B); 2 patients, with miconazole; and 1 patient, with amphotericin B. Excluding 6 unevaluable cases, antifungal treatment was efficacious in 75% (21/28) of the patients with positive fungal culture and in 68% (23/34) of patients diagnosed by other means. Received: November 1, 2001 / Accepted: April 15, 2002 RID="*"     

Micafungin

OBJECTIVE: To review the pharmacology, mycology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of micafungin, an echinocandin antifungal agent. DATA SOURCES: A MEDLINE search, restricted to English language, was conducted from 1978 to November 2003. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy and the Infectious Diseases Society of America from 1996 to 2003 and information available through the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION: In vitro and preclinical studies, as well as Phase II and III clinical trials, were evaluated to summarize the clinical efficacy and safety of micafungin. All published and unpublished trials and abstracts citing micafungin were selected. DATA SYNTHESIS: Micafungin has shown in vitro activity against many yeasts and a variety of molds. Micafungin can be administered only parenterally. Efficacy has been illustrated in open noncomparative studies of esophageal candidiasis in HIV-infected patients and in comparative trials as antifungal prophylaxis in patients undergoing hematopoietic stem-cell transplantation. Adverse events appear mild and limited; the most commonly reported adverse events include hyperbilirubinemia, nausea, and diarrhea. CONCLUSIONS: Micafungin has activity against Aspergillus spp. and a variety of Candida spp., including azole-resistant strains. Micafungin demonstrates efficacy in the treatment of esophageal candidiasis in HIV-infected patients and appears superior to fluconazole as antifungal prophylaxis in patients undergoing hematopoietic stem-cell transplantation. Based on case reports and in vitro efficacy, micafungin may prove to be a clinically useful agent in the treatment of other fungal diseases; however, these indications await the results of clinical trials.     

Undiagnosed invasive candidiasis: incorporating non-culture diagnostics into rational prophylactic and preemptive antifungal strategies

The insensitivity of blood cultures for diagnosing invasive candidiasis fuels prophylactic and preemptive antifungal treatment. Assays like serum β-D-glucan or mannan/anti-mannan detection can identify blood culture-negative invasive candidiasis, but their roles in guiding antifungal therapy are undefined. We propose that non-culture tests can be incorporated into rational management strategies, based on clinical setting. As an example, β-D-glucan sensitivity/specificity for blood culture-negative, deep-seated candidiasis is approximately 60/75%. In intensive care units with <1 or 3% invasive candidiasis rates, positive/negative predictive values are <2/>99% and 6/98%, respectively. With pre-test likelihoods of 10 and 33%, positive/negative predictive values are 20/94% and 54/79%, respectively. Based on these data, negative and positive β-D-glucan results likely will be most useful for discontinuing prophylaxis among low-risk to moderate-risk patients (pre-test likelihoods ～3–10%), and triggering preemptive therapy among moderate-risk to high-risk patients (pre-test likelihoods ～10–25%), respectively. In extremely high-risk patients, universal prophylaxis is likely to be the best strategy.     

Caspofungin for the treatment of less common forms of invasive candidiasis

OBJECTIVES: Caspofungin has demonstrated efficacy in invasive candidiasis. However, in a comparative study, most patients (>83%) had candidaemia. Therefore, we performed a study in patients with non-fungaemic invasive candidiasis. PATIENTS AND METHODS: Adults with proven non-fungaemic invasive candidiasis or probable chronic disseminated candidiasis (CDC) received caspofungin primary or salvage monotherapy. Most patients received 50 mg daily following a 70 mg loading dose. Patients with endocarditis, osteomyelitis or septic arthritis received caspofungin at 100 mg daily and were allowed dose escalation up to 150 mg. Primary efficacy endpoint was the overall response at end of caspofungin therapy. A favourable overall response required complete resolution of symptoms and either eradication of Candida or radiographic resolution. RESULTS: All 48 patients enrolled had confirmed infection and received>or=1 dose of caspofungin. At study entry, 8% were neutropenic. The mean APACHE II score was 14.3. Most infections were due to Candida albicans (60%) or Candida glabrata (14%). The overall success at end of caspofungin therapy was 81%. Success by site of infection was as follows: peritonitis 77% (10/13), abdominal abscess 89% (8/9), CDC 88% (7/8), osteomyelitis/septic arthritis 100% (4/4), endocarditis 33% (1/3) and multiple sites 75% (6/8). Outcomes were similar across Candida spp. None of the patients had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Overall mortality until 12 week follow-up was 23%. CONCLUSIONS: In deep-seated invasive candidiasis, including peritonitis, abdominal abscesses, CDC and arthritis, caspofungin was effective and safe at regular doses and up to 100 mg daily.