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.     

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 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.     

Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients

OBJECTIVE: To assess the efficacy of a preemptive antifungal therapy in preventing proven candidiasis in critically ill surgical patients. DESIGN: Before/after intervention study, with 2-yr prospective and 2-yr historical control cohorts. SETTING: Surgical intensive care unit (SICU) in a university-affiliated hospital. PATIENTS: Nine hundred and thirty-three patients, 478 in the prospective group and 455 in the control group, with SICU stay > or =5 days. INTERVENTIONS: During the prospective period, systematic mycological screening was performed on all patients admitted to the SICU, immediately at admittance and then weekly until discharge. A corrected colonization index was used to assess intensity of Candida mucosal colonization. Patients with corrected colonization index > or =0.4 received early preemptive antifungal therapy (fluconazole intravenously: loading dose 800 mg, then 400 mg/day for 2 wks). MEASUREMENTS AND MAIN RESULTS: End points of this study were the frequency of proven candidiasis, especially SICU-acquired candidiasis. During the retrospective period, 32 patients of 455 (7%) presented with proven candidiasis: 22 (4.8%) were imported and 10 (2.2%) were SICU-acquired cases. During the prospective period, 96 patients with corrected colonization index > or =0.4 of 478 received preemptive antifungal treatment and only 18 cases (3.8%) of proven candidiasis were diagnosed; all were imported infections. Candida infections occurred more frequently in the control cohort (7% vs. 3.8%; p = .03). Incidence of SICU-acquired proven candidiasis significantly decreased from 2.2% to 0% (p < .001, Fisher test). Incidence of proven imported candidiasis remained unchanged (4.8% vs. 3.8%; p = .42). No emergence of azole-resistant Candida species (especially Candida glabrata, Candida krusei) was noted during the prospective period. CONCLUSIONS: Targeted preemptive strategy may efficiently prevent acquisition of proven candidiasis in SICU patients. Further studies are being performed to assess cost-effectiveness of this strategy and its impact on selection of azole-resistant Candida strains on a long-term basis.     

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.     

Preclinical assessment of the efficacy of mycograb,a human recombinant antibody against fungal HSP90

Mycograb (NeuTec Pharma plc) is a human genetically recombinant antibody against fungal heat shock protein 90 (HSP90). Antibody to HSP90 is closely associated with recovery in patients with invasive candidiasis who are receiving amphotericin B (AMB). Using in vitro assays developed for efficacy assessment of chemotherapeutic antifungal drugs, Mycograb showed activity against a wide range of yeast species (MICs against Candida albicans [fluconazole [FLC]-sensitive and FLC-resistant strains], Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, 128 to 256 microg/ml). Mycograb (4 or 8 microg/ml) showed synergy with AMB, the fractional inhibitory index being 0.09 to 0.31. Synergy was not evident with FLC, except for FLC-sensitive C. albicans. Murine kinetics showed that Mycograb at 2 mg/kg produced a maximum concentration of drug in serum of 4.7 microg/ml, a half-life at alpha phase of 3.75 min, a half-life at beta phase of 2.34 h, and an area under the concentration-time curve from 0 to t h of 155 microg. min/ml. Mycograb (2 mg/kg) alone produced significant improvement in murine candidiasis caused by each species: (i). a reduction (Scheffe's test, P < 0.05) in the mean organ colony count for the FLC-resistant strain of C. albicans (kidney, liver, and spleen), C. krusei (liver and spleen), C. glabrata (liver and spleen), C. tropicalis (kidney), and C. parapsilosis (kidney, liver, and spleen) and (ii). a statistically significant increase in the number of negative biopsy specimens (Fisher's exact test, P < 0.05) for C. glabrata (kidney), C. tropicalis (liver and spleen), and C. parapsilosis (liver). AMB (0.6 mg/kg) alone cleared the C. tropicalis infection but failed to clear infections caused by C. albicans, C. krusei, C. glabrata, or C. parapsilosis. Synergy with AMB, defined as an increase (Fisher's exact test, P < 0.05) in the number of negative biopsy specimens compared with those obtained using AMB alone, occurred with the FLC-resistant strain of C. albicans (kidney), C. krusei (spleen), C. glabrata (spleen), and C. parapsilosis (liver and spleen). Only by combining Mycograb with AMB was complete resolution of infection achieved for C. albicans, C. krusei, and C. glabrata.     

Micafungin: the US perspective

Invasive fungal infections cause considerable morbidity and mortality in nosocomial settings and amongst immunocompromised hosts. Invasive candidiasis and aspergillosis remain the most common invasive fungal infections, with Candida spp. constituting the fourth most common bloodstream infection in the USA. Currently available antifungal therapies include the polyene, antimetabolite, allylamine, azole and echinocandin drug classes. Micafungin, approved in March 2005 by the Food and Drug Administration for use in the USA, has shown safety and efficacy for the treatment of candidiasis and aspergillosis in clinical trials in Japan, Europe and South Africa. Micafungin holds promise as a first-line treatment option for candidiasis, as well as prophylaxis against invasive fungal infections during periods of neutropenia in high-risk patients.     

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.     

Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients.

Because the use of fluconazole prophylaxis had been associated with an increased rate of Candida krusei infections at The John Hopkins Oncology Center, early empiric amphotericin B plus flucytosine were given to febrile neutropenic patients colonized by C. krusei. By this practice, the proportion of fungemias attributable to C. krusei was low (12.5%) in patients receiving fluconazole over a 6-month interval. However, Torulopsis (Candida) glabrata assumed a much higher proportion of fungemias (75%) among patients receiving fluconazole. In vitro susceptibility testing combined with this clinical experience suggests that some T. glabrata isolates are not susceptible to fluconazole and can cause breakthrough infections in patients receiving fluconazole.     

The outcome of candiduria in pediatric patients

The presence of Candida in the urine of a seriously ill, pediatric patient presents a management problem because of a lack of information concerning the natural history of candiduria and its relationship to disseminated candidiasis. In this retrospective study, the outcome of candiduria was examined in a group of 54 pediatric patients to determine any predictors of disseminated candidiasis. Medical records were reviewed to identify urine collection methods, Candida colony counts, results of cultures from other body sites, antifungal therapy, and clinical course. Six (11%) of the 54 patients had evidence of systematic Candida infection. In only two of these patients was candiduria the first evidence of disseminated candidiasis. Invasive infection was associated with candiduria more frequently in neonates and patients with central venous catheters and/or immunosuppressive therapy. Urine colony counts were not helpful for assessing the risk of invasive disease. Candiduria appears to be of little consequence in patients who are generally healthy. However, candiduria in high-risk patients, even in the presence of perineal candidal infection or an indwelling urinary catheter, should prompt a careful evaluation for disseminated infection.     

Antifungal susceptibility of South African oral yeast isolates from HIV/AIDS patients and healthy individuals

The in vitro antifungal susceptibility profile of 589 oral yeast isolates from HIV/AIDS patients and healthy South Africans was determined against amphotericin B, nystatin, 5-fluorocytosine (5-FC), clotrimazole, miconazole, ketoconazole, itraconazole and fluconazole. The broth microdilution method of the National Committee on Clinical Laboratory Standards was used and MIC(50) and MIC(90) determined. A 100% susceptibility to fluconazole was observed among the 466 isolates of Candida albicans. Among C. krusei, the second most common isolate, only 2.6% of isolates were susceptible to fluconazole and itraconazole. Despite the lack of previous exposure to antifungal agents, very little difference was observed in the antifungal profile between the South African isolates and isolates from the United States (U.S.), Canada and South America. South Africa has a particularly high incidence of HIV-infection and oral candidiasis is the most common oral complication in these patients. This study provides important baseline data as the isolates were collected prior to fluconazole being made freely available to HIV/AIDS patients attending government health clinics.     

Candida krusei fungaemia: antifungal susceptibility and clinical presentation of an uncommon entity during 15 years in a single general hospital

BACKGROUND: Candida krusei fungaemia is an uncommon entity described in immunocompromised patients previously exposed to azole agents. METHODS: From 1988 to 2003, 13 episodes of C. krusei fungaemia (2.3% of all fungaemias) were detected in our institution and compared with 39 Candida albicans controls. Susceptibility testing was carried out with the modified microdilution method according to NCCLS recommendations. RESULTS: Underlying conditions were: HIV infection (4), haematological malignancies (4), organ transplantation (2), abdominal surgery (2) and lactose intolerance (1). Nine patients (69%) were not neutropenic. In comparison with C. albicans, patients with C. krusei infection had more commonly received antifungal agents (54% versus 15%, P = 0.006), had a haematological disease (31% versus 3%, P = 0.03), or a transplant (15% versus 3%, P = 0.08), were on corticosteroids (47% versus 13%, P = 0.01) and were neutropenic (31% versus 0%, P < 0.001). Patients with C. albicans had more surgical interventions (41% versus 15%, P = 0.09) and bladder catheters (61% versus 31%, P = 0.05). The most common origin for C. albicans was a catheter (41% versus 0%; P = 0.006) whereas for C. krusei the most common origin was unknown (69% versus 20%; P = 0.001). C. krusei presented more commonly with skin lesions in neutropenic patients (23% versus 5%; P = 0.05). Multivariate analysis of these differential characteristics showed that the only factor that independently predicted the presence of C. krusei fungaemia was the administration of antifungal agents before the fungaemia (RR: 6.4; P=0.009; 95%CI 1.6-25.99). Overall mortality of C. krusei fungaemia was 38% (C. albicans 49%). Except for voriconazole (MIC90 0.125 mg/L), azoles and 5-flucytosine had poor activity against C. krusei, whereas amphotericin (MIC90 1 mg/L) and LY-303366 (MIC90 0.06 mg/L) showed good activity. CONCLUSION: C. krusei fungaemia incidence remains low despite widespread use of azoles. It may occur outside the setting of cancer patients with previous antifungal use. The presence of skin lesions should be a warning sign.     

Micafungin for the prophylaxis and treatment of Candida infections

Invasive fungal infection is a significant cause of morbidity and mortality worldwide. The incidence of these infections is steadily increasing. In addition, strains resistant to many commonly used antifungal agents are becoming more prevalent. Many new antifungals have become commercially available in recent years, which have vastly improved the ability to treat these infections effectively. Micafungin is one of three commercially available echinocandins available for use in the USA. This class of agents possess a unique mechanism of action that helps to reduce toxicity while maintaining potent antifungal activity. Micafungin is currently approved for the treatment of esophageal candidiasis in adults and is the only in its class approved for the prophylaxis of Candida infection in patients who have undergone hematopoietic stem cell transplantation. It was also recently approved in the USA for the treatment of candidemia and other forms of invasive candiaisis (acute disseminated candiaisis, Candida peritonitis and abscess). In general, micafungin is well tolerated and has favorable safety and drug-interaction profiles.     

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.     

Susceptibility of Candida dubliniensis to salivary histatin 3

Candida dubliniensis is a recently described Candida species associated with oral candidiasis in human immunodeficiency virus (HIV)-infected patients and patients with AIDS. The majority of C. dubliniensis clinical isolates tested to date are susceptible to the commonly used antifungal drugs, including fluconazole, ketoconazole, itraconazole, and amphotericin B. However, the appearance of fluconazole-resistant C. dubliniensis strains in this patient group is increasing. Histatins are a family of basic histidine-rich proteins present in human saliva which have therapeutic potential in the treatment of oral candidiasis. The mechanism of action of histatin is distinct from that of commonly used azole and polyene drugs. Characterization of the antifungal activity of histatin has mainly been carried out using C. albicans but it is also effective in killing C. glabrata and C. krusei. Here we report that C. dubliniensis is also susceptible to killing by histatin 3. The concentration of histatin 3 giving 50% killing (the IC(50) value) ranged from 0.043 to 0.196 mg/ml among different strains of C. dubliniensis. The least-susceptible C. dubliniensis strain, P9224, was found to internalize histatin at a lower rate than the C. albicans reference strain CA132A. The dissociation constant (K(d)) for the least-susceptible strain (C. dubliniensis 9224) was ninefold higher than that for the C. albicans reference strain. These results suggest that histatin 3 may have potential as an effective antifungal agent, particularly in the treatment of oral candidiasis in HIV-infected patients and patients with AIDS in which resistance to the commonly used antifungal drug fluconazole has emerged.     

Real-time antifungal susceptibility screening aids management of invasive yeast infections in immunocompromised patients

We examined the utility of a semi-solid agar antifungal susceptibility screening (SAAS) test in real-time management of eight immunocompromised patients with invasive yeast infections. Tests of amphotericin B and fluconazole concentrations of 0.5 and 2 mg/L and 1, 8 and 40 mg/L, respectively, were performed on Candida albicans (two), Candida tropicalis (two), Candida krusei (one), Candida glabrata (one) and Trichosporon species (spp.) (two). All but the Trichosporon spp. and C. glabrata isolates were resistant to fluconazole at > or = 40 mg/L, and patients were successfully managed accordingly. Real-time antifungal susceptibility screening can assist in clinical management of invasive yeast infections.     

293例妊娠妇女阴道念珠菌病的病原学特征及耐药率分析

目的通过对妊娠妇女阴道念珠菌病患者阴道分泌物进行直接镜检、分离培养鉴定及体外药敏试验来了解妊娠妇女阴道念珠菌病的病原学特征及其对常用抗真菌药物的敏感性。方法采用超高倍显微镜对患者阴道分泌物进行直接镜检。用科玛嘉念珠菌显色培养基和Vitek60全自动微生物鉴定仪对分离的念珠菌进行菌种鉴定，并采用Rosco纸片扩散法进行体外抗真菌药物敏感试验。结果共分离出293株念珠菌，其中自念珠菌217株、光滑念珠菌48株、热带念珠菌24株、克柔念珠菌1株、近平滑念珠菌3株。药敏试验结果显示对氟康唑的耐药率分别为5．07％、31．25％、20．83％、100．00％、33．33％。所有菌株均对两性霉素B和制霉菌素敏感。结论目前阴道念珠菌感染仍以白念珠菌感染为主，但其他非白念珠菌感染有明显上升趋势。分离的白念珠菌对唑类抗真菌药物仍较敏感，非白念珠菌对唑类药物的耐药率有所上升，应加强念珠菌的检测和药物敏感性分析。     

The European Confederation of Medical Mycology (ECMM) survey of candidaemia in Italy: antifungal susceptibility patterns of 261 non-albicans Candida isolates from blood

OBJECTIVES: To analyse the in vitro antifungal susceptibility of 261 non-albicans Candida bloodstream strains isolated during the European Confederation of Medical Mycology survey of candidaemia performed in Lombardia, Italy (September 1997-December 1999). METHODS: In vitro susceptibility to flucytosine, fluconazole, itraconazole, posaconazole and voriconazole was determined using the broth microdilution method described in the NCCLS M27-A guidelines. Etest strips were used to assess susceptibility to amphotericin B. In vitro findings were correlated with the patient's underlying condition and previous antifungal treatment. RESULTS: MICs (mg/L) at which 90% of the strains were inhibited were, respectively, 2 for flucytosine, 8 for fluconazole, 0.5 for itraconazole, 0.25 for voriconazole and 0.25 for posaconazole. Amphotericin B MIC endpoints were <0.50 mg/L in all the isolates tested. Flucytosine resistance was detected in 19 isolates (7%), mainly among Candida tropicalis strains (30%). Innate or secondary fluconazole resistance was detected in 13 strains (5%). Among the 13 patients with fluconazole-resistant Candida bloodstream infection, three were HIV positive, including one treated with fluconazole for oral candidosis; the four who were HIV negative had received the azole during the 2 weeks preceding the candidaemia. Cross-resistance among fluconazole and other azoles was a rare event. CONCLUSIONS: Resistance is still uncommon in non-albicans Candida species recovered from blood cultures. However, in fungaemias caused by C. tropicalis, Candida glabrata and Candida krusei, there is a high prevalence of resistance to fluconazole and flucytosine. Fluconazole resistance should be suspected in patients treated previously with azoles, mainly those with advanced HIV infection.     

Invasive Candida species infections: a 5 year population-based assessment

OBJECTIVES: Candida species have emerged as important causes of invasive infections and rates of resistance to standard antifungal therapies are rising. The objective of this study was to define the occurrence of, risk factors for, and antifungal susceptibilities of invasive Candida species infections in a large Canadian health region. METHODS: Population-based surveillance was conducted for invasive Candida species infections in the Calgary Health Region during a 5 year period and susceptibility testing was performed. RESULTS: The annual incidence of invasive Candida species infection was 2.9 per 100,000 population (0.2 and 2.8 per 100,000 for central nervous system and bloodstream infection, respectively). The very young and elderly were at highest risk for invasive Candida species infections. Several risk factors for developing invasive Candida species infection were identified with chronic haemodialysis, organ transplant recipient, and cancer patients at highest risk. Thirty percent (56/184; 43 susceptible, dose-dependent and 13 resistant) of isolates demonstrated reduced susceptibility to fluconazole. Only one (1%) isolate had reduced susceptibility to amphotericin B and six (3%) and three (2%) isolates had minimum inhibitory concentrations of >or=1 mg/L to voriconazole and caspofungin, respectively. Overall, 40% of patients died in-hospital for an annual mortality rate of 1.2 per 100,000. CONCLUSIONS: Candida species are an important cause of invasive infection and patients with co-morbidities and extremes of age are at highest risk. Alternatives to fluconazole should be considered for initial empiric therapy in patients with severe invasive Candida species infections.     

Antifungal prophylaxis in neutropenic patients with hematologic malignancies: is there a real benefit?

Invasive fungal infections have been reported with an increasing incidence over the last 20 years. Fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies. Therefore, in neutropenic patients different regimens of antifungal prophylaxis have been performed for more than 20 years, but the effect of antifungal prophylaxis is controversial. A long duration of neutropenia, impaired cell-mediated immunity as well as continuous corticosteroid therapy and sustained immunosuppression for graft-versus-host disease in patients treated with allogeneic bone marrow transplantation are known risk factors for invasive mycosis. Since early diagnosis of invasive fungal infection is difficult, strategies to prevent fungal infections seem to be attractive. The introduction of triazoles have provided us with a better armamentarium to prevent fungal infections. In this review, the current strategies of antifungal prophylaxis are discussed. Antifungal prophylaxis has been effective in reducing candida infection, however, there has been no proven successful prevention of invasive aspergillosis. In addition, there is no clearly proven benefit of antifungal prophylaxis regarding the reduction in the overall mortality. Thus the best way to reduce invasive fungal-related mortality will be early diagnosis and preemptive therapeutic approaches.