Efficacy of anidulafungin in 539 patients with invasive candidiasis: a patient-level pooled analysis of six clinical trials.

Objectives: To evaluate the efficacy of anidulafungin for the treatment of candidaemia and invasive candidiasis in a large dataset, including patients with deep-seated tissue candidiasis, neutropenia and infection due to non- albicans Candida species. Methods: Data were pooled from six prospective, multicentre, multinational studies: four open-label, non-comparative studies of anidulafungin and two double-blind, double-dummy, randomized studies of anidulafungin versus caspofungin (clinical trial registrations: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351 and NCT00805740; ClinicalTrials.gov). In all studies, patients with culture-confirmed invasive candidiasis received a single intravenous (iv) loading dose of anidulafungin 200 mg on day 1, followed by 100 mg once-daily. Switch to oral fluconazole or voriconazole was permitted after 5-10 days of iv treatment in all studies except one. Antifungal treatment (iv plus oral therapy if applicable) was maintained for ≥14 days after the last positive Candida culture. The primary endpoint was successful global response at end of iv therapy (EOivT) in the modified ITT (mITT) population. Results: In total, 539 patients were included (mITT population). The most common baseline Candida species were Candida albicans (47.9%), Candida glabrata (21.0%), Candida tropicalis (13.7%), Candida parapsilosis (13.2%) and Candida krusei (3.5%). Median duration of anidulafungin iv treatment was 10.0 days. The global response success rate at EOivT was 76.4% (95% CI 72.9%-80.0%). All-cause mortality was 13.0% on day 14 and 19.1% on day 28. Adverse events (AEs) were consistent with the known AE profile for anidulafungin. Conclusions: These data demonstrate that anidulafungin is effective for treatment of candidaemia and invasive candidiasis in a broad patient population.

Pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes.

INTRODUCTION: Pseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype-specific P. aeruginosa in critically ill patients under appropriate antimicrobial therapy management. METHODS: A retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by P. aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a phase IIa studyconducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis. RESULTS: The prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%), and O1 (8%). Serotypes with a prevalence of less than 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes, 19% mortality, 70% clinical resolution, 11% clinical continuation, and 5% clinical recurrence were recorded. Age and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) were predictive risk factors associated with probability of death and lower clinical resolution for P. aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was, respectively, 8% and 21%; clinical resolution with O6 and O11 was, respectively, 75% and 57%. CONCLUSIONS: In P. aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of P. aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the two serotypes most frequently encountered in critically ill patients.

The safety and efficacy of high-dose daptomycin combined with rifampicin for the treatment of Gram-positive osteoarticular infections.

PURPOSE: Treatment of Gram-positive osteoarticular infections requires an adequate surgical approach combined with intensive antimicrobial therapy. The aim of this study was to evaluate the safety and efficacy of a combined regimen of high-dose daptomycin and rifampicin, in patients with various types of Gram-positive osteoarticular infections. METHODS: This single centre, non-comparative, prospective study evaluated the safety and efficacy of a combined regimen of intravenous daptomycin (8 mg/kg/day) and oral rifampicin (600 mg/day) in patients with Gram-positive osteoarticular infections, with a minimal follow-up of one year. Creatine phosphokinase, transaminases, bilirubinaemia, and serum creatinine, were measured at baseline and regular intervals. RESULTS: The median daily doses of daptomycin and rifampicin, administered for a median duration of 21 (range, 10-122) days to 16 patients (median age, 63.5 years; 11 males, five females) presenting with staphylococcal (n = 15) or streptococcal (n = 1) osteoarticular infections, were 8.15 (range, 6.6-8.9) mg/kg/day and 600 (range, 600-900) mg/day, respectively. The combined regimen of daptomycin and rifampicin was well tolerated by all except one patient, without requiring treatment adjustment or discontinuation. One patient developed allergic responses probably due to rifampicin after 42 days. Fifteen (94 %) patients showed favourable clinical and microbiological outcomes. CONCLUSIONS: The combined regimen of high-dose daptomycin and rifampicin was well tolerated and may provide a useful alternative to standard glycopeptide therapy for Gram-positive osteoarticular infections.

Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia.

OBJECTIVES: Nosocomial Pseudomonas aeruginosa pneumonia remains a major concern in critically ill patients. We explored the potential impact of microorganism-targeted adjunctive immunotherapy in such patients. PATIENTS AND METHODS: This multicentre, open pilot Phase 2a clinical trial (NCT00851435) prospectively evaluated the safety, pharmacokinetics and potential efficacy of three doses of 1.2 mg/kg panobacumab, a fully human monoclonal anti-lipopolysaccharide IgM, given every 72 h in 18 patients developing nosocomial P. aeruginosa (serotype O11) pneumonia. RESULTS: Seventeen out of 18 patients were included in the pharmacokinetic analysis. In 13 patients receiving three doses, the maximal concentration after the third infusion was 33.9 ±â€Š8.0 µg/mL, total area under the serum concentration-time curve was 5397 ±â€Š1993 µg h/mL and elimination half-life was 102.3 ±â€Š47.8 h. Panobacumab was well tolerated, induced no immunogenicity and was detected in respiratory samples. In contrast to Acute Physiology and Chronic Health Evaluation II (APACHE II) prediction, all 13 patients receiving three doses survived, with a mean clinical resolution in 9.0 ±â€Š2.7 days. Two patients suffered a recurrence at days 17 and 20. CONCLUSIONS: These data suggest that panobacumab is safe, with a pharmacokinetic profile similar to that in healthy volunteers. It was associated with high clinical cure and survival rates in patients developing nosocomial P. aeruginosa O11 pneumonia. We concluded that these promising results warrant further trials.

Report of a successful treatment of pulmonary Cunninghamella bertholletiae infection with liposomal amphotericin and posaconazole in a child with GvHD and review of the literature.

Zygomycosis is an emerging, opportunistic fungal infection particularly affecting immunocomprised patients. We report the case of a 10-year-old girl who developed pulmonary zygomycosis because of Cunninghamella bertholletiae 1 year after undergoing bone marrow transplantation complicated with severe cutaneous and digestive graft-versus-host disease. Treatment with surgery and liposomal amphotericin B followed by posaconazole successfully treated the infection.

Correction to: Catheter retention as a consequence rather than a cause of unfavorable outcome in candidemia.

In the original publication the members of the FUNGINOS network were provided in such a way that they could not be indexed as collaborators on PubMed.

Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study.

OBJECTIVES: Breakthrough candidemia (BTC) on fluconazole was associated with non-susceptible Candida spp. and increased mortality. This nationwide FUNGINOS study analyzed clinical and mycological BTC characteristics. METHODS: A 3-year prospective study was conducted in 567 consecutive candidemias. Species identification and antifungal susceptibility testing (CLSI) were performed in the FUNGINOS reference laboratory. Data were analyzed according to STROBE criteria. RESULTS: 43/576 (8%) BTC occurred: 37/43 (86%) on fluconazole (28 prophylaxis, median 200 mg/day). 21% BTC vs. 23% non-BTC presented severe sepsis/septic shock. Overall mortality was 34% vs. 32%. BTC was associated with gastrointestinal mucositis (multivariate OR 5.25, 95%CI 2.23-12.40, p < 0.001) and graft-versus-host-disease (6.25, 1.00-38.87, p = 0.05), immunosuppression (2.42, 1.03-5.68, p = 0.043), and parenteral nutrition (2.87, 1.44-5.71, p = 0.003). Non-albicans Candida were isolated in 58% BTC vs. 35% non-BTC (p = 0.005). 63% of 16 BTC occurring after 10-day fluconazole were non-susceptible (Candida glabrata, Candida krusei, Candida norvegensis) vs. 19% of 21 BTC (C. glabrata) following shorter exposure (7.10, 1.60-31.30, p = 0.007). Median fluconazole MIC was 4 mg/l vs. 0.25 mg/l (p < 0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy. CONCLUSIONS: Outcomes of BTC and non-BTC were similar. Fluconazole non-susceptible BTC occurred in three out of four cases after prolonged low-dose prophylaxis. This implies reassessment of prophylaxis duration and rapid de-escalation of empirical therapy in BTC after short fluconazole exposure.

A prospective hospital-based study of the clinical impact of non-severe acute respiratory syndrome (Non-SARS)-related human coronavirus infection.

BACKGROUND: In addition to the human coronaviruses (HCoVs) OC43 and 229E, which have been known for decades to cause infection in humans, 2 new members of this genus have recently been identified: HCoVs NL63 and HKU1. Their impact as a cause of respiratory tract disease in adults at risk for complications needs to be established. METHODS: We prospectively assessed the clinical impact of coronavirus infection (excluding cases of severe acute respiratory syndrome) among hospitalized adults. All patients with respiratory disease for whom bronchoalveolar lavage was performed were screened by reverse-transcriptase polymerase chain reaction for the presence of all 4 HCoVs. RESULTS: HCoV was identified in 29 (5.4%) of 540 bronchoalveolar lavage fluid specimens from 279 subjects (mean age, 51 years; 63% male). HCoV OC43 was identified most frequently (12 isolates), followed by 229E (7 isolates), NL63 (6 isolates), and HKU1 (4 isolates). In all, 372 (69%) of 540 bronchoalveolar lavage fluid specimens were negative for bacteria, and 2 persons were coinfected with other respiratory viruses. Transplantation was the most common underlying condition. Of the 29 patients who had HCoV identified in their bronchoalveolar lavage fluid specimens, 9 (31%) were hospitalized in the intensive care unit, 22 (76%) presented to the hospital with acute respiratory symptoms, 16 (55%) presented with cough and/or sputum, 13 (45%) presented with dyspnea, 16 (55%) had experienced prior respiratory infection, and 18 (62%) had a new infiltrate that was visible on chest radiograph. The most frequent final diagnosis was a lower respiratory tract infection. CONCLUSIONS: The recently discovered HCoVs NL63 and HKU1 contribute significantly to the overall spectrum of coronavirus infection. Our study also suggests that coronaviruses contribute to respiratory symptoms in most cases.

A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis.

BACKGROUND: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. METHODS: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. RESULTS: Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. CONCLUSIONS: Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.

Recurrent bacteremia with Helicobacter cinaedi: case report and review of the literature.

BACKGROUND: Helicobacter cinaedi is a rare pathogen in humans, occurring mostly in immuno-compromised patients, with a high potential for recurrence. We describe a case of a patient with lymphoma hospitalized for chemotherapy. CASE PRESENTATION: At admission, the patient presented with an indolent and non-prurigenic macular rash around her implantable venous access device. Gram staining of blood cultures revealed the presence of spiral-shaped gram-negative rods that could not be grown upon subculture. Helicobacter cinaedi was identified by PCR. No other symptoms or pathology were observed in a whole body CT scan. The implantable venous access device was removed and empiric therapy by ceftriaxone and gentamicin for 2 weeks was initiated, followed by peroral clarithromycin 2 x 500 mg/day and later by levofloxacin 2 x 500 mg/day for 7 weeks. Oncologic remission was achieved 3 months later. However, the patient was re-hospitalized 2 months later for fever, shivering, reappearance of the macular non-prurigenic rash, diarrhea, cough and asthenia. Blood cultures grew H. cinaedi. Multiple investigations could not identify the source. Empiric antibiotic therapy of ceftriaxone and doxycycline was started for 2 weeks with resolution of symptoms, followed by an oral combination of amoxicillin, metronidazole and doxycycline for 2 months; doxycycline was continued for another month. Bacteremia has not recurred for a period of 19 months. CONCLUSION: Although H. cinaedi is considered to be a low virulent bacteria, its potential to cause recurrent bacteremia should not be underestimated. H. cinaedi could have an endovascular source of infection and should be treated for an adequate duration with combined antibiotherapy.

Invasive aspergillosis: is treatment with "inexpensive" amphotericin B cost saving if "expensive" voriconazole is only used on demand?

BACKGROUND: Voriconazole for the treatment of invasive aspergillosis (IA) shows superior clinical outcome and tolerability compared to conventional amphotericin B. However, the latter is often used as initial treatment due to lower drug acquisition costs. Therefore we performed a cost-effectiveness analysis. METHODS: A decision analytic model was designed to compare the cost-effectiveness of a regimen of voriconazole followed by conventional amphotericin B to a regimen of conventional amphotericin B followed by voriconazole. Patients initiated on treatment either completed initial therapy or switched to second line therapy due to toxicity or non-response. Probability of a switch was based on clinical trial data and local rates of renal toxicity. Resource use in the hospital was taken from the Global Comparative Aspergillosis (GCA) study. Costs were based on local drug acquisition costs, local cost estimates for hospitalisation and adjusted additional costs of amphotericin B-induced acute renal failure from the literature. Effectiveness was defined as survival at 12 weeks from the GCA study. An incremental cost-effectiveness ratio was estimated as the incremental cost per life saved comparing voriconazole to conventional amphotericin B. RESULTS: Based on this model, initial therapy of IA with voriconazole reduced total costs when compared to initial therapy with conventional amphotericin B (CHF 37 878/patient vs CHF 49 861/patient) and resulted in better survival at 12 weeks, making it the dominant treatment in terms of incremental cost-effectiveness. Results were most sensitive to alternative assumptions of the incidence of acute renal failure, but cost savings were sustained for voriconazole over a wide range of values. CONCLUSION: Considering that initial therapy with voriconazole is both cost-saving and results in better clinical outcomes, voriconazole is the dominant cost-effective option for initial therapy of IA, despite very low drug acquisition costs of conventional amphotericin B.

Treatment options of invasive fungal infections in adults.

A panel of infectious disease specialists, clinical microbiologists and hospital epidemiologists of the five Swiss university hospitals reviewed the current literature on the treatment of invasive fungal infections in adults and formulated guidelines for the management of patients in Switzerland. For empirical therapy of Candida bloodstream infection, fluconazole is the drug of choice in non-neutropenic patients with no severe sepsis or septic shock or recent exposure to azoles. Amphotericin B deoxycholate or caspofungin would be the treatment option for patients with previous azole exposure. In neutropenic patients, empirical therapy with amphotericin B deoxycholate is considered first choice. In patients with severe sepsis and septic shock, caspofungin is the drug of first choice. For therapy of microbiologically-documented Candida infection, fluconazole is the drug of choice for infections due to C. albicans, C. tropicalis or C. parapsilosis. When infections are caused by C. glabrata or by C. krusei, caspofungin or amphotericin B deoxycholate are first line therapies. Treatment guidelines for invasive aspergillosis (IA) were stratified into primary therapy, salvage therapy and combination therapy in critically ill patients. Voriconazole is recommended for primary (ie upfront) therapy. Caspofungin, voriconazole (if not used for primary therapy) or liposomal amphotericin B are recommended for salvage therapy for refractory disease. Combination therapy with caspofungin plus voriconazole or liposomal amphotericin B should be considered in critically ill patients. Amphotericin B deoxycholate is recommended as initial therapy for the empirical therapy in patients with neutropenia and persistent fever with close monitoring of adverse events.

Use of high-dose liposomal amphotericin B: efficacy and tolerance.

Fungal infections have become increasingly prevalent over the past decade. Amphotericin B deoxycholate (AmBd) (Fungizone) has been the treatment of choice despite its association with significant high adverse effects, and notably severe high nephrotoxicity. However, liposomal ampotericin B (L-AmB) (AmBisome) has now become the first-line treatment due to its lower nephrotoxicity but without any loss of clinical efficacy. As illustrated in published reports, a higher dose of L-AmB may be prescribed in the case of unresponsiveness to treatment at normal dosage levels. Based on existing evidence from animal models of invasive fungal infections and the earlyclinical experience, L-AmB used athigher doses for invasive fungal infections is a new treatment option.

[Variations between 2 ECG as predictors of atrial fibrillation: Cohort study]. / Diferencias entre 2 electrocardiogramas sinusales como predictoras de fibrilación auricular: estudio de cohorte.

OBJETIVE: To evaluate the association between delta variations in the parameters of 2 sinusal ECG with atrial fibrillation (AF) onset. METHOD: Retrospective cohort of 9,975 adult patients and members of the prepaid system at Hospital Italiano de Buenos Aires from Argentina, who had at least 2 sinusal ECG between 2006 and 2011. Population was followed up for detection of AF. All measurements and electrocardiographic deltas (differences between the 2 ECG) were standardized. Hazard ratio (HR) was estimated for the development of AF for each delta of the different ECG parameters using a Cox regression model. RESULTS: During a median follow up of 3.5 years, 189 patients (1.89%) developed AF. Heart rate delta, ST interval delta and P wave amplitude were predictors of AF. Hazard ratio Adjusted for clinical characteristics and ECGbasal values was 0,86 (CI95%: 0.75-0.98, p=0.024) for heart rate delta, 1.12 (CI95%: 0.98-1.27, p=0.082) for ST interval delta and 1.21 (CI95%: 1.05-1.38, p=0.006) for P wave amplitude delta. CONCLUSION: Differences of heart rate and P wave amplitude between ECG's measurements may predict AF, independently of clinical features and ECGbasal values.

Invasive candidiasis: comparison of management choices by infectious disease and critical care specialists.

OBJECTIVE: To compare the management of invasive candidiasis between infectious disease and critical care specialists. DESIGN AND SETTING: Clinical case scenarios of invasive candidiasis were presented during interactive sessions at national specialty meetings. Participants responded to questions using an anonymous electronic voting system. PATIENTS AND PARTICIPANTS: Sixty-five infectious disease and 51 critical care physicians in Switzerland. RESULTS: Critical care specialists were more likely to ask advice from a colleague with expertise in the field of fungal infections to treat Candida glabrata (19.5% vs. 3.5%) and C. krusei (36.4% vs. 3.3%) candidemia. Most participants reported that they would change or remove a central venous catheter in the presence of candidemia, but 77.1% of critical care specialists would start concomitant antifungal treatment, compared to only 50% of infectious disease specialists. Similarly, more critical care specialists would start antifungal prophylaxis when Candida spp. are isolated from the peritoneal fluid at time of surgery for peritonitis resulting from bowel perforation (22.2% vs. 7.2%). The two groups equally considered Candida spp. as pathogens in tertiary peritonitis, but critical care specialists would more frequently use amphotericin B than fluconazole, caspofungin, or voriconazole. In mechanically ventilated patients the isolation of 10(4) Candida spp. from a bronchoalveolar lavage was considered a colonizing organism by 94.9% of infectious disease, compared to 46.8% of critical care specialists, with a marked difference in the use of antifungal agents (5.1% vs. 51%). CONCLUSIONS: These data highlight differences between management approaches for candidiasis in two groups of specialists, particularly in the reported use of antifungals.

Infection and rejection in liver transplant patients: a 10-year Swiss single-centre experience.

INTRODUCTION: Graft rejection and infection remain major morbidities following orthotopic liver transplantation (OLT). Rejection treatment may be associated with an increased rate of infectious complications. The aim of this study was to determine the relationship between rejection, rejection therapy and the risk of associated infections. MATERIALS AND METHODS: A retrospective study of all adult patients undergoing OLT between July 1987 and July 1997 at a single university medical centre was carried out. Data for all transplant recipients were collected using predetermined definitions for infectious complications. RESULTS: One hundred OLTs were performed on 98 patients (two patients received a second transplant). The cohort consisted of 33 women and 65 men with a mean age of 47 years. Seventy-eight patients developed a total of 228 infectious episodes: 107 bacterial, 101 viral, 17 fungal and 3 protozoan. The majority of infections occurred within the first month of OLT. Thirty patients without rejection developed 42 infectious episodes, whereas 70 patients with at least one treated rejection episode developed 186 infectious episodes. The overall rate of infection was 44.4 episodes per 1000 patient-days in the 30 days before rejection, and 94.4 episodes per 1000 patient-days in the 30 days following rejection treatment. CONCLUSIONS: Infections occurred more frequently during the first month post-transplantation. Following OLT, rejection is associated with a higher incidence of infection, mainly of viral origin, concurrent with increased immunosuppressive therapy.

Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 1991-2000.

Candida species are among the most common bloodstream pathogens in the United States, where the emergence of azole-resistant Candida glabrata and Candida krusei are major concerns. Recent comprehensive longitudinal data from Europe are lacking. We conducted a nationwide survey of candidemia during 1991-2000 in 17 university and university-affiliated hospitals representing 79% of all tertiary care hospital beds in Switzerland. The number of transplantations and bloodstream infections increased significantly (P<.001). A total of 1137 episodes of candidemia were observed: Candida species ranked seventh among etiologic agents (2.9% of all bloodstream isolates). The incidence of candidemia was stable over a 10-year period. C. albicans remained the predominant Candida species recovered (66%), followed by C. glabrata (15%). Candida tropicalis emerged (9%), the incidence of Candida parapsilosis decreased (1%), and recovery of C. krusei remained rare (2%). Fluconazole consumption increased significantly (P<.001). Despite increasing high-risk activities, the incidence of candidemia remained unchanged, and no shift to resistant species occurred.

Secular trends of candidemia over 12 years in adult patients at a tertiary care hospital.

The incidence of fungal infections has been increasing for the last 3 decades, especially among neutropenic, cancer, and critically ill patients. These infections are associated with high mortality rates. We retrospectively reviewed medical charts of adult patients with fungemia from 1989 to 2000 at our institution. The characteristics of the population groups served by the hospital were described. Of 328 patients with fungemia, we reviewed 315 (96%) medical records, and focused on those with candidemia (n = 294). The species distribution in patients with candidemia showed that the most commonly identified species were Candida albicans (66%), followed by C. glabrata (17%), and C. parapsilosis (6%). The incidence of candidemia ranged from 0.2 to 0.46 per 10,000 patient-days with the highest incidence in 1993 and the lowest in 1997. Although most studies show an increased incidence of candidemia, we observed a reduction over the study period. Furthermore, we observed no shift from C. albicans to non-albicans Candida species despite a significant increase in the use of fluconazole. The overall mortality among patients with candidemia was 44%, with the highest rate in patients over 65 years (52%). Factors independently associated with higher mortality were patient age greater than 65 years, intensive care unit admission, and underlying cancer.

Management of Candida species infections in critically ill patients.

Invasive candidiasis is a feared infection with mortality similar to that of septic shock (40-60%). Improved knowledge of its pathophysiology and the availability of new compounds for antifungal therapy and prophylaxis have contributed to improving the prognosis of severe candidal infections among immunosuppressed patients at the possible cost of the emergence of non-albicans strains of candida with lower susceptibility to azoles. This review focuses on the management of invasive deep-seated candidiasis in critically ill, non-immunocompromised patients. We discuss antifungal use, indications, potential benefit, and main secondary effects. Prevention strategies include pre-emptive antifungal therapy and azole-based prophylaxis. For patients at lower initial risk, pre-emptive therapy should be based on a management strategy that takes into account the presence of definite risk factors and the dynamics of candida colonisation. Among critically ill patients, azole prophylaxis is effective and is not associated with acquisition of resistance; it must be restricted to highly selected groups of patients at high risk only.

Epidemiology of Candida species infections in critically ill non-immunosuppressed patients.

A substantial proportion of patients become colonised with Candida spp during hospital stay, but only few subsequently develop severe infection. Clinical signs of severe infection manifest early but lack specificity until late in the course of the disease, thus representing a particular challenge for diagnosis. Mostly nosocomial, invasive candidiasis occurs in only 1-8% of patients admitted to hospitals, but in around 10% of patients housed in intensive care units where it can represent up to 15% of all nosocomial infections. We review the epidemiology of invasive candidiasis in non-immunocompromised, critically ill patients with special emphasis on disease trends over time, pathophysiology, diagnostic approach, risk factors, and impact. Recent epidemiological data suggesting that the emergence of non-albicans candida strains with reduced susceptibility to azoles, previously linked to the use of new antifungals for empiric and prophylactic therapy in immunocompromised patients, may not have occurred in the critically ill. Management of invasive candidiasis in these patients will be addressed in the December issue of The Lancet Infectious Diseases.