Jorge Garbino

Fungemia in HIV-Infected Patients: A 12-Year Study in a Tertiary Care Hospital

Opportunistic infections caused by fungi are common in human immunodeficiency virus (HIV)-infected patients. We focused on severe infections as indicated by detectable fungemia. Medical charts available for patients having positive blood cultures with fungi at the University of Geneva Hospital were retrospectively (1989 to 2000) reviewed. Of 328 patients with fungemia during the study period, 315 (96%) medical charts were accessible. Of these 315 patients, 37 (12.2%) were HIV-positive, and 13 (35.1%) died within 6 months from their episode of fungemia. This was a lower mortality rate than for the HIV seronegative patients (45.8%). The median and average age of the 34 HIV-positive patients was 37.2 years, and 24 (64.9%) were males. Cryptococcus neoformans (n = 14) and Candida albicans (n = 12) were the most frequently identified species, followed by Candida glabrata (n = 3), of which 3 were mixed C. albicans + C. glabrata, Histoplasma capsulatum (n = 2), and Penicillium marneffei (n = 2). The frequency decreased significantly (p < 0.007) from the time period 1993 to 1996 (n = 21) to the period 1997 to 2000 (n = 6). Fungemias in HIV-infected patients have declined significantly since 1996. This coincides with the introduction of highly active antiretroviral therapy (HAART).

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.

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.

Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients.

ObjectivePhase III study to confirm a trend observed in a previous phase II study showing that a single dose of lenercept, human recombinant p55 tumor necrosis factor receptor-immunoglobulin G1 (TNFR55-IgG1) fusion protein, decreased mortality in patients with severe sepsis or early septic shock. DesignMulticenter, double-blind, phase III, placebo-controlled, randomized study. SettingA total of 108 community and university-affiliated hospitals in the United States (60), Canada (6) and Europe (42). PatientsA total of 1,342 patients were recruited who fulfilled the entry criteria within the 12-hr period preceding the study drug administration. InterventionAfter randomization, an intravenous dose of 0.125 mg/kg lenercept or placebo was given. The patient was monitored for up to 28 days, during which standard diagnostic, supportive, and therapeutic care was provided. Measurements and Main Results The primary outcome measure was 28-day all-cause mortality. Baseline characteristics were as follows: a total of 1,342 patients were randomized; 662 received lenercept and 680 received placebo. The mean age was 60.5 yrs (range, 17–96 yrs); 39% were female; 65% had medical admissions, 8% had scheduled surgical admissions, and 27% had unscheduled surgical admissions; 73% had severe sepsis without shock, and 27% had severe sepsis with early septic shock. Lenercept and placebo groups were similar at baseline with respect to demographic characteristics, simplified acute physiology score II-predicted mortality, profiles of clinical site of infection and microbiological documentation, number of dysfunctioning organs, and interleukin-6 (IL-6) plasma concentration. Lenercept pharmacokinetics were similar in severe sepsis and early septic shock patients. Tumor necrosis factor was bound in a stable manner to lenercept as reflected by the accumulation of total serum tumor necrosis factor &agr; concentrations. There were 369 deaths, 177 on lenercept (27% mortality) and 192 on placebo (28% mortality). A one-sided Cochran-Armitage test, stratified by geographic region and baseline, predicted 28-day all-cause mortality (simplified acute physiology score II), gave a p value of .141 (one-sided). Lenercept treatment had no effect on incidence or resolution of organ dysfunctions. There was no evidence that lenercept was detrimental in the overall population. ConclusionLenercept had no significant effect on mortality in the study population.

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.

Management of candidiasis 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.

Nocardiosis: updated clinical review and experience at a tertiary center.

Nocardiosis is a rare opportunistic disease that affects mainly patients with deficient cell-mediated immunity, such as those with acquired immunodeficiency syndrome (AIDS) or transplant recipients. Pulmonary disease is the most common presentation in immunosuppressed patients and approximately one-third have a disseminated disease. Primary cutaneous nocardiosis is more frequently observed in immunocompetent patients with direct inoculation of the organism through professional exposure. The diagnosis can be challenging, as signs and symptoms are not specific and a high index of clinical of suspicion is necessary. Although gram stain, modified acid-fast stain, and cultures remain as the standard diagnostic tools, novel molecular techniques have changed the taxonomy of these organisms and, in some instances, have facilitated their identification. The disease has a marked tendency to recur and a high morbidity and mortality rate in immunosuppressed patients. Treatment is usually prolonged and an associated antibiotic treatment is preferred for severe disease. Although sulfonamides in combination with other antibiotics are still the treatment of choice, other associations such as imipenem plus amikacin are preferred in some centers. Linezolid is a useful alternative therapeutic agent due to its oral availability and activity against most of the isolates studied. Twenty-eight cases of nocardiosis were diagnosed at our center between January 1989 and April 2009. We report the epidemiologic characteristics of Nocardia spp. observed in our institution and discuss the risk factors, clinical features, diagnosis, and management of the disease.

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.

A Prospective Hospital-Based Study of the Clinical Impact of Non–Severe Acute Respiratory Syndrome (Non-SARS)–Related Human Coronavirus Infection

Abstract 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.

Respiratory viruses in bronchoalveolar lavage: a hospital-based cohort study in adults

Background: The epidemiology of respiratory viruses and their potential clinical impact when recovered in lower respiratory specimens has not been established in the hospital setting. A study was performed to investigate the association between positive viral detection and respiratory infection in an at-risk population. Methods: 299 adult patients who underwent bronchoalveolar lavage (BAL) procedures were enrolled in a hospital-based prospective cohort study. Descriptive epidemiology is presented of 17 different respiratory viruses detected by reverse transcription-polymerase chain reaction assays in BAL fluid specimens. Multivariate analysis was conducted to identify the clinical characteristics independently associated with the presence of virus. Results: Of 522 BAL fluid specimens analysed, 81% were collected in adult transplant recipients or other immunocompromised patients. Overall, PCR assays identified viral nucleic acid in 91 BAL fluid samples (17.4%). Similar rates of virus-positive BAL fluid were found in the different subpopulations studied (p = 0.113). Coronaviruses were the most frequent (32.3%), followed by rhinovirus (22.6%), parainfluenza (19.5%), influenza (9.7%), respiratory synctial virus (8.6%), human metapneumovirus (4.2%) and bocavirus (3.1%). Multivariate analysis using mixed models showed that respiratory viral infections were associated with a lack of antibiotic treatment response (OR 2.2, 95% CI 1.2 to 4.1) and the absence of radiological infiltrate (OR 0.3, 95% CI 0.2 to 0.8). In lung transplant recipients in whom a respiratory infection was suspected, the respiratory viral detection rate was 24.4% compared with 13.8% overall in other patients (p = 0.02). Conclusions: In this cohort of hospitalised adults, respiratory viruses detected in BAL fluid specimens were associated with respiratory symptoms, absence of radiological infiltrates and a poor response to antibiotic therapy.