Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants With Late-Onset Infection.

Importance: Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. Objective: To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. Design, Setting, and Participants: A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (<33 weeks) very low-birth-weight infants. Exposures: Late-onset (>72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. Main Outcomes and Measures: The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. Results: In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks' completed gestation did not reduce the association of the nSOFA score with infection-related mortality. Conclusions and Relevance: The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population.

Cryptococcal meningitis in an immunocompetent patient.

Cryptococcal meningitis is a fungal infection that is most commonly thought of as an opportunistic infection affecting immunocompromised patients, classically patients with Human Immunodeficiency (HIV) infection. It is associated with a variety of complications including disseminated disease as well as neurologic complications including intracranial hypertension, cerebral infarcts, vision loss and other neurologic deficits. It is diagnosed by lumbar puncture with CSF studies, including fungal culture and cryptococcal antigen testing. We present a case of cryptococcal meningitis and fungemia in a previously healthy male patient who presented after multiple emergency department visits with persistent headache. After multiple visits, he underwent a lumbar puncture consistent with cryptococcal infection, and he was admitted to the hospital for initiation of antifungal therapy. His workup revealed no known underlying condition leading to immune compromise.

Secondary free-flap reconstruction following ablation for acute invasive fungal sinusitis.

OBJECTIVE: Acute invasive fungal sinusitis (AIFS) is a frequently fatal infection for which extensive and debilitating surgical debridement is a mainstay of therapy. Resulting defects are often composite in nature, mandating free tissue-transfer reconstruction. Outcomes data for free flap reconstruction are limited. The purpose of this study was to examine surgical outcomes and survival in patients undergoing free flap transfer following invasive fungal sinusitis. STUDY DESIGN: Retrospective case series. METHODS: Between 1995 and 2015, patients undergoing operative debridement for AIFS were identified. Surgical records were used to identify survivors of acute infection who subsequently underwent free flap reconstructive surgery. Patient demographics, cause of immune compromise, defect description, flap type, perioperative complications, indications for revision surgery, functional outcomes, and long-term survival were reviewed. RESULTS: Forty-four patients were treated for AIFS, of those, 30 (68%) survived acute infection. Ten patients underwent maxillectomy, six with orbital exenteration, and were designated candidates for reconstruction. Eight patients underwent reconstruction. Median time from debridement to reconstruction was 67.5 days. Flap types included latissimus dorsi, scapula, anterolateral thigh, rectus, radial forearm, and fibula. Median follow-up was 7.7 months. No perioperative complications were encountered, and all subjects remained disease-free, able to speak and eat normally without prosthetic supplementation. Seven patients (87%) are currently alive. CONCLUSION: Reconstruction of defects left by invasive fungal sinusitis using free-tissue transfer resulted in successful flap survival, with no disease recurrence for all defects and flap types reviewed. Survivors of AIFS are able to tolerate midface reconstruction, with favorable functional outcomes and survival rates. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:815-819, 2017.

Efficacy and safety of itraconazole use in infants.

BACKGROUND: Itraconazole has been used to treat fungal infections, in particular invasive fungal infections in infants or neonates in many countries. DATA SOURCES: Literature search was conducted through Ovid EMBASE, PubMed, ISI Web of Science, CNKI and Google scholarship using the following key words: "pediatric" or "infant" or "neonate" and "fungal infection" in combination with "itraconazole". Based on the literature and our clinical experience, we outline the administration of itraconazole in infants in order to develop evidence-based pharmacotherapy. RESULTS: Of 45 articles on the use of itraconazole in infancy, 13 are related to superficial fungal infections including tinea capitis, sporotrichosis, mucosal fungal infections and opportunistic infections. The other 32 articles are related to systemic fungal infections including candidiasis, aspergillosis, histoplasmosis, zygomycosis, trichosporonosis and opportunistic infections as caused by Myceliophthora thermophila. CONCLUSION: Itraconazole is safe and effective at a dose of 5 mg/kg per day in a short duration of therapy for superficial fungal infections and 10 mg/kg per day for systemic fungal infections in infants. With a good compliance, it is cost-effective in treating infantile fungal infections. The profiles of adverse events induced by itraconazole in infants are similar to those in adults and children.

Epidemiology of invasive aspergillosis and risk factors in non neutropaenic patients.

INTRODUCTION: Invasive aspergillosis is a major cause of mortality in allogeneic bone marrow transplant recipients and patients treated for blood malignancies. The diagnostic tools, treatments and preventive strategies, essentially developed for neutropaenic patients, have not been assessed in populations whose immune systems are considered to be competent. STATE OF THE ART: Beside the standard picture of chronic Aspergillus infection, the incidence of invasive aspergillosis is increasing in non neutropaenic patients, such as those with chronic lung diseases or systemic disease treated with long-term immunosuppressive drugs and solid organ transplant recipients. This study reviews the specific features of invasive aspergillosis in non neutropaenic subjects (NNS) and discusses the value of the diagnostic tools and treatment in this population. PROSPECTS: A better understanding of the pathophysiology and the epidemiological characteristics of invasive aspergillosis would provide a means of adapting the staging and classification of the disease for NNS. CONCLUSIONS: Invasive aspergillosis is under diagnosed in NNS who may already be colonised when they receive immunosuppressive treatment; this can lead to an adverse outcome in patients who are considered to be a moderate risk population.

Nosocomial candidaemia in children: results of a 9-year study.

The aim of this study was to determine changes in the incidence of nosocomial candidaemia and to evaluate the risk factors, demographic features, treatment and clinical outcome associated with candidaemia in a Turkish tertiary care paediatric unit within a 9-year period. The data of children who were diagnosed as nosocomial candidaemia, were examined in this study. Between January 1997 and December 2005, a total of 102 nosocomial candidaemia episodes were identified in 102 patients. The rate of nosocomial candidaemia in our clinic increased from 3.2 cases per 1000 admissions in 1997-1999, to 5.5 per 1000 admissions in 2000-2002 and to 6.9 per 1000 admissions in 2003-2005 (P = 0.003). The species most frequently causing candidaemia were Candida albicans (39.2%), Candida parapsilosis (21.6%) and Candida tropicalis (15.7%). The mortality of C. albicans (37.5%), was significantly higher than the mortality of non-albicans species (17.7%) (P = 0.04). Independent risk factors associated with candidaemia-related deaths by logistic regression analysis were disseminated candidiasis (odds ratio, 5.7; P = 0.01), paediatric intensive care unit stay (odds ratio, 8.1; P = 0.001), prolonged antibiotics therapy (odds ratio, 5.2; P = 0.014), use of total parenteral nutrition (odds ratio, 4.4; P = 0.038) and mechanical ventilation (odds ratio, 4.9; P = 0.01). The rate of nosocomial candidaemia in our clinic increased >2-fold during the study period.

Invasive candidiasis in long-term patients at a multidisciplinary intensive care unit: Candida colonization index, risk factors, treatment and outcome.

The incidence of fungal infections in hospitalized patients has increased, and due to demographic changes and increasingly advanced medical methods, the intensive care units (ICU) have emerged as epicentres for fungal infections. The aim of the present study was to investigate Candida colonization pattern and colonization index (CI), in combination with other risk factors and its relation to invasive candida infection (ICI), in 59 consecutive patients with at least 7 d length of stay (LOS) at a multidisciplinary ICU. Surveillance samples were collected on d 7 and then weekly during the ICU stay. In addition, immunological status was monitored by measuring the histocompatibility leukocyte antigen-DR (HLA-DR). In the present study with a patient population burdened by several risk factors for ICI, 17% acquired an invasive infection. Overall ICU mortality was 30%. We could demonstrate that both a high colonization index and recent extensive gastroabdominal surgery were significantly correlated with ICI, while a decreased level of HLA-DR (< or = 70%) was not predictive for ICI in this high-risk population. The results indicate that ICU patients exposed to extensive gastroabdominal surgery would benefit from early antifungal prophylaxis.

Candidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study.

The purpose of this study was to compare the risk factors, clinical manifestations, and outcome of candidemia in immunocompromised (IC) and nonimmunocompromised (NIC) critically ill patients. Data were collected prospectively over a 2-year period (02/2000-01/2002) from patients in a 25-bed, medical-surgical intensive care unit (ICU). Eligible for participation in this study were patients who developed candidemia during their ICU stay. Patients under antifungal therapy and with a confirmed systemic fungal infection prior to the diagnosis of candidemia were excluded. Cultures of blood, urine, and stool were performed for all patients in the study, and all patients underwent endoscopy/biopsy of the esophagus for detection of Candida. Smears and/or scrapings of oropharyngeal and esophageal lesions were examined for hyphae and/or pseudohyphae and were also cultured for yeasts. During the study period, 1,627 patients were hospitalized in the ICU, 57% for primary medical reasons and 43% for surgical reasons. After application of the study's inclusion and exclusion criteria, 24 patients with candidemia (9 IC and 15 NIC) were analyzed. Total parenteral nutrition was more common in IC than in NIC patients (9/9 [100%] vs 8/15 [53%], p = 0.02). Oropharyngeal candidiasis was detected in 5 of 9 (55.5%) IC patients and in 1 of 15 (6.5%) NIC patients (p = 0.015). Esophageal candidiasis was also more common in IC than in NIC patients (4/9 [44%] vs 0/15 [0%], p = 0.012). Among the 9 IC patients, all except 2 died, resulting in a crude mortality of 78%; among the 15 NIC patients, 9 died, resulting in a crude mortality of 60% (p > 0.05). Autopsy was performed in two IC and in six NIC patients, with disseminated candidiasis found in one IC patient. Oropharyngeal and esophageal candidiasis are frequent in IC patients with candidemia. In contrast, this coexistence is rare in NIC critically ill patients with Candida bloodstream infections. A high mortality was noted in both IC and NIC critically ill patients with candidemia.

Candidemia due to Candida tropicalis: clinical, epidemiologic, and microbiologic characteristics of 188 episodes occurring in tertiary care hospitals.

Candida tropicalis is the 2nd most frequent agent of candidemia in Brazil (20-24%). We attempted to characterize the epidemiology, microbiology, and outcome of candidemia due to C. tropicalis by comparing patients with candidemia due to C. tropicalis with those with candidemia due to Candida albicans. Among the 924 episodes of candidemia, 188 (20%) were caused by C. tropicalis. These cases were compared with 384 candidemias due to C. albicans. C. tropicalis was the 2nd most frequent species in adults (21.6%) and elderly patients (23.2%), and 3rd in neonates (11.9%) and children (18.5%). Cancer was the most frequent underlying disease, and in adults and elderly patients, diabetes was the 2nd most frequent underlying disease. The only difference between C. tropicalis and C. albicans candidemia was a higher proportion of neutropenic patients in C. tropicalis candidemia. C. tropicalis is a leading cause of candidemia in Brazil, and its epidemiology is similar to that of C. albicans.

Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality.

BACKGROUND: Invasive aspergillosis (IA) is a leading cause of infection-related mortality following hematopoietic cell transplantation (HCT). The aim of this study was to determine the probability of survival and prognostic factors associated with outcomes over a long period of time. METHODS: Cases of proven and probable IA diagnosed in HCT recipients at the Fred Hutchinson Cancer Research Center from 1 January 1990 through 31 December 2004 were included. Patient data were collected from a prospectively maintained database and by retrospective clinical chart review. Survival was estimated using Kaplan-Meier curves, and Cox regression models were used for multivariable analyses. RESULTS: Four hundred five cases were identified. The probability of survival at 90 days after diagnosis was higher for patients identified as having IA between 2002 and 2004 than for patients whose IA was diagnosed in preceding years (45% vs. 22%; P<.001). Risk factors independently associated with all-cause mortality include impairment in pulmonary function before HCT, receipt of human leukocyte antigen-mismatched stem cells, neutropenia, elevated bilirubin and creatinine levels, receipt of corticosteroids at > or =2 mg/kg per day, disseminated and proven IA, and IA occurring >40 days after HCT. Factors associated with a decreased risk of all-cause mortality included receipt of nonmyeloablative conditioning and peripheral blood stem cells. In a subanalysis of attributable mortality restricted to patients receiving antifungal therapy, receipt of voriconazole was independently associated with protection from IA-related death. CONCLUSIONS: There has been a significant decrease in mortality in patients with a diagnosis of IA following HCT in recent years, coinciding with multiple changes in transplantation practices, including use of nonmyeloablative conditioning regimens, receipt of peripheral blood stem cells, more prompt diagnosis of IA, and use of voriconazole.

Inflammatory response and clinical course of adult patients with nosocomial bloodstream infections caused by Candida spp.

Candida spp. are an important cause of nosocomial bloodstream infection (nBSI) and are associated with significant morbidity and mortality. An historical cohort study was performed to evaluate the clinical course of 60 randomly selected adult patients with nBSIs caused by Candida spp. Patients with BSI caused by Candida albicans (n = 38) and non-albicans spp. (n = 22) were compared with 80 patients with Staphylococcus aureus BSI by serial systemic inflammatory response syndrome (SIRS) and APACHE II scores. The patients had a mean age of 52 years, the length of hospital stay before BSI averaged 21 days, and 57% of patients required care in an intensive care unit before BSI. The mean APACHE II score was 17 on the day of BSI, and 63% of BSIs were caused by C. albicans. Antifungal therapy within the first 24 h of onset of BSI was appropriate in 52% of patients. Septic shock occurred in 27% of patients, and severe sepsis in an additional 8%. Overall mortality was 42%, and the 7-day mortality rate was 27%. The inflammatory response and clinical course were similar for patients with BSI caused by C. albicans and non-albicans spp. In univariate analysis, progression to septic shock was correlated with high overall mortality, as was an APACHE II score >25 at the onset of BSI. In multivariate analysis, the APACHE II score at the onset of BSI and a systemic inflammatory response independently predicted overall mortality, but the 7-day mortality rate was only predicted independently by the APACHE II score. Clinical course and mortality in patients with Candida BSI were predicted by systemic inflammatory response and APACHE II score, but not by the infecting species.

A 9-year study comparing risk factors and the outcome of paediatric and adults with nosocomial candidaemia.

Although there are numerous studies of candidaemia in adults, data on paediatrics are still limited. The aim of this study was to compare risk factors, aetiology, therapy, and the outcome of nosocomial candidaemia among paediatric and adult patients in a large Brazilian tertiary hospital (1995-2003). During this period, 78 paediatrics and 113 adults were studied. Species other than Candida albicans caused 78.2% of episodes of candidaemia in paediatrics. Compared to adults, paediatrics received more frequently broad-spectrum antibiotics, vasopressors, blood transfusions, arterial catheter, chest tube, cardiothoracic surgery, mechanical ventilation, and parenteral nutrition. Candidaemia caused by Candida parapsilosis was more common in paediatrics, as was the isolation of Candida spp. from catheters. Amphotericin B treatment was more common in paediatrics. Mortality rate was higher in adults than in paediatrics with nosocomial candidaemia. We reinforce the necessity of continuous epidemiologic surveillance to follow the dynamics of candidaemia.

Effect of Candida albicans septicemia on the cardiovascular function of rabbits.

Candida albicans is an opportunistic pathogen that causes life-threatening systemic infection in immunocompromised host. However, little is known about the effects of yeast on the cardiovascular functions. This study examined the effects of C. albicans septicemia on the heart and vessel functions and nitric oxide (NO) production in infected rabbits. Anaesthetized animals were challenged with intravenous C. albicans (6 x 10(8)/kg) or saline and the blood pressure of rabbits were measured over 5 h. After that response of the isolated thoracic aorta, right atrium and left papillary muscle were recorded. Blood pressure significantly decreased in the infected rabbits during the septicemia but in the control animals it was stable. The blood nitrite levels and NO-synthases (eNOS, iNOS) expression and tissue nitrite levels in the heart and aorta were similar in the both groups. In the aorta isolated from C. albicans-infected rabbits, acetylcholine-induced endothelium-dependent relaxation was decreased, but contractions induced by phenylephrine were potentiated. The NOS inhibitor, L-N(G)-nitro-arginine methyl ester (L-NAME)-induced contraction increase in the right atrium was depressed by the yeast-infection. In the heart and aorta, microscopic examination revealed no tissue invasion of C. albicans. These results indicate the ability of C. albicans-induced septicemia to destroy NO-related responses of the heart and aorta and may have important implications for functional damage to endothelium and the regulation of cardiovascular functions. In addition, NOS induction and NO over-production are not stimulated by systemic C. albicans infection, which would alter the host immune reaction and homeostasis.

A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects.

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Differences in clinical and laboratory diagnostic characteristics of penicilliosis marneffei in human immunodeficiency virus (HIV)- and non-HIV-infected patients.

We compared the clinical and laboratory features of human immunodeficiency virus (HIV)- and non-HIV-infected patients with penicilliosis marneffei. HIV-infected patients had a higher incidence of fungemia. A total of 85.7% of the HIV-negative patients had underlying diseases including hematologic malignancies or had received therapy with corticosteroids or cytotoxic agents. By a Penicillium marneffei-specific mannoprotein Mp1p enzyme-linked immunosorbent assay, serum antigen titers were found to be higher in HIV-positive patients, whereas serum antibody levels were found to be higher in HIV-negative patients.

Improving efficacy of antifungal therapy by polymerase chain reaction-based strategy among febrile patients with neutropenia and cancer.

Early detection of fungal infections in and corresponding early treatment of febrile patients with neutropenia and cancer have been important issues and continue to be major challenges for clinicians. The use of nested PCR to make therapeutic decisions was studied. Sequential blood samples obtained from 42 patients with neutropenia and cancer were tested by nested PCR and culture. Instead of the empirical antifungal therapy strategy, amphotericin B treatment was initiated only for patients who had 2 consecutive positive results by nested PCR. A reduced mortality rate was observed for febrile patients with neutropenia and cancer who had fungal infections. Thus, this strategy, combined with the nested PCR for early detection of fungal infection in febrile patients with neutropenia, may be used as a guideline for antifungal therapy.

Candidal and bacterial bloodstream infections in premature neonates: a case-control study.

Nosocomial bloodstream infections (BSI) in premature neonates are an important cause of morbidity and mortality. The early and efficient diagnosis of a neonatal BSI and the differentiation between bacterial and fungal BSI remains a challenging task. We compared the clinical features and blood test results in preterm infants with proven candidal or bacterial BSI in order to identify potential risk factors for developing a candidal BSI. Preterm infants with proven candidal BSI were significantly more prematurely born (mean age of gestation 27.7 vs. 29.8 weeks), had previously received significantly more antibiotics of multiple classes (mean 4.4 vs. 1.2) for significantly longer periods (mean 19.3 vs. 3.2 days), were ventilated more intensively, had a significantly longer stay at the neonatal intensive care unit before the onset of the BSI (mean 26.5 vs. 9.4 days), and had C-reactive protein values even higher than in preterm infants with a bacterial BSI (mean 90 vs. 71 mg l(-1)). The presence of thrombocytopenia ( < 150 x 10(9) cells l(-1)) in all the preterm infants with candidal BSI was a significant difference. No differences were seen with regard to birth-weight, use of central intravascular catheters, total parenteral nutrition, white blood cell count and differentiation. In conclusion, candidal BSI can be strongly expected after the third week of admittance in the most premature neonates on a respirator and treated with multiple classes of antibiotics for a prolonged period of time. The presence of these risk factors in a 'septic' premature infant on antibiotic treatment justifies the empiric use of antifungals.

Experimental model of progressive disseminated trichosporonosis in mice with latent trichosporonemia.

Trichosporon asahii and Trichosporon mucoides are the most common strains of fungi that cause disseminated trichosporonosis, a severe opportunistic infection in immunocompromised hosts. We have previously established a nested PCR assay using serum samples for detection of both strains. Here we describe a new experimental animal model for investigating the underlying mechanisms of disseminated trichosporonosis. T. asahii (OMU239, a clinical isolate from a patient with acute myelogenous leukemia) and 8-week-old ICR male mice were used in all experiments. A suspension of T. asahii (3 x 10(6) CFU/animal) was injected into the caudal vein of each mouse after immunosuppression with cyclophosphamide (200 mg/kg of body weight/day for 2 days) and prednisolone (30 mg/kg/day for 1 day). Mice were then divided into four subgroups (R0, R1, R2, and R3) based on the time of reimmunosuppression. The latter was performed using the same drugs 1 week (group R1), 2 weeks (group R2), and 3 weeks (group R3) after fungal infection. Reimmunosuppression was not performed in group R0. The 5-week-survival rates of mice after T. asahii infection were 0% for group R1, 50% for group R2, 80% for group R3, and 80% for group R0. There was a significant difference in the survival rates between group R1 and either group R0 or R3 (P < 0.05). Fungal clearance in peripheral blood and various organs of group R1 and R2 was delayed relative to that of group R0 but was similar to the control in group R3 in spite of reimmunosuppression. Our results suggest that the critical period for the development of disseminated trichosporonosis in our model is shorter than 3 weeks after T. asahii infection. We concluded that mice during this critical period were in a state of latent trichosporonemia. Comparison of the survival rates suggests that the nested PCR assay was more useful than blood culture and glucuronoxylomannan antigen assay in the detection of this latent trichosporonemia.

Fungemia during murine cryptococcosis sheds some light on pathophysiology.

We studied fungemia over time in outbred mice infected with Cryptococcus neoformans and looked at its relationship with the intravenous (i.v.) inoculum size, tissue burden and survival. Fungemia was evaluated by culture of 10 microl of peripheral blood from living mice or by culture of buffy coats from sacrificed animals. For all inoculum sizes studied, fungemia could last several weeks after the i.v. inoculation. Individual susceptibility of outbred mice to cryptococcal infection was evidenced by variations in the course, duration and magnitude of fungemia and tissue localizations. These results suggest that the fungus can recirculate after the initial i.v. inoculation. Fungemia, assessed by culture of buffy coats, correlated with the extent of infection in the spleen, lung or brain (P<<0.001) on day 1 after inoculation but only with yeast burden in lung or spleen on day 8, thus demonstrating that brain reacts differently to C. neoformans infection than other organs. Comparison of blood culture techniques and examination of smears suggest that cryptococci might circulate within leucocytes. Finally, quantitative blood cultures may accurately assess the fungal load during experimental cryptococcosis.