Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study.

OBJECTIVES: To evaluate the morbidity and mortality of Candida fungemia and to assess the efficacy of low- vs high-dose amphotericin B and fluconazole vs amphotericin B in patients with candidemia. METHODS: Multicenter, prospective, observational study of 427 consecutive patients with candidemia. RESULTS: The mortality rate for patients with candidemia was 34%. The mortality rate for patients with catheter-related candidemia in whom the catheters were retained was significantly higher than that of patients in whom the catheters were removed (41% vs 21%, P < .001). We found no overall difference in mortality in patients treated with low-dose (total amphotericin B dose of < or = 500 mg) (13%) vs high-dose amphotericin B (total amphotericin B dose of > 500 mg) (15%), but the group treated with a low dose had fewer side effects (40%) than those treated with a high dose (55%) (P = .03). Fluconazole was as efficacious as amphotericin B in the therapy of candidemia, even when stratified by risk factors for mortality. Fewer side effects were seen with fluconazole (12%) compared with amphotericin B (44%) (P < .001). CONCLUSIONS: In selected patients with candidemia, low-dose amphotericin B was as efficacious as high-dose amphotericin B. Based on other studies and ours, fluconazole seems to be an alternative therapeutic option to amphotericin B in selected patients.

cFLIP is critical for oligodendrocyte protection from inflammation.

Neuroinflammation associated with degenerative central nervous system disease and injury frequently results in oligodendrocyte death. While promoting oligodendrocyte viability is a major therapeutic goal, little is known about protective signaling strategies. We report that in highly purified rat oligodendrocytes, interferon gamma (IFNγ) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNFα)-induced cytotoxicity. IFNγ protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-κB activation. Although NF-κB activation also occurred transiently in the absence of IFNγ and presence of TNFα, this activation was not sufficient to prevent induction of the TNFα-responsive cell death pathway. Genetic inhibition of NF-κB translocation to the nucleus abrogated IFNγ-mediated protection and did not change the cell death induced by TNFα, suggesting that NF-κB activation via IFNγ induces a different set of responses than activation of NF-κB via TNFα. A promising candidate is the NF-κB target cFLIP (cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFNγ-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNFα and short hairpin RNA knockdown of cFLIP-abrogated IFNγ -mediated protection. To determine the relevance of our in vitro finding to the more complex in vivo situation, we determined the impact on oligodendrocyte death of regional cFLIP loss of function in a murine model of neuroinflammation. Our data show that downregulation of cFLIP during inflammation leads to death of oligodendrocytes and decrease of myelin in vivo. Taken together, we show that IFNγ-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNFα-induced cell death.

The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance.

OBJECTIVES: To assess the changing epidemiology of candidemia in the 1990s, to evaluate the clinical implications for the presence of non-Candida albicans in blood, and to evaluate the presence of antifungal resistance in relation to prior antifungal administration. DESIGN: Multicenter prospective observational study of patients with positive blood cultures for Candida species or Torulopsis glabrata. SETTING: Four tertiary care medical centers. RESULTS: Four hundred twenty-seven consecutive patients were enrolled. The frequency of candidemia due to non-C. albicans species significantly increased in each hospital throughout the 3.5-year study period (P = 0.01). Thirteen percent of candidemias occurred in patients who were already receiving systemic antifungal agents. Candidemias developing while receiving antifungal therapy were more likely caused by non-C. albicans species than by C. albicans species (P = 0.0005). C. parapsilosis and C. krusei were more commonly seen with prior fluconazole therapy, whereas T. glabrata was more commonly seen with prior amphotericin B therapy. Candida species isolated during episodes of breakthrough candidemia exhibited a significantly higher MIC to the antifungal agent being administered (P < 0.001). CONCLUSION: In this large scale study, the non-C. albicans species, especially T. glabrata, emerged as important and frequent pathogens causing fungemia. This finding has major clinical implications given the higher complication and mortality rate associated with the non-C. albicans species. The change in the pattern of candidemia might be partly attributed to the increase in number of immunocompromised hosts and the widespread use of prophylactic or empiric antifungal therapy. This is an ominous sign given the in vitro resistance of the non-C. albicans species to currently available antifungal agents.

Guidelines for treatment of chronic depression in the aphasic patient.

This article defines the language disorder of aphasia and the motor speech disorders of apraxia of speech and the dysarthrias. Discussion includes depression and the five definable sets of behaviors related to the phenomenon: motor-expressive behaviors, affective, cognitive, motivational, and somatic, and the relationship of self-concept to both depression and visual and verbal thought. Detailed discussion of treatment of chronic depression inpatients with non-organic reactive factors is presented. These include positive reinforcement of desirable behaviors, avoidance of verbal punishment, labeling the disorder for the client and family, and time structuring or scheduling to assist in motivation. In addition, implementation of support from family, friends, and social relationships, tolerance of expressions of frustration and anger by the client, and environmental manipulation are considered therapeutic interventions.

Effect of lead acetate on N-(4'-fluoro-4-biphenyl)acetamide-induced renal carcinogenesis in the rat.

This study assessed the effect of lead acetate (Pb) on N-(4'-fluoro-4-biphenyl)acetamide (FBPA)-induced renal carcinogenesis. A quantitative investigation was performed to determine the effects of Pb on the numerical density (Nv) and percent volume (%V) of FBPA-induced renal tubular hyperplasia and microscopic nodules. A secondary goal was to evaluate, on a quantitative basis, the role of these putative premalignant lesions in the development of renal carcinoma. Additionally, by quantifying the number per unit area of karyomegalic cells, their relationship to the neoplastic process was examined. Generally, Pb was found to accelerate the onset and development of all renal lesions. Karyocytomegaly did not serve as an indicator of the degree of carcinogenicity of any of the treatment regimens.

Rejection criteria for endotracheal aspirates from adults.

Although criteria have been established to assess the quality of sputum specimens, no criteria for assessing the quality of endotracheal suction aspirates (ETSA) exist. Therefore, we compared the Gram stain (GS) and culture results for 504 consecutive ETSA specimens. Results recorded for GS included the numbers of squamous epithelial cells (SEC) and polymorphonuclear leukocytes (PML) per low-power field (LPF) (magnification, x100) as well as the quantities and types of organisms per high-power field (HPF) (magnification, x1,000). Culture results were quantitated by organism. Only 15% of ETSA specimens tested by GS contained > 10 SEC per LPF, and 21, 20, and 59% had < or = 10, 11 to 24, and > or = 25 PML per LPF, respectively. For 40% of ETSA specimens, no organisms were visible by GS. Of these specimens, 40% were sterile, 48% grew normal oropharyngeal flora (NF) only, 5% grew 1+ NF (i.e., > 10 colonies in the first quadrant) and 1+ gram-negative rods (GNR), and 7% grew < or = 1+ GNR either alone or in mixed culture. The mean numbers of organisms recovered from ETSA with < or = 10 SEC per LPF and > 10 SEC per LPF were 2.35 and 4.05, respectively. We therefore recommend that ETSA specimens that show no organisms by GS be rejected, in addition to those with > 10 SEC per LPF. Application of these rejection criteria enabled us to reject 847 (41%) of 2,068 ETSA specimens over a 6-month period. This represents a saving of approximately $66,000/year in unnecessary laboratory charges to patients.

Comparison of commercial kits for detection of cryptococcal antigen.

Although kits to detect cryptococcal antigen are used widely to diagnose cryptococcal infection, the comparative performance of commercially available assays has not been evaluated in the past decade. Therefore, we compared the sensitives and specificities of five commercially available kits for detecting cryptococcal antigen (four latex agglutination test kits--Calas [Meridian Diagnostics])--Crypto-LA [International Biological Labs], Myco-Immune [MicroScan], and Immy [Immunomycologics]--and an enzyme immunoassay kit, Premier [Meridian Diagnostics]) with culture for the diagnosis of cryptococcal meningitis and fungemia. Of 182 cerebrospinal fluid (CSF) and 90 serum samples submitted for cryptococcal antigen and fungal culture, 49 (19 and 30 samples, respectively) from 20 patients had a culture positive for Cryptococcus neoformans. For CSF specimens, the sensitivities and specificities of all kits were comparable (sensitivity, 93 to 100%; specificity, 93 to 98%). There was a significant difference in sensitivities of the kits when serum samples were tested with the International Biological Labs and MicroScan kits, which do not pretreat serum with pronase. These kits were less sensitive (sensitivity, 83%) than the Immy and Meridian latex kits (sensitivity, 97%), which do pretreat with pronase. The sensitivity of the Meridian enzyme immunoassay kit was comparable to that of the pronase-containing latex kits. These kits were of equivalent specificities (93 to 100%) when testing serum. Some of the currently available kits have limitations that need to be recognized for proper interpretation of results. Specifically, the use of pronase on serum samples reduces the number of false-positive results, and a titer of < or = 1:4 can be a false-positive result when CSF samples are being tested.

Disseminated infection with rapidly growing mycobacteria.

Disseminated infection with the rapidly growing mycobacteria Mycobacterium chelonae and Mycobacterium fortuitum is uncommon. Only eight cases were diagnosed at Duke University Medical Center (Durham, NC) over the last 14 years. We identified 46 other cases by review of the medical literature since 1960. We categorized these 54 cases into three groups according to underlying disease and outcome. Group 1 comprised patients with no identified immune defect, a kidney transplant, collagen vascular disease, or chronic renal failure; these patients usually presented with skin involvement and responded well to antimicrobial therapy (survival rate, 90%). Group 2 comprised patients with cell-mediated immune deficiency, lymphoma, or leukemia; they presented with widespread, multiorgan involvement and severe illness. The survival rate in this group was only 10%. Patients in group 3 (who had other underlying diseases) had intermediately severe illnesses and intermediate responses to therapy. These groups provide the basis for an understanding of disseminated infection secondary to rapidly growing mycobacteria and of the profound effect that unresolved immunosuppression has on survival.