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Biomedical subjects

P H Chandrasekar

Publications and source records attributed to P H Chandrasekar.

At least 19 recordsLinked to original sources
PubMed2006

Micafungin: a new echinocandin.

Micafungin, a potent inhibitor of 1,3-beta-D-glucan synthase, has become the second available agent in the echinocandins class that is approved for use in clinical practice. This agent shares with caspofungin an identical spectrum of in vitro activity against Candida albicans, non-albicans species of Candida, and Aspergillus species, as well as several but not all pathogenic molds. If anything, its in vitro activity appears to be superior to that of caspofungin, although the clinical relevance of this observation is unclear. The clinical role of micafungin appears to be similar to that of caspofungin, although clinical data are still lacking at this stage, with initial approval only for treatment of esophageal candidiasis and prophylaxis in subjects with neutropenia. Pharmacokinetic and pharmacodynamic studies and reports of adverse effects and safety have reported similar but not identical results to those of other agents in the echinocandin class. Factors such as acquisition costs and the potential for resistance development may be more relevant to its widespread use than in vitro and in vivo data comparisons with caspofungin.

Animals↗
PubMed2005

Effectiveness of amphotericin B lipid complex (ABLC) treatment in allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis (IA).

A total of 85 allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis treated with amphotericin B lipid complex (ABLC) were identified from the Collaborative Exchange of Antifungal Research (CLEAR) database. Of these patients, 78% (66/85) presented with pulmonary aspergillosis. Graft-versus-host disease (GVHD) was present in 24 of 85 patients. The response rate to ABLC was 31% (26/85) overall and 21% (5/24) in patients with GVHD. The overall response rate to first-line ABLC treatment was 41% (11/27). Four of nine (44%) patients with GVHD responded to first-line treatment with ABLC, while only one of 13 (8%) responded to ABLC as second-line therapy. Five of 18 (28%) and four of 14 (29%) patients, respectively, responded to sequential or concurrent treatment with ABLC and itraconazole. None of seven patients responded who continued receiving itraconazole after the start of ABLC therapy. At the end of ABLC therapy, serum creatinine had doubled in 12% of patients (10/85), and 2% (2/85) had developed a requirement for dialysis. These data suggest that ABLC, especially when administered as first-line therapy, can result in clinical response even in the most immunocompromised patients, that is, HCT recipients with GVHD, with minimal effects on renal function.

Adolescent↗
PubMed2005

Antifungal resistance in Aspergillus.

There are currently few data on drug resistance in Aspergillus, but the recent development of susceptibility tests have made it possible, to some extent, to study resistance in azoles and polyenes. This paper reviews the limited data available. The increased incidence of aspergillosis and the introduction of newer drugs make it important to continue to monitor closely trends in antifungal drug resistance.

Antifungal Agents↗
PubMed2004

Efficacy of voriconazole plus amphotericin B or micafungin in a guinea-pig model of invasive pulmonary aspergillosis.

The efficacy of voriconazole in combination with amphotericin B or micafungin was studied in a transiently neutropenic guinea-pig model of invasive pulmonary aspergillosis. Guinea-pigs treated with the antifungal drugs, alone or in two-drug combinations, had an improved survival rate and reduced fungal burden in the lungs compared to untreated control animals. The efficacy of monotherapy and combination therapy was similar; activity was neither enhanced nor reduced with the two-drug combinations. Further studies of efficacy, dosing and optimal regimens for antifungal combinations are warranted.

Amphotericin B↗
PubMed2004

In-vitro activity of nikkomycin Z alone and in combination with polyenes, triazoles or echinocandins against Aspergillus fumigatus.

The in-vitro activity of nikkomycin Z was investigated in combination with polyenes, triazoles or echinocandins against 20 clinical isolates of Aspergillus fumigatus with the fractional inhibitory concentration index (FICI) method. The drug interactions were classified as synergic (FICI < or = 0.5), no interaction (FICI > 0.5, but FICI < or = 4) or antagonistic (FICI > 4). The fungicidal activity of nikkomycin Z alone and in combination with a representative echinocandin (caspofungin) or triazole (voriconazole) was also examined with time-kill experiments and fungal cell viability assays. Two-drug combinations of nikkomycin Z with amphotericin B (FICI 3.59 +/- 0.57), amphotericin B lipid complex (FICI 3.95 +/- 0.74), liposomal amphotericin B (FICI 3.62 +/- 0.98), itraconazole (FICI 2.0 +/- 0.0), voriconazole (FICI 1.07 +/- 0.37), posaconazole (FICI 2.20 +/- 0.44) or ravuconazole (FICI 1.76 +/- 0.44) showed no interactions, but the pairwise combination of nikkomycin Z with caspofungin (FICI 0.22 +/- 0.19) or micafungin (FICI 0.35 +/- 0.27) showed synergic activity against A. fumigatus. Time-kill studies and fungal cell viability assays showed that neither nikkomycin Z nor caspofungin alone possessed fungicidal activity against A. fumigatus, whereas a combination of these two drugs at concentrations > or = 2 mg/L (> or = 0.031 x the concentration of drug that produced no visible growth) killed germinated conidia within 24 h in a concentration-dependent manner. These data suggest that two-drug combinations of nikkomycin Z with echinocandins, but not with polyenes and triazoles, have a synergic effect against A. fumigatus.

Aminoglycosides↗
PubMed2002

Caspofungin.

Available systemically effective antifungal agents for the treatment of invasive fungal infections are few. With the increasing recognition of a need for newer antifungal drugs, caspofungin has been introduced as the first member of a new class of compounds called echinocandins. This paper reviews the chemistry and mechanism of action of caspofungin, its activity in vitro and in animal models, and clinical pharmacokinetics,clinical efficacy and safety in patients.

Animals↗
PubMed2001

Low infectious morbidity after intensive chemotherapy and autologous peripheral blood progenitor cell transplantation in the outpatient setting for women with breast cancer.

Autologous peripheral blood progenitor cell (PBPC) transplantation is increasingly employed in the outpatient setting, yet data on early complications following PBPC transplantation are scant. We evaluated 105 women with high-risk primary or metastatic breast cancer who were treated at a single institution during 1996--1997. The mean duration of neutropenia (absolute neutrophil count, <500 cells/mm(3)) was 7.5 days. Twenty-nine percent of women remained afebrile throughout the neutropenic period. Of the remaining 71%, most (64 of 75) had fever of unknown origin. Infections, mostly of mild severity, occurred in 34% of women; these infections included bacteremia due to gram-positive organisms, catheter site infection, cellulitis, pneumonia, oral candidiasis, herpes simplex virus infection, and vaginitis. Fifty percent of PBPC transplant recipients required hospital admission, usually because of persistent fever; the mean duration of hospitalization was 3 days. No deaths or serious adverse events occurred. Such reduced infectious morbidity may be a consequence of minimal oral and/or gastrointestinal mucositis associated with the conditioning regimen and broad-spectrum antimicrobial prophylaxis used for this patient population.

Adult↗
PubMed2001

Aspergillus: rising frequency of clinical isolation and continued susceptibility to antifungal agents, 1994-1999.

We investigated the frequency of clinical isolation and the in vitro susceptibility to antifungal agents of Aspergillus species obtained from patients at the Detroit Medical Center from January 1994 to December 1999. During this period, 593 clinical isolates of Aspergillus species [406 A. fumigatus, 68%; 82 A. niger, 14%; 42 A. flavus, 7%; 63 Aspergillus spp., 11%] were recovered from hospitalized patients. From January 1996 to December 1999, approximately 2.5-4.5 fold yearly increase of the number of aspergillus isolates occurred compared to that of 1994. Conidial suspensions from clinical isolates were prepared and their in vitro susceptibility to amphotericin B and three azoles were determined. All four agents examined were extremely active. The minimum inhibitory concentrations (MIC(90)) (microg/mL) of amphotericin B, itraconazole, voriconazole and posaconazole for A. fumigatus (n = 406) were 0.5, 1.0, 0.5 and 0.25. Similar values were noted for non-A. fumigatus isolates. A year-to-year comparison of the MIC(90) of the four agents for A. fumigatus and non-A. fumigatus isolates over the 6-year study period showed no significant differences. Our study showed a steady increase in the frequency of clinical isolation of Aspergillus species; and the organism has remained susceptible to amphotericin B/triazoles without any change in susceptibility levels during the 6-year study period.

Amphotericin B↗
PubMed2001

Isolation and in vitro susceptibility to amphotericin B, itraconazole and posaconazole of voriconazole-resistant laboratory isolates of Aspergillus fumigatus.

OBJECTIVES: To select voriconazole-resistant mutants of Aspergillus fumigatus in the laboratory from drug-susceptible clinical isolates and examine their in vitro susceptibility to amphotericin B and investigational azoles, and to compare the intramycelial accumulation of voriconazole in the resistant isolates with that in the susceptible parent. METHODS: Voriconazole-resistant Aspergillus fumigatus isolates were selected in the laboratory from three highly susceptible (MIC < or = 0.5 mg/L) clinical isolates by stepwise selection on peptone yeast extract glucose (PYG) agar containing 0.5 mg and 4 mg voriconazole/L. Twenty-three colonies that grew in the presence of 4 mg voriconazole/L on PYG agar (frequency 1.9 x 10(-8)) were tested for their in vitro susceptibility to amphotericin B, itraconazole, voriconazole and posaconazole by a broth macrodilution technique. The accumulation of voriconazole in the mycelia of two representative resistant isolates (VCZ-W42 and VCZ-W45) was determined by a previously described bioassay. RESULTS: The geometric mean MICs (mg/L) of amphotericin B, itraconazole, voriconazole and posaconazole for these isolates were 0.45 +/- 0.19, 0.69 +/- 0.45, 5.24 +/- 3.74 and 0.27 +/- 0.18, respectively. A comparison of the geometric mean MICs of the antifungals obtained for the resistant isolates to those of the susceptible parents showed 1.15-, 2.76-, 16.90- and 1.42-fold increases, respectively, for amphotericin B, itraconazole, voriconazole and posaconazole, suggesting that low-level cross-resistance exists between the azole antifungals. The susceptible parent and the resistant isolates accumulated similar amounts of voriconazole. CONCLUSIONS: These results suggest that spontaneous mutants of Aspergillus fumigatus resistant to voriconazole could emerge among clinical isolates under selection pressure and that the observed reduced in vitro susceptibility to voriconazole may not be due to reduced accumulation of the drug in the mycelia.

Amphotericin B↗
PubMed2001

Inhibition of H(+)-ATPase-mediated proton pumping in Cryptococcus neoformans by a novel conjugated styryl ketone.

We investigated the in vitro susceptibility of clinical isolates of Cryptococcus neoformans to the novel conjugated styryl ketone NC1175 by broth microdilution. The MIC(90) and the MFC of NC1175 for C. neoformans were 1 and 2 mg/L, respectively. NC1175 at low concentrations (1-4 mg/L) completely inhibited the glucose-induced acidification of the external medium caused by the extrusion of intracellular protons mediated by the plasma membrane located H(+)-ATPase. These data suggest that NC1175 is a fungicidal agent for C. neoformans and its possible cellular target(s) include the H(+)-ATPase.

Antifungal Agents↗
PubMed2000

Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Adults and children in the United States get two to six colds per year. Evidence that zinc is effective therapy for colds is inconsistent. OBJECTIVE: To test the efficacy of zinc acetate lozenges in reducing the duration of symptoms of the common cold. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Detroit Medical Center, Detroit, Michigan. PATIENTS: 50 ambulatory volunteers recruited within 24 hours of developing symptoms of the common cold. INTERVENTION: Participants took one lozenge containing 12.8 mg of zinc acetate or placebo every 2 to 3 hours while awake as long as they had cold symptoms. MEASUREMENTS: Subjective symptom scores for sore throat, nasal discharge, nasal congestion, sneezing, cough, scratchy throat, hoarseness, muscle ache, fever, and headache were recorded daily for 12 days. Plasma zinc and proinflammatory cytokine levels were measured on day 1 and after participants were well. RESULTS: Forty-eight participants completed the study (25 in the zinc group and 23 in the placebo group). Compared with the placebo group, the zinc group had shorter mean overall duration of cold symptoms (4.5 vs. 8.1 days), cough (3.1 [95% CI, 2.1 to 4.1] vs. 6.3 [CI, 4.9 to 7.7] days), and nasal discharge (4.1 [CI, 3.3 to 4.9] vs. 5.8 [CI, 4.3 to 7.3] days) and decreased total severity scores for all symptoms (P < 0.002, test for treatment x time interaction). Mean changes in soluble interleukin-1 receptor antagonist level differed nonsignificantly between the zinc group and the placebo group (difference between changes, -89.4 pg/mL [CI, -243.6 to -64.8 pg/mL]). CONCLUSION: Administration of zinc lozenges was associated with reduced duration and severity of cold symptoms, especially cough. Improvement in clinical symptoms with zinc treatment may be related to a decrease in proinflammatory cytokine levels; however, in this study, the observed differences between changes in cytokine levels in zinc and placebo recipients were not significant.

Adult↗
PubMed2000

Efficacy of voriconazole against invasive pulmonary aspergillosis in a guinea-pig model.

We compared the efficacies of amphotericin B and voriconazole against invasive pulmonary aspergillosis in a guinea-pig model. A susceptible isolate of Aspergillus fumigatus was used to produce the infection. Voriconazole-treated animals had significantly better survival and decreased fungal burden in the lungs as compared with controls. Although no statistical difference was seen between the efficacies of voriconazole and amphotericin B, a trend favouring voriconazole was noted. Thus, voriconazole, with its cidal activity, may be an attractive alternative to potentially toxic amphotericin B in the treatment of invasive pulmonary aspergillosis.

Amphotericin B↗