L. Kovanda - Academia.edu (original) (raw)

Papers by L. Kovanda

Research paper thumbnail of In vitro combination of isavuconazole with micafungin or amphotericin B deoxycholate against medically important molds

Antimicrobial agents and chemotherapy, 2014

Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combinati... more Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Our in vitro combination studies showed that isavuconazole and micafungin are synergistically active against Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Cunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.

Research paper thumbnail of Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants

Clinical Pharmacology & Therapeutics, 2009

Due to the risk of central nervous system infection, relatively high weight-based echinocandin do... more Due to the risk of central nervous system infection, relatively high weight-based echinocandin dosages may be required for successful treatment of invasive candidiasis and candidemia in young infants. This open-label study assessed safety and pharmacokinetics of micafungin in 13 young infants (> 48 hours of age and < 120 days of life) with suspected candidemia or invasive candidiasis. Infants weighing ≥ 1,000 g and < 1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4 to 5 days. Mean baseline weight and gestational age were 2101 g and 688 g, and 30 weeks and 25 weeks, in the 7 and 10 mg/kg/day groups, respectively. Median pharmacokinetic values for the 7 and 10 mg/kg/day groups, respectively, were: AUC 0-24 , 258.1 and 291.2 μg•h/ml; Cl ss/wt, 0.45 and 0.57 ml/min/kg; C max, 23.3 and 24.9 μg/ml; and Vd ss/wt, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day were well tolerated and provided exposure that was demonstrated in animal model to be adequate for central nervous system coverage.

Research paper thumbnail of Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Antimicrobial Agents and Chemotherapy, 2014

The aim of this analysis was to identify therapeutic micafungin regimens for children that produc... more The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg·h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;17 years.

Research paper thumbnail of Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis

Transplant Infectious Disease, 2009

Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem... more Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis. Transpl Infect Dis 2009: 11: 89^93. All rights reserved Abstract: We describe herein 98 hematopoietic stem cell transplant (HSCT) recipients with invasive aspergillosis (IA) (refractory in 83) who received micafungin either alone (8 patients) or in combination with other licensed antifungal therapies (OLAT) (90 patients). Of the 8 monotherapy patients, 4 were failing OLAT, received de novo micafungin, or were intolerant to prior OLAT (2 patients each). Of the 90 patients treated with combination, 7 had de novo IA and 83 had refractory infection. Most patients (81) had pulmonary IA, 42 (43%) had graft-versus-host disease (GVHD), and 26 (27%) were neutropenic (absolute neutrophil count o500 cells/mm 3 ) at onset of treatment.

Research paper thumbnail of Pharmacokinetics of an Elevated Dosage of Micafungin in Premature Neonates

The Pediatric Infectious Disease Journal, 2009

Background-Determining the safety and pharmacokinetics of antifungal agents in neonates is import... more Background-Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/day) dose of micafungin.

Research paper thumbnail of O140 Micafungin versus caspofungin in patients with invasive candidiasis or candidaemia: a Phase III, randomised, double-blind, parallel group, non-inferiority study

International Journal of Antimicrobial Agents, 2007

% MRSA % MSSA PVL(+) PVL(−) PVL(+) PVL(−) Infection type, % abscess 70.5 (67/95)* 26.3 (15/57) 68... more % MRSA % MSSA PVL(+) PVL(−) PVL(+) PVL(−) Infection type, % abscess 70.5 (67/95)* 26.3 (15/57) 68.0 (68/100)* 48.2 (79/164) Deep infections, % 33.6 (32/95) 38.6 (22/57) 26.0 (26/100) 34.1 (56/164) WBC > 10 4 , % 32.2 (28/87) 21.3 (10/47) 41.4 (36/87) 31.0 (45/145) Temperature >38ºC 14.7 (14/95)* 42.1 (24/57) 44.0 (44/100) 40.2 (66/164) CRP > 50 mg/dL 28.0 (26/93)* 51.9 (28/54) 36.2 (34/94) 41.4 (67/162) Conclusion: PVL-positive MRSA and MSSA were widely prevalent in cSSSI. The presence of PVL in both MRSA and MSSA was significantly associated with abscess compared to wound infections or cellulitis in this cSSSI trial. Lower fever and CRP levels in patients with PVL-positive MRSA infections may indicate impaired host responses to PVL-positive S. aureus. The presence of PVL was associated with lowest cure rates in patients with MRSA infections; however, cure rates in patients treated with BPR exceeded 90%.

Research paper thumbnail of P973 An analysis of the efficacy of micafungin in Candida infections caused by non-albicans Candida species in phase III trials

International Journal of Antimicrobial Agents, 2007

Fungal infections in the immunocompromised host S257 tolerated. No dose adjustments of either mic... more Fungal infections in the immunocompromised host S257 tolerated. No dose adjustments of either micafungin or itraconazole are required when the two compounds are co-administered.

Research paper thumbnail of Factors related to survival and treatment success in invasive candidiasis or candidemia: a pooled analysis of two large, prospective, micafungin trials

European Journal of Clinical Microbiology & Infectious Diseases, 2010

Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remai... more Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remain unacceptably high. It is important to reach a more complete understanding of the risk factors underlying poor outcomes in patients with invasive Candida infections. Micafungin therapy has been assessed in two phase 3 trials compared to either liposomal amphotericin B or caspofungin. The availability of this large dataset allows the analyses of non-drug factors associated with survival and treatment success. A multivariate regression analysis was performed on data from the two trials separately and as a pooled analysis (N=1,070). Analysis outcomes were survival at 42 days post-initiation of therapy and treatment success. For the pooled analysis, treatment success was significantly more likely for candidemia than invasive candidiasis. Both survival and treatment success were significantly less likely for the non-removal of catheter versus removal, Asian-Indians versus Caucasians, APACHE II score >20 to ≤30 and >30 versus ≤20, age ≥70 years versus <50 years, baseline corticosteroids, and persistent neutropenia. Survival was also significantly less likely for treatment in other regions versus North America and for patients with renal failure at baseline. These findings help to define nonantifungal drug factors that may impact survival and treatment success in invasive candidiasis or candidemia.

Research paper thumbnail of Impact of early catheter removal during treatment of invasive candidiasis: analysis from two phase 3 micafungin trials

Critical Care, 2009

There is considerable uncertainty about the reproducibility of the various instruments used to me... more There is considerable uncertainty about the reproducibility of the various instruments used to measure dyspnea, their ability to reflect changes in symptoms, whether they accurately reflect the patient's experience and if its evolution is similar between acute heart failure syndrome patients and nonacute heart failure syndrome patients. URGENT was a prospective multicenter trial designed to address these issues. Methods Patients were interviewed within 1 hour of first physician evaluation, in the emergency department or acute care setting, with dyspnea assessed by the patient using both a five-point Likert scale and a 10-point visual analog scale (VAS) in the sitting (60º) and then supine (20º) position if dyspnea had not been considered severe or very severe by the sitting versus decubitus dyspnea measurement. Results Very good agreements were found between the five-point Likert and VAS at baseline (0.891, P <0.0001) and between changes (from baseline to hour 6) in the five-point Likert and in VAS (0.800, P <0.0001) in acute heart failure (AHF) patients. Lower agreements were found when changes from baseline to H6 measured by Likert or VAS were compared with the seven-point comparative Likert (0.512 and 0.500 respectively) in AHF patients. The worse the dyspnea at admission, the greater the amplitude of improvement in the first 6 hours; this relationship is stronger when dyspnea is measured with VAS (Spearman's rho coefficient = 0.672) than with the five-point Likert (0.272) (both P <0.0001) in AHF patients. By the five-point Likert, only nine patients (3% (1% to 5%)) reported an improvement in their dyspnea, 177 (51% (46% to 57%)) had no change, and 159 (46% (41% to 52%)) reported worse dyspnea supine compared with sitting up in AHF patients. The PDA test with VAS was markedly different between AHF and non-AHF patients. Conclusions Both clinical tools five-point Likert and VAS showed very good agreement at baseline and between changes from baseline to tests performed 6 hours later in AHF patients. The PDA test with VAS was markedly different between AHF and non-AHF patients. Dyspnea is improved within 6 hours in more than threequarters of the patients regardless of the tool used to measure the change in dyspnea. The greater the dyspnea at admission, the greater the amplitude of improvement in the first 6 hours.

Research paper thumbnail of Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis

Clinical Infectious Diseases, 2007

Invasive candidiasis is an important cause of morbidity and mortality among patients with health ... more Invasive candidiasis is an important cause of morbidity and mortality among patients with health care-associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis.

Research paper thumbnail of Isavuconazole Therapy Protects Immunosuppressed Mice from Mucormycosis

Research paper thumbnail of Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

Research paper thumbnail of Use of Pharmacokinetic-Pharmacodynamic Analyses To Optimize Therapy with the Systemic Antifungal Micafungin for Invasive Candidiasis or Candidemia

Antimicrobial Agents and Chemotherapy, 2011

were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and ... more were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC 50 s and MIC 90 s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (<3,000) AUC/MIC ratios (P ‫؍‬ 0.005). For patients with Candida parapsilosis, AUC/MIC ratios of >285 were predictive of a higher mycological response (P ‫؍‬ 0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of >3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of >285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.

Research paper thumbnail of P981 Efficacy of micafungin in patients with deep, invasive Candida infections

International Journal of Antimicrobial Agents, 2007

Extended therapy with HD-CAP was tolerated without serious hepatic or renal impairment. Reversibl... more Extended therapy with HD-CAP was tolerated without serious hepatic or renal impairment. Reversible hyperbilirubinaemia may infrequently occur during HD-CAP therapy.

Research paper thumbnail of In vitro combination of isavuconazole with micafungin or amphotericin B deoxycholate against medically important molds

Antimicrobial agents and chemotherapy, 2014

Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combinati... more Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Our in vitro combination studies showed that isavuconazole and micafungin are synergistically active against Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Cunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.

Research paper thumbnail of Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants

Clinical Pharmacology & Therapeutics, 2009

Due to the risk of central nervous system infection, relatively high weight-based echinocandin do... more Due to the risk of central nervous system infection, relatively high weight-based echinocandin dosages may be required for successful treatment of invasive candidiasis and candidemia in young infants. This open-label study assessed safety and pharmacokinetics of micafungin in 13 young infants (> 48 hours of age and < 120 days of life) with suspected candidemia or invasive candidiasis. Infants weighing ≥ 1,000 g and < 1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4 to 5 days. Mean baseline weight and gestational age were 2101 g and 688 g, and 30 weeks and 25 weeks, in the 7 and 10 mg/kg/day groups, respectively. Median pharmacokinetic values for the 7 and 10 mg/kg/day groups, respectively, were: AUC 0-24 , 258.1 and 291.2 μg•h/ml; Cl ss/wt, 0.45 and 0.57 ml/min/kg; C max, 23.3 and 24.9 μg/ml; and Vd ss/wt, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day were well tolerated and provided exposure that was demonstrated in animal model to be adequate for central nervous system coverage.

Research paper thumbnail of Population Pharmacokinetics of Micafungin and Its Metabolites M1 and M5 in Children and Adolescents

Antimicrobial Agents and Chemotherapy, 2014

The aim of this analysis was to identify therapeutic micafungin regimens for children that produc... more The aim of this analysis was to identify therapeutic micafungin regimens for children that produce the same micafungin exposures known to be effective for the prevention and treatment of Candida infections in adults. Pediatric pharmacokinetic data from 229 patients between the ages of 4 months and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;17 years were obtained from four phase I and two phase III clinical trials. Population pharmacokinetic models were used to simulate the proportion of children who had a steady-state area under the concentration-time curve at 24 hours (AUC24) of micafungin within the 10th to 90th percentile range observed in a population of adults receiving a dose of micafungin with established efficacy for invasive candidiasis (100 mg/day), i.e., 75 to 139 μg·h/ml. Simulated pediatric dosages of 0.5 to 5 mg/kg of body weight/day were explored. A two-compartment model was used that incorporated body weight as a predefined covariate for allometric scaling of the pharmacokinetic parameters. During construction of the model, aspartate aminotransferase and total bilirubin were also identified as covariates that had a significant effect on micafungin clearance. A dose of 2 mg/kg resulted in the highest proportion of children within the predefined micafungin AUC24 target range for invasive candidiasis. Cutoffs of 40 or 50 kg for weight-based dosing resulted in heavier children being appropriately dosed. Thus, dose regimens of 1, 2, and 3 mg/kg/day micafungin are appropriate for the prevention of invasive candidiasis, the treatment of invasive candidiasis, and the treatment of esophageal candidiasis, respectively, in children aged 4 months to &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;17 years.

Research paper thumbnail of Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis

Transplant Infectious Disease, 2009

Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem... more Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis. Transpl Infect Dis 2009: 11: 89^93. All rights reserved Abstract: We describe herein 98 hematopoietic stem cell transplant (HSCT) recipients with invasive aspergillosis (IA) (refractory in 83) who received micafungin either alone (8 patients) or in combination with other licensed antifungal therapies (OLAT) (90 patients). Of the 8 monotherapy patients, 4 were failing OLAT, received de novo micafungin, or were intolerant to prior OLAT (2 patients each). Of the 90 patients treated with combination, 7 had de novo IA and 83 had refractory infection. Most patients (81) had pulmonary IA, 42 (43%) had graft-versus-host disease (GVHD), and 26 (27%) were neutropenic (absolute neutrophil count o500 cells/mm 3 ) at onset of treatment.

Research paper thumbnail of Pharmacokinetics of an Elevated Dosage of Micafungin in Premature Neonates

The Pediatric Infectious Disease Journal, 2009

Background-Determining the safety and pharmacokinetics of antifungal agents in neonates is import... more Background-Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/day) dose of micafungin.

Research paper thumbnail of O140 Micafungin versus caspofungin in patients with invasive candidiasis or candidaemia: a Phase III, randomised, double-blind, parallel group, non-inferiority study

International Journal of Antimicrobial Agents, 2007

% MRSA % MSSA PVL(+) PVL(−) PVL(+) PVL(−) Infection type, % abscess 70.5 (67/95)* 26.3 (15/57) 68... more % MRSA % MSSA PVL(+) PVL(−) PVL(+) PVL(−) Infection type, % abscess 70.5 (67/95)* 26.3 (15/57) 68.0 (68/100)* 48.2 (79/164) Deep infections, % 33.6 (32/95) 38.6 (22/57) 26.0 (26/100) 34.1 (56/164) WBC > 10 4 , % 32.2 (28/87) 21.3 (10/47) 41.4 (36/87) 31.0 (45/145) Temperature >38ºC 14.7 (14/95)* 42.1 (24/57) 44.0 (44/100) 40.2 (66/164) CRP > 50 mg/dL 28.0 (26/93)* 51.9 (28/54) 36.2 (34/94) 41.4 (67/162) Conclusion: PVL-positive MRSA and MSSA were widely prevalent in cSSSI. The presence of PVL in both MRSA and MSSA was significantly associated with abscess compared to wound infections or cellulitis in this cSSSI trial. Lower fever and CRP levels in patients with PVL-positive MRSA infections may indicate impaired host responses to PVL-positive S. aureus. The presence of PVL was associated with lowest cure rates in patients with MRSA infections; however, cure rates in patients treated with BPR exceeded 90%.

Research paper thumbnail of P973 An analysis of the efficacy of micafungin in Candida infections caused by non-albicans Candida species in phase III trials

International Journal of Antimicrobial Agents, 2007

Fungal infections in the immunocompromised host S257 tolerated. No dose adjustments of either mic... more Fungal infections in the immunocompromised host S257 tolerated. No dose adjustments of either micafungin or itraconazole are required when the two compounds are co-administered.

Research paper thumbnail of Factors related to survival and treatment success in invasive candidiasis or candidemia: a pooled analysis of two large, prospective, micafungin trials

European Journal of Clinical Microbiology & Infectious Diseases, 2010

Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remai... more Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remain unacceptably high. It is important to reach a more complete understanding of the risk factors underlying poor outcomes in patients with invasive Candida infections. Micafungin therapy has been assessed in two phase 3 trials compared to either liposomal amphotericin B or caspofungin. The availability of this large dataset allows the analyses of non-drug factors associated with survival and treatment success. A multivariate regression analysis was performed on data from the two trials separately and as a pooled analysis (N=1,070). Analysis outcomes were survival at 42 days post-initiation of therapy and treatment success. For the pooled analysis, treatment success was significantly more likely for candidemia than invasive candidiasis. Both survival and treatment success were significantly less likely for the non-removal of catheter versus removal, Asian-Indians versus Caucasians, APACHE II score >20 to ≤30 and >30 versus ≤20, age ≥70 years versus <50 years, baseline corticosteroids, and persistent neutropenia. Survival was also significantly less likely for treatment in other regions versus North America and for patients with renal failure at baseline. These findings help to define nonantifungal drug factors that may impact survival and treatment success in invasive candidiasis or candidemia.

Research paper thumbnail of Impact of early catheter removal during treatment of invasive candidiasis: analysis from two phase 3 micafungin trials

Critical Care, 2009

There is considerable uncertainty about the reproducibility of the various instruments used to me... more There is considerable uncertainty about the reproducibility of the various instruments used to measure dyspnea, their ability to reflect changes in symptoms, whether they accurately reflect the patient's experience and if its evolution is similar between acute heart failure syndrome patients and nonacute heart failure syndrome patients. URGENT was a prospective multicenter trial designed to address these issues. Methods Patients were interviewed within 1 hour of first physician evaluation, in the emergency department or acute care setting, with dyspnea assessed by the patient using both a five-point Likert scale and a 10-point visual analog scale (VAS) in the sitting (60º) and then supine (20º) position if dyspnea had not been considered severe or very severe by the sitting versus decubitus dyspnea measurement. Results Very good agreements were found between the five-point Likert and VAS at baseline (0.891, P <0.0001) and between changes (from baseline to hour 6) in the five-point Likert and in VAS (0.800, P <0.0001) in acute heart failure (AHF) patients. Lower agreements were found when changes from baseline to H6 measured by Likert or VAS were compared with the seven-point comparative Likert (0.512 and 0.500 respectively) in AHF patients. The worse the dyspnea at admission, the greater the amplitude of improvement in the first 6 hours; this relationship is stronger when dyspnea is measured with VAS (Spearman's rho coefficient = 0.672) than with the five-point Likert (0.272) (both P <0.0001) in AHF patients. By the five-point Likert, only nine patients (3% (1% to 5%)) reported an improvement in their dyspnea, 177 (51% (46% to 57%)) had no change, and 159 (46% (41% to 52%)) reported worse dyspnea supine compared with sitting up in AHF patients. The PDA test with VAS was markedly different between AHF and non-AHF patients. Conclusions Both clinical tools five-point Likert and VAS showed very good agreement at baseline and between changes from baseline to tests performed 6 hours later in AHF patients. The PDA test with VAS was markedly different between AHF and non-AHF patients. Dyspnea is improved within 6 hours in more than threequarters of the patients regardless of the tool used to measure the change in dyspnea. The greater the dyspnea at admission, the greater the amplitude of improvement in the first 6 hours.

Research paper thumbnail of Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis

Clinical Infectious Diseases, 2007

Invasive candidiasis is an important cause of morbidity and mortality among patients with health ... more Invasive candidiasis is an important cause of morbidity and mortality among patients with health care-associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis.

Research paper thumbnail of Isavuconazole Therapy Protects Immunosuppressed Mice from Mucormycosis

Research paper thumbnail of Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

Research paper thumbnail of Use of Pharmacokinetic-Pharmacodynamic Analyses To Optimize Therapy with the Systemic Antifungal Micafungin for Invasive Candidiasis or Candidemia

Antimicrobial Agents and Chemotherapy, 2011

were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and ... more were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC 50 s and MIC 90 s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (<3,000) AUC/MIC ratios (P ‫؍‬ 0.005). For patients with Candida parapsilosis, AUC/MIC ratios of >285 were predictive of a higher mycological response (P ‫؍‬ 0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of >3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of >285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.

Research paper thumbnail of P981 Efficacy of micafungin in patients with deep, invasive Candida infections

International Journal of Antimicrobial Agents, 2007

Extended therapy with HD-CAP was tolerated without serious hepatic or renal impairment. Reversibl... more Extended therapy with HD-CAP was tolerated without serious hepatic or renal impairment. Reversible hyperbilirubinaemia may infrequently occur during HD-CAP therapy.