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Biomedical subjects

Susan Hadley

Publications and source records attributed to Susan Hadley.

15 recordsLinked to original sources
PubMed2006

Daptomycin in the treatment of vancomycin-resistant Enterococcus faecium bacteremia in neutropenic patients.

OBJECTIVE: Vancomycin resistant enterococcal (VRE) blood stream infection (BSI) in neutropenic patients is associated with poor outcome. We report our experience in treating VRE BSI in febrile, neutropenic patients with daptomycin, a recently licensed lipopeptide with bactericidal activity against VRE. PATIENTS AND METHODS: Patients with fever, neutropenia and VRE BSI were treated with more than one dose of daptomycin (either 6 mg/kg/day or 4 mg/kg/day) in an open label, emergency-use trial. Patients were then assessed for clinical and microbiological cures and survival. MIC's of isolates to daptomycin were determined. RESULTS: Nine febrile, neutropenic patients with VRE BSI received daptomycin. Four of 9 courses (44%) had clinical and/or microbiologic cure. Two of the 5 who failed cure died within 3 days of initiation of daptomycin. Five subjects survived to 30 days after the onset of BSI. CONCLUSIONS: Use of daptomycin in neutropenic patients with VRE BSI deserves further study as a treatment for VRE BSI in neutropenic patients.

Adult↗
PubMed2006

Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial.

BACKGROUND: Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. METHODS: We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. RESULTS: Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. CONCLUSIONS: Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

Antifungal Agents↗
PubMed2006

Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections.

BACKGROUND: Invasive fungal infections are found most frequently in immunosuppressed and critically ill hospitalized patients. Antifungal therapy is often required for long periods. Safety data from the clinical development program of the triazole antifungal agent, posaconazole, were analyzed. METHODS: A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole in 2 phase II/III open-label clinical trials. Also, 109 of these patients received posaconazole therapy for > or = 6 months. Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these studies. RESULTS: Treatment-emergent, treatment-related adverse events were reported in 38% of the overall patient population. The most common treatment-related adverse events were nausea (8%) and vomiting (6%). Treatment-related serious adverse events occurred in 8% of patients. Low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%) were reported as adverse events. Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for < 6 months and > or = 6 months. CONCLUSIONS: Prolonged posaconazole treatment was associated with a generally favorable safety profile in seriously ill patients with refractory invasive fungal infections. Long-term therapy did not increase the risk of any individual adverse event, and no unique adverse event was observed with longer exposure to posaconazole.

Adolescent↗
PubMed2005

Empirical anti-Candida therapy among selected patients in the intensive care unit: a cost-effectiveness analysis.

BACKGROUND: Mortality from invasive candidiasis is high. Low culture sensitivity and treatment delay contribute to increased mortality, but nonselective early therapy may result in excess costs and drug resistance. OBJECTIVE: To determine the cost-effectiveness of anti-Candida strategies for high-risk patients in the intensive care unit (ICU). DESIGN: Cost-effectiveness decision model. DATA SOURCES: Published data to 10 May 2005, identified from MEDLINE and Cochrane Library searches, ICU databases, expert estimates, and actual hospital costs. TARGET POPULATION: Patients in the ICU with suspected infection who have not responded to antibacterial therapy. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Fluconazole, caspofungin, amphotericin B, or lipid formulation of amphotericin B given as either empirical or culture-based therapy and no anti-Candida therapy. OUTCOME MEASURES: Incremental life expectancy and incremental cost per discounted life-year (DLY) saved. RESULTS OF BASE-CASE ANALYSIS: Ten percent of the target population will have invasive candidiasis. Empirical caspofungin therapy is the most effective strategy but is expensive (295,115 dollars per DLY saved). Empirical fluconazole therapy is the most reasonable strategy (12,593 dollars per DLY saved) and decreases mortality from 44.0% to 30.4% in patients with invasive candidiasis and from 22.4% to 21.0% in the overall target cohort. RESULTS OF SENSITIVITY ANALYSIS: Empirical fluconazole therapy is reasonable for likelihoods of invasive candidiasis greater than 2.5% or fluconazole resistance less than 24.0%. For higher resistance levels, empirical caspofungin therapy is preferred. For low prevalences of invasive candidiasis, culture-based fluconazole is reasonable. For prevalences exceeding 60%, empirical caspofungin therapy is reasonable. For caspofungin to be reasonable at a prevalence of 10%, its cost must be reduced by 58%. LIMITATIONS: Less severe illness and limited use of broad-spectrum antimicrobial agents, typical of smaller hospitals, could result in a lower risk for invasive candidiasis. CONCLUSIONS: In patients in the ICU with suspected infection who have not responded to antibiotic treatment, empirical fluconazole should reduce mortality at an acceptable cost. The use of empirical strategies in low-risk patients is not justified.

Amphotericin B↗
PubMed2005

Fungal arthritis and osteomyelitis.

Fungal arthritis and osteomyelitis are uncommon diseases and generally present in an indolent fashion. The incidence of fungal bone and joint dis-ease is increasing with an increase in the prevalence of factors predisposing to invasive fungal disease, such as the use of central venous catheters, broad spectrum antibiotics, immunosuppression, and abdominal surgery. Definitive diagnosis relies on bone or synovial culture or biopsy. Successful management has traditionally consisted of amphotericin B in combination with surgical debridement. Given the rarity of this disease, treatment is not well defined, but reports of success with the use of azole antifungal agents, including itraconazole, fluconazole, voriconazole, and posaconazole, are promising.

AIDS-Related Opportunistic Infections↗
PubMed2004

The clinical impact of ganciclovir prophylaxis on the occurrence of bacteremia in orthotopic liver transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection or receipt of a CMV-seropositive donor liver has been shown to be an independent predictor of bacteremia in orthotopic liver transplant (OLT) recipients. However, prevention of CMV infection through use of intense CMV prophylaxis has not been examined to assess the impact on bacteremia in liver transplant recipients. METHODS: We analyzed the impact of CMV prophylaxis on rates of bacteremia by examining 192 consecutive OLT recipients during a 2-year follow-up period. RESULTS: There were 29 episodes of bacteremia. Univariate analysis of risk factors for bacteremia showed that invasive fungal disease, initial anti-lymphocyte immunosuppression, treatment for rejection, and use of solumedrol were significantly associated with increased risk. Receipt of >or=14 days of ganciclovir prophylaxis (hazard ratio [HR], 0.40; 95% CI [confidence interval], 0.18-0.87; P=.02), end-to-end biliary anastomosis, and receipt of <10 units of red blood cells (RBCs) were significantly associated with a decreased risk. Three-variable analysis controlling for end-to-end anastomosis and use of <10 units of RBCs, showed that use of >or=14 days of ganciclovir was still associated with a reduced risk of bacteremia (HR, 0.44; 95% CI, 0.20-0.98; P=.0437). CONCLUSIONS: Among factors associated with bacteremia, use of prophylactic ganciclovir is independently associated with a significant reduction of bacteremia in OLT recipients.

Adult↗
PubMed2004

Impact of real-time fungal susceptibility on clinical practices.

PURPOSE OF REVIEW: In the past two decades standardized in-vitro antifungal susceptibility tests have been developed in response to increasing invasive fungal infections. Our purpose is to review the utility of real-time Candida antifungal susceptibility testing and its effects on clinical outcomes in the context of the new antifungal agents, existing antifungal susceptibility testing methods, and the changing epidemiology and susceptibilities of Candida spp. RECENT FINDINGS: New antifungal agents active against Candida spp. are now available. Caspofungin is approved for the treatment of invasive candidiasis but standardized antifungal susceptibility testing has not been developed. The newer triazoles, such as voriconazole, posaconazole and ravuconazole, are not yet approved for invasive candidiasis. As infections caused by non-albicans Candida spp. with growing resistance to fluconazole increase, antifungal susceptibility testing may be important to guide therapy. Unfortunately, few studies exist describing the impact of real-time antifungal susceptibility testing on the treatment of invasive fungal infections. SUMMARY: Newer antifungal agents with broader anti-Candida activity, fewer adverse events and minimal resistance are currently available. The challenge clinicians face is choosing when to use these agents appropriately, while considering the changing Candida epidemiology and susceptibility trends without over-treating fluconazole-sensitive pathogens. Unfortunately, the correlation of antifungal susceptibility testing results by any method and clinical outcome is mostly lacking. We suggest that a concerted examination of the utility of real-time antifungal susceptibility testing and its effect on clinical outcomes by guiding appropriate antifungal therapy for high-risk patients with invasive candidiasis is warranted.

Antifungal Agents↗
PubMed2004

Comparison of the semisolid agar antifungal susceptibility test with the NCCLS M38-P broth microdilution test for screening of filamentous fungi.

Antifungal susceptibility testing of pathogenic molds is being developed. A simple screening semisolid agar antifungal susceptibility (SAAS) test accurately measures susceptibilities of yeasts. The performance of the SAAS screening test for filamentous fungi was assessed by comparing MICs of four antifungals (amphotericin B [AMB], AMB lipid complex [ABEL], itraconazole [ITZ], and posaconazole [POS]) for 54 clinical mold isolates with the results of the National Committee for Clinical Laboratory Standards (NCCLS) proposed broth microdilution method (M38-P). The SAAS test utilized inocula stabbed into tubes of 0.5% semisolid heart infusion agar. In both tests MICs were read after incubation at 35 degrees C for 48 h. The isolates tested were Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, other Aspergillus spp., Fusarium spp., Penicillium sp., Mucor sp., Scedosporium prolificans, Trichophyton sp., and an unidentified dematiaceous mold. Concordance of test results was determined as the percent agreement of MICs +/- 1 dilution. The overall agreement between the tests for each drug was as follows: AMB, 94%; ABEL, 83%; ITZ, 94%; POS, 94%. For the Aspergillus spp., all but one were susceptible to ITZ by SAAS test; all were susceptible to POS (MIC range, 0.25 to 4 micro g/ml). Three of six non-Aspergillus molds that were resistant to AMB and ABEL by SAAS (MIC >/= 2 micro g/ml) were also resistant by the NCCLS test. The SAAS test compared favorably to the NCCLS broth microdilution test for molds, and most of the clinical isolates tested were susceptible to all four drugs.

Agar↗
PubMed2003

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.

Adult↗
PubMed2003

Valerian.

Valerian is a traditional herbal sleep remedy that has been studied with a variety of methodologic designs using multiple dosages and preparations. Research has focused on subjective evaluations of sleep patterns, particularly sleep latency, and study populations have primarily consisted of self-described poor sleepers. Valerian improves subjective experiences of sleep when taken nightly over one- to two-week periods, and it appears to be a safe sedative/hypnotic choice in patients with mild to moderate insomnia. The evidence for single-dose effect is contradictory. Valerian is also used in patients with mild anxiety, but the data supporting this indication are limited. Although the adverse effect profile and tolerability of this herb are excellent, long-term safety studies are lacking.

Humans↗
PubMed2002

Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever.

BACKGROUND: Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative. METHODS: In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy. RESULTS: A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03). CONCLUSIONS: Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

Adolescent↗
PubMed2002

Real-time antifungal susceptibility screening aids management of invasive yeast infections in immunocompromised patients.

We examined the utility of a semi-solid agar antifungal susceptibility screening (SAAS) test in real-time management of eight immunocompromised patients with invasive yeast infections. Tests of amphotericin B and fluconazole concentrations of 0.5 and 2 mg/L and 1, 8 and 40 mg/L, respectively, were performed on Candida albicans (two), Candida tropicalis (two), Candida krusei (one), Candida glabrata (one) and Trichosporon species (spp.) (two). All but the Trichosporon spp. and C. glabrata isolates were resistant to fluconazole at > or = 40 mg/L, and patients were successfully managed accordingly. Real-time antifungal susceptibility screening can assist in clinical management of invasive yeast infections.

Adult↗
PubMed2002

Candidemia as a cause of septic shock and multiple organ failure in nonimmunocompromised patients.

OBJECTIVE: To describe outcomes of septic shock and multiple organ failure arising from candidemia. DESIGN: Secondary cohort analysis of data from the placebo arm of the North American Septic Shock Trial (NORASEPT II), the largest prospective, randomized, double-blind, controlled multiple center study of septic shock conducted to date, with predetermined end point analysis of outcomes. SETTING: Adult intensive care units in 105 hospitals in the United States and Canada. SUBJECTS: A cohort of ten purely candidemic patients in septic shock were compared with a cohort of 376 purely bacteremic patients in septic shock. Patients were not immunocompromised, because patients on corticosteroids, with neutropenia, or posttransplantation were excluded from enrollment in NORASEPT II. MEASUREMENTS AND MAIN RESULTS: Demographic variables, baseline characteristics, 28-day mortality rates, and multiple organ failure were compared for the two cohorts. Candidemic patients were more likely to have a history of underlying renal failure at baseline and to require dialysis at onset of septic shock. Both causes of septic shock are associated with an extremely high severity of illness (Acute Physiology and Chronic Health Evaluation II: candidemic septic shock, 32 +/- 10; bacteremic septic shock, 30 +/- 8; p =.44). More than 70% of patients with candidemia and septic shock were in multiple organ failure at days 3, 7, and 14; patients with candidemic septic shock sustained persistent multiple organ failure and showed delayed recovery from multiple organ failure compared with patients with bacteremic septic shock. Mortality rate at 28 days was 60% in candidemic septic shock and 46% in bacteremic septic shock (p =.38). CONCLUSIONS: Candidemia with septic shock is infrequent in nonimmunocompromised patients but has a very high mortality rate, a high likelihood of associated multiple organ failure, and possibly a delayed recovery from multiple organ failure. Patients with candidemic septic shock are more likely to have underlying renal failure at baseline.

APACHE↗