Gary Garber

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.

Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients

A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1∶:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due toCandida glabrata orCandida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p=0.39; one-sided 95% Cl, −8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p=0.66: one-sided 95% Cl, −12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p=0.52; chi-square test) and remained similar throughout the course of follow-up. Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.

Tolevamer, a Novel Nonantibiotic Polymer, Compared with Vancomycin in the Treatment of Mild to Moderately Severe Clostridium difficile–Associated Diarrhea

BACKGROUND Current antibiotic therapies for Clostridium difficile-associated diarrhea have limitations, including progression to severe disease, recurrent C. difficile-associated diarrhea, and selection for nosocomial pathogens. Tolevamer, a soluble, high-molecular weight, anionic polymer that binds C. difficile toxins A and B is a unique nonantibiotic treatment option. METHODS In this 3-arm, multicenter, randomized, double-blind, active-controlled, parallel-design phase II study, patients with mild to moderately severe C. difficile-associated diarrhea were randomized to receive 3 g of tolevamer per day (n = 97), 6 g of tolevamer per day (n = 95), or 500 mg of vancomycin per day (n = 97). The primary efficacy parameter was time to resolution of diarrhea, defined as the first day of 2 consecutive days when the patient had hard or formed stools (any number) or < or = 2 stools of loose or watery consistency. RESULTS In the per-protocol study population, resolution of diarrhea was achieved in 48 (67%) of 72 patients receiving 3 g of tolevamer per day (median time to resolution of diarrhea, 4.0 days; 95% confidence interval, 2.0-6.0 days), in 58 (83%) of 70 patients receiving 6 g of tolevamer per day (median time to resolution of diarrhea, 2.5 days; 95% confidence interval, 2.0-3.0 days), and in 73 (91%) of 80 patients receiving vancomycin (median time to resolution of diarrhea, 2.0 days; 95% confidence interval, 1.0-3.0 days). Tolevamer administered at a dosage of 6 g per day was found to be noninferior to vancomycin administered at a dosage of 500 mg per day with regard to time to resolution of diarrhea (P = .02) and was associated with a trend toward a lower recurrence rate. Tolevamer was well tolerated but was associated with an increased risk of hypokalemia. CONCLUSIONS Tolevamer, a novel polystyrene binder of C. difficile toxins A and B, effectively treats mild to moderate C. difficile diarrhea and merits further clinical development.

Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study.

Objective:To investigate community-acquired pneumonia (CAP) as a cause of severe sepsis in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial and to evaluate the effect of drotrecogin alfa (activated) (DrotAA) in this subgroup. Design:Retrospective analysis of the severe CAP subgroup in the PROWESS trial. Setting:Tertiary care institutions in 11 countries. Interventions:DrotAA (n = 850), 24 &mgr;g·kg−1·hr−1 for 96 hrs, or placebo (n = 840). Participants:The 1,690 patients with severe sepsis enrolled in the PROWESS trial. Measurements and Main Results:Patients were classified as having CAP if lung was the primary site of infection and if they were enrolled directly from home (private residence) with ≤4 days in the hospital before receipt of study drug in the PROWESS trial. Survival at 28 days, hospital discharge, and 90 days was compared in DrotAA and placebo groups in the CAP subgroup of PROWESS and CAP subgroups based on disease severity. Of the 1,690 PROWESS patients, 35.6% (DrotAA, n = 324; placebo, n = 278) were classified as severe CAP. Of these severe CAP patients, 26.1% had Streptococcus pneumoniae infections. Within CAP, 79.1% were enrolled by the end of the second calendar day in the hospital, and approximately 90% of CAP patients were at high risk of death according to the Pneumonia Severity Index category. Based on their dependence on vasopressors, 59% of CAP patients were judged at high risk of death. Biomarkers of coagulation and inflammation were markedly abnormal in severe CAP patients. In severe CAP patients treated with DrotAA, a relative risk reduction in mortality of 28% was observed at 28 days, with a relative risk reduction in mortality of 14% observed at 90 days from the start of study drug infusion. The survival benefit was most pronounced in severe CAP patients with S. pneumoniae and in severe CAP patients at high risk of death as indicated by Acute Physiology and Chronic Health Evaluation II score of ≥25, Pneumonia Severity Index score of ≥4, or CURB-65 (confusion, urea, respiratory rate, blood pressure, age) score of ≥3. Conclusions:CAP associated with a high Pneumonia Severity Index score, bacteremia, or an intense coagulation and inflammatory response requiring intensive care unit care were indicators of a high risk of death from severe sepsis. In patients with severe sepsis resulting from CAP, a readily identifiable disease, DrotAA, improved survival compared with placebo.

Treatment of Infections Caused by Metronidazole-Resistant Trichomonas vaginalis

SUMMARY Infections with the sexually transmitted protozoan Trichomonas vaginalis are usually treated with metronidazole, a 5-nitroimidazole drug derived from the antibiotic azomycin. Metronidazole treatment is generally efficient in eliminating T. vaginalis infection and has a low risk of serious side effects. However, studies have shown that at least 5% of clinical cases of trichomoniasis are caused by parasites resistant to the drug. The lack of approved alternative therapies for T. vaginalis treatment means that higher and sometimes toxic doses of metronidazole are the only option for patients with resistant disease. Clearly, studies of the treatment and prevention of refractory trichomoniasis are essential. This review describes the mechanisms of metronidazole resistance in T. vaginalis and provides a summary of trichomonicidal and vaccine candidate drugs.

Reduced Plasma Concentrations of Antituberculosis Drugs in Patients with HIV Infection

Patients who have advanced HIV disease with or without diarrhea may not adequately absorb antituberculosis drugs [1-4]. In theory, the resulting lower drug exposure may contribute to acquired drug resistance and reduced effectiveness of antituberculosis treatment [5, 6]. Some authors [7, 8] have advocated direct observation of drug therapy and therapeutic drug monitoring in patients who are coinfected with Mycobacterium tuberculosis and HIV. Most pharmacokinetic studies [1] of antituberculosis drug therapy have used a single blood sample to estimate drug absorption, but a single sample does not provide a reliable measure of total systemic drug exposure. Our objectives were to comprehensively evaluate the pharmacokinetics of commonly used antituberculosis agents in HIV-seropositive patients at different stages of disease (including patients with diarrhea) and to compare the results with those seen in healthy persons. Methods Participants Forty-eight persons who did not have tuberculosis participated in the study, which was conducted at two medical centers. Participants were 12 healthy volunteers who were not known to be seropositive for HIV infection (group I); 12 HIV-seropositive, asymptomatic patients who had CD4+ T-cell counts greater than 300 cells/mm3 (group II); 12 HIV-seropositive, symptomatic patients who had CD4+ T-cell counts less than 200 cells/mm3 (group III); and 12 HIV-seropositive, symptomatic patients who had CD4+ T-cell counts less than 200 cells/mm3 and persistent diarrhea (defined as more than three loose stools per day for at least 30 days) (group IV). As defined by the Centers for Disease Control and Prevention classification system for HIV infection [9], asymptomatic persons were classified as having stage IA or IIA infection and symptomatic persons were classified as having stage IIIB or IIIC infection. Symptomatic patients had at least one AIDS-defining illness or related illness [9]. Exclusion criteria were age younger than 18 years, pregnancy, results of liver function tests that were more than five times normal, serum creatinine levels greater than 200 mol/L, neutrophil counts less than 109/L, hemoglobin levels less than 100 g/L, active opportunistic disease, and known hypersensitivity to any of the study medications. The Research Ethics Boards of the Ottawa General Hospital, Ottawa, Ontario, Canada, and the Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, approved the study. All participants provided written informed consent. Drug Administration and Blood Sampling Study participants received 300 mg of isoniazid, 600 mg of rifampin, 1000 mg of pyrazinamide, and 1000 mg of ethambutol, which were administered as individual drugs simultaneously each morning for 3 days. Therapy with other medications was stopped at least 24 hours before the study and for its duration (5 days). After a 10-hour overnight fast, participants received final doses of all medications with 300 mL of water on the morning of day 4. Participants were allowed to eat 3 hours after they received the drugs. On day 4, venous blood samples were collected immediately before participants were given the drugs and 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours afterward. Plasma was harvested within 30 minutes of blood collection and stored at 80C. Ascorbic acid was added to plasma aliquots to prevent oxidation of rifampin. To measure the absorptive function of the intestines, participants received 25 grams of D-xylose with 400 mL of water 24 hours after they received the final dose of the antituberculosis drugs [10]. Separation from isoniazid was necessary to prevent possible malabsorption of isoniazid by hydrazone formation with D-xylose [11]. Blood samples were collected before the participants received D-xylose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, and 5 hours afterward. Plasma was harvested and stored at 80C. Plasma Drug and Pharmacokinetic Analysis We measured isoniazid, rifampin, and pyrazinamide concentrations with high-performance liquid chromatography according to methods described elsewhere [12-14]. Analytic difficulties precluded the measurement of ethambutol. A colorimetric method was used to measure D-xylose [10]. We compared the plasma drug concentrations with time data using noncompartmental methods. These data included the highest observed drug concentration (Cmax), the time to Cmax (tmax), the terminal disposition half-life (t1/2,z), and the area under the plasma concentration-time curve (AUC) over the 24-hour dosing interval. Outcome Measures Total systemic drug exposure was measured by the AUC, and peak systemic drug exposure was measured by Cmax. Decreases in AUC reflected reduced drug bioavailability rather than increased drug clearance if t1/2,z was unchanged and corresponding decreases in Cmax were noted. Statistical Analysis Mean pharmacokinetic variables between groups were evaluated by analysis of variance. The model included the effects of group status and isoniazid acetylator status. Summary statistics for all variables except t (max) were based on geometric means. The appropriateness of the log-transformation for stabilizing intragroup variances was judged by using the Bartlett test for homogeneity of variance. Three linear orthogonal contrasts were tested to determine the effects of HIV infection (the mean of group I compared with the average of the means of groups II, III, and IV), severity of HIV disease (the mean of group II compared with the average of the means of groups III and IV), and diarrhea (the mean of group III compared with the mean of group IV) on pharmacokinetic variables [15]. A set of contrasts was tested by using orthogonal polynomials to determine whether a linear trend, a quadratic trend, or both was apparent between group order and group geometric mean [15]. The significance level for the test of each contrast was set at 0.05. The association between the AUC of the drugs being studied and that of D-xylose was evaluated by ordinary linear regression. Results Pill counts, questioning of participants, and predosing drug levels showed that all participants seemed to adhere to the dosing regimen. Demographic characteristics are shown in Table 1. Table 1. Demographic Characteristics of Study Participants Participants were classified as fast acetylators if they had an isoniazid t1/2,z of less than 130 minutes [16]. There were 4, 10, 6, and 7 fast acetylators in groups I, II, III and IV, respectively. Analysis of variance showed a significant effect of acetylator status for total drug exposure (AUC) and t1/2,z. Fast acetylators had shorter half-lives and lower AUC values than did slow acetylators. Mean pharmacokinetic data for each drug are shown in Table 2. The trend analyses indicated a significant linear decrease in mean AUC with group order for pyrazinamide (P = 0.0002) and a significant linear decrease in mean Cmax for rifampin (P = 0.006) and isoniazid (P = 0.046). Table 2. Mean Pharmacokinetic Variables of Antituberculosis Drugs for the Three Orthogonal Contrasts* Consistent with the trend for decreasing AUC and Cmax values from group I to group IV, statistically significant decreases of 18% to 41% in these variables were seen for some of the group contrasts for each drug (Table 2). Significant positive relations existed between D-xylose AUC05 and pyrazinamide AUC024 (P < 0.005; r2 = 0.17) and rifampin AUC024 (P < 0.001; r2 = 0.31), but a significant relation did not exist between D-xylose AUC and isoniazid AUC024 for fast (P > 0.2; r2 = 0.026) and slow acetylators (P > 0.2; r2 = 0.002). Discussion Our pharmacokinetic study showed that total systemic drug exposure was reduced for rifampin by 32% and for pyrazinamide by 24% in persons with HIV infection compared with healthy controls. A significant trend of decreased exposure for pyrazinamide occurred in patients with later-stage HIV disease. The reduction in total exposure probably reflects decreased bioavailability. Isoniazid was generally well absorbed in HIV-infected patients compared with healthy controls, which may partially explain a lack of correlation with the D-xylose AUC. The 39% decrease in peak exposure and 0.74-hour increase in time to peak exposure suggest that diarrhea reduced the rate of isoniazid absorption in symptomatic patients. Malabsorption from gastrointestinal malfunction probably contributes to the cause of reduced bioavailability. The significant correlation between the D-xylose AUC and rifampin and pyrazinamide AUC implies an absorptive defect, although the test for D-xylose explained only as much as 31% of the variability in drug AUC. Malabsorption has been suggested elsewhere as the reason for low concentrations of rifampin in serum [17], persistent fever in an HIV-negative man being treated for pulmonary tuberculosis [17], and potentially subtherapeutic levels of rifampin in persons who were infected with both HIV and M. tuberculosis [1, 3, 4]. However, gastrointestinal malfunction may also increase rifampin clearance by reducing its reabsorption in enterohepatic circulation. This may explain why rifampin was associated with the largest decreases in total and peak exposure. Gastrointestinal malfunction is common in HIV-infected patients [18], and subclinical enteropathy in early stages of HIV disease has recently been well described [19]. The clinical significance of our findings for persons infected with both M. tuberculosis and HIV is unclear; none of our patients had tuberculosis or clinical outcomes that could be evaluated. All peak concentrations seen in our study were above the minimum inhibitory concentrations for sensitive organisms [20]: 0.025 to 0.05 g/mL for isoniazid, 0.005 to 0.2 g/mL for rifampin, and 12.5 g/mL for bactericidal concentration of pyrazinamide. However, this finding does not determine whether plasma levels correlate with adequate antituberculosis activity in infected tissue. A substantial reduction in total drug exposure may have clinical conseque

A randomized controlled psycho-education intervention trial: Improving psychological readiness for successful HIV medication adherence and reducing depression before initiating HAART

Abstract The purpose of this study was to evaluate a novel psycho-educational intervention intended to increase patients’ medication preparedness and treatment adherence skills before initiating highly active antiretroviral therapy (HAART). Sixty-three HIV-positive patients not currently on antiretroviral therapy participated in a randomized controlled trial of a standardized, four-session psycho-educational intervention (Supportive Therapy for Adherence to Antiretroviral Treatment; STAART). Session topics included learning techniques to increase medication adherence and learning effective strategies to cope with stress and depression. Patients completed psychological questionnaires assessing psychological readiness to initiate HAART and depressed mood. They completed both measures at study baseline and at four-weeks post-baseline. After controlling for baseline medication readiness scores, intervention patients (n=30) reported significantly higher mean medication readiness following the STAART intervention (four-weeks post-baseline) (27.3±6.9) compared to controls (n=33; 24.6±9.9; p<0.05). Among depressed patients (n=27), those receiving the intervention (n=15) reported significantly lower mean depression scores at four-weeks post-baseline (22.5±12.9) compared to controls (n=12; 27±9.9; p<0.05). The STAART intervention enhanced HIV treatment readiness by better preparing patients prior to initiating HAART. It was also beneficial for reducing depressive symptoms in depressed, HIV-positive patients.

Factors influencing pandemic influenza vaccination of healthcare workers???A systematic review

INTRODUCTION Maintaining the health and availability of Health care workers (HCW) is an essential component of pandemic preparedness. A key to protecting HCW during the H1N1 pandemic was influenza vaccination. Numerous researchers have reported on factors influencing H1N1 vaccination behaviour in various HCW groups. This systematic review aims to inform future influenza vaccine interventions and pandemic planning processes via the examination of literature in HCW H1N1 vaccination, in order to identify factors that are (1) unique to pandemic influenza vaccination and (2) similar to seasonal influenza vaccination research. METHODS We conducted a comprehensive review of literature (MEDLINE, PubMed, EMBASE, PsycINFO, CINHAL, AMED, Cochrane Library, ProQuest, and grey literature sources) published between January 2005 and December 2011 to identify studies relevant to HCW pH1N1 vaccine uptake/refusal. RESULTS 20 publications sampling HCW from different geographic regions are included in this review. H1N1 vaccine coverage was found to be variable (9-92%) across HCW populations, and self-reported vaccine status was the most frequently utilized predictor of pandemic vaccination. HCW were likely to accept the H1N1 vaccine if they perceived, (1) the H1N1 vaccine to be safe, (2) H1N1 vaccination to be effective in preventing infection to self and others (i.e. loved ones, co-workers and patients), and (3) H1N1 was a serious and severe infection. Positive cues to action, such as the access of scientific literature, trust in public health communications and messaging, and encouragement from loved ones, physicians and co-workers were also found to influence HCW H1N1 uptake. Previous seasonal influenza vaccination was found to be an important socio-demographic predictor of vaccine uptake. Factors unique to HCW pandemic vaccine behaviour are (1) lack of time and vaccine access related barriers to vaccination, (2) perceptions of novel and rapid pandemic vaccine formulation, and (3) the strong role of mass media on vaccine uptake. CONCLUSIONS Many of the factors that influenced HCW pandemic vaccination decisions have previously been reported in seasonal influenza vaccination literature, but some factors were unique to pandemic vaccination. Future influenza vaccine campaigns should emphasize the benefits of vaccination and highlight positive cues to vaccination, while addressing barriers to vaccine uptake in order to improve vaccine coverage among HCW populations. Since pandemic vaccination factors tend be similar among different HCW groups, successful pandemic vaccination strategies may be effective across numerous HCW populations in pandemic scenarios.

Rate of Infectious Complications during Interferon-Based Therapy for Hepatitis C Is Not Related to Neutropenia

The relationship between infectious complications and neutropenia was evaluated in recipients of interferon-based therapy for hepatitis C followed at The Ottawa Hospital Viral Hepatitis Clinic from June 2000 to May 2005. One hundred ninety-two patients received 211 courses of therapy (5707 person-weeks of therapy). No patients received granulocyte colony-stimulating factor. Sixty-seven infectious complications occurred in 57 patients (1.17 infections per 100 person-weeks of therapy). The median time to infection was 17 weeks after the start of therapy. Age, sex, weight, race, human immunodeficiency virus status, stage and grade of biopsy, and type of interferon were not correlated with infection rate by Cox regression analysis. The rates of total, fungal, viral, and bacterial infections did not correlate with nadir neutrophil count or magnitude of decrease from baseline. Neutrophil count is not correlated with infection rate in recipients of interferon-based therapy for hepatitis C. Reduction in interferon dose and/or dosing with granulocyte colony-stimulating factor in those with neutropenia is not supported by this analysis.

Detection of surface and cytoplasmic CD4 on blood monocytes from normal and HIV-1 infected individuals

CD4 on blood monocytes is generally regarded as being found on a subset of blood monocytes. However, our results show that all monocytes are CD4+ but the number of molecules per cell is lower than T cells. We have performed immunofluorescent (flow cytometry, microscopy) analysis of monocytes from normal donors and HIV-1-infected patients using anti-CD4 (Leu-3a) and the monocyte-specific marker anti-CD14 (Leu-M3) monoclonal antibodies. Specifically: (1) 91% of monocytes from normal individuals show dual positivity for CD14 and CD4 (n = 14) as measured by flow cytometry; (2) 76% of monocytes expressed surface bound CD4 and CD14 when an enhanced two colour immunofluorescence microscopic technique was employed; (3) all CD14+ monocytes stained with an intensity of 3+(-)4+ for cytoplasmic CD4. Few monocytes were CD14- and CD4+. Cell surface CD4 expression was blocked with unconjugated anti-CD4 prior to staining; (4) the staining intensity for cytoplasmic CD4 in T cells was negligible; (5) CD4 expression on monocytes obtained from patients was as observed with normal individuals. The conclusion drawn is that all monocytes are CD4+ and the CD4 expression in monocytes is mainly cytoplasmic. Thus, all monocytes are potentially infectable with HIV-1.