Voriconazole therapeutic drug monitoring: results of a prematurely discontinued randomized multicenter trial.

BACKGROUND: Voriconazole (VOR) levels are highly variable, with potential implications to both efficacy and safety. We hypothesized that VOR therapeutic drug monitoring (TDM) will decrease the incidence of treatment failures and adverse events (AEs). METHODS: We initiated a prospective, randomized, non-blinded multicenter study to compare clinical outcomes in adult patients randomized to standard dosing (clinician-driven) vs. TDM (doses adjusted based on levels). VOR trough levels were obtained on day 5, 14, 28, and 42 (or at completion of drug; ± 3 days). Real-time dose adjustments were made to maintain a range between 1-5 µg/mL on the TDM-arm, while levels were assessed retrospectively in the standard-arm. Patient questionnaires were administered to assess subjective AEs. RESULTS: The study was discontinued prematurely, after 29 patients were enrolled. Seventeen (58.6%) patients experienced 38 AEs: visual changes (22/38, 57.9%), neurological symptoms (13/38, 34.2%), and liver abnormalities (3/38, 7.9%). VOR was discontinued in 7 (25%) patients because of an AE (4 standard-arm, 3 TDM-arm). VOR levels were frequently out of range in the standard-arm (8 tests >5 µg/mL; 9 tests <1 µg/mL). Three dose changes occurred in the TDM-arm for VOR levels <1 µg/mL. Levels decreased over time in the standard-arm, with mean VOR levels lower at end of therapy compared to TDM (1.3 vs. 4.6 µg/mL, P = 0.008). CONCLUSIONS: VOR TDM has become widespread clinical practice, based on known variability in drug levels, which impaired accrual in this study. Although comparative conclusions are limited, observations of variability and waning levels over time support TDM.

Sporadic Legionnaires' disease: the role of domestic electric hot-water tanks.

Sporadic community-acquired legionellosis (SCAL) can be acquired through contaminated aerosols from residential potable water. Electricity-dependent hot-water tanks are widely used in the province of Quebec (Canada) and have been shown to be frequently contaminated with Legionella spp. We prospectively investigated the homes of culture-proven SCAL patients from Quebec in order to establish the proportion of patients whose domestic potable hot-water system was contaminated with the same Legionella isolate that caused their pneumonia. Water samples were collected in each patient's home. Environmental and clinical isolates were compared using pulsed-field gel electrophoresis. Thirty-six patients were enrolled into the study. Legionella was recovered in 12/36 (33%) homes. The residential and clinical isolates were found to be microbiologically related in 5/36 (14%) patients. Contaminated electricity-heated domestic hot-water systems contribute to the acquisition of SCAL. The proportion is similar to previous reports, but may be underestimated.

Concentration of antifungal agents within host cell membranes: a new paradigm governing the efficacy of prophylaxis.

Posaconazole prophylaxis has proven highly effective in preventing invasive fungal infections, despite relatively low serum concentrations. However, high tissue levels of this agent have been reported in treated patients. We therefore hypothesized that the intracellular levels of antifungal agents are an important factor in determining the success of fungal prophylaxis. To examine the effect of host cell-associated antifungals on the growth of medically important molds, we exposed cells to antifungal agents and removed the extracellular drug prior to infection. Epithelial cells loaded with posaconazole and its parent molecule itraconazole, but not other antifungals, were able to inhibit fungal growth for at least 48 h and were protected from damage caused by infection. Cell-associated posaconazole levels were 40- to 50-fold higher than extracellular levels, and the drug was predominantly detected in cellular membranes. Fungistatic levels of posaconazole persisted within epithelial cells for up to 48 h. Therefore, the concentration of posaconazole in mammalian host cell membranes mediates its efficacy in prophylactic regimens and likely explains the observed discrepancy between serum antifungal levels and efficacy.

Pediatric antifungal therapy. Part II: neonatal infections.

The management of neonatal fungal infections poses several challenges, including the fact that the choices of available agents are limited, given the paucity of data relating to the use of newer antifungal agents in the group of infants. The information summarized herein represents in part the consensus of a group of clinicians involved in the care of neonates at risk of and with fungal infections. The document addresses the prophylaxis and treatment of fungal infections in neonates. It highlights the role of current and emerging antifungal agents, including the lipid amphotericin B products, echinocandins and triazoles.

Pediatric antifungal therapy. Part I: focus on febrile neutropenia, invasive aspergillosis, combination antifungal therapy and invasive candidiasis in immunocompromised pediatric patients.

The number of available antifungal agents has significantly increased in recent years. These agents are starting to take over niches that were previously occupied by conventional amphotericin B. For many of these agents, pediatric data from randomized trials are generally lacking and clinicians are faced with extrapolating from data generated in adult patients. This notwithstanding, this report summarizes recommendations that define the roles of newer antifungal agents in the treatment of selected scenarios among immunocompromised pediatric patients. The report includes the outcome of a Canadian conference on the use of antifungal agents in children, supplemented by literature reviews and incorporating information from existing national or international guidelines, where appropriate. The focus of the report is on febrile neutropenia, invasive aspergillosis, combination antifungal therapy and selected aspects of the management of invasive candidiasis.

Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis.

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 <500 cells/mm(3)) at onset of treatment. Successful response was seen in 25/98 (26%); an additional 12 patients achieved stable disease. Response was seen in 2/9 (22%) in de novo treatment, 21/87 (24%) in refractory patients, and 2/2 (100%) in toxicity failure patients. Additionally, response was seen in 22 of the 90 (24%) patients treated with combination therapy, and in 3 of 8 (38%) patients who were treated with micafungin alone. No significant differences in responses were found based on type of HSCT, GVHD status, site of IA, or Aspergillus species, and no significant toxicity was seen. Micafungin was well tolerated, even at high doses, and is a reasonable option for treatment of IA in this high-risk patient population.

A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.

BACKGROUND: The empirical treatment of febrile, neutropenic patients with cancer requires antibacterial regimens active against both gram-positive and gram-negative pathogens. This study was performed to demonstrate the noninferiority of monotherapy with piperacillin-tazobactam, compared with cefepime. METHODS: We conducted a randomized-controlled, open-label, multicenter clinical trial among high-risk patients from 34 university-affiliated tertiary care medical centers in the United States, Canada, and Australia who were undergoing treatment for leukemia or hematopoietic stem cell transplantation and were hospitalized for empirical treatment of febrile neutropenic episodes. Patients received piperacillin-tazobactam (4.5 g every 6 h) or cefepime (2 g every 8 h) intravenously. The primary outcome was success (defined by defervescence without treatment modification) at 72 h of treatment, end of treatment, and test of cure in the modified intent-to-treat analysis. Secondary outcomes included time to defervescence, microbiological efficacy, the additional use of glycopeptide antibiotics, emergence of resistant bacteria, and safety. RESULTS: For 528 subjects (265 received piperacillin-tazobactam and 263 received cefepime), success rates were 57.7% and 48.3%, respectively (P = .04) at the 72-h time point, 39.6% and 31.6% (P = .06) at end of treatment, and 26.8% and 20.5% (P = .11) at the test-of-cure visit. The analyses demonstrated noninferiority for piperacillin-tazobactam at all time points (P< or = .0001). Treatment with piperacillin-tazobactam was independently associated with treatment success in multivariate analysis (odds ratio, 1.65; 95% confidence interval, 1.04-2.64; P = .035). Both regimens were well tolerated. CONCLUSIONS: This study demonstrates the noninferiority and safety of piperacillin-tazobactam monotherapy, compared with cefepime, for the empirical treatment of high-risk febrile neutropenic patients with cancer.

What is the clinical significance of infusing hematopoietic cell grafts contaminated with bacteria?

Although hematopoietic stem cell (HSC) products are routinely cultured for sterility, bacterial contamination of these products is rarely observed and little is known about the clinical consequences of infusing contaminated grafts. We retrieved the sterility cultures of bone marrow and peripheral HSC grafts from 938 patients transplanted at our center from January 1990 to July 2005. Fever, septicemia and other adverse events were assessed for up to 14 days following infusion of the graft. Out of the 1502 grafts collected during this 15-year period, 15 (1.0%) had a positive sterility culture (11 Gram-positive cocci, 2 Gram-positive bacilli and 2 Gram-negative bacilli). No correlation was observed between the graft contamination rate and the extent of graft manipulation or the patient's underlying condition. Thirteen recipients were transplanted with contaminated grafts. Five patients were treated with specific pre-emptive antibiotics. Only one episode of Staphylococcus epidermidis bacteremia possibly related to a contaminated graft was observed on day +5. As the infusion of contaminated grafts with Gram-positive skin contaminants rarely results in unfavorable clinical outcomes, close patient monitoring without the use of specific pre-emptive antibiotics could be appropriate and could avoid antibiotic-associated adverse events.

What is the clinical significance of positive blood cultures with Aspergillus sp in hematopoietic stem cell transplant recipients? A 23 year experience.

Hematopoietic stem cell (HSC) transplantation is the most frequent underlying predisposing condition to invasive aspergillosis. However, the significance of positive blood culture with Aspergillus sp in this particular population remains uncertain. We retrospectively reviewed all blood cultures performed in 1453 patients who received HSC transplant at our institution between 1980 and 2002. We identified 19 patients with positive blood cultures with Aspergillus sp. Only one of these patients had clinical, histologic or microbiologic evidence of invasive aspergillosis. Thus, even in a population at highest risk for invasive aspergillosis, positive blood cultures with Aspergillus sp remain unusual, and cannot be readily associated with invasive aspergillosis. A case by case assessment by treating physicians of the clinical and radiologic parameters should be systematically made to establish the significance of aspergillemia. Single bottle positivity, obtained with the lysis-centrifugation blood culture system, is a common indicator of pseudoaspergillemia.

Predicting nitrate leaching under potato crops using transfer functions.

Nitrate leaching is a major issue in many cultivated soils. Models that predict the major processes involved at the field scale could be used to test and improve management practices. This study aims to evaluate a simple transfer function approach to predict nitrate leaching in sandy soils. A convective lognormal transfer (CLT) function is convoluted with functional equations simulating N mineralization, plant N uptake, N fertilizer dissolution, and nitrification at the soil surface to predict solute concentrations under potato (Solanum tuberosum L.) and barley (Hordeum vulgare L.) fields as a function of drainage water. Using this approach, nitrate flux concentrations measured in drainable lysimeters (1-m soil depth) were reasonably predicted from 29 Apr. 1996 to 3 Dec. 1996. With average application rates of 16.9 g m(-2) of N fertilizer in potato crops, mean nitrate-leaching losses measured under potato were 8.5 g N m(-2). Tuber N uptake averaged 9.7 g N m(-2) and soil mineral N at start (spring) and end (fall) of N mass balance averaged 1.7 and 4.5 g N m(-2), respectively. Soil N mineralization was estimated by difference (4.3 g N m(-2) on average) and was small compared with N fertilization. Small nitrate flux concentrations at the beginning of the cropping season (May) resulted mainly from initial soil nitrate concentrations. Measured and predicted nitrate flux concentrations significantly increased at mid-season (July-August) following important drainage events coupled with complete dissolution and nitrification of N fertilizers, and declining N uptake by potato plants. Decreases in nitrate concentrations before the end of year (November-December) underlined the predominant effect of N fertilizers applied for the most part at planting acting as a pulse input of solute.

Evaluation of the in vitro activity of caspofungin against bloodstream isolates of Candida species from cancer patients: comparison of Etest and NCCLS reference methods.

The in vitro activity of caspofungin (CAS) was compared with the activity of fluconazole, itraconazole and amphotericin B against 178 bloodstream Candida spp. from cancer patients. The activities were assessed using the reference NCCLS M-27A microdilution method and the Etest method. With both the NCCLS microdilution reference method and the Etest method, CAS was the most active agent (MIC90s 0.19-0.5 mg/l) against Candida albicans, C. glabrata and C. tropicalis. CAS showed substantial activity against azole-resistant Candida. The percentages of agreement within +/-2 dilutions between the NCCLS reference microdilution method and Etest MICs ranged from 81 to 97%. CAS showed good in vitro activity against invasive azole-susceptible and azole-resistant Candida isolates. The CAS Etest MICs correlated well with the NCCLS reference MICs and may provide more choice for laboratories in assessing the activity of antifungal agents. The clinical correlation of these in vitro observations needs to be established.

Solute transport modeling under cultivated sandy soils and transient water regime.

Drainable lysimeters offer the possibility to integrate heterogeneous solute leaching conditions caused by row crops and transient water regime, and to conveniently measure water and solute fluxes at the drainage outlet. To compare solute leaching behavior in and around drainable lysimeters operating under a transient water regime in potato (Solanum tuberosum L.) fields, parameters of the convective lognormal transfer (CLT) function model were fitted using bromide (Br-) flux concentrations (Cf) measured in lysimeters and from Br- resident concentrations (Cr) measured in adjacent soil cores. Expected mean values Ez(I) obtained from Cr and Cf CLT parameters were equivalent and well correlated (R2 = 0.78). However, estimated median values mu of the CLT function were smaller when derived from Cr (1.05 to 1.28) compared with Cf (1.23 to 2.14). Most mu values were also smaller than previously reported values for a 30-cm reference depth, indicating that 50% of solute mass would leach more readily in these coarse sandy soils. Higher variance and dispersion of Cr compared with those of Cf could be related to a smaller sampling support (sample size/sampling area) in the case of Cr measured by soil coring, or to disruption of solute transport mechanisms in the repacked lysimeter. Retained Br- in the top soil layer after 12 to 17 cm of cumulative drainage was indicated by measured Cr. Neither CLT function simulated well residual topsoil Cr values, indicating that Br- plant cycling or preferential flow probably interfered even though tuber Br- uptake was relatively small.

In vitro activity of three new triazoles and one echinocandin against Candida bloodstream isolates from cancer patients.

The in vitro activities of voriconazole, posaconazole, ravuconazole and micafungin were compared with those of fluconazole, itraconazole, ketoconazole, flucytosine and amphotericin B against 164 candidaemia isolates recovered from cancer patients in two Canadian centres. The MIC(50) results for ravuconazole, voriconazole, posaconazole and micafungin were 0.01, 0.03, 0.12 and 0.25 mg/L, respectively. The new antifungal agents showed substantial activity against isolates demonstrating in vitro resistance to fluconazole and itraconazole. These results suggest that the newer antifungal agents possess promising activity against invasive Candida isolates, particularly against those with reduced susceptibility to fluconazole and itraconazole.

Development and evaluation of a PCR method for detection of the Clostridium difficile toxin B gene in stool specimens.

A PCR assay detecting Clostridium difficile toxin B gene in stool specimens was compared to the cytotoxicity assay as the reference standard for the diagnosis of C. difficile antibiotic-associated diarrhea (CDAD). Overall, 118 stool samples were tested. All of the specimens that were negative by the cytotoxicity assay (59 out of 118) were also negative by the PCR method (specificity of 100%). Of the 59 cytotoxin-positive samples, 54 were PCR positive (sensitivity of 91.5%). This PCR method is promising for rapid diagnosis of CDAD.

In vitro activity of a novel ketolide ABT-773 against invasive strains of Streptococcus pneumoniae.

New ketolides such as ABT-773 are a promising group of antibiotics in an era of increasing antibiotic resistance. We tested 704 invasive strains of Streptococcus pneumoniae collected from 1990 to 1998. Overall resistance was 8.3, 4.6, 4.5 and 3.6% for penicillin, cefuroxime, erythromycin and clarithromycin, respectively. By using a recommended breakpoint for susceptibility of <0.5 mg/L, no strains showed reduced susceptibility to ABT-773. ABT-773 was very active against all penicillin-resistant strains (MIC > 2 mg/L, with a mean geometric mean <0.06 mg/L), and against all 33 erythromycin-resistant strains, irrespective of the mode of resistance [mef- or erm(B)-mediated]. ABT-773 is a very active and promising agent against invasive strains of S. pneumoniae, including multiresistant strains.

A nosocomial outbreak of fluoroquinolone-resistant Streptococcus pneumoniae.

Over the course of a 20-month period, in a hospital respiratory ward in which ciprofloxacin was often used as empirical antimicrobial therapy for lower respiratory tract infections (LRTIs), 16 patients with chronic bronchitis developed nosocomial LRTIs caused by penicillin- and ciprofloxacin-resistant Streptococcus pneumoniae (serotype 23 F). The minimum inhibitory concentration (MIC) of ciprofloxacin for all isolates from the first 9 patients was 4 microg/mL, in association with a parC mutation. Isolates from the subsequent 7 patients all had a ciprofloxacin MIC of 16 microg/mL, in association with an additional mutation in gyrA. The MICs for this isolate were 8 microg/mL of levofloxacin (resistant), 2 microg/mL of moxifloxacin and gatifloxacin (intermediately resistant), and 0.12 microg/mL of gemifloxacin. This outbreak demonstrates the ability of S. pneumoniae to acquire multiple mutations that result in increasing levels of resistance to the fluoroquinolones and to be transmitted from person to person.

Prevalence and antifungal susceptibility of 442 Candida isolates from blood and other normally sterile sites: results of a 2-year (1996 to 1998) multicenter surveillance study in Quebec, Canada.

During a 2-year surveillance program (1996 to 1998) in Quebec, Canada, 442 strains of Candida species were isolated from 415 patients in 51 hospitals. The distribution of species was as follows: Candida albicans, 54%; C. glabrata, 15%; C. parapsilosis, 12%; C. tropicalis, 9%; C. lusitaniae, 3%; C. krusei, 3%; and Candida spp., 3%. These data, compared to those of a 1985 survey, indicate variations in species distribution, with the proportions of C. glabrata and C. parapsilosis increasing by 9 and 4%, respectively, and those of C. albicans and C. tropicalis decreasing by 10 and 7%, respectively. However, these differences are statistically significant for C. glabrata and C. tropicalis only. MICs of amphotericin B were > or =4 microg/ml for 3% of isolates, all of which were non-C. albicans species. Three percent of C. albicans isolates were resistant to flucytosine (> or =32 microg/ml). Resistance to itraconazole (> or =1 microg/ml) and fluconazole (> or =64 microg/ml) was observed, respectively, in 1 and 1% of C. albicans, 14 and 9% of C. glabrata, 5 and 0% of C. tropicalis, and 0% of C. parapsilosis and C. lusitaniae isolates. Clinical data were obtained for 343 patients. The overall crude mortality rate was 38%, reflecting the multiple serious underlying illnesses found in these patients. Bloodstream infections were documented for 249 patients (73%). Overall, systemic triazoles had been administered to 10% of patients before the onset of candidiasis. The frequency of isolation of non-C. albicans species was significantly higher in this group of patients. Overall, only two C. albicans isolates were found to be resistant to fluconazole. These were obtained from an AIDS patient and a leukemia patient, both of whom had a history of previous exposure to fluconazole. At present, it appears that resistance to fluconazole in Quebec is rare and is restricted to patients with prior prolonged azole treatment.