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.

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.

Species-specific regulation of alternative splicing in the C-terminal region of the p53 tumor suppressor gene.

Alternative splicing occurs in the C-terminal region of the p53 tumor suppressor gene between two alternative 3' splice sites in intron 10. This alternative splicing event has been detected in murine cells, but not in rat or human tissues. In this paper, we have characterized the pattern of p53 alternative splicing in cell lines from five different species. Our results confirm that p53 alternative splicing is species-specific, being detected only in cell lines of rodent origin. Using transient transfection assays, we have established that the rat p53 gene undergoes efficient alternative splicing in both mouse and rat cell lines, thus demonstrating that it has all the necessary cis -acting sequences to be alternatively spliced. In contrast, we were unable to detect any usage of the human alternative 3' splice site under the same experimental conditions. Thus, the low levels or absence of alternatively spliced p53 mRNA in rat and human cell lines seems to be the result of different mechanisms. Our results support the hypothesis that there are species-specific mechanisms implicated in the regulation of p53 activity.

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.

Naloxone and focal epilepsy: a study with depth electrodes.

Intravenous injections of naloxone (0.8 to 2.4 mg) were given to patients with focal epilepsy who had had electrodes implanted in cortical and subcortical structures. There were no changes in interictal spike activity, responses to electrical stimulation, of frequency of spontaneous seizures. These data do not support the hypothesis that opiate peptides are involved in human focal epilepsy.

Sleep and temporal lobe epilepsy: a case study with depth electrodes.

We studied a patient with hippocampal epilepsy who had frequent nocturnal and diurnal seizures. Depth electrode recording showed that focal seizure discharges in the right hippocampus were of shorter duration in REM and non-REM sleep. However, awakening, especially from REM sleep or shortly after a REM period, facilitated the occurrence of a generalized seizure. There was no ultradian fluctuation in frequency or duration of seizure during diurnal recording. Night terrors (but not nightmares) disappeared after right temporal lobectomy, suggesting that pavor nocturnus was an ictal manifestation in this case.

Sleep spindles in the human hippocampus: normal or epileptic activity?

Spindles of 12-14 Hz were recorded in the hippocampus of 13 epileptics during sleep. This activity was more prominent in patients in whom the hippocampal region was not the site of the primary focus and in whom the electrical activity was normal during wakefulness. Spindles were more numerous during stage 2 non-rapid-eye-movement sleep, especially in patients who had seizures in this stage. It is postulated that this activity is either a normal activity of human brain or an evoked response of the hippocampus to an epileptic afferent discharge. In either case, hippocampal spindles may contribute to the triggering of nocturnal seizures.

Severe bronchospasm followed by respiratory arrest during thallium-dipyridamole imaging.

We describe the occurrence of sudden severe bronchospasm and respiratory arrest following dipyridamole infusion in a patient with chronic obstructive pulmonary disease predominantly of the emphysematous type. The severe reaction was unexpected because the patient had tolerated well withdrawal of aminophylline derivatives for 48 hours and was receiving chronic prednisone 20 mg qd. Although the diagnostic and prognostic gains from dipyridamole imaging far outweigh the small risk associated with the test, patients with chronic pulmonary obstructive disease must be closely monitored during thallium-dipyridamole imaging.

Varicella-zoster screening and management programs in healthcare facilities in Canada.

A 24-question survey on varicella-zoster screening programs and control measures for varicella-zoster infections was sent to 170 Canadian healthcare facilities. The results indicated that 60% of Canadian healthcare facilities have well-established preemployment varicella-zoster screening programs for healthcare workers. Overall, 30% of healthcare facilities impose work restrictions for susceptible healthcare workers, 49% use negative-pressure rooms for varicella-zoster management, and 28% have a policy to discharge susceptible exposed patients. Large variations exist among Canadian healthcare facilities in their varicella-zoster infection control policies.

Successful treatment of Pseudomonas meningitis and septicemia in a leukemic neutropenic adult.

Pseudomonas aeruginosa is thought to be one of the main species of bacteria producing infection in leukemic patients, especially in those with neutropenia. Although bacteremia is frequent, hematogenous spread causing secondary meningitis is rarely seen. The mortality rate is extremely high. This is believed to be the first report of a successfully treated secondary meningitis caused by Pseudomonas aeruginosa in an adult leukemic patient with a decreased neutrophil count. The patient was treated with intravenous Carbenicillin and gentamicin, and intrathecal gentamicin. The good clinical response was supported by a prompt return of the CSF to normal and by appropriate CSF antimicrobial concentration and bacteriostatic activity.

Trends in antibiotic resistance of staphylococci over an eight-year period: differences in the emergence of resistance between coagulase positive and coagulase-negative staphylococci.

The antimicrobial susceptibilities of 1058 Staphylococcus aureus and 2,163 coagulase-negative staphylococci (CNS) isolates obtained from clinical specimen between 1988 and 1995, were determined against 13 anti-staphylococcal antibiotics. During the study period the resistance of Staphylococcus aureus to ciprofloxacin, ceftazidime, and norfloxacin increased significantly by 7%, 4%, and 6%, respectively (p < or = 0.001). By comparison, the antibiotic resistance of CNS to ceftazidime, oxacillin, norfloxacin, ciprofloxacin, fusidic acid, and cefoxitin increased by 20%, 17%, 15%, 14%, 12% and 10%, respectively (p < or = 0.001). Invasive and noninvasive S. aureus had similar antibiotic resistance, whereas CNS invasive isolates were more resistant than noninvasive isolates to every antibiotics, except vancomycin and fusidic acid. These differences were significant (p < 0.001) for oxacillin, cefoxitin, and clindamycin. Our observations confirm that staphylococci and particularly CNS isolates show an important rate of increased resistance to the standard antimicrobials used for therapy, and that the rate of emergence of resistance differ considerably between coagulase-positive and coagulase-negative staphylococci.

A new urea broth-based test to detect Helicobacter pylori presence in upper gastrointestinal biopsies.

The aim of this study was to evaluate the performance of a simple and inexpensive homemade urea test (U-test) to detect Helicobacter pylori in upper digestive tract biopsies. We tested and compared the U-test with three other diagnostic methods: the Clo-test, and culture and pathology in 110 patients randomly chosen at the endoscopy clinic. When using culture and/or pathology as the "gold standard," H. pylori was found to exist in 54 patients. Pathology was positive in 50 cases (92.5%), culture in 49 (90.7%), the U-test in 45 (83.3%), and the Clo-test in 43 (79.6%). With regard to culture pathology, the sensitivities of the U-test and the Clo-test were 83.3% and 79.5%, respectively. Specificity was 100% for both methods. The kappa coefficient calculation between the U-test and the Clo-test was 0.98. The results show that the U-test is a reliable, fast, and inexpensive method for detecting H. pylori in upper gastrointestinal biopsies.

In vitro synergism of ceftriaxone combined with aminoglycosides against Pseudomonas aeruginosa.

The antipseudomonal activities of ceftriaxone (CEF) or ceftazidime (CAZ), each combined with tobramycin (TOB) or netilmicin (NET), against 90 clinically significant Pseudomonas aeruginosa isolates were examined both by checkerboard and time-kill assays. As expected, susceptibility testing of single antibiotics by agar dilution demonstrated good activity for CAZ (89% susceptible), TOB (94%), and NET (58%), but poor activity for CEF (15%). Checkerboard studies revealed striking synergy (FIC indices < or = 0.5) for CEF, however, in combination with either TOB (72%) or NET (81%), compared with CAZ-TOB (44%) or CAZ-NET (60%) (P < 0.01, respectively). No antagonism (FIC indices > or = 4) was found in any of these combinations. The MIC90s of CEF, CAZ, or aminoglycosides in the combinations were reduced at least fourfold: CEF, from > 128 to 32 mg/liter; CAZ, from 16 to 4 mg/liter; TOB, from 4 to 0.5 mg/liter; and NET, from 32 to 4 mg/liter. With CEF and NET, the percentage of strains sensitive to < or = 8 mg/liter of both drugs alone and in combination increased from 9% to 69%. Results of the time-kill assay for CEF-NET agreed reasonably well with the checkerboard method (Spearman rank correlation coefficient, 0.40, P < or = 0.01), and generated a bactericidal outcome in 60% (24 of the 40 isolates), when tested with combinations at 1/4 MBC of either antibiotic alone. Importantly, concentrations of CEF and aminoglycoside combinations that demonstrated synergy by either checkerboard or time-kill assays were achievable in serum clinically. These data suggest a unique interaction of CEF-aminoglycoside combinations against P. aeruginosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative evaluation of the MB/BacT and BACTEC 460 TB systems for the detection of mycobacteria from clinical specimens: clinical relevance of higher recovery rates from broth-based detection systems.

New broth-based detection systems have higher recovery rates of mycobacteria from clinical specimens than traditional cultures on solid media. The clinical significance of this higher sensitivity rate is largely unknown. We prospectively evaluated the performances of two liquid media detection systems (the MB/BacT system and the BACTEC 460 TB system) and an egg-based Lowenstein-Gruft solid medium (LG) on the recovery rates of mycobacteria from 849 clinical specimens. Mycobacteria (other then M. gordonae) were detected in 51 (6.0%) specimens. In 12/51 (23%) specimens, mycobacteria (five mycobacterium tuberculosis (MtB) and seven non-M tuberculosis complex (MOTT) were recovered only from the broth-based systems. Review of the patients' clinical charts revealed that failure of LG to recover Mtb were due to nonmycobacterial overgrowth and antibiotic treatment. The recovered MOTT were all clinically nonsignificant. Higher sensitivity of broth-based mycobacteria detection systems is largely due to their capability to recover mycobacteria from treated tuberculous patients or from partially decontaminated specimens. The high recovery rates of nonclinically significant MOTT could potentially increase inappropriate use of antibiotics.

14q+ abnormality with probable t(8;14)(q24;q32) in a young Haitian immigrant with acquired immunodeficiency syndrome and concomitant Burkitt's-like lymphoma.

Cytogenetic analyses were carried out in a young Haitian immigrant with acquired immunodeficiency syndrome and concomitant Burkitt's-like lymphoma associated with massive bone marrow infiltration. A characteristic 14q+ abnormality was found in all bone marrow cells examined. Although chromosome abnormality involving band 8q24 was not evident in all the cells examined, some karyotypes show that the typical t(8;14)(q24;q32) is most probably present. No other complex rearrangements could be identified. This is the first report of concomitant acquired immunodeficiency syndrome and Burkitt's-like lymphoma in the Haitian community. Our cytogenetic findings provide further evidence for the role of specific chromosomal rearrangements in Burkitt's-like lymphoma oncogenesis in the setting of acquired immunodeficiency syndrome.

Primary renal mucormycosis.

Primary renal mucormycosis is a rare infection capable of acute illness with sepsis. Few cases have been reported. We report a case of an acute primary renal mucormycosis and review the published reports. The incidence of primary renal mucormycosis has risen in recent years. The most frequently reported underlying predisposing disorders are human immunodeficiency virus infection, intravenous drug abuse, and diabetes mellitus. Primary renal mucormycosis should be suspected in patients with an immunocompromising illness or particular risk factors, when persistent flank pain and fever with sterile urine not responding to appropriate antibiotics are associated with enlarged heterogeneous kidneys.