Potency of Anidulafungin Compared to Nine Other Antifungal Agents Tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: Results from the Global SENTRY Antimicrobial Surveillance Program (2008)

The SENTRY Antimicrobial Surveillance Program regularly monitors global susceptibility rates for a spectrum of both novel and established antifungal agents. Anidulafungin and the other echinocandins displayed sustained, excellent activity against Candida spp. and Aspergillus fumigatus, with ≥98% of MIC results at ≤2 μg/ml. Six yeast isolates (all Candida glabrata) showing caspofungin MIC values of ≥0.5 μg/ml were further analyzed for potential fks hot spot (HS) mutations; three isolates had confirmed mutations in the fks1 HS1 region (S645P), and three exhibited mutations in the fks2 HS1 region (S645F and S645P).Opportunistic fungal infections are increasing in incidence (18) and are associated with high rates of morbidity and mortality (1, 11, 13). The rise in prevalence of individuals with short-term neutropenia (cancer patients undergoing chemotherapy regimens), long-term immunosuppression (organ transplant patients), immune system disorders (patients with HIV/AIDS), or central venous catheters has coincided with the increased occurrence of problematic opportunistic fungal infections (11). At this time, only a limited number of azole and echinocandin antifungal agents are available for therapeutic intervention against these infections.Anidulafungin (9, 14-17) is a novel semisynthetic agent that targets cell wall structural integrity via noncompetitive inhibition of β-1,3-d-glucan synthesis, resulting in cell rupture and death. Excellent broad-spectrum in vitro and in vivo activities against a variety of fungal pathogens have been demonstrated (16). We present here contemporary data (2008) from the global SENTRY Antimicrobial Surveillance Program comparing the activity of anidulafungin to those of nine additional antifungal agents by use of reference methods (5-7).A collection of 1,201 clinical yeasts from bloodstream infections (BSI) and 79 molds from pneumonias (lower respiratory tract infections [LRTI]) in the United States, Europe, Latin America, and the Asia-Pacific region (APAC) was processed by Clinical and Laboratory Standards Institute (CLSI) methods and included (in rank order) Candida albicans (587 isolates), C. glabrata (218), C. parapsilosis (196), C. tropicalis (126), C. krusei (24), C. lusitaniae (19), C. dubliniensis (12), C. guilliermondii (4), C. kefyr (4), C. famata (3), C. rugosa (2), C. haemulonii (1), C. inconspicua (1), C. lambica (1), C. norvegensis (1), C. pelliculosa (1), and C. sake (1). The collection also included Cryptococcus neoformans (43 isolates), Aspergillus fumigatus (60), and 19 other molds (data not shown: Aspergillus flavus [3], Aspergillus niger [3], Fusarium spp. [4], Penicillium spp. [3], Rhizopus spp. [2], Bipolaris sp. [1], and Mucor sp. [1], as well as 2 molds not identified to the species level). Laboratories were instructed to submit unique BSI and LRTI isolates obtained in consecutive order, allowing prevalence of the fungal isolates in participating centers to be determined.All fungal isolates were identified at the participant''s medical center by established laboratory methods in use at each institution and confirmed at the central reference laboratory (JMI Laboratories, North Liberty, IA) using Vitek (bioMerieux, Hazelwood, MO) and conventional reference procedures (12, 19). All yeasts were tested by broth microdilution using the CLSI M27-A3 (5) standardized reference method. Preparation of inocula for molds followed procedures described in the CLSI M38-A2 reference method for filamentous fungi (7). Quality control (QC) isolates C. krusei ATCC 6258 and C. parapsilosis ATCC 22019 were used, and all QC results were within published ranges (6).Anidulafungin and voriconazole (Pfizer, Inc., New York, NY), amphotericin B, fluconazole, itraconazole, ketoconazole, and flucytosine (Sigma Chemical Co., St. Louis, MO), caspofungin (Merck Research Laboratories, Rahway, NJ), micafungin (Astellas Toyama Co., Ltd., Toyama, Japan), and posaconazole (Schering-Plough Research Institute, Kenilworth, NJ) were obtained as standard powders and prepared according to CLSI guidelines (5-7). The final concentration ranges (in μg/ml) were as follows: for anidulafungin, 0.001 to 32; for caspofungin and micafungin, 0.008 to 16; for amphotericin B, 0.12 to 8; for flucytosine and fluconazole, 0.5 to 64; for itraconazole, 0.015 to 2; and for posaconazole, voriconazole, and ketoconazole, 0.06 to 8. Antifungal dilution testing ranges were selected for maximal capture of MIC₅₀ and MIC₉₀ wild-type and mutant populations, including expanded ranges for newer and investigational agents to detect organism populations exhibiting potential resistance to these compounds. MIC values (yeasts and molds) and 90% minimal effective concentrations (MEC₉₀) (echinocandins, molds only) were determined as described in the CLSI reference methods (5, 7).Table ​Table11 displays the in vitro activities of 10 antifungal agents tested against yeast BSI isolates collected from the 2008 SENTRY Program. Anidulafungin was the most active agent against (MIC₉₀ in μg/ml) C. albicans (0.06), C. glabrata (0.12), C. tropicalis (0.06), and C. krusei (0.12) and was less potent against C. parapsilosis (MIC₉₀, 2 μg/ml) and C. guilliermondii (data not shown). The echinocandin potency against A. fumigatus was greatest for anidulafungin (MEC₉₀, 0.002 μg/ml) and caspofungin (MEC₉₀, 0.008 μg/ml) (Table ​(Table1).1). The results demonstrate the expanded utility of these agents against the most common mold species identified in lower respiratory tract infections.

TABLE 1.

In vitro activities of anidulafungin and nine other selected antifungal agents tested against yeast BSI isolates and mold LRTI isolates from the 2008 SENTRY Antimicrobial Surveillance Program (North America, Latin America, Europe, and Asia-Pacific region)

An overdose death involving the insufflation of extended-release oxymorphone tablets

Two cases are reported involving the abuse of extended-release oxymorphone hydrochloride tablets (Opana? ER) in combination with alprazolam (Xanax?). Two juvenile females were discovered unresponsive and hypoxic by a male acquaintance. The trio had reportedly crushed and snorted Opana ER tablets and consumed Xanax for recreational purposes. Emergency personnel were able to stabilize one female. The second female was pronounced dead at the scene. Blood and urine samples from the surviving female were collected at the trauma center between 48 and 96 h post incident. Toxicology results showed the presence of oxymorphone, doxylamine, dextromethorphan, alprazolam, α-hydroxyalprazolam, oxazepam, and temazepam in her urine. No drugs were detected in her blood. Toxicology on the deceased female revealed the presence of 0.13 mg/L oxymorphone and 0.04 mg/L alprazolam in her blood. Gastric contents contained 0.25 and 0.93 mg/L of oxymorphone and alprazolam, respectively. Oxymorphone, alprazolam, and α-hydroxyalprazolam were present in her urine. Quantitative results were achieved by gas chromatography-mass spectrometry monitoring selected ions for the oxime-oxymorphone-trimethylsilyl derivative, alprazolam, and the α-hydroxyalprazolam tert-butyldimethylsilyl derivative. The established linearity ranges for the opiate and benzodiazepine methods were 0.050-3.000 and 0.025-1.000 mg/L, respectively. The cause of death was reported as multiple drug toxicity, and the manner of death was accidental.     

Novel approaches in the pharmacotherapy of skeletal-related events in metastatic castrate-resistant prostate cancer

Biphosphonates have long been the standard of care for antiresorptive treatment of bone metastases from castrate-resistant prostate cancer (mCRPC). Although the indication has historically been mostly palliative, response rates in skeletal-related events (SRE) remain low. Denosumab has been shown to be effective in prolonging time to first SRE in clinical settings, however, critical questions remain on its ability to affect bone metastases in mCRPC. The landscape for research progress in reducing SREs using novel pharmacotherapies is growing rapidly, with several agents in clinical trials. This focused review outlines the most promising investigational drugs for treating bone metastases in mCRPC.     

Anaplastic lymphoma kinase is dynamically expressed on subsets of motor neurons and in the peripheral nervous system

During embryonic development, complex events, such as cellular proliferation, differentiation, survival, and guidance of axons, are orchestrated and regulated by a variety of extracellular signals. Receptor tyrosine kinases mediate many of these events, with several playing critical roles in neuronal survival and axonal guidance. It is evident that not all the receptor tyrosine kinases that play key roles in regulating neuronal development have been identified. In this study, we have characterized the spatial-temporal expression profile of a recently identified receptor tyrosine kinase, anaplastic lymphoma kinase (ALK), in embryonic chick by means of whole-mount in situ hybridization in conjunction with immunohistochemistry. Our findings reveal that Alk is expressed in sympathetic and dorsal root ganglia as early as stage 19. In addition, mRNA is expressed from stage 23/24 (E4) to stage 39 (E13) in discrete motor neuron subsets of chick spinal cord along with a select group of muscles that are innervated by one of these particular motor neuron clusters. Expression within the spinal cord is coincident with the onset and duration of motor neuron programmed cell death and during the period of musculature innervation and synapse formation. Hence, the data presented here identify ALK as a novel candidate receptor for regulating critical events in the development of neurons in both the central and the peripheral nervous systems.     

Brain lactate responses during visual stimulation in fasting and hyperglycemic subjects: a proton magnetic resonance spectroscopy study at 1.5 Tesla

Proton magnetic resonance spectroscopy ((1)H-MRS) studies showing increased lactate during neural activation support a broader role for lactate in brain energy metabolism than was traditionally recognized. Proton MRS measures of brain lactate responses have been used to study regional brain metabolism in clinical populations. This study examined whether variations in blood glucose influence the lactate response to visual stimulation in the visual cortex. Six subjects were scanned twice, receiving either saline or 21% glucose intravenously. Using (1)H-MRS at 1.5 Tesla with a long echo time (TE=288 ms), the lactate doublet was visible at 1.32 ppm in the visual cortex of all subjects. Lactate increased significantly from resting to visual stimulation. Hyperglycemia had no effect on this increase. The order of the slice-selective gradients for defining the spectroscopy voxel had a pronounced effect on the extent of contamination by signal originating outside the voxel. The results of this preliminary study demonstrate a method for observing a consistent activity-stimulated increase in brain lactate at 1.5 T and show that variations in blood glucose across the normal range have little effect on this response.     

Rule-based categorization deficits in focal basal ganglia lesion and Parkinson's disease patients

Patients with basal ganglia (BG) pathology are consistently found to be impaired on rule-based category learning tasks in which learning is thought to depend upon the use of an explicit, hypothesis-guided strategy. The factors that influence this impairment remain unclear. Moreover, it remains unknown if the impairments observed in patients with degenerative disorders such as Parkinson's disease (PD) are also observed in those with focal BG lesions. In the present study, we tested patients with either focal BG lesions or PD on two categorization tasks that varied in terms of their demands on selective attention and working memory. Individuals with focal BG lesions were impaired on the task in which working memory demand was high and performed similarly to healthy controls on the task in which selective-attention demand was high. In contrast, individuals with PD were impaired on both tasks, and accuracy rates did not differ between on and off medication states for a subset of patients who were also tested after abstaining from dopaminergic medication. Quantitative, model-based analyses attributed the performance deficit for both groups in the task with high working memory demand to the utilization of suboptimal strategies, whereas the PD-specific impairment on the task with high selective-attention demand was driven by the inconsistent use of an optimal strategy. These data suggest that the demands on selective attention and working memory affect the presence of impairment in patients with focal BG lesions and the nature of the impairment in patients with PD.