Species-specific Susceptibility Research Articles

Acute fipronil intoxication in Squirrel Monkey (Saimiri sciureus)

A biocidal product in gel form containing 0.05% fipronil active substance was used for pest control in the habitat of thirteen Squirrel Monkey (Saimiri sciureus) in a zoo. Following the application, sudden death was observed in three primates. Routine bacteriological, histopathological and toxicological analyses on one cadaver and tissue samples from the cadaver did not produce any pathogenic agent, pesticide and any pathognomonic findings. In an attempt to investigate the presence of known fipronil intoxication biomarkers, fipronil and fipronil sulfone, we applied modified QuEChERS extraction processes on tissue samples and determined the fipronil and fipronil sulfone levels as 27.1-3.5 μg/kg in cutaneous tissue and 13.8-47.2 μg/kg in brain tissue, respectively, by using UHPLC Q-Orbitrap Mass Spectrometer. In the light of the anamnesis, necropsy, microbiology and histopathology results, and after evaluating the presence of fipronil-fipronil sulfone in tissues, we considered that the deaths could have resulted from acute fipronil toxicity due to species-specific active substance susceptibility.

Inter-specific transpiration differences between aspen, spruce, and pine in a sky-island ecosystem of the North American Great Basin

Semiarid forests may face future challenges because of climate change-exacerbated soil droughts. Because the risk and rate of tree mortality from soil drying can vary widely between co-occurring species, inter-specific differences in tree response need to be evaluated for designing science-driven best-management strategies specifically tailored to iconic sky-island ecosystems. We analyzed sap flow of quaking aspen (Populus tremuloides), Engelmann spruce (Picea engelmannii), and limber pine (Pinus flexilis) for five consecutive years (2014–2018) at a remote, high-elevation site in the North American Great Basin. Our results revealed species-specific responses of sap flow to declining soil moisture. For quaking aspen, multi-year sap-flow trajectories mimicked growing-season depletion of soil moisture. Ample cool-season precipitation in 2017 diminished the summer drought impact on sap flow of Engelmann spruce and limber pine, indicating that the two conifers could tap a deeper soil water reservoir than the deciduous species. Since species-specific transpiration response to soil droughts was driven by shifting precipitation regimes, our findings suggest niche partitioning in the rhizosphere among coexisting tree species. In addition, spruce and pine rapidly downregulated canopy conductance with decreasing soil water availability, whereas aspen canopy conductance was insensitive to soil drying. This physiological characteristic allows quaking aspen to maximize resource acquisition when growing conditions are favorable, but poses a risk of hydraulic failure and subsequent mortality under soil drying. Overall, we found contrasting hydrological niches and physiological strategies between co-occurring tree species in semiarid, high-elevation ecosystems. We also emphasize the value of long-term, in-situ observations to determine species-specific susceptibility to environmental changes in remote mountain areas.

Aggressive tree killer or natural thinning agent? Assessing the impacts of a globally important forest insect

Invasive insects and pathogens are prominent tree mortality agents in forests around the world, and the magnitude of their impacts is increasing. Comparative studies across multiple populations can be helpful for the development of new insights and innovative management strategies. We used the Sirex woodwasp, Sirex noctilio Fabricius, as a model system to compare invasion impacts across a range of ecological contexts around the globe: native woodwasps colonizing native trees, invasive woodwasps in non-native plantation trees, and invasive woodwasps attacking native trees. Across 133 stands of eight pine species on four continents, tree mortality associated with S. noctilio attack was positively correlated with stand basal area and stand density, and was mostly confined to smaller, suppressed trees. Larger average tree size and greater distances between trees were linked to lower levels of tree mortality. To more deeply assess the impacts of tree loss due to this pest, we examined mortality in vigorous trees, defined as those with a stem diameter greater than or equal to 90% of the mean diameter for trees in the stand. Sirex noctilio- related mortality in vigorous trees was rare, with one exception where Pinus contorta stands in Argentina lost as many as 300 vigorous trees ha−1. Pine species varied dramatically in their susceptibility to S. noctilio: for example, these losses in P. contorta were in stark contrast to very low mortality in P. ponderosa, the other pine species grown in Argentina. Surprisingly, location did not alter patterns in the influence of stand basal area on tree susceptibility for individual species. Most notably, Pinus radiata had the same relationship between basal area and tree mortality when grown in Spain (where S. noctilio is native and not considered a meaningful forest pest) and South Africa (where S. noctilio is a problematic invasive). Our findings suggest that the availability of optimal pine hosts is a key driver of S. noctilio-related tree mortality across continents and management regimes. Important variables that influence host availability include species-specific susceptibility and environmental and management-related factors that promote or limit the number of stressed trees present both within stands and across the regional forest or plantation landscape.

Effect of the exposure to oxidation and malondialdehyde on turkey and rabbit meat protein oxidative stability.

The present study aimed at evaluating the effect of the exposure to a strong oxidative environment (100mM NaClO) and the concurrent incubation with different malondialdehyde (MDA) concentrations (0 to 5mM) on protein carbonylation, free thiol groups, total heme pigments, and on the relative concentration of the different myoglobin (Mb) derivatives in turkey thigh and rabbit hind leg meat to elucidate their eventual role in inducing oxidative modifications on the protein fraction. With regard to turkey meat, the addition of a strong oxidant resulted in remarkably higher (P < 0.001) carbonyls along with a reduction in free thiol groups (which become undetectable). The relative concentration of MbO2 and MetMb was significantly affected (P < 0.001) and total heme pigment was reduced by 62% when fresh meat is compared to its oxidized counterpart. The addition of MDA 2.5mM (or greater) resulted in a 1.4-fold increase in carbonyls and a tendency (P = 0.07) has been observed for free thiol groups whose content decreased as the MDA level increased. Overall, the aforementioned results are in agreement with those obtained on rabbit hind leg meat in which a three-fold increase (P < 0.001) in carbonyls and a remarkably higher (P < 0.001) MetMb content coupled with a 53% reduction in free thiol groups were found. No significant differences ascribable to MDA addition were found. In conclusion, exposing turkey and rabbit meat to the same environment resulted in distinctive oxidative changes that might be related to the compositional traits and a species-specific susceptibility of the meat toward oxidation. PRACTICAL APPLICATION: Protein and lipid oxidation have been investigated in different meat types; nevertheless, the knowledge concerning the interaction between these two phenomena is limited. According to their compositional traits (high Polyunsaturated fatty acids (PUFA) and heme pigment content), turkey and rabbit leg meats are particularly susceptible to oxidation. Providing information concerning the oxidative stability of turkey thigh and rabbit hind leg meat exposed to strong oxidative conditions and to a concurrent increasing content of a secondary product of lipid oxidation, the findings of the present study can be useful when proper processing strategies and storage conditions have to be implemented for manufacturing processed products.

Comparative analysis of viruses in four bee species collected from agricultural, urban, and natural landscapes.

Managed honey bees (Apis mellifera L.) and wild bees provide critical ecological services that shape and sustain natural, agricultural, and urban landscapes. In recent years, declines in bee populations have highlighted the importance of the pollination services they provide and the need for more research into the reasons for global bee losses. Several stressors cause declining populations of managed and wild bee species such as habitat degradation, pesticide exposure, and pathogens. Viruses, which have been implicated as a key stressor, are able to infect a wide range of species and can be transmitted both intra- and inter-specifically from infected bee species to uninfected bee species via vertical (from parent to offspring) and/or horizontal (between individuals via direct or indirect contact) transmission. To explore how viruses spread both intra- and inter-specifically within a community, we examined the impact of management, landscape type, and bee species on the transmission of four common viruses in Nebraska: Deformed wing virus (DWV), Israeli acute paralysis virus (IAPV), Black queen cell virus (BQCV), and Sacbrood virus (SBV). Results indicated the prevalence of viruses is significantly affected (P < 0.005) by bee species, virus type, and season, but not by landscape or year (P = 0.290 and 0.065 respectively). The higher prevalence of DWV detected across bee species (10.4% on Apis mellifera, 5.3% on Bombus impatiens, 6.1% on Bombus griseocollis, and 22.44% on Halictus ligatus) and seasons (10.8% in early-mid summer and 11.4% in late summer) may indicate a higher risk of interspecific transmission of DWV. However, IAPV was predominately detected in Halictus ligatus (20.7%) and in late season collections (28.1%), which may suggest species-specific susceptibility and seasonal trends in infection rates associated with different virus types. However, there were limited detections of SBV and BQCV in bees collected during both sampling periods, indicating SBV and BQCV may be less prevalent among bee communities in this area.

Native Gammarus fossarum affects species composition of macroinvertebrate communities: evidence from laboratory, field enclosures, and natural habitat

Despite the fact that native species of amphipods have been recognized as active predators similarly to invasive species, little is known about their predatory impact on aquatic communities. In this study, we used a laboratory experiment, a field enclosure experiment, and an analysis of natural community data to demonstrate how Gammarus fossarum affects the species composition of benthic communities by imposing survival selection on its prey. Our laboratory single-prey experiment brought a clear evidence that tube-less chironomids are vulnerable prey and that the predation rate on the tube-dwelling chironomids decreases with increasing tube toughness (from the soft tubes made of detritus to the hard tubes made of sand or calcium carbonate grains). We found that the introduction of G. fossarum to field enclosures significantly changed the species composition of a macroinvertebrate community at an experimental spring fen site. The soft-bodied, slow moving, and tube-less taxa were depleted the most. It appears that the observed patterns were a result of predator’s preference rather than encounter rate. Survival selection was detected also in natural communities across a large spatial scale. In accordance with the experiments, high densities of G. fossarum limited the proportion or abundance of vulnerable prey. Our study (1) provides the first convincing evidence that biotic interactions have a structuring effect on the spring fen communities, (2) documents how the predatory effect in a community depends on an interplay between the prey handling behaviour of the predator and species-specific susceptibility of prey, and (3) shows that an omnivorous native amphipod may have a strong impact on aquatic communities despite it is regarded less aggressive than its invasive relatives.

Species-specific susceptibility to white plague disease in three common Caribbean corals

White plague disease has caused widespread coral mortality and affects over 30 Caribbean coral species, yet how different coral species respond to disease exposure has not been tested experimentally. This study quantified white plague transmission from Orbicella franksi to three susceptible and abundant coral species in the U.S. Virgin Islands: Orbicella annularis, Siderastrea siderea, and Porites astreoides. White plague was observed in 83% of tested O. annularis corals within 5.8 ± 1.1 (mean ± SE) d, 42% of S. siderea corals within 9.1 ± 1.4 d, and 17% of P. astreoides corals within 12 ± 0.87 d. Results from this study indicate that: (1) O. annularis is significantly more susceptible to white plague than S. siderea and P. astreoides, and (2) white plague infection occurs more rapidly in O. annularis than in P. astreoides. These results are important for understanding how multi-species diseases may impact coral species assemblages.

Regional coral disease outbreak overwhelms impacts from a local dredge project.

A repeated-measures coral monitoring program established as part of the PortMiami expansion program provided an unparalleled opportunity to quantify the levels of coral mortality that resulted from both local dredging stress and as a result of climate-related bleaching stress and the subsequent outbreak of a white-plague-like disease (WPD) epizootic. By comparing measured rates of coral mortality at 30 sites throughout Miami-Dade County to predicted mortality levels from three different coral mortality scenarios, we were able to evaluate the most likely source of coral mortality at both the local and regional levels during the 2014-2016 coral bleaching and WPD event. These include scenarios that assume (1) local dredging increases coral disease mortality, (2) regional climate-related stress is the proximal driver of coral disease mortality, and (3) local and regional stressors are both responsible for coral disease mortality. Our results show that species-specific susceptibility to disease is the determining factor in 93.3% of coral mortality evaluated throughout Miami-Dade County, whereas local dredging stress only accurately predicted coral mortality levels 6.7% of the time. None of the monitoring locations adjacent to the PortMiami expansion had levels of coral mortality that exceeded predictions when coral community composition was taken into account. The novel result of this analysis is that climate-mediated coral disease mortality was more than an order of magnitude (14x) more deadly than even the largest marine construction project performed in the USA, and that until climate change is addressed, it is likely that local attempts to manage coral resilience will continue to fail.

A Revised Species Concept for Opportunistic Mucor Species Reveals Species-Specific Antifungal Susceptibility Profiles.

Recently, the species concept of opportunistic Mucor circinelloides and its relatives has been revised, resulting in the recognition of its classical formae as independent species and the description of new species. In this study, we used isolates of all clinically relevant Mucor species and performed susceptibility testing using the EUCAST reference method to identify potential species-specific susceptibility patterns. In vitro susceptibility profiles of 101 mucoralean strains belonging to the genus Mucor (72), the closely related species Cokeromyces recurvatus (3), Rhizopus (12), Lichtheimia (10), and Rhizomucor (4) to six antifungals (amphotericin B, natamycin, terbinafine, isavuconazole, itraconazole, and posaconazole) were determined. The most active drug for all Mucorales was amphotericin B. Antifungal susceptibility profiles of pathogenic Mucor species were specific for isavuconazole, itraconazole, and posaconazole. The species formerly united in M. circinelloides showed clear differences in their antifungal susceptibilities. Cokeromyces recurvatus, Mucor ardhlaengiktus, Mucor lusitanicus (M. circinelloides f. lusitanicus), and Mucor ramosissimus exhibited high MICs to all azoles tested. Mucor indicus presented high MICs for isavuconazole and posaconazole, and Mucor amphibiorum and Mucor irregularis showed high MICs for isavuconazole. MIC values of Mucor spp. for posaconazole, isavuconazole, and itraconazole were high compared to those for Rhizopus and the Lichtheimiaceae (Lichtheimia and Rhizomucor). Molecular identification combined with in vitro susceptibility testing is recommended for Mucor species, especially if azoles are applied in treatment.

Updates on Nocardia Skin and Soft Tissue Infections in Solid Organ Transplantation.

Due to their immunocompromised status, solid organ transplant (SOT) recipients are at risk for Nocardia infections. These infections often necessitate early invasive diagnostics alongside prolonged, often combination antimicrobial therapy. This review summarizes the importance of this pathogen in skin and soft tissue infections (SSTIs) in SOT recipients inclusive of recently reported cases in the literature and an update on the epidemiology, diagnostics, and management. Six studies with 13 isolated SSTIs due to Nocardia have been published in the last 5years in SOT recipients. The most common underlying type of transplant was kidney and time from transplantation to infection varied from 6months to 16years. Misdiagnosis was frequent. Available identified species included N. brasiliensis (2), N. farcinica (2), N. flavorosea (1), N. abscessus (1), N. anaemiae (1), N. asteroides (1), N. nova (1), and N. vinacea (1). Treatment choice and duration varied widely, and trimethoprim-sulfamethoxazole was utilized most often with no documented infection relapse. Nocardia SSTIs can occur both in isolation and as a component of a disseminated infection. Overall, isolated Nocardia SSTIs are uncommon in SOT recipients and are often initially misdiagnosed. They present multiple challenges to the clinician including evaluation for potential co-pathogens and/or non-infectious processes and ruling out the presence of disseminated infection. While trimethoprim-sulfamethoxazole remains the agent of choice for management of most isolated SSTIs, therapy must be tailored to the individual patient based on species-specific susceptibility patterns and formal susceptibility testing, site(s) of infection, and patient tolerability.

Patterns of acoustical activity of bats prior to and 10 years after WNS on Fort Drum Army Installation, New York

Previous acoustic surveys, netting, and count data have shown that overall bat activity patterns have shifted among most species between pre- and post-white-nose syndrome (WNS) years in much of North America where WNS has occurred. However, the significance of these changes is based on the species-specific susceptibility to WNS. We used acoustically recorded echolocation passes obtained at Fort Drum, New York to describe changes in bat activity pre-WNS (2004–2007) to post-WNS (2008–2018). We examined seasonal and yearly changes in bat activity as they relate to the presence of WNS at hibernacula near (<25 km) Fort Drum. A priori, we expected that overall activity for communal hibernating species would be less in years following WNS, and migratory bats or those hibernating bats that are less affected by WNS would show no response or a positive response, due to niche relaxation/competitive release. Our results indicated both an overall and seasonal decrease in activity for Myotis spp. post-WNS. For WNS-susceptible species, our results reflect the high level of mortality in regional winter hibernacula post-WNS and possibly variable reproductive effort and recruitment thereafter. Although migratory bats did show increases in post-WNS activity throughout the summer, we found little evidence that community displacement was occurring on a nightly level by any species. The continuous spread of WNS across North America has had strong negative effects on bat populations of affected species, and our research identifies how individual species (both impacted and non-impacted) respond to WNS.

Associations between environmental pollutants and larval amphibians in wetlands contaminated by energy-related brines are potentially mediated by feeding traits

Energy production in the Williston Basin, located in the Prairie Pothole Region of central North America, has increased rapidly over the last several decades. Advances in recycling and disposal practices of saline wastewaters (brines) co-produced during energy production have reduced ecological risks, but spills still occur often and legacy practices of releasing brines into the environment caused persistent salinization in many areas. Aside from sodium and chloride, these brines contain elevated concentrations of metals and metalloids (lead, selenium, strontium, antimony and vanadium), ammonium, volatile organic compounds, hydrocarbons, and radionuclides. Amphibians are especially sensitive to chloride and some metals, increasing potential effects in wetlands contaminated by brines. We collected bed sediment and larval amphibians (Ambystoma mavortium, Lithobates pipiens and Pseudacris maculata) from wetlands in Montana and North Dakota representing a range of brine contamination history and severity to determine if contamination was associated with metal concentrations in sediments and if metal accumulation in tissues varied by species. In wetland sediments, brine contamination was positively associated with the concentrations of sodium and strontium, both known to occur in oil and gas wastewater, but negatively correlated with mercury. In amphibian tissues, selenium and vanadium were associated with brine contamination. Metal tissue concentrations were higher in tadpoles that graze compared to predatory salamanders; this suggests frequent contact with the sediments could lead to greater ingestion of metal-laden materials. Although many of these metals may not be directly linked with energy development, the potential additive or synergistic effects of exposure along with elevated chloride from brines could have important consequences for aquatic organisms. To effectively manage amphibian populations in wetlands contaminated by saline wastewaters we need a better understanding of how life history traits, species-specific susceptibilities and the physical-chemical properties of metals co-occurring in wetland sediments interact with other stressors like chloride and wetland drying.

Environmental fate and impact assessment of thiobencarb application in California rice fields using RICEWQ

Thiobencarb is a commonly used herbicide in Northern California rice fields. Released paddy water containing thiobencarb may pose ecological risks to non-targeted organisms. In this research, the Rice Water Quality Model (RICEWQ) is equilibrium tested and then calibrated using monitoring data at field level. Then it is employed to assess the environmental fate and impacts of thiobencarb in the Colusa Basin, and the effects of different management practices on water use and thiobencarb exposures. The model predicted thiobencarb concentrations from rice fields for multiple years throughout the Basin, using input from California Pesticide Use Reporting (PUR) database, and assessed both the temporal/spatial distribution of thiobencarb exposure and potential acute toxicity on non-target organisms.Our study indicated that RICEWQ can accurately reflect the initial partitioning of thiobencarb in both paddy water and soil phases and capture the dynamics of thiobencarb at field level after calibration. Mandatory water holding is critical for reducing thiobencarb exposure in released paddy water. A thirty-day holding time reduces thiobencarb concentrations by 64% relative to a 6-day holding practice. The geo-spatial pattern of exposure in the study domain indicates the differing extents of pollutant levels and their distribution over space. “Risk zones” for different species were identified based on the geospatial patterns of thiobencarb exposure and the species-specific susceptibilities of various non-target species to thiobencarb.

Antimicrobial susceptibility testing of Mycobacteroides (Mycobacterium) abscessus complex, Mycolicibacterium (Mycobacterium) fortuitum, and Mycobacteroides (Mycobacterium) chelonae.

The drug susceptibility of rapidly growing mycobacteria (RGM) varies among isolates. Treatment strategies similarly differ depending on the isolate, and for some, no clear strategy has been identified. This complicates clinical management of RGM. Following Clinical and Laboratory Standards Institute standard M24-A2, we assessed the susceptibility of 140 RGM isolates to 14 different antimicrobial drugs by measuring their minimal inhibitory concentrations (MICs). We also investigated the correlation of clarithromycin (CAM) MICs with the erm(41) and rrl gene mutations in the Mycobacteroides (Mycobacterium) abscessus complex, the rrl mutation in Mycobacteroides (Mycobacterium) chelonae, and the erm(39) mutation in Mycolicibacterium (Mycobacterium) fortuitum to determine the contribution of these mutations to CAM susceptibility. The five species and subspecies examined included 48 M.abscessus subsp. abscessus isolates (34.3%), 35 (25.0%) being M.abscessus subsp. massiliense, and two (1.4%) being M.abscessus subsp. bolletii. The M.abscessus complex accounted for 85 isolates (60.7%) in total, whereas 43 isolates (30.7%) were M.fortuitum, and 12 (8.6%) were M.chelonae. Our results demonstrated species-specific susceptibility to antimicrobials. In most cases, susceptibility to CAM could be predicted based on genetic pattern, but since one isolate did not fit that pattern, MIC values needed to be measured. Some isolates also exhibited rates of resistance to other drugs that differed from those previously reported in other locations, indicating that accurate identification of the bacterial isolate and use of the correct method for determining MIC are both important for the diagnosis of RGM.

Human evolutionary loss of epithelial Neu5Gc expression and species-specific susceptibility to cholera.

While infectious agents have typical host preferences, the noninvasive enteric bacterium Vibrio cholerae is remarkable for its ability to survive in many environments, yet cause diarrheal disease (cholera) only in humans. One key V. cholerae virulence factor is its neuraminidase (VcN), which releases host intestinal epithelial sialic acids as a nutrition source and simultaneously remodels intestinal polysialylated gangliosides into monosialoganglioside GM1. GM1 is the optimal binding target for the B subunit of a second virulence factor, the AB5 cholera toxin (Ctx). This coordinated process delivers the CtxA subunit into host epithelia, triggering fluid loss via cAMP-mediated activation of anion secretion and inhibition of electroneutral NaCl absorption. We hypothesized that human-specific and human-universal evolutionary loss of the sialic acid N-glycolylneuraminic acid (Neu5Gc) and the consequent excess of N-acetylneuraminic acid (Neu5Ac) contributes to specificity at one or more steps in pathogenesis. Indeed, VcN was less efficient in releasing Neu5Gc than Neu5Ac. We show enhanced binding of Ctx to sections of small intestine and isolated polysialogangliosides from human-like Neu5Gc-deficient Cmah-/- mice compared to wild-type, suggesting that Neu5Gc impeded generation of the GM1 target. Human epithelial cells artificially expressing Neu5Gc were also less susceptible to Ctx binding and CtxA intoxication following VcN treatment. Finally, we found increased fluid secretion into loops of Cmah-/- mouse small intestine injected with Ctx, indicating an additional direct effect on ion transport. Thus, V. cholerae evolved into a human-specific pathogen partly by adapting to the human evolutionary loss of Neu5Gc, optimizing multiple steps in cholera pathogenesis.

In Vivo Pharmacokinetics and Pharmacodynamics of APX001 against Candida spp. in a Neutropenic Disseminated Candidiasis Mouse Model.

APX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for Candida albicans (n = 5), C. glabrata (n = 5), and C. auris (n = 4). MIC values ranged from 0.002 to 0.03 mg/liter for C. albicans, from 0.008 to 0.06 mg/liter for C. glabrata, and from 0.004 to 0.03 mg/liter for C. auris Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration (Cmax) values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC0-inf) values of 0.87 to 70.0 mg · h/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed against C. albicans K1, with total doses ranging from 4 to 1,024 mg/kg/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK/PD index best correlated with efficacy on the basis of the reduction in the number of CFU/kidney at 24 h. The 24-h free-drug AUC/MIC ratio (fAUC0-24/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [R2] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg/kg of APX001 administered every 6 h for a 24-h duration with C. albicans and a 96-h study duration with C. glabrata and C. auris The dose required to achieve 50% of the maximum effect (ED50) and stasis fAUC/MIC targets were as follows: for C. albicans, 3.67 ± 3.19 and 20.60 ± 6.50, respectively; for C. glabrata, 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and for C. auris, 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstrated in vitro and in vivo APX001A and APX001 potency, respectively, against C. albicans, C. glabrata, and C. auris. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target for C. glabrata suggests that species-specific susceptibility breakpoints should be explored.

Species-specific susceptibility to cannabis-induced convulsions.

Background and PurposeNumerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ9‐tetrahydrocannabinol (THC), variously reported to be pro‐ and anticonvulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling.Experimental ApproachCannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract‐treated rats and treatment‐naïve rat, mouse, chicken, dog and human tissue.Key ResultsProlonged exposure to cannabis extracts caused spontaneous, generalized seizures, subserved by epileptiform discharges in rats, but not dogs, and produced higher THC, but lower 11‐hydroxy‐THC (11‐OH‐THC) and CBD, plasma concentrations in rats versus dogs. In the same rats, prolonged exposure to cannabis also impaired cannabinoid type 1 receptor (CB1 receptor)‐mediated signalling. Profiling CB1 receptor expression, basal activity, extent of activation and sensitivity to THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract‐induced seizures (rat) than one that did not (dog).Conclusions and ImplicationsSustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis‐induced convulsions from animal models.Linked ArticlesThis article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc

Predators modify biogeographic constraints on species distributions in an insect metacommunity.

Theory describing the positive effects of patch size and connectivity on diversity in fragmented systems has stimulated a large body of empirical work, yet predicting when and how local species interactions mediate these responses remains challenging. We used insects that specialize on milkweed plants as a model metacommunity to investigate how local predation alters the effects of biogeographic constraints on species distributions. Species-specific dispersal ability and susceptibility to predation were used to predict when patch size and connectivity should shape species distributions, and when these should be modified by local predator densities. We surveyed specialist herbivores and their predators in milkweed patches in two matrix types, a forest and an old field. Predator-resistant species showed the predicted direct positive effects of patch size and connectivity on occupancy rates. For predator-susceptible species, predators consistently altered the impact of biogeographic constraints, rather than acting independently. Finally, differences between matrix types in species' responses and overall occupancy rates indicate a potential role of the inter-patch environment in mediating the joint effects of predators and spatial drivers. Together, these results highlight the importance of local top-down pressure in mediating classic biogeographic relationships, and demonstrate how species-specific responses to local and regional constraints can be used to predict these effects.

Antimicrobial susceptibility and MIC distribution of 41 drugs against clinical isolates from China and reference strains of nontuberculous mycobacteria

To treat nontuberculous mycobacteria (NTM) infections more optimally, further research pertaining to mycobacterial susceptibility to antimicrobial agents is required. A total of 82 species of NTM reference strains and 23 species of NTM clinical isolates were included. Minimum inhibitory concentrations (MICs) for 41 drugs were determined using the microdilution method in cation-adjusted Mueller–Hinton broth. The results showed that most of the NTM were susceptible to aminoglycosides, quinolones, three macrolides (clarithromycin, azithromycin and roxithromycin), cefmetazole, linezolid and capreomycin. Rapidly growing mycobacterium strains were additionally susceptible to cefoxitin, clofazimine, rifapentine, doxycycline, minocycline, tigecycline, meropenem and sulfamethoxazole, whereas slowly growing mycobacterium strains were additionally susceptible to rifabutin. This study on the susceptibility of NTM includes the largest sample size of Chinese clinical isolates and reference strains. NTM species-specific drug susceptibility patterns suggested that it is urgent to identify the species of NTM, to normalise the treatment of NTM infectious disease and to clarify the resistance mechanisms of NTM.

Evaluation of PNA-FISH method for direct identification of Candida species in blood culture samples and its potential impact on guidance of antifungal therapy

Early antifungal therapy has a major influence on survival in candidemia. Rapid identification of the species has importance for the treatment, prediction of the species-specific primary resistance and variable antifungal susceptibility. Recently, molecular-based methods attempt to reduce the time between the positive signal of a blood culture and identification of the fungus. PNA-FISH (Peptide nucleic acid fluorescence in situ hybridization) assay distinguishes a number of frequently isolated Candida species in groups following the growth in blood culture. The aim of this study was to investigate the correlation of the species identified by PNA-FISH with conventional identification methods in yeast positive blood cultures and its influence on the selection of antifungal therapy. Specimens of adult patients diagnosed as yeast with Gram stain in signal-positive blood cultures between August to December 2013, were included in the study. The strains were concomitantly cultivated by subculturing from the blood culture bottles onto solid media and identified by conventional methods (germ tube test, ID32C and morphology on cornmeal Tween 80 agar). Rapid species identification was performed by Yeast Traffic Light PNA-FISH, which generates green flourescence for Candida albicans and Candida parapsilosis, yellow for Candida tropicalis, and red for Candida krusei and Candida glabrata. C.tropicalis was identified as a single species whereas the others were identified in pairs. The time points when the yeast positive blood culture bottle was received by the mycology laboratory and reporting of the species identification results by PNA-FISH and the conventional methods were recorded. Seven C.albicans, six C.glabrata, three C.parapsilosis, one C.tropicalis, one C.krusei, one Cryptococcus neoformans, one Saprochaete capitata (Blastoschizomyces capitatus), one C.albicans and Candida dubliniensis, one C.krusei and C.dubliniensis, and one C.glabrata and C.parapsilosis were identified by conventional methods in 23 specimens. Results of PNA-FISH and conventional methods were in full agreement in 19 of the 23 specimens (82.6%). Two specimens were negative by PNA-FISH and yielded S.capitata and C.neoformans which were not included in the test panel. In three specimens that were infected with multiple species, PNA-FISH detected only one of the species. On the other hand and in one specimen, PNA-FISH detected a second species (C.glabrata or C.krusei) that could not be isolated and identified conventionally. Species identification were obtained 72 hours (mean) earlier with PNA-FISH. PNA-FISH provided accurate species identification that were consistent with conventional methods. However and expectedly, it failed to detect species that were not included in the test panel. During the study period, 13 of the 23 patients have passed away. Apart from six patients died prior to blood culture positivity and the one that could not get any antifungal therapy during hospital stay, 16 patients received antifungal treatment. Of sixteen patients who received antifungal therapy, initial antifungal treatment was fluconazole for five and echinocandin for 10 patients. Fluconazole and amphotericin B combination was preferred for one patient. In this study, PNA-FISH result had an influence on the modification of the antifungal treatment of only for one patient in accordance with the clinical findings. We conclude that the utility of PNA-FISH method appeared to be limited in our center since the assay cannot differentiate C.albicans and C.parapsilosis, the two commonly isolated species among our candidemia isolates. However, advantages of the assay might be more pronounced for the centers where C.glabrata is a relatively more frequent species.