Clinical-pathological findings induced by Histophilus somni isolated in subacute cardiac death in feedlot cattle.

The purpose of this report is to provide information about the different presentations of cardiac and extra-cardiac histophilosis and, to assess the antimicrobial (ATM) susceptibility of Histophilus somni isolated from these cardiac lesions to different ATM agents commonly used for treating bovine bacterial respiratory pathogens. Eight feedlot calves, which died after suffering from food rejection, apathy, hyperthermia, cough and nasal mucous discharge, and lack of response to ATM therapy, were studied. Cardiac lesions observed at necropsy included valvular/mural endocarditis, myocardial infarction, and necrotizing myocarditis, miliar non-suppurative myocarditis, myocardic necrotic sequestrum, and/or pericarditis. Histopathological, bacteriological and molecular studies confirmed the presence of a fastidious microorganism in the affected organs. H. somni showed no resistance to most ATM tested (ceftiofur, gamithromycin, enrofloxacin, florfenicol, tilmicosin). The results obtained in this study confirmed that H. somni was the main cause of the subacute cardiac lesions associated with hyperthermia, apathy and respiratory signs observed in cattle examined in this research. These presentations must be considered by veterinary practitioners in order to establish a rational therapeutic.

Antinematodic effect of Enterococcus faecalis CECT7121 using Trichinella spiralis as a model of nematode infection in mice.

Nematode infections affect a significant percentage of the human population worldwide, especially in developing countries. There are a small number of drugs available to treat these infections, with variable outcomes. Therefore, the potential use of probiotics to help control parasitic infections has emerged as a suitable option. The main goal of this work was to assess the antinematodic effect of the probiotic Enterococcus faecalis CECT7121 (EFCECT7121) in vitro and in vivo, using Trichinella spiralis as a nematode model of infection. The in vitro assay showed a reduction in T. spiralis larvae viability of 31.6% when compared with the control group (6.3%) after 48 h incubation with EFCECT7121. Nevertheless, the isolated antimicrobial peptide AP7121 when inoculated at different concentrations did not reveal any larvicidal effect. Different EFCECT7121 treatment schemes in mice were evaluated, and the reduction of the enteral and parenteral burden of T. spiralis was determined. In addition, the protective effect of EFCECT7121 combined with the conventional anthelmintic albendazole (ABZ, 5 mg/kg) was also assessed. The oral administration of EFCECT7121 previous T. spiralis infection produced a reduction in the larvae per gram (LPG) of mice muscle tissue ranging from 32.8 to 47.9% on the 28th day post-infection. ABZ alone and the combination EFCECT7121 + ABZ produced a reduction of the LPG of muscle tissue of 62 and 60.7%, respectively. Results obtained in the current work support the hypothesis that probiotics such as EFCECT7121 have an antinematodic effect, and their combination with conventional anthelmintic drugs may result useful for improving clinical and parasitological outcomes.

Whole genome sequencing and de novo assembly of Staphylococcus pseudintermedius: a pangenome approach to unravelling pathogenesis of canine pyoderma.

BACKGROUND: Staphylococcus pseudintermedius is the main aetiological agent of canine pyoderma. Whole genome sequencing is the most comprehensive way of obtaining relevant genomic information about micro-organisms. HYPOTHESIS/OBJECTIVES: Oxford Nanopore technology enables quality sequencing and de novo assembly of the whole genome of S. pseudintermedius. Whole genome analysis of S. pseudintermedius may help to better understand the pathogenesis of canine pyodermas. METHODS AND MATERIALS: Twenty-two strains of S. pseudintermedius isolated from the skin of five healthy dogs and 33 strains isolated from skin of 33 dogs with pyoderma were analysed. DNA was extracted and sequenced using Oxford Nanopore MinION, a new technology that delivers longer reads in a hand-held device. The pangenome was analysed and visualised with Anvi'o 6.1. RESULTS: Nanopore technology allowed the sequencing and de novo assembly of the genomes of 55 S. pseudintermedius strains isolated from healthy dogs and from dogs with pyoderma. The average genome size of S. pseudintermedius was 2.62 Mbp, with 48% being core genome. Pyoderma isolates contained a higher number of antimicrobial resistance genes, yet the total number of virulence factors genes did not change between isolates from healthy dogs and from dogs with pyoderma. Genomes of meticillin-resistant S. pseudintermedius (MRSP) strains were larger than those of meticillin-susceptible (MSSP) strains (2.80 Mbp versus 2.59 Mbp), as a consequence of a greater presence of antimicrobial resistance genes, phages and prophages. CONCLUSIONS AND CLINICAL IMPORTANCE: This technique allows much more precise and easier characterisation of canine S. pseudintermedius populations and may lead to a better understanding of the pathogenesis of canine pyodermas.

The antimicrobial effect behind Cannabis sativa.

The development of multidrug-resistant bacteria has revealed the need for new antimicrobial compounds. Cannabis sativa preparations have a long history of medical applications, including the treatment of infectious diseases. This review collects the information about the activity of C. sativa extracts and its main components (cannabinoids and terpenes) against pathogenic bacteria and fungus, to assess its potential using as antimicrobial agents.

Gram-positive bacteriocins: usage as antimicrobial agents in veterinary medicine.

Antimicrobial resistance is a worldwide spread phenomenon that affects both human and veterinary medicine. This issue has led to a "One Health" approach in order to coordinate efforts and set back the development of drug-resistant microbes. In the search for alternatives therapies, bacteriocins or antimicrobial peptides have proven to be effective both in vitro and in vivo for multiples pathogens, even those resistant to many classic antibiotics. Gram-positive bacteriocins have been the most studied to the present. The use of bacteriocins as therapeutically active molecules is limited mainly due to difficulties in production, purification, delivery systems and regulatory approvals. To overcome some of these limitations, biotechnological and nanotechnological approaches are evaluated. Bacteriocins proved to be a good complement for conventional antibiotics therapy. Antimicrobial peptides are nowadays included in the veterinary products such as udder disinfectant for dairy cattle and dermatological medicated wipe for topical use on dogs, cats, and horses. But there are other potential uses to explore in the veterinary field for both companion and production animals.

Design of novel oral ricobendazole formulation applying melting solidification printing process (MESO-PP): An innovative solvent-free alternative method for 3D printing using a simplified concept and low temperature.

This paper describes a melting solidification printing process (MESO-PP) capable of obtaining printed oral solid dosage forms in a safe, versatile, and robust manner avoiding the use of solvents and high temperatures. MESO-PP and Gelucire® 50/13 (fatty polyethylene glycol esters) as ink can be used to obtain a floating sustained-release system with the aim of improving the dissolution and absorption of drugs, such as ricobendazole (RBZ), which have a low and erratic bioavailability. Gelucire 50/13 can be considered a good material to formulate inks using MESO-PP. As a model, the RBZ allowed us to assess that there were no changes in crystallinity and the API-ink interactions were ruled out using TGA, DSC, XRD and FT-IR assays. A batch of printlets, obtained using MESO-PP, fulfilled USP requirements regarding uniformity of mass (827 ± 9 mg) and drug content (211 ± 5 mg). Hardness and friability were 39.23 ± 9.65 N and 1.07 ± 0.5% respectively, just above the 1% USP tablet-friability limit. It was possible to obtain tablets of different sizes with high precision (r2 = 0.995). In vitro dissolution test showed that the printlet had a sustained-release of RBZ (only 7% after 15 min), that erosion was the predominant mechanism for drug release (n-value of Korsmeyer-Peppas equation = 0.991; r2 = 0.99) and that changes in the internal structures modify the release. Consequently, MESO-PP can be considered an excellent alternative to obtain solid pharmaceutical dosage forms with variable geometries for different pharmaceutical applications.

Ricobendazole nanocrystals obtained by media milling and spray drying: Pharmacokinetic comparison with the micronized form of the drug.

Helminthic infections are produced by different types of worms and affect millions of people worldwide. Benzimidazole compounds such as ricobendazole (RBZ) are widely used to treat helminthiasis. However, their low aqueous solubility leads to poor gastrointestinal dissolution, absorption and potential lack of efficacy. The formulation of nanocrystals (NCs) have become the strategy of preference for hydrophobic drugs. In this work, we prepared RBZ NCs (RBZ-NCs) by an optimized combination of bead milling and spray-drying. Following the physicochemical characterization, a comparative pharmacokinetic evaluation of RBZ-NCs was performed in dogs using as controls a micronized powdered form of RBZ (mRBZ) and a physical mixture of drug and stabilizer 1:1 (PM). The particle size of the redispersed RBZ-NCs was 181.30 ± 5.93 nm, whereas DSC, PXRD and FTIR analyses demonstrated that the active ingredient RBZ remained physicochemically unchanged after the manufacture process. RBZ-NCs exhibited improved in vitro biopharmaceutical behaviour when compared to mRBZ. Consequently, the pharmacokinetic trial demonstrated a significant increase in the drug oral absorption, with an AUC0-∞ 1.9-fold higher in comparison to that obtained in animals treated with mRBZ. This novel formulation holds substantial potential for the development of new/alternative treatments for helminth infections both in human and veterinary medicine.

Albendazole-lipid nanocapsules: Optimization, characterization and chemoprophylactic efficacy in mice infected with Echinococcus granulosus.

Cystic echinococcosis (CE), which is caused during the metacestode larval stage of Echinococcus granulosus, is a life-threatening disease and is very difficult to treat. At present, the FDA-approved antihelmintic drugs are mebendazole (MBZ), albendazole (ABZ) and its principal metabolite ABZ sulfoxide (ABZSO), but as these have a therapeutic efficacy over 50%, underlining the need for new drug delivery systems. The aim of this work was the optimization and characterization of previously developed ABZ lipid nanocapsules (ABZ-LNCs) and evaluate their efficacy in mice infected with E. granulosus. LNCs were prepared by the phase inversion technique and characterized in terms of size, surface charge, drug loading, and in vitro stability followed by an in vivo proof-of-concept using a murine model infected with E. granulosus. Stable particle dispersions with a narrow size distribution and high efficiency of encapsulation (≥90%) were obtained. ABZ-LNCs showed a greater chemoprophylactic efficacy than ABZ suspension administered by the oral route as 4 out of the 10 ABZ-LNCs treated mice did not develop any cysts, whereas the infection progressed in all mice from the ABZ suspension group. Regarding the ultrastructural studies of cysts, mice treated with ABZ-LNCs or ABZ suspension revealed changes in the germinal layer. However, the extent of the damage appeared to be greater after ABZ-LNC administration compared to the suspension treatment. These results suggest that ABZ-LNCs could be a promising novel candidate for ABZ delivery to treat CE.

Albendazole nanocrystals in experimental alveolar echinococcosis: Enhanced chemoprophylactic and clinical efficacy in infected mice.

Human alveolar echinococcosis is caused by the fox tapeworm Echinococcus multilocularis and is usually fatal if left untreated. Medical treatment with albendazole (ABZ) remains an effective option. However, due to its low aqueous solubility, ABZ is poorly and erratically absorbed following oral administration resulting in low drug levels in plasma and liver distribution. Thus, there arises the need to find a simple, efficient and scalable method to produce new ABZ formulations with increased bioavailability. Bearing this in mind, ABZ nanocrystals (ABZ-NCs) appears to be a useful tool to achieve this goal. The aim of the current study was to investigate the chemoprophylactic and clinical efficacy of an ABZ-NC formulation on mice infected with E. multilocularis. In the chemoprophylactic efficacy study, mean weight of the cysts recovered from the ABZ-NC group was 50% lower than that recorded from untreated mice, whereas the treatment with ABZ suspension did not show preventive effect. The viability of protoscoleces isolated from ABZ-NC treated mice was significantly lower than control groups. In the clinical efficacy studies, both ABZ formulations resulted in a reduction in the mean weight of the cysts obtained from mice, however only the treatment with the nanosuspension revealed significant differences (P < 0.05) compared to the control groups. Treatment with ABZ-NCs reduced the weight of the cysts by 77% and the viability of their protoscoleces to 34%. All these results coincided with the tissue damage determined at the ultrastructural level. The enhanced chemoprophylactic and clinical efficacy of ABZ-NCs observed in this study could be attributed to an increase in the oral bioavailability of the drug. In a next step, we will characterize the cyst concentration profile after the administration of ABZ-NCs in mice infected with E. multilocularis.

Self-dispersible nanocrystals of albendazole produced by high pressure homogenization and spray-drying.

Albendazole (ABZ) is a broad-spectrum antiparasitic drug used in the treatment of human or animal infections. Although ABZ has shown a high efficacy for repeated doses in monogastric mammals, its low aqueous solubility leads to erratic bioavailability. The aim of this work was to optimize a procedure in order to obtain ABZ self-dispersible nanocrystals (SDNC) by combining high pressure homogenization (HPH) and spray-drying (SD). The material thus obtained was characterized and the variables affecting both the HPH and SD processes were studied. As expected, the homogenizing pressure and number of cycles influenced the final particle size, while the stabilizer concentration had a strong impact on SD output and redispersion of powders upon contact with water. ABZ SDNC were successfully obtained with high process yield and redispersibility. The characteristic peaks of ABZ were clearly identified in the X-ray patterns of the processed samples. A noticeable increase in the dissolution rate was observed in the aqueous environment.

Argentinean Society of Experimental Pharmacology: Brief history and main scientific contributions to the discipline.

Argentina Biomedical Science has been historically strong. The development of Human and Veterinary Pharmacology in our country as a pivotal discipline has been acknowledged worldwide because of the quality of its contributions. Argentinean Society of Experimental Pharmacology (SAFE) is a non- profit association whose research fields include Experimental and Clinical Pharmacology. SAFE main goals are described as follow (a) To meet active researchers for studying concerns regarding Experimental and Clinical Pharmacology (b) To launch an initiative for development of the discipline in mainly our country and other collaborative countries worldwide (c) To spread the pharmacological know-how obtained from different research teams (d) To strengthen relations between pharmacologists (e) To facilitate the presentation and discussion of scientific papers. This current article shows the SAFE's more important scientific contribution to pharmacology through its former research scientists to the present.

Clinical and microbiological features of bacteremia caused by Enterococcus faecalis.

INTRODUCTION: Enterococcus faecalis is a frequent etiologic agent of invasive infections in hospitalized patients. The aim of this study was to analyze clinical and microbiological features of bacteremia caused by E. faecalis. METHODOLOGY: Between 2011 and 2013, significant bacteremia caused by E. faecalis in hospitalized patients was studied. Patient characteristics, comorbid conditions, and 14-day mortality were recorded. Virulence genes esp, gelE, and cylA; opsonophagocytosis resistance; resistance to bactericidal effect of normal serum; beta lactamase production; and susceptibility to ampicillin, vancomycin, teicoplanin, gentamicin, and streptomycin were investigated. RESULTS: E. faecalis strains were recovered from 33 bacteremic patients. Polymicrobial bacteremia was diagnosed in 2 patients; 10 patients died. Virulence genes were found in strains from both deceased patients and survivors. Sources of bacteremia included urinary tract infections (36.4%), vascular catheters (15.1%), abscesses (9.1%), and unknown (48.5%). Underlying diseases included cancer (30.3%), diabetes (36.4%), cirrhosis (6.1%), renal (36.4%), and chronic obstructive pulmonary disease (2.0%). Co-morbidities included alcohol use (26.1%); glucocorticoid therapy (19.0%); prior antibiotic therapy (60.6%); and central venous (21.2%), arterial (12.1%), and urinary (63.6%) catheters. Also, 57.6% of patients came from the intensive care unit (ICU); 33.3% had mechanical ventilation. Significant mortality-associated conditions included polymicrobial bacteremia, oncological disease, APACHE II score ≤ 20, ICU stay, renal disease, central venous catheter, and mechanical ventilation. CONCLUSIONS: Outcome of patients was associated with their status and not with the presence of virulence genes in E. faecalis strains. A significant percentage of bacteremia had undetermined origin. An alternate origin may be the gastrointestinal tract, through translocation.

Cystic echinococcosis therapy: Albendazole-loaded lipid nanocapsules enhance the oral bioavailability and efficacy in experimentally infected mice.

Therapeutic failures attributed to medical management of cystic echinococcosis (CE) with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and hydatid cysts. Lipid nanocapsules (LNCs) represent nanocarriers designed to encapsulate lipophilic drugs, such as ABZ. The goals of the current work were: (i) to characterize the plasma and cyst drug exposure after the administration of ABZ as ABZ-LNCs or ABZ suspension (ABZ-SUSP) in mice infected with Echinococcus granulosus, and ii) to compare the clinical efficacies of both ABZ formulations. Enhanced ABZ sulphoxide (ABZ-SO) concentration profiles were obtained in plasma and cysts from ABZ-LNC treated animals. ABZSO exposure (AUC0-LOQ) was significantly higher in plasma and cyst after the ABZ-LNC treatments, both orally and subcutaneously, compared to that observed after oral administration of ABZ-SUSP. Additionally, ABZSO concentrations measured in cysts from ABZ-LNC treated mice were 1.7-fold higher than those detected in plasma. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the ABZ-LNCs, while ABZ-SUSP did not reach differences with the untreated control group. This new pharmacotechnically-based strategy could be a potential alternative to improve the treatment of human CE.

Comparative plasma exposure of albendazole after administration of rapidly disintegrating tablets in dogs.

The main objectives of this study were (a) to evaluate the in vitro performance of the rapid disintegration tablets as a way to improve the solid dispersions and (b) to study the in vivo pharmacokinetics of the albendazole modified formulation in dogs. Rapid disintegration of tablets seems to be a key factor for efficiency of solid dispersions with regard to improvement of the albendazole bioavailability. The in vivo assays performed on dogs showed a marked increase in drug plasma exposure when albendazole was given in solid dispersions incorporated into rapid disintegration tablets compared with conventional solid dosage form.

Enhanced dissolution and systemic availability of albendazole formulated as solid dispersions.

Solid dispersions (SDs) containing the anthelmintic compound albendazole (ABZ) and either Pluronic 188 (P 188) or polyethylene glycol 6000 (PEG 6000) as hydrophilic carriers were formulated. Drug-polymers interactions in solid state were investigated using different techniques. Only a 4% of total ABZ was dissolved at 5 min post-incubation, reaching dissolution rates of 32.8% (PEG 6000) and 69.4% (P 188) in SDs. In this way, P 188 was substantially more efficient as ABZ dissolution promoter in comparison to PEG 6000, especially at the initial stages of the dissolution processes (<30 min). An increased systemic availability (p < 0.001) was obtained when ABZ was administered as ABZ-P 188 SDs, with a 50% enhancement in systemic exposure (AUC values) compared to treatment with an ABZ suspension. Consistently, the Cmax increased 130% (p < 0.001) following treatment with P 188 based SD ABZ formulation. For the ABZ-PEG 6000 SD formulation, the favorable effect on ABZ systemic availability did not reached statistical significance compared to the control group. The study reported here showed the utility of pharmacokinetic assays performed on mice as a model for preliminary drug formulation screening studies.

Nematodicidal activity of flubendazole and its reduced metabolite on a murine model of Trichinella spiralis infection.

BACKGROUND: Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound. The parent FLBZ is metabolized to its reduced (R-FLBZ) and hydrolyzed (H-FLBZ) metabolites. There are no data on the potential nematodicidal activity of R-FLBZ, the main plasma metabolite found in sheep and mice. The goal of the current work was to assess the efficacy of FLBZ and R-FLBZ against Trichinella spiralis in a mouse model. METHODS: Both compounds were administered to Balb/c mice infected with T. spiralis as either a cyclodextrin aqueous solution or as a carboxymethylcellulose suspension. Treatments were performed orally (5 mg/kg) at 1 day after infection with T. spiralis. The efficacy of the treatments was assessed at day 6 after infection. RESULTS: While the efficacy obtained for FLBZ and R-FLBZ administered as a solution was 94 and 98%, respectively, the efficacies obtained after the treatment with FLBZ suspensions were 38% (FLBZ) and 64% (R-FLBZ). CONCLUSION: Under the current experimental conditions, a high nematodicidal efficacy of both FLBZ and R-FLBZ administered as solution preparations was observed.

Comparative performances of flubendazole and albendazole in cystic echinococcosis: ex vivo activity, plasma/cyst disposition, and efficacy in infected mice.

The need to identify improved therapy against cystic echinococcosis (CE) has motivated pharmacology-based research. The comparative pharmacological performances of the benzimidazole compounds flubendazole (FLBZ) and albendazole (ABZ) were addressed here. The goals of the work were as follows: (i) to evaluate the ex vivo activities of FLBZ, ABZ, and their respective metabolites against Echinococcus granulosus protoscoleces, (ii) to compare the plasma and cyst disposition kinetics for the two drugs in infected mice, and (iii) to compare the clinical efficacies of FLBZ and ABZ against CE in mice. For the ex vivo study, E. granulosus protoscoleces were incubated with FLBZ, reduced FLBZ (R-FLBZ), ABZ, and ABZ-sulfoxide (ABZSO) (10 nmol/ml). Protoscolex viability was monitored by the methylene blue exclusion test and scanning electron microscopy (SEM). For the pharmacokinetic study, BALB/c mice with CE were allocated to two different groups and orally treated with either FLBZ or ABZ (5 mg/kg of body weight), both formulated as a cyclodextrin-based solution. Blood and cyst samples were taken up to 12 h posttreatment and analyzed by high-performance liquid chromatography (HPLC). For the efficacy study, CE-infected BALB/c mice were divided into three groups: the unmedicated control group and the FLBZ- and ABZ-treated groups. Oral treatments were performed twice a day during 25 days. After treatment, all animals were killed and the weight of the cysts was recorded. Loss of protoscolex viability was observed after drug incubation. FLBZ was detected in plasma (area under the concentration-versus-time curve [AUC] = 1.8 µg · h/ml) and cysts (AUC = 0.3 µg · h/g) collected from treated infected animals. Conversely, ABZSO was the only active molecule measured in plasma (AUC = 4.4 µg·h/ml) and cysts (AUC = 1.5 µg·h/g) after ABZ treatment. FLBZ induced a 90% reduction in cyst weight in comparison to those collected from untreated control mice (P < 0.05). However, no differences in cyst weight were observed between the ABZ-treated (8.2 g) and unmedicated control (10.5 g) groups. Due to these results, we consider flubendazole to have great potential to become a drug of choice in the treatment of cystic echinococcosis.

Chemoprophylactic activity of flubendazole in cystic echinococcosis.

BACKGROUND: Cystic echinococcosis (CE) is an important public health problem worldwide. Flubendazole, administered in tablets, has shown poor in vivo efficacy against CE in humans. However, flubendazole prepared as a solution caused a marked reduction in hydatid cysts developed in mice. The goal of the current work was to compare the chemoprophylactic effect of flubendazole formulated either as a hydroxypropyl-ß-cyclodextrin solution or as a carboxymethylcellulose suspension in secondary CE in mice. METHODS: Balb/C mice were infected with Echinococcus granulosus protoscoleces. One day after infection, the animals were allocated into 3 different experimental groups: unmedicated control and treated at the time point of infection with flubendazole either prepared as a solution or suspension given twice a day during 15 days. Six months after infection, the animals were sacrificed to collect and weight parasitic cysts. Cyst samples recovered from infected mice of each experimental group were prepared for both scanning and transmission electron microscopy. RESULTS: Both flubendazole formulations induced a significant reduction in cyst weight compared to the cysts recovered from the unmedicated control animals. Both formulations showed similar flubendazole-induced ultrastructural morphological changes. CONCLUSION: Flubendazole offers a great potential to become a drug of choice in the preventive treatment of cystic echinococcosis.

Albendazole treatment in cystic echinococcosis: pharmacokinetics and clinical efficacy of two different aqueous formulations.

The pharmacokinetic (PK) behaviour and clinical efficacy of albendazole (ABZ) against hydatid cysts in mice were assessed after treatment with two different ABZ pharmaceutical formulations. BalbC mice received ABZ (0.5 mg/kg) prepared either as solution or suspension (50 microg/ml) for oral administration (PK study). Blood samples were collected up to 16 h post-treatment and processed to measure ABZ/metabolites concentrations in plasma. The clinical efficacy assessment was performed in BalbC mice infected 8 months earlier with Echinococcus granulosus protoscoleces. Infected animals were allocated into three experimental treatment groups: (a) untreated control, (b) ABZ-solution treated, (c) ABZ-suspension treated. Both treated groups received ABZ (0.5 mg/kg) administered under two different therapeutic schemes: dosing every 48 h over 30 days (regimen I) or treated every 12 h during 15 days (regimen II). Experimental mice were sacrificed 12 h after treatment, and cysts were recovered, weighed and processed for transmission electron microscopy. Enhanced ABZ sulphoxide (the main ABZ metabolite) concentration profiles were measured in animals treated with the ABZ solution. Any positive clinical response was obtained after treatment every 48 h (30 days therapy). However, consistent with the observed PK results, both ABZ formulations were clinically effective in infected mice treated with a 12-h dosing interval (15 days therapy).