Plasmodium infections result in clinical presentations that range from asymptomatic to severe malaria, resulting in ∼1 million deaths annually. Despite this toll on humanity, the factors that determine disease severity remain poorly understood. Here, we show that the gut microbiota of mice influences the pathogenesis of malaria. Genetically similar mice from different commercial vendors, which exhibited differences in their gut bacterial community, had significant differences in parasite burden and mortality after infection with multiple Plasmodium species. Germfree mice that received cecal content transplants from "resistant" or "susceptible" mice had low and high parasite burdens, respectively, demonstrating the gut microbiota shaped the severity of malaria. Among differences in the gut flora were increased abundances of Lactobacillus and Bifidobacterium in resistant mice. Susceptible mice treated with antibiotics followed by yogurt made from these bacterial genera displayed a decreased parasite burden. Consistent with differences in parasite burden, resistant mice exhibited an elevated humoral immune response compared with susceptible mice. Collectively, these results identify the composition of the gut microbiota as a previously unidentified risk factor for severe malaria and modulation of the gut microbiota (e.g., probiotics) as a potential treatment to decrease parasite burden.

SummaryReasons for performing study: Serum amyloid A (SAA) in synovial fluid has recently been used as a marker for septic arthritis in horses but the effects of repeated intra-articular (IA) administration of amikacin on synovial SAA concentrations are unknown. Objectives: To report the effect of repeated IA administration of amikacin on SAA, total protein (TP), nucleated cell count (NCC) and differential NCC in synovial fluid of healthy equine joints. Methods: A controlled, 2 period crossover study was performed on 5 clinically healthy horses. Each intercarpal joint received one of 2 treatments every 48 h for 5 consecutive times: arthrocentesis alone (control group) or arthrocentesis combined with IA administration of 500 mg of amikacin (treatment group). Clinical and lameness examinations were performed daily. Serum SAA and synovial SAA, TP, NCC and differential NCC were measured and statistically compared. Significance level was set at P<0.05. Results: Horses remained healthy and nonlame throughout the study. Baseline values for all variables were not significantly different between groups. Values for TP in the treatment group were significantly higher than in the control group after the first sample (P<0.05). In both groups NCC increased significantly (P<0.05) after the first sample. No significant changes were identified in differential NCC. In both groups, all synovial and most serum SAA concentrations remained below the lower limit of quantification. Conclusions: Repeated IA administration of amikacin caused increased values of TP and NCC in synovial fluid, with some TP concentrations falling within the range reported for septic arthritis. In contrast, synovial SAA concentrations did not increase in either group. Potential relevance: Synovial SAA could serve as a more reliable marker than TP and NCC when evaluating a joint previously sampled or treated with amikacin.

SummaryReasons for performing study: Antimicrobial intravenous regional limb perfusion (IV-RLP) is clinically performed on anaesthetised or sedated horses with or without regional anaesthesia. To date, no scientific data is available on the clinical and pharmacokinetic effects of these anaesthetic protocols on antimicrobial IV-RLP, which is believed to result in better tourniquet efficiency due to decreased movement. Objective:To determine the effects of regional or general anaesthesia on the clinical and synovial pharmacokinetic parameters of amikacin administered by IV-RLP to horses. Methods:Eight healthy horses received 4 treatments of amikacin IV-RLP in a randomised, blinded, cross-over design: standing sedation without regional anaesthesia (CNT), standing sedation with intravenous regional anaesthesia (IVA), standing sedation with perineural regional anaesthesia (PNA) or general anaesthesia (GA). Synovial fluid amikacin concentrations were measured over 24 hours and regional pharmacokinetic parameters calculated. Heart and respiratory rates, visual analogue scale (VAS) of discomfort, number of times the limb was lifted and number of additional sedations administered were recorded. ANOVA cross-over analysis was applied with significance level at P < 0.05. Results:Amikacin concentrations and regional pharmacokinetic parameters did not differ significantly among treatments. Scores of VAS (mean ± SD) were significantly lower with PNA (19 ± 15) versus IVA (69 ± 36) or CNT (81 ± 13) (P < 0.001). Significantly less lifting of the limb (mean ± SD) occurred with PNA (20 ± 20) versus CNT (54 ± 22) (P < 0.04). Conclusions:Perineural regional anaesthesia before IV-RLP was most effective in providing comfort to standing, sedated horses without significantly affecting the regional pharmacokinetic parameters of amikacin. High variability of synovial amikacin concentrations was present.Potential relevance: The comfort of horses undergoing standing IV-RPL can be increased by performing perineural anaesthesia prior to treatment. The use of general anaesthesia for IV-RLP is not justified based on this study.

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The objective of this study was to assess the pharmacokinetics of tulathromycin in pulmonary and bronchial epithelial lining fluid (PELF and BELF) from pigs. Clinically healthy pigs were allocated to two groups of 36 animals each. All animals were treated with tulathromycin (2.5 mg/kg/i.m). Animals in group 2 were also challenged intratracheally with lipopolysaccharide from Escherichia coli 3 h prior to tulathromycin administration. Both PELF and BELF samples were harvested using bronchoalveolar lavage fluid and bronchial micro-sampling probes, respectively. Samples were taken for 17 days post-tulathromycin administration. No statistical differences in the concentration of tulathromycin were observed in PELF between groups. The concentration vs. time profile in BELF was evaluated only in Group 1. Tulathromycin distributed rapidly and extensively into the airway compartments. The time to maximal (Tmax ) concentration was 6 h postdrug administration in PELF but 72 h post-tulathromycin administration for BELF. In group 2, the Tmax was seen at 24 h post-tulathromycin administration. The area under the concentration time curve (h*ng/mL) was 522 000, 348 000 and 1 290 000 for PELFGroup-1 , PELFGroup-2 , and BELFGroup-1 , respectively. Tulathromycin not only distributed rapidly into intra-airway compartments at relatively high concentrations but also resided in the airway lining fluid for a long time (>4 days).

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The objective of the study was to assess the pharmacokinetics of tulathromycin in lung tissue homogenate (LT) and plasma from healthy and lipopolysaccharide (LPS)-challenged pigs. Clinically healthy pigs were allocated to two dosing groups of 36 animals each (group 1 and 2). All animals were treated with tulathromycin (2.5 mg/kg). Animals in group 2 were also challenged intratracheally with LPS from Escherichia coli (LPS-Ec) 3 h prior to tulathromycin administration. Blood and LT samples were collected from all animals during 17-day post-tulathromycin administration. For LT, one sample from the middle (ML) and caudal lobes (CL) was taken. The concentration of tulathromycin was significantly lower in the ML after the intratracheal administration of LPS-E. coli (P < 0.02). In healthy pigs and LPS-challenged animals, the distribution of the drug into the lungs was rapid and persisted at high levels for 17-day postadministration. The distribution of the drug within the lung seems to be homogenous, at least between the middle and caudal lobes within dosing groups. The concentration versus time profile of the drug and pharmacokinetic parameters in two different lung areas (middle and caudal lobe) were consistent within the groups. The clinical significance of these findings is unknown.