Identification and florfenicol-treatment of pseudomonas putida infection in gilthead seabream (Sparus aurata) fed on tilapia-trash-feed.

The present study aimed to determine the major cause of the high mortality affecting farmed gilthead seabream (Sparus aurata) and controlling this disease condition. Fifteen diseased S. aurata were sampled from a private fish farm located at Eldeba Triangle, Damietta, fish showed external skin hemorrhages, and ulceration. Bacterial isolates retrieved from the diseased fish were identified biochemically as Pseudomonas putida and then confirmed by phylogenetic analysis of the 16 S rRNA gene sequence. P. putida was also isolated from three batches of tilapia-trash feed given to S. aurata. Biofilm and hemolytic assay indicated that all P. putida isolates produced biofilm, but 61.11% can haemolyse red blood cells. Based on the antibiotic susceptibility test results, P. putida was sensitive to florfenicol with minimum inhibitory concentrations ranging between 0.25 and 1.0 µg mL- 1, but all isolates were resistant to ampicillin and sulfamethoxazole-trimethoprim. Pathogenicity test revealed that P. putida isolate (recovered from the tilapia-trash feed) was virulent for S. aurata with LD50 equal to 4.67 × 107 colony forming unit (CFU) fish- 1. After intraperitoneal (IP) challenge, fish treated with 10 mg kg- 1 of florfenicol showed 16.7% mortality, while no mortality was recorded for the fish group that received 20 mg kg- 1. The non-treated fish group showed 46.7% mortality after bacterial challenge. HPLC analysis of serum florfenicol levels reached 1.07 and 2.52 µg mL- 1 at the 5th -day post-drug administration in the fish groups received 10 and 20 mg kg- 1, respectively. In conclusion, P. putida was responsible for the high mortality affecting cultured S. aurata, in-feed administration of florfenicol (20 mg kg- 1) effectively protected the challenged fish.

Florfenicol urinary excretion and its potential for treating canine urinary tract infections.

The canine urinary excretion of florfenicol was evaluated to explore its potential for treating urinary tract infections. Nine healthy male intact purpose-bred Beagles and four healthy client-owned dogs each received a single oral dose of florfenicol 20 mg/kg (300 mg/mL parenteral solution) with food. All voluntary urinations were collected for 12 h. Although florfenicol is reportedly bitter tasting, 7/9 Beagles and 4/4 client-owned dogs completely ingested the florfenicol and were enrolled; salivation (n = 1) and headshaking (n = 3) were observed. The last measured urine florfenicol concentrations were variable: Beagles (0.23-3.19 mcg/mL), Pug (3.01 mcg/mL) English Setter (21.29 mcg/mL), Greyhound (32.68 mcg/mL), and Standard Poodle (13.00 mcg/mL). Urine half-life was similar for the Beagles and the Pug, 0.75-1.39 h, whereas the half-life was 1.70-1.82 h for the English Setter, Greyhound, and Standard Poodle. Larger breed dogs exceeded 8 mcg/mL florfenicol (wild-type cutoff) in their urine at 12 h, whereas the Beagles and Pug had <8 mcg/mL; it is unclear if this is an individual, breed, or size difference. These data suggest oral florfenicol may need to be administered q6-12h for canine urinary tract infections, but further data are needed (more enrolled dogs, multiple-dose regimens) before considering clinical trials or breed-specific differences.

Effects of starvation on the pharmacokinetics and optimal dosages of florfenicol and associated serum biochemistry in Asian seabass (Lates calcarifer).

Starvation has influence on physiology and pharmacokinetic (PK) characteristics of many drugs in land animals. However, similar PK information in fish is lacking. The current study examined the effects of starvation on fish PK, taking florfenicol (FF) in Asian seabass as an example. FF was orally administered at a single dose of 10 mg/kg into 35-day starved fish reared at 25 and 30°C and the serum FF concentration was analyzed by HPLC-FLD. At 30°C, the absorption and elimination half-lives of the starved fish were increased by 30% (from 0.44 to 0.57 h) and 55% (from 7.2 to 11.18 h), respectively. The volume of distribution, clearance, and area under the curve were changed from 1.25 to 0.71 L/kg, 0.120 to 0.044 L/kg/h, and 88 to 228 h·µg/ml, respectively. Similar starvation-induced PK changes were also observed at 25°C. The serum biochemical parameters, mainly the alanine aminotransferase, aspartate aminotransferase, and glucose levels, were significantly reduced in the starvation group. Overall, FF absorption, distribution, and elimination rates were reduced by starvation, resulting in four to five times lower optimal dosage than the non-starved fish. Drug treatment in starved fish should be treated with caution as overdosing and/or tissue residues could perceivably occur.

Cutaneous mucosal immune-parameters and intestinal immune-relevant genes expression in streptococcal-infected rainbow trout (Oncorhynchus mykiss): A comparative study with the administration of florfenicol and olive leaf extract.

This study evaluated changes in cutaneous mucosal immunity (total protein (TP) and immunoglobulin (TIg), lysozyme, protease, esterase, and alkaline phosphatase (ALP)) and some immune-related genes expression (tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-8, hepcidin-like antimicrobial peptides (HAMP), and immunoglobulin M (IgM)) in the intestine of rainbow trout (Oncorhynchus mykiss) orally-administrated florfenicol (FFC) and/or olive leaf extract (OLE), experimentally infected with Streptococcus iniae. The juvenile fish (55 ± 7.6 g) were divided into different groups according to the use of added OLE (80 g kg-1 food), the presence/absence of FFC (15 mg kg-1 body weight for 10 consecutive days), and the streptococcal infectivity (2.87 × 107 CFU mL-1 as 30% of LD50-96h). The extract's chemical composition was analyzed using the high-performance liquid chromatography (HPLC) system. The skin mucus and intestine of fish were sampled after a 10-day therapeutic period for all groups, and their noted indices were measured. Our results signified that the oleuropein, quercetin, and trans-ferulic acid were the most obvious active components of OLE which were found by HPLC analysis. The combined use of OLE and FFC could lowered some skin mucus immunological indices (e.g., TP, TIg, and ALP), and the gene expression of inflammatory cytokines (e.g., TNF-α and IL-1ß) of rainbow trout. Moreover, lysozyme and protease activities respectively were invigorated by the FFC and OLE treatment. Also, the use of OLE as a potential medicine induced the gene expression of HAMP. As the prevention approach, it would be recommended to find the best dose of OLE alone or in combination with the drug through therapeutics period before the farm involved in the streptococcal infection.

Pharmacokinetics of thiamphenicol in Japanese quails (Coturnix japonica) after single intravenous and oral administrations.

Thiamphenicol (TP) pharmacokinetics were studied in Japanese quails (Coturnix japonica) following a single intravenous (IV) and oral (PO) administration at 30 mg/kg BW. Concentrations of TP were determined with HPLC and were analyzed by a noncompartmental method. After IV injection, elimination half-life (t1/2λz ), total body clearance (Cltot ) volume of distribution at steady state (Vdss ), and mean residence time (MRT) of TP were 3.83 hr, 0.19 L/hr/kg, 0.84 L/kg, and 4.37 hr, respectively. After oral administration of TP, the peak plasma concentration (Cmax ) was 19.81 µg/ml and was obtained at 2.00 hr (tmax ) postadministration. Elimination half-life (t1/2λz ) and mean absorption time (MAT) were 4.01 hr and 1.56 hr, respectively. The systemic bioavailability following oral administration of TP was 78.10%. TP therapy with an oral dosage of 30 mg/kg BW is suggested for a beneficial clinical effect in quails.

Depletion of florfenicol and florfenicol amine in eggs of laying hens and growing pullets after oral administration.

In this study, we carried out two experiments to evaluate depletion of florfenicol (FF) and its metabolite florfenicol amine (FFA) in eggs from growing pullets and laying hens. Eggs were collected, and the egg white and yolk were separated. FF and FFA were analysed by liquid chromatography-tandem mass spectrometry. In the first experiment, 30 laying hens were given FF capsules at 50 mg/kg·bw-1 daily for 5 d. FF + FFA was detectable in egg white (1,190 µg/kg) on day 1 of treatment and increased slowly thereafter. After treatment, the residues decreased rapidly and were not detected by day 11. In yolk, residues were detected at a lower concentration on day 1 and increased dramatically to 3308 µg/kg at the end of treatment. The residues remained steady over the next 4 days post-treatment, followed by a rapid drop. Residues were not detectable on day 15 post-treatment. In the second experiment, four groups (B1 through B4) of growing pullets were treated in the same manner for 25, 20, 15, and 10 days before egg primiparity. FF and FFA were not detectable in the eggs of group B1; however, they were detectable in egg whites and yolks of groups B2, B3, and B4. The highest total concentrations of FF and FFA detected in egg white and yolk of group B4 were 3,190 µg/kg and 3,214 µg/kg, respectively. Thereafter, concentrations decreased until no more residues were detected in egg whites or yolks on days 17 and 21 post-treatment, respectively. Therefore, drug treatment should be stopped at least 21 d before primiparity of growing pullets to guarantee food safety.

Bath immersion pharmacokinetics of florfenicol in Nile tilapia (Oreochromis niloticus).

Drug administration by immersion can be a preferable method in certain conditions especially for treating small-sized, anorexic, or valuable fish. Pharmacokinetic information regarding bath treatment is considerably lacking in comparison to other common administration routes. The current study aimed to investigate if immersion can be an effective route to administer florfenicol (FF) for treatment in Nile tilapia. Nile tilapia reared at 28°C were immersed with FF solution at concentrations of 50, 100, 200, 500, and 500/200 (3 hr/117 hr) ppm for 120 hr and moved to drug-free freshwater for another 24 hr. The serum FF concentration in 100, 200, and 500/200 ppm groups reached steady-state at 12 hr with concentrations of 2.44, 3.04, and 5.26 µg/ml, respectively, which were about 2% of the bathing concentrations. The target therapeutic levels of 1-4 µg/ml were attained and maintained within 1-12 hr, depending on the immersion concentration and the target MIC. Serum FF reached the target with shorter time at higher bathing concentration. Following the 120-hr bath, the serum FF declined with the first-order half-life of approximately 10 hr. A minimum of 100 ppm FF is required for treatment purpose, and an initial high loading concentration followed by maintenance concentration is a plausible way to reach in vivo therapeutic level in short time. Greater than 99% of the residual FF in the bathing water could be removed within 15 min by 0.05% NaOCl. Our results indicated that bath immersion is a promising potential route for FF administration in Nile tilapia.

Poloxamer modified florfenicol instant microparticles for improved oral bioavailability.

Surfactants can improve the hydrophobicity of poorly water-soluble drugs and increase the stability of microparticles by reducing surface tension. This study describes that surfactant-engineered florfenicol instant microparticles (FIMs) increase bioavailability through a micellar solubilization mechanism. The FIMs were prepared by a modified emulsification method, and the optimal prescription was obtained by a combination of single factor investigation and response surface methodology. The microparticles prepared in this study reduce the polymer materials while increasing the drug content. FIM has a smaller particle size and modification of poloxamer, resulting in better solubility and higher bioavailability. The in vitro solubility of FIM is 1.43 times higher than that of the bulk drug, and the dissolution equilibrium can be achieved in 10 minutes. Compared with florfenicol, FIM showed a decrease in Tmax in the plasma concentration curve, with a peak concentration of 1.43 times and an area of 1.41 times. Considering the advantages of in vitro/in vivo performance and ease of preparation, FIMs may have great application prospects in pharmacy research.

Effects of the dietary inclusion of a probiotic or prebiotic on florfenicol pharmacokinetic profile in broiler chicken.

We evaluated the effect of prebiotic or probiotic as feed additives on florfenicol kinetic in broilers feed. Unsexed two hundred, thirty-five-day-old broiler chickens, were put in four equal groups (n = 50). The first group was administrated florfenicol intravenous at 30 mg/kg body weight (BW) only once dosage without pre- or probiotic administration to determine the bioavailability. While, the second group was administrated florfenicol (intracrop routes; a dosage of 30 mg/kg BW for five progressive days) without pre- or probiotic co-administration. The third and the fourth groups were administrated the same dose of florfenicol (intracrop route) for five successive days, followed by 10 days of prebiotic or probiotic treatment respectively. The plasma florfenicol % was identified by high-pressure liquid chromatography (HPLC) after the first florfenicol administration (intravenous or intracrop routes) in all groups. Then, the residual levels of florfenicol were determined in liver, kidney and muscle tissues from the second, third and fourth groups which were exposed to florfenicol orally. Our results demonstrated that broilers pre-treated with prebiotic or probiotic significantly increased Cmax , AUC0- t , AUC0-inf as well as AUMC values, while significant drop was recorded in V/F and CL/F. Prebiotic or probiotic influenced the cumulative effect of florfenicol in liver and kidney tissues of treated birds.

Effects of oral florfenicol on intestinal structure, function and microbiota in mice.

Many kinds of antibiotics have effects on intestinal structure and function. In the current experimental study, we evaluate the effect of oral florfenicol on intestinal barrier in mice. Thirty adult male mice were randomly divided into two groups, the group none (N) and the group florfenicol (F), the mice in group F were orally administered florfenicol 100 mg/kg body weight (BW) for 7 days. At day 8, mice were euthanized and sampled for the analysis of alterations in genes and proteins from jejunum, jejunum morphology and microbiota analysis. Administration of florfenicol caused higher liver index (P < 0.05). In the jejunum, mucosa injury and villus rupture, compared with the group N, the villus length and V/C (villus length/crypt depth) in group F were marked decrease (P < 0.01). The transcription level of Muc2 and occludin in group F were significantly lower than those in group N (P < 0.01 or P < 0.05). The expression of APRIL, IL-17, IL-22, BAFF and sIgA on protein level were significantly down-regulated (P < 0.01 or P < 0.05), while the expression of IL-10, TGF-ß, IL-6, IL-4 were significantly up-regulated (P < 0.01) in group F. The abundances of bacteria in Firmicutes and Lactobacillus decreased significantly (P < 0.01) in group F. Our results indicated that oral administration of florfenicol might have a negative impact on functions of intestinal mucosal barrier, immune system and the intestinal microbiota.

Probiotic, antibiotic and combinations in Nile tilapia juveniles culture.

This study aimed to evaluate the effect of the commercial probiotic (Saccharomyces cerevisiae), antibiotic (florfenicol), and its combination for Nile tilapia culture. The experiment was arranged in a completely randomized design with five replications, and five treatments diets: Control: water and diet without additives; YD: yeast in the diet (1 g Kg-1); AW: antibiotic in the water (0.002 g L-1); AWYD: antibiotic in the water, and yeast in the diet (0.002 g L-1 and 1 g Kg-1); and AD: antibiotic in the diet (0.01 g kg-1). The growth parameters as total and standard length, weight, weight gain, biomass, Fulton's condition factor, specific growth rate and plasma cortisol of tilapia did not show the difference between the treatments. The survival rates and food conversion rate of fish were greater in treatment with florfenicol included in the diet. The commercial probiotic did not improve growth or survival. The administration of the antibiotic florfenicol in the water needs more studies. The inclusion of the antibiotic in the diet promotes growth and survival in Nile tilapia juvenile.

Effects of anemoside B4 on pharmacokinetics of florfenicol and mRNA expression of CXR, MDR1, CYP3A37 and UGT1E in broilers.

Pulsatillae radix, a traditional Chinese medicine (TCM), is often used in combination with florfenicol for treatment of intestinal infection in Chinese veterinary clinics. Anemoside B4 (AB4) is the major effective saponin in Pulsatillae radix. This study aimed to investigate whether the pharmacokinetics of florfenicol in broilers was affected by the combination of AB4. In this study, broilers were given AB4 (50 mg/kg BW), or 0.9% sodium chloride solution by oral administration for 7 days. They were then fed florfenicol orally (30 mg/kg BW) on the eighth day. The results showed that the AUC(0-∞), MRT(0-∞), t1/2z and Cmax of florfenicol were significantly decreased, and the Vz/F and CLz/F were significantly increased by AB4; the mRNA expression levels of CXR, CYP3A37 and MDR1 (except CXR and CYP3A37 in the liver) were up-regulated by AB4. In conclusion, AB4 altered the pharmacokinetics of florfenicol, resulting in lower plasma concentrations of florfenicol, this was probably related to the mRNA expression of CXR, CYP3A37 and MDR1 in the jejunum and liver (except CXR and CYP3A37) increased by AB4. The implications of these findings on the effect of traditional Chinese medicine containing AB4 on the effectiveness of florfenicol in veterinary practice deserve study.

Pharmacokinetics of florfenicol in blunt-snout bream (Megalobrama amblycephala) at two water temperatures with single-dose oral administration.

The pharmacokinetics and residue elimination of florfenicol (FFC) and its metabolite florfenicol amine (FFA) were studied in healthy blunt-snout bream (Megalobrama amblycephala, 50 ± 10 g). The study was conducted with a single-dose (25 mg/kg) oral administration at a water temperature of 18 or 28°C, while in the residue elimination study, fish were administered at 25 mg/kg daily for three consecutive days by oral gavage to determine the withdrawal period (WDT) at 28°C. The FFC and FFA levels in plasma and tissues (liver, kidneys and muscle) were analysed using high-performance liquid chromatography (HPLC). A no-compartment model was used to analyse the concentration versus time data of M. amblycephala. In the two groups at 18 and 28°C, the maximum plasma concentration (Cmax ) of FFC was 5.89 and 6.21 µg/ml, while the time to reach Cmax (Tmax ) was 5.97 and 2.84 hr, respectively. These suggested that higher temperature absorbed more drug and more quickly at M. amblycephala. And the elimination half-life (T1/2 kß ) of FFC was calculated as 26.75 and 16.14 hr, while the total body clearance (CL) was 0.09 and 0.15 L kg-1  hr-1 , and the areas under the concentration-time curves (AUCs) were 265.87 and 163.31 µg hr/ml, respectively. The difference demonstrated that the elimination rate of FFC in M. amblycephala at 28°C was more quickly than that at 18°C. The results of FFA showed the same trend in tissues of M. amblycephala. After multiple oral doses (25 mg/kg daily for 3 days), the k (eliminate rate constant) of FFA in M. amblycephala muscle was 0.017, the C0 (initial concentration) was 3.07 mg/kg, and the WDT was 10 days (water temperature 28°C).

Pharmacokinetic-pharmacodynamic modelling for the determination of optimal dosing regimen of florfenicol in Nile tilapia (Oreochromis niloticus) at different water temperatures and antimicrobial susceptibility levels.

Optimized dosing regimen is key to the effective use of antibacterials and to minimizing drug-related side effects. The current study established a pharmacokinetic-pharmacodynamic (PK-PD) model for the determination of optimal antibacterial dosing regimen in fish taken into consideration the temperature-dependent PK and the pathogen-dependent antimicrobial susceptibility, using florfenicol (FF) in Nile tilapia as an example. The calculated optimal dosages significantly varied by temperature and target MIC levels, ranging from 2.23 (MIC 1 µg/ml at 24°C) to 34.88 mg kg-1  day-1 (MIC 4 µg/ml at 32°C). The appropriateness of the calculated dosages was successfully verified by the in vivo studies. After 5 days of oral administration of the calculated optimal dosage at 24°C, the predicted plasma drug values were in line with the mean observed Cmin(ss) while at 28 and 32°C underestimation of the Cmin(ss) in a dose-dependent manner was observed and likely due to the occurrence of non-linear PK at high dosages. The averaged serum protein binding of FF was 19.1%. Our results demonstrated the appropriateness and clinical applicability of the developed PK-PD approach for the determination of optimal dosing regimens at given temperatures and MICs. Saturation metabolism and PK non-linearity of FF in tilapia warrant further study.

Development and Characterization of Florfenicol-Loaded BSA Nanoparticles as Controlled Release Carrier.

Florfenicol (FLO) is a broad-spectrum fluorinated antibiotic used for the treatment of bacterial diseases such as bovine respiratory disease (BRD) in cattle. FLO is a poorly soluble drug in aqueous solution, and its encapsulation in various nanovehicles has been reported to be less than 30%. In this context, the use of bovine serum albumin (BSA) as a nanocarrier for FLO is an interesting approach. BSA is a biocompatible, biodegradable, nontoxic, and nonimmunogenic natural protein, allowing the vehiculization of hydrophilic and hydrophobic drugs with a well-tolerated administration. The present work focuses on the fabrication and characterization of florfenicol-loaded BSA (FLO-BSA NPs), incorporation efficiency, and in vitro release pattern. FLO-BSA NPs nanoparticles were successfully obtained by a simple, low-cost and in a few steps method. The physicochemical properties of the obtained nanoparticles such as size (~ 120 nm), polydispersity index (0.04), and zeta potential (approximately - 40 mV) suggest a high colloidal stability and suitable characteristics for drug delivery. The drug loading reveals a high incorporation of florfenicol in the nanoparticles, in which 33.6 molecules of FLO are encapsulated per each molecule of BSA. The in vitro release profile exhibits an initial stage characterized by the burst effect and then a prolonged release of FLO from the albumin matrix, which is compatible with the Higuchi model and which follows a Fickian diffusion. The results together suggest a suitable tool for future investigations in drug delivery field in order to use this nanomaterial in food, pharmaceutical, and veterinary industry.

HPLC-DAD analysis of florfenicol and thiamphenicol in medicated feedingstuffs.

A simple and reliable method using liquid chromatography with diode array detector was developed for the simultaneous determination of florfenicol and thiamphenicol in medicated feed. The analytes were extracted from the minced feed with methanol and ethyl acetate (1:1, v/v). Next, the extract was further cleaned up by dispersive solid phase extraction using anhydrous magnesium sulfate, PSA and C18 sorbents. Finally, 1 mL of extract was evaporated, the residue resuspended in Milli-Q water, and filtered. The method was validated in-house at medicated levels, in the concentration range 10-300 µg/mL (50-1500 mg/kg). Values of <6.5% and <6.0% were found, respectively, for repeatability and within-laboratory reproducibility. The LODs for the two fenicols were 2.4-5.3 mg/kg, while the LOQs were 3.8-5.6 mg/kg. The expanded uncertainty was estimated to be in the range of 10.0-14.5%, depending on the analyte. Recoveries varied from 81.7% to 97.5%. The methodology was applied to the analysis of animal feedingstuffs collected from poultry and pig farms.

Development and application of a population physiologically based pharmacokinetic model for florfenicol and its metabolite florfenicol amine in cattle.

Florfenicol (FF) is used in cattle to treat respiratory diseases but could result in tissue residues. This study aimed to develop a population physiologically based pharmacokinetic (PBPK) model to predict the concentrations of FF and its metabolite, florfenicol amine (FFA), in cattle after four different routes of administration, and to calculate and compare the withdrawal intervals (WDIs) with approved withdrawal times based on different marker residues and their MRLs or tolerances. A flow-limited PBPK model including both FF and FFA sub-models were developed with published data using acslXtreme. This model predicted FF and FFA concentrations in tissues and plasma/serum after intramuscular or subcutaneous administration. Based on the model, the WDIs of 46 and 58 days were calculated to ensure that total residue concentrations (FF + FFA) in 95th percentile of the population after intramuscular and subcutaneous administration were below the MRL, respectively. WDIs were calculated as 44 and 47 days to ensure that FFA concentrations after intramuscular and subcutaneous administration fell below tolerances in 99th percentile of the population, respectively. WDIs were longer than the corresponding label in China, US, and EU. This model provides a useful tool to predict tissue residues of FF and FFA in cattle to improve food safety.

Oral administration of antibiotics increased the potential mobility of bacterial resistance genes in the gut of the fish Piaractus mesopotamicus.

BACKGROUND: Aquaculture is on the rise worldwide, and the use of antibiotics is fostering higher production intensity. However, recent findings suggest that the use of antibiotics comes at the price of increased antibiotic resistance. Yet, the effect of the oral administration of antibiotics on the mobility of microbial resistance genes in the fish gut is not well understood. In the present study, Piaractus mesopotamicus was used as a model to evaluate the effect of the antimicrobial florfenicol on the diversity of the gut microbiome as well as antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) using a metagenomic approach. RESULTS: The total relative abundance of ARGs and MGEs significantly increased during the antibiotic exposure. Additionally, phage integrases, transposases, and transposons flanking ARGs accumulated in the gut microbiome of P. mesopotamicus because of the antibiotic exposure. MGEs co-occurring with ARGs showed a significant positive correlation with the total ARGs found. Furthermore, shifts in the gut microbiome towards well-known putative pathogens such as Salmonella, Plesiomonas, and Citrobacter were observed following florfenicol treatment. Mainly Plesiomonas and Citrobacter harbored genes that code for multidrug and phenicol efflux pumps. Moreover, several genes related to RNA processing and modification, cell motility, SOS response, and extracellular structure were enriched due to the antibiotic application. The observed effects were visible during the complete application phase and disappeared at the post-exposure phase. CONCLUSIONS: Our findings suggest that the oral administration of antibiotics increases the potential for MGE-mediated exchange of ARGs in the gut of fish and could contribute to the enrichment and dispersion of ARGs in aquaculture systems. Importantly, this increase in the potential for ARGs exchange could be an effect of changes in community structure and/or ARG mobilization.

Resistant cutoff values and optimal scheme establishments for florfenicol against Escherichia coli with PK-PD modeling analysis in pigs.

Florfenicol, a structural analog of thiamphenicol, has broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria. This study was conducted to investigate the epidemiological, pharmacokinetic-pharmacodynamic cutoff, and the optimal scheme of florfenicol against Escherichia coli (E. coli) with PK-PD integrated model in the target infectious tissue. 220 E. coli strains were selected to detect the susceptibility to florfenicol, and a virulent strain P190, whose minimum inhibitory concentration (MIC) was similar to the MIC50 (8 µg/ml), was analyzed for PD study in LB and ileum fluid. The MIC of P190 in the ileum fluid was 0.25 times lower than LB. The ratios of MBC/MIC were four both in the ileum and LB. The characteristics of time-killing curves also coincided with the MBC determination. The recommended dosages (30 mg/kg·body weight) were orally administrated in healthy pigs, and both plasma and ileum fluid were collected for PK study. The main pharmacokinetics (PK) parameters including AUC24 hr , AUC0-∞ , Tmax , T1/2 , Cmax , CLb, and Ke were 49.83, 52.33 µg*h/ml, 1.32, 10.58 hr, 9.12 µg/ml, 0.50 L/hr*kg, 0.24 hr-1 and 134.45, 138.71 µg*hr/ml, 2.05, 13.01 hr, 16.57 µg/ml, 0.18 L/hr*kg, 0.14 hr-1 in the serum and ileum fluid, respectively. The optimum doses for bacteriostatic, bactericidal, and elimination activities were 29.81, 34.88, and 36.52 mg/kg for 50% target and 33.95, 39.79, and 42.55 mg/kg for 90% target, respectively. The final sensitive breakpoint was defined as 16 µg/ml. The current data presented provide the optimal regimens (39.79 mg/kg) and susceptible breakpoint (16 µg/ml) for clinical use, but these predicted data should be validated in the clinical practice.

Comparison of florfenicol pharmacokinetics in Exopalaemon carinicauda at different temperatures and administration routes.

Florfenicol is a broad-spectrum antibacterial drug. Exopalaemon carinicauda is important in the prawn aquaculture industry in China. Florfenicol pharmacokinetics in E. carinicauda were studied at different temperatures and via different routes of administration to provide a scientific basis for the rational use of drugs for E. carinicauda production. At water temperatures of 22 ± 0.4°C and 28 ± 0.3°C, after intramuscular (IM) injection and oral (per ora (PO)) administration of florfenicol at 10 mg/kg body weight (BW) and 30 mg/kg BW, respectively, the florfenicol concentration in the plasma, hepatopancreas, gills, muscles, and carapace of E. carinicauda was determined by high-performance liquid chromatography. After IM injection at different temperatures, the metabolism of florfenicol in E. carinicauda conformed to a two-compartment open model with zero-order absorption. After PO administration, the metabolism of florfenicol in E. carinicauda was consistent with a two-compartment open model with first-order absorption. Using an identical administration route but different water temperatures, the metabolism of florfenicol in E. carinicauda was quite different. Overall, florfenicol was absorbed rapidly and distributed widely in E. carinicauda, but elimination was slow and the bioavailability was not high. A low temperature and PO administration resulted in a low elimination rate.