CN111986773A - Method for administering doxycycline hydrochloride and florfenicol to respiratory pathogenic bacteria based on PK/PD model - Google Patents
Method for administering doxycycline hydrochloride and florfenicol to respiratory pathogenic bacteria based on PK/PD model Download PDFInfo
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- 229960003760 florfenicol Drugs 0.000 title claims abstract description 84
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title claims abstract description 67
- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 title claims abstract description 54
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Abstract
The invention discloses a drug delivery method of doxycycline hydrochloride and florfenicol to respiratory pathogenic bacteria based on a PK/PD model, which comprises the following steps that doxycycline hydrochloride and florfenicol respectively have optimal combined drug ratio to actinobacillus pleuropneumoniae and haemophilus parasuis, under the optimal combined drug ratio to the doxycycline hydrochloride and the florfenicol, the doxycycline hydrochloride and the florfenicol are used for detecting the in vitro drug sensitivity to the actinobacillus pleuropneumoniae and the haemophilus parasuis under the independent and combined conditions, and the distribution of MIC is counted; the doxycycline hydrochloride and florfenicol injection is prepared into a dosage scheme of the actinobacillus pleuropneumoniae and the haemophilus parasuis for preventing, treating and eradicating diseases, and finally the dosage scheme of the component with smaller therapeutic dose in the combined medicine components is taken as a final dosage scheme.
Description
Technical Field
The invention relates to the technical field of PK-PD models, in particular to a method for administering doxycycline hydrochloride and florfenicol to respiratory pathogenic bacteria based on a PK/PD model.
Background
Actinobacillus pleuropneumoniae and haemophilus parasuis both have high pathogenicity on pigs and have the greatest threat to the development of the breeding industry, and mainly cause respiratory diseases mainly including porcine infectious pleuropneumonia, pleuritis and arthritis.
With the increasing severity of drug resistance of actinobacillus pleuropneumoniae and haemophilus parasuis to antibiotics, more and more drugs cannot be used for clinical treatment of actinobacillus pleuropneumoniae and haemophilus parasuis, florfenicol and doxycycline are widely applied to clinical veterinary treatment of porcine respiratory diseases by virtue of the characteristics of wide antibacterial spectrum, strong activity and the like, but due to unreasonable selection and abuse of drugs, drug resistance appears to a great extent, clinical causes are complex, mixed infection of various diseases is often shown, and good treatment effect is difficult to achieve by single drug use. The use of two or more antibacterial agents to exert drug interactions can suitably improve the therapeutic efficacy, so optimizing the dosing regimen of combination is of paramount importance. The Pharmacokinetic-pharmacodynamic (PK/PD) combination model integrates the relationship among medicines, organisms and pathogenic bacteria. The PK/PD combined model is used for the formulation and optimization of a dosing scheme, can provide scientific basis for the formulation of an antibiotic dosing scheme, and aims to standardize the application of florfenicol and doxycycline in the treatment of diseases caused by actinobacillus pleuropneumoniae and haemophilus parasuis, enhance the treatment effect and slow down the generation of drug resistance of the actinobacillus pleuropneumoniae and the haemophilus parasuis.
Disclosure of Invention
The invention aims to solve the problems and provide a method for administering doxycycline hydrochloride and florfenicol to respiratory pathogenic bacteria based on a PK/PD model, which can provide scientific data support for administration in the breeding industry, can scientifically guide clinical administration, and more effectively treat respiratory diseases such as porcine infectious pleuropneumonia, multiple cellulose serositis, meningitis, arthritis and the like, has high safety, can effectively reduce the generation of drug resistance of haemophilus parasuis and actinobacillus pleuropneumoniae to the florfenicol and doxycycline, and improves the stable development and economic benefit of the breeding industry, and the like, and is explained in detail in the following.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides a method for administering doxycycline hydrochloride and florfenicol to respiratory tract pathogenic bacteria based on a PK/PD model, which comprises the following steps:
step 1: determining the optimal combined drug proportion of doxycycline hydrochloride and florfenicol to actinobacillus pleuropneumoniae and haemophilus parasuis respectively, detecting the in vitro drug sensitivity of the doxycycline hydrochloride and the florfenicol to the actinobacillus pleuropneumoniae and haemophilus parasuis under the condition of single and combined detection under the optimal combined drug proportion of the doxycycline hydrochloride and the florfenicol, and counting the distribution of MIC;
step 2: determining MIC, MBC, MPC, PAE and sterilization curves of actinobacillus pleuropneumoniae and haemophilus parasuis by adopting in vitro and in vivo pharmacodynamic experimental methods to obtain PD parameters;
and step 3: selecting healthy animals and diseased animals, establishing a disease infection model, calculating by adopting a liquid chromatography method and a urea nitrogen detection method to obtain a PK parameter of the combination of doxycycline hydrochloride and florfenicol on actinobacillus pleuropneumoniae and haemophilus parasuis, and determining an in-vivo sterilization curve;
and 4, step 4: selecting corresponding PK-PD parameters according to the in-half body sterilization curve obtained in the step 3, substituting the PK-PD parameters into pharmacokinetic software, and simulating pharmacodynamic data in alveolar fluid of a healthy group and a diseased group in a Sigmoid Emax PK-PD model equation to obtain different antibacterial effects (E)1＝0，E2＝-3，E3-4, representing PK-PD values under inhibition, treatment and eradication), and substituting into the dose formula to obtain the inhibition, treatment and eradication doses, respectively.
And 5: and (3) simulating the growth change of pathogenic bacteria along with the change of the in-vivo drug concentration under the inhibitory dose, the therapeutic dose and the eradication dose obtained in the step (4) by using Mlxplore software, and determining the drug administration interval, thereby obtaining three drug administration methods for preventing diseases, treating diseases and completely eradicating diseases.
Preferably, the in vitro and in vivo pharmacodynamic experiment method is that according to MIC distribution and experiment requirements, a strain at MIC90 of doxycycline hydrochloride and florfenicol combined medication is selected to carry out serotype identification and a mouse virulence experiment, MIC90 is the lowest drug concentration for inhibiting 90% of bacterial growth, the pig actinobacillus pleuropneumoniae and haemophilus parasuis with stronger pathogenicity at MIC90 are screened out through the serotype identification and the mouse virulence experiment, in vitro and in vivo pharmacodynamic experiments are carried out, and MIC, MBC, MPC, PAE and sterilization curves of the screened actinobacillus pleuropneumoniae and haemophilus parasuis of doxycycline hydrochloride and florfenicol are measured to obtain PD parameters.
Preferably, the step 3 comprises selecting animals of healthy groups and diseased groups and pathogenic strains, establishing a disease infection model, carrying out intramuscular injection of drugs on the animals of the healthy groups and the diseased groups, collecting plasma at different time points before and after administration, collecting alveolar lavage fluid by a bronchoscope-alveolar sampler, determining an intra-molecular sterilization curve by the alveolar lavage fluid obtained at different time points, detecting drug concentrations in the alveolar lavage fluid and the plasma by a liquid chromatography method, determining an original drug concentration in the alveolar lavage fluid by a urea nitrogen detection method, and calculating related PK parameters by Winnolin software; .
Preferably, the pharmacokinetic software in step 4 is Winnonlin software.
Preferably, the optimal combination ratio in step 1 is determined by a broth micro-chessboard method, and additive or synergistic effects are determined by FIC formula, and MIC distribution is determined by an agar method.
Preferably, in the step 2, the serotype of the actinobacillus pleuropneumoniae with stronger pathogenicity is selected to be a type 5 strain, the serotype 5 strain of the haemophilus parasuis with stronger pathogenicity is selected, and a mouse virulence experiment is carried out on the MIC90 strain in the actinobacillus pleuropneumoniae serotype 5 strain, wherein the specific experiment process comprises the following steps:
selecting 57 KM healthy mice, each strain is a group, each group comprises 3 strains, injecting 0.2mL of bacterial liquid with the concentration of 1 × 107CFU/mL, 1 × 108CFU/mL and 1 × 109CFU/mL in an abdominal cavity sterile manner, observing the survival state of the mice at regular time every day, observing for 3 days, recording the survival condition of each group of mice every day, observing the mice killed by the toxin-attacking strain for pathological change, dissecting, performing bacteria-splitting culture on the infected part, identifying the mice as positive through PCR (polymerase chain reaction), judging the mice as successfully infected, selecting the strain with stronger toxicity, and performing a virulence experiment on the haemophilus parasuis mice as with actinobacillus pleuropneumoniae.
Preferably, the dosage formula in step 4 is as follows:
in the Dose formula, Dose represents the administered Dose; (AUC/MIC) ex denotes pharmacokinetic parameters (PK parameters) in vivo; CL/F represents bioavailability-corrected body clearance; MIC is the MIC value of the bacteria; fu represents the proportion of free drug concentration.
Preferably, the dosing interval in step 5 is selected from the group consisting of doxycycline hydrochloride and florfenicol in florfenicol at the dose of actinobacillus pleuropneumoniae in pigs.
Has the advantages that: the method comprises the steps of preparing a drug delivery scheme of doxycycline hydrochloride and florfenicol injection on actinobacillus pleuropneumoniae and haemophilus parasuis under three drug delivery purposes of preventing, treating and eradicating diseases, and finally taking the drug delivery scheme of a component with a smaller therapeutic dose in combined drug components as a final drug delivery scheme, so that the method can be used for effectively treating respiratory diseases such as porcine infectious pleuropneumonia, multiple cellulose serositis, meningitis and arthritis and relieving the generation of bacterial drug resistance, scientifically guiding clinical medication, and providing a solution for clinical mixed infection.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is the MIC profile of florfenicol in combination with doxycycline (1:1) against 131 strains of A. pleuropneumoniae;
FIG. 2 is the MIC profile of florfenicol in combination with doxycycline (1:1) against 115 strains of Haemophilus parasuis;
figure 3 is an in vitro sterilization curve of doxycycline hyclate-florfenicol against a. pleuropneumoniae BW1 strain;
FIG. 4 is an in vitro bactericidal curve of doxycycline hydrochloride-florfenicol against Haemophilus parasuis 55 strain;
figure 5 is an in-vivo bactericidal profile of doxycycline hyclate-florfenicol in alveolar lavage fluid against a strain of actinobacillus pleuropneumoniae BW 1.
FIG. 6 is an in-half bactericidal curve of doxycycline hydrochloride-florfenicol in alveolar lavage fluid against Haemophilus parasuis 55 strain;
FIG. 7 is a plot of intramuscular injection of doxycycline hydrochloride-florfenicol (20mg/kg b.w) in pigs versus half-log dose of florfenicol in the alveolar fluid of Haemophilus parasuis;
FIG. 8 is a plot of intramuscular injection of doxycycline hydrochloride-florfenicol (20mg/kg b.w) in pigs versus half log doxycycline in alveolar fluid of Haemophilus parasuis;
FIG. 9 is a plot of intramuscular injection of doxycycline hydrochloride-florfenicol (20mg/kg b.w) to half-log florfenicol in the alveolar fluid of Actinobacillus pleuropneumoniae in pigs;
FIG. 10 is a plot of intramuscular injection of doxycycline hydrochloride-florfenicol (20mg/kg b.w) to pigs versus half log doxycycline in the alveolar fluid of Actinobacillus pleuropneumoniae;
FIG. 11 is a graph of Mlxpolre software simulating bacterial growth under different dosing regimens.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
Referring to fig. 1 to 11, the present invention provides a method for administering doxycycline hydrochloride and florfenicol to respiratory pathogens based on a PK/PD model, comprising the steps of:
step 1: 131 actinobacillus pleuropneumoniae and 115 haemophilus parasuis which are collected from a laboratory are taken as strain samples, the optimal combined drug proportion of doxycycline hydrochloride and florfenicol to the actinobacillus pleuropneumoniae and the haemophilus parasuis is determined, under the optimal combined drug proportion of the doxycycline hydrochloride and the florfenicol, the doxycycline hydrochloride and the florfenicol are used for detecting the in vitro drug sensitivity to the actinobacillus pleuropneumoniae and the haemophilus parasuis under the independent and combined conditions, and the distribution of MIC is counted; the optimal combination ratio is determined by adopting a trace broth chessboard method, and the optimal combination ratio of doxycycline hydrochloride and florfenicol to the porcine actinomyces pleuropneumoniae and haemophilus parasuis is determined to be 1:1, and judging additive or synergistic action by FIC formula, and determining MIC distribution by agar method. The FIC formula is as follows:
in the FIC formula, the FIC index is less than or equal to 0.5 and is a synergistic effect; the FIC index is 0.5 and the FIC is less than or equal to 1, and the additive effect is achieved; the FIC index is more than 1 and less than or equal to 2, which is irrelevant; FIC index >2 is antagonistic. The florfenicol and doxycycline are combined to have an additive or synergistic effect, 131 strains of actinobacillus pleuropneumoniae and 115 strains of haemophilus parasuis collected from a laboratory are taken as strain samples, MIC distribution data of the combined florfenicol and doxycycline on the haemophilus parasuis and the actinobacillus pleuropneumoniae are determined by an agar method, and strains of MIC90 are obtained, wherein the MIC90 of the haemophilus parasuis is 1/1 mu g/mL, and the MIC90 of the actinobacillus pleuropneumoniae is 2/2 mu g/mL. As shown in figures 1 and 2 of the specification.
Step 2: determining MIC, MBC, MPC, PAE and sterilization curves of actinobacillus pleuropneumoniae and haemophilus parasuis by adopting in vitro and in vivo pharmacodynamic experimental methods to obtain PD parameters; selecting a serotype of actinobacillus pleuropneumoniae with stronger pathogenicity as a type 5 strain, selecting a serotype 5 strain of haemophilus parasuis with stronger pathogenicity, and carrying out a mouse virulence experiment on an MIC90 strain in the serotype 5 strain of actinobacillus pleuropneumoniae, wherein the specific experimental process comprises the following steps:
selecting 57 KM healthy mice, each strain is a group, each group comprises 3 strains, injecting 0.2mL of bacterial liquid with the concentration of 1 × 107CFU/mL, 1 × 108CFU/mL and 1 × 109CFU/mL in an abdominal cavity sterile manner, observing the survival state of the mice at regular time every day, observing for 3 days, recording the survival condition of each group of mice every day, observing the mice killed by the toxin-attacking strain for pathological change, dissecting, performing bacteria-splitting culture on the infected part, identifying the mice as positive through PCR (polymerase chain reaction), judging the mice as successfully infected, selecting the strain with stronger toxicity, and performing a virulence experiment on the haemophilus parasuis mice as with actinobacillus pleuropneumoniae. The actinobacillus pleuropneumoniae selects MIC90 strain BW1 with stronger toxicity, Haemophilus parasuis mice virulence experiment is the same as actinobacillus pleuropneumoniae, finally selects strain with number 55, MIC and MBC in vitro and in half body are measured by trace broth dilution method and are shown in tables 1 and 2, and MIC distribution is shown in figures 1 and 2. The selected strains were then subjected to in vivo and in vitro sterilization curve measurements as shown in FIGS. 3, 4, 5, 6.
TABLE 1 doxycycline hydrochloride and florfenicol combination (1:1) MIC and MBC in vitro and in vivo against BW1 strain
Note: FF is florfenicol; doxycycline hydrochloride is doxycycline hydrochloride.
TABLE 2 combination of florfenicol and doxycycline (1:1) MIC and MBC in vitro and in vivo against 55 strains of bacteria
Note: FF is florfenicol; doxycycline hydrochloride is doxycycline hydrochloride.
And step 3: selecting healthy animals and diseased animals, establishing a disease infection model, calculating by adopting a liquid chromatography method and a urea nitrogen detection method to obtain a PK parameter of the combination of doxycycline hydrochloride and florfenicol on actinobacillus pleuropneumoniae and haemophilus parasuis, and determining an in-vivo sterilization curve, wherein the PK parameter is shown in the attached figure 5 of the specification; the step 3 comprises selecting animals of a healthy group and a diseased group and pathogenic strains, establishing a disease infection model, carrying out intramuscular injection on the animals of the healthy group and the diseased group, collecting plasma at different time points before and after administration, collecting alveolar lavage fluid by a bronchoscope alveolar sampler, determining an intra-half body sterilization curve by the alveolar lavage fluid obtained at different time points, detecting the drug concentration in the alveolar lavage fluid and the drug concentration in the plasma at different time points by liquid chromatography, determining the original drug concentration in the alveolar fluid by a urea nitrogen detection method, and calculating related PK parameters by Winnolin software; as shown in tables 3, 4, 5, 6, 7, 8.
TABLE 3 intramuscular injection of doxycycline hydrochloride and florfenicol (20mg/kg b.w) in pigs at drug concentrations in healthy alveolar fluid (n ═ 6)
TABLE 4 intramuscular injection of doxycycline hydrochloride-florfenicol (20mg/kg b.w) in pigs drug concentration in healthy and diseased Actinobacillus pleuropneumoniae alveolar fluid (n ═ 6)
Note: ND represents lower than LOD.
TABLE 5 intramuscular injection of doxycycline hydrochloride-florfenicol (20mg/kg b.w) in pigs drug concentration in healthy and diseased haemophilus parasuis alveolar fluid (n ═ 6)
TABLE 6 intramuscular injection (20mg/kg b.w) of doxycycline hydrochloride, mono formulation and florfenicol alveolar liquid pharmacokinetic parameters (n ═ 6)
Note: k12: a first order rate constant for drug transport from the central chamber to the peripheral chamber; k21: a first order rate constant for drug transport from the peripheral chamber to the central chamber; AUC: area under the curve when taking medicine; cmax: peak concentration of drug; tmax: time to peak; t1/2 α: half-life of absorption; t1/2. beta.: elimination of half-life; CL/F: bioavailability-corrected body clearance; V1/F: a bioavailability-corrected central compartment distribution volume; V2/F: bioavailability corrected peripheral compartment distribution volume.
TABLE 7 intramuscular injection (20mg/kg b.w) of doxycycline hydrochloride-florfenicol into pigs the pharmacokinetic parameters of the alveolar fluid of A. pleuropneumoniae in healthy and diseased groups (n ═ 6)
TABLE 8 intramuscular injection (20mg/kg b.w) of doxycycline hydrochloride-florfenicol into pigs the pneumolysin alveolar fluid of Haemophilus parasuis in the healthy and diseased groups (n ═ 6)
And 4, step 4: selecting corresponding PK-PD parameters according to the in-half body sterilization curve obtained in the step 3, substituting the PK-PD parameters into pharmacokinetic software, and simulating pharmacodynamic data in alveolar fluid of a healthy group and a diseased group in a Sigmoid Emax PK-PD model equation to obtain different antibacterial effects (E)1＝0，E2＝-3， E3-4, representing PK-PD values under inhibition, treatment and eradication), and substituting into the dose formula to obtain the inhibition, treatment and eradication doses, respectively.
The bactericidal effect shown in alveolar fluid after the combination of doxycycline hydrochloride and florfenicol has the characteristics of concentration dependence and certain time dependence. The choice of PK-PD parameters in vivo can therefore be determined by model fitting between the (AUC24h/MIC) ex parameter values and the bacterial log reduction. The fit of the in vivo PK-PD model was to simulate the relationship between the in vivo bactericidal curve data and corresponding PK-PD parameter values for healthy and diseased groups in vivo, as shown in tables 9 and 10 below. Wherein, (AUC24h/MIC) ex is the concentration of drugs including florfenicol and doxycycline at different time points in alveolar lavage fluid of healthy and diseased groups, which is determined by HPLC, and then multiplied by the in-half incubation time of 24h and divided by the minimum inhibitory concentration. The bacterial log reduction value is the bacterial log change between 24h and 0h after the bacteria are cultured in alveolar fluid of healthy groups and diseased groups.
TABLE 9 PK-PD parameter values and antibacterial Effect values in alveolar fluid half of patients with Haemophilus parasuis
Note: FF: florfenicol; DOX: doxycycline hydrochloride
TABLE 10 Pneumoniae disease groups PK-PD parameter values and antibacterial Effect values in alveolar fluid half
Note: (AUC24h/MIC) ex is the in-vivo PK-PD parameter value; e is the difference between the log values of the bacterial titers 24h after the alveolar lavage fluid inoculation culture at each time point.
The bacteriostatic E is 0, which indicates that the logarithmic change of bacteria before and after culture has no great difference, can inhibit the growth of bacteria and has a prevention effect; the treatment E-3 shows that 99.9 percent of bacteria can be killed after the culture is carried out for a proper time, and the treatment effect is achieved; the eradication of E-4 means that 99.99 percent of bacteria can be killed after the culture is carried out for a proper time, pathogenic bacteria can be eradicated, and the eradication effect is achieved. In the method for treating the haemophilus parasuis by using doxycycline hydrochloride-florfenicol in three doses, in order to better cure the mixed infection diseases, the larger of the two bacterial doses, namely the dosage scheme of the actinobacillus pleuropneumoniae is selected, and then the smaller of the combined medicine components is selected as the final dose. The final prevention dose of the doxycycline hydrochloride-florfenicol on the actinobacillus pleuropneumoniae and the haemophilus parasuis is 1.5mg/kg b.w, the treatment dose is 4.5mg/kg b.w, and the eradication dose is 8mg/kg b.w.
TABLE 11 intramuscular injection (20mg/kg b.w) of florfenicol and doxycycline in pigs results of model fitting of healthy and diseased haemophilus parasuis alveolar fluid Sigmoid Emax (n ═ 6)
Note: emax is the difference between the log value of a blank alveolar lavage fluid inoculated culture after 24h and the log value of an initial inoculated colony; e0 is the maximum difference between the log values of the initial inoculated colonies and the alveolar lavage fluid samples before and after 24h of inoculation and culture; c is a half-internal PK-PD parameter value; EC50 is the half-in vivo PK-PD parameter value at which 50% of maximal bactericidal effect was produced in alveolar lavage fluid samples; n is a Hill coefficient, describes the slope of the half-in-vivo PK-PD parameter value and the effect E after linearization, and determines the gradient of the S-shaped curve relation;
TABLE 12 intramuscular injection (20mg/kg b.w) of florfenicol and doxycycline into pigs results of model fitting of healthy and diseased Actinobacillus pleuropneumoniae alveolar fluid Sigmoid Emax (n ═ 6)
And 5: and (3) simulating the growth change of pathogenic bacteria along with the change of the in-vivo drug concentration under the inhibitory dose, the therapeutic dose and the eradication dose obtained in the step (4) by using Mlxplore software, and determining the drug administration interval, thereby obtaining three drug administration methods for preventing diseases, treating diseases and completely eradicating diseases.
The in vitro and in vivo pharmacodynamic experiment method comprises the steps of selecting a bacterial strain at an MIC90 position of doxycycline hydrochloride and florfenicol combined drug to carry out serotype identification and a mouse virulence experiment according to MIC distribution and experiment requirements, wherein MIC90 is the lowest drug concentration for inhibiting 90% of bacterial growth, screening out actinobacillus pleuropneumoniae and haemophilus parasuis with stronger pathogenicity at an MIC90 position through the serotype identification and the mouse virulence experiment, carrying out in vitro and in vivo pharmacodynamic experiments, and determining MIC, MBC, MPC, PAE and sterilization curves of the doxycycline hydrochloride and the florfenicol on the screened actinobacillus pleuropneumoniae and haemophilus parasuis respectively to obtain PD parameters.
The pharmacokinetic software in the step 4 is Winnonlin software.
The dosage formula in the step 4 is as follows:
in the Dose formula, Dose represents the administered Dose; (AUC/MIC) ex denotes pharmacokinetic parameters (PK parameters) in vivo; CL/F represents bioavailability-corrected body clearance; MIC is the MIC value of the bacteria; fu represents the proportion of free drug concentration.
TABLE 13 dosage of florfenicol and doxycycline for different purposes of administration
Note: HPS: haemophilus parasuis; APP: actinobacillus pleuropneumoniae, FF: florfenicol; DOX: doxycycline hydrochloride.
The dosing interval in step 5 is selected to be at a dosage of doxycycline hydrochloride and florfenicol in florfenicol to porcine actinobacillus pleuropneumoniae. The growth of bacteria at three doses (prevention, treatment, eradication) and at different dosing intervals was predicted by simulation with the mlxpore software to obtain the optimal dosing regimen and dosing interval. As can be seen from FIG. 7, 1.50mg/kg b.w can achieve the bacteriostatic action at the interval of 24h, and both 4.50mg/kg b.w and 8.00mg/kg b.w can achieve the bactericidal effect; when the administration interval is 12 hours, although the sterilization effect can be achieved after 2.25mg/kg b.w and 4.00mg/kg b.w are injected for two days, the bacteriostatic effect can not be achieved by the administration dosage of 0.75mg/kg b.w. In conclusion, the clinical recommended regimen is finally established as 24h dosing interval, 4.5mg/kg b.w, and 2d of continuous dosing.
The doxycycline hydrochloride-florfenicol injection is prepared into a drug delivery scheme of the doxycycline hydrochloride-florfenicol injection for the actinobacillus pleuropneumoniae and haemophilus parasuis under the three drug delivery purposes of preventing, treating and eradicating diseases, and finally the drug delivery scheme of the component with smaller therapeutic dose in the combined drug components is taken as the final drug delivery scheme, so that the doxycycline hydrochloride-florfenicol injection is used for effectively treating respiratory diseases such as porcine infectious pleuropneumonia, multiple-occurring cellulosic serositis, meningitis, arthritis and the like, simultaneously relieving the generation of bacterial drug resistance, scientifically guiding clinical medication, and providing a solution for clinical mixed infection.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of changes or substitutions within the technical scope of the present invention, and all such changes or substitutions are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (8)
1. A method for administering doxycycline hydrochloride and florfenicol to respiratory pathogens based on a PK/PD model is characterized by comprising the following steps:
step 1: determining the optimal combined drug proportion of doxycycline hydrochloride and florfenicol to actinobacillus pleuropneumoniae and haemophilus parasuis respectively, detecting the in vitro drug sensitivity of the doxycycline hydrochloride and the florfenicol to the actinobacillus pleuropneumoniae and the haemophilus parasuis under the independent and combined conditions under the optimal combined drug proportion of the doxycycline hydrochloride and the florfenicol, and counting the distribution of MIC;
step 2: determining MIC, MBC, MPC, PAE and sterilization curves of actinobacillus pleuropneumoniae and haemophilus parasuis by adopting in vitro and in vivo pharmacodynamic experimental methods to obtain PD parameters;
and step 3: selecting healthy animals and diseased animals, establishing a disease infection model, calculating by adopting a liquid chromatography method and a urea nitrogen detection method to obtain a PK parameter of the combination of doxycycline hydrochloride and florfenicol on actinobacillus pleuropneumoniae and haemophilus parasuis, and determining an in-vivo sterilization curve;
and 4, step 4: selecting corresponding PK-PD parameters according to the in-half body sterilization curve obtained in the step 3, substituting the PK-PD parameters into pharmacokinetic software, and simulating pharmacodynamic data in alveolar fluid of a healthy group and a diseased group in a Sigmoid Emax PK-PD model equation to obtain different antibacterial effects (E)1＝0，E2＝-3，E3-4, representing PK-PD values under inhibition, treatment and eradication), into a dose formula to yield an inhibitory, therapeutic and eradication dose, respectively.
And 5: and (3) simulating the growth change of pathogenic bacteria along with the change of the in-vivo drug concentration under the inhibitory dose, the therapeutic dose and the eradication dose obtained in the step (4) by using Mlxplore software, and determining the drug administration interval, thereby obtaining three drug administration methods for preventing diseases, treating diseases and completely eradicating diseases.
2. The method of claim 1 for the administration of doxycycline hydrochloride and florfenicol to a pathogenic bacteria of the respiratory tract based on a PK/PD model, wherein: the in vitro and in vivo pharmacodynamic experiment method comprises the steps of selecting a bacterial strain at an MIC90 position of doxycycline hydrochloride and florfenicol combined medication according to MIC distribution and experiment requirements to carry out serotype identification and a mouse virulence experiment, wherein MIC90 is the lowest drug concentration for inhibiting 90% of bacterial growth, screening out actinobacillus pleuropneumoniae and haemophilus parasuis with stronger pathogenicity at an MIC90 position through the serotype identification and the mouse virulence experiment, carrying out in vitro and in vivo pharmacodynamic experiments, and determining MIC, MBC, MPC, PAE and sterilization curves of the doxycycline hydrochloride and the florfenicol on the screened actinobacillus pleuropneumoniae and haemophilus parasuis respectively to obtain PD parameters.
3. The method of claim 1 for the administration of doxycycline hydrochloride and florfenicol to a pathogenic bacteria of the respiratory tract based on a PK/PD model, wherein: the step 3 comprises selecting healthy animals, diseased animals and pathogenic strains, establishing a disease infection model, carrying out intramuscular injection on the animals of the healthy animals and the diseased animals, collecting plasma at different time points before and after administration, collecting alveolar lavage fluid by using a bronchoscope alveolar sampling instrument, determining an intra-half body sterilization curve by using the alveolar lavage fluid obtained at different time points, detecting the drug concentration in the alveolar lavage fluid obtained at different time points and the drug concentration in the plasma by using a liquid chromatography, determining the original drug concentration in the alveolar lavage fluid by using a urea nitrogen detection method, and calculating by using Winnolin software to obtain related PK parameters; .
4. The method of claim 1 for the administration of doxycycline hydrochloride and florfenicol to a pathogenic bacteria of the respiratory tract based on a PK/PD model, wherein: the pharmacokinetic software in the step 4 is Winnonlin software.
5. The method of claim 1 for the administration of doxycycline hydrochloride and florfenicol to a pathogenic bacteria of the respiratory tract based on a PK/PD model, wherein: the optimal combination ratio in the step 1 is determined by adopting a trace broth chessboard method, the additive or synergistic effect is determined by an FIC formula, and the MIC distribution is determined by an agar method.
6. The method of claim 1 for the administration of doxycycline hydrochloride and florfenicol to a pathogenic bacteria of the respiratory tract based on a PK/PD model, wherein: in the step 2, the serotype of actinobacillus pleuropneumoniae with stronger pathogenicity is selected to be a type 5 strain, the serotype 5 strain of haemophilus parasuis with stronger pathogenicity is selected, and an MIC90 strain in the serotype 5 of actinobacillus pleuropneumoniae is subjected to a mouse virulence experiment, wherein the specific experimental process is as follows:
selecting 57 KM healthy mice, each strain is a group, each group comprises 3 strains, injecting 0.2mL of bacterial liquid with 1 × 107CFU/mL, 1 × 108CFU/mL and 1 × 109CFU/mL in an abdominal cavity sterile manner, observing the survival state of the mice at regular time every day, observing for 3 days and recording the survival condition of each group of mice every day, observing the mice killed by the virus attacking strain for pathological change, dissecting, performing bacteria division culture on infected parts, identifying the mice as positive by PCR (polymerase chain reaction), judging the mice as successfully infected, selecting the strains with stronger toxicity, and performing a virulence experiment on the haemophilus parasuis mice with actinobacillus pleuropneumoniae.
7. The method of claim 1 for the administration of doxycycline hydrochloride and florfenicol to a pathogenic bacteria of the respiratory tract based on a PK/PD model, wherein: the dosage formula in the step 4 is as follows:
in the Dose formula, Dose represents the administered Dose; (AUC/MIC) ex denotes pharmacokinetic parameters (PK parameters) in vivo; CL/F represents bioavailability-corrected body clearance; MIC is the MIC value of the bacteria; fu represents the proportion of free drug concentration.
8. The method of claim 1 for the administration of doxycycline hydrochloride and florfenicol to a pathogenic bacteria of the respiratory tract based on a PK/PD model, wherein: the dosing interval in step 5 is selected to be at a dosage of doxycycline hydrochloride and florfenicol in florfenicol to porcine actinobacillus pleuropneumoniae.
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