The PK/PD Interactions of Doxycycline against Mycoplasma gallisepticum

Zhang, Nan; Gu, Xiaoyan; Ye, Xiaomei; Wu, Xun; Zhang, Bingxu; Zhang, Longfei; Shen, Xiu; Jiang, Hongxia; Ding, Huanzhong

doi:10.3389/fmicb.2016.00653

Cited by 33 publications

(39 citation statements)

References 39 publications

(42 reference statements)

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“…MIC values in the present study using the liquid method were similar to previous studies [13, 18, 23, 24]. For the five antimicrobial agents, the MIC determination for tilmicosin was very sensitive to inoculum effects.…”

Section: Discussionsupporting

confidence: 88%

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin

Zhang

et al. 2017

PLoS ONE

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Mycoplasma gallisepticum is a common etiological cause of a chronic respiratory disease in chickens; its increasing antimicrobial resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. Mutant selection window (MSW) determination was used to investigate the propensity for future resistance induction by danofloxacin, doxycycline, tilmicosin, tylvalosin and valnemulin. Killing of M. gallisepticum strain S6 by these antimicrobials was also studied by incubating M. gallisepticum into medium containing the compounds at the minimal concentration that inhibits colony formation by 99% (MIC99) and the mutant prevention concentration (MPC). Based on the morphology and colony numbers of M. gallisepticum on agar plates, the four kinds of sera in the order of the applicability for culturing M. gallisepticum were swine serum > horse serum > bovine serum > mixed serum. The MPC/MIC99 values for each agent were as follows: danofloxacin > tilmicosin > tylvalosin > doxycycline > valnemulin. MPC generated more rapid and greater magnitude killing than MIC99 against M. gallisepticum. Under exposure of 105–109 CFU/mL at MPC drug levels, valnemulin had the slowest rate of reduction in viable organisms and danofloxacin had the highest rate of reduction.

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Section: Discussionsupporting

confidence: 88%

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin

Zhang

et al. 2017

PLoS ONE

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“…They showed that polymyxin B had rapid and concentration-dependent bactericidal activity against P. aeruginosa, and that the effect was diminished if the amount of bacteria was increased. Also, study of the effect of doxycycline against Mycoplasma gallisepticum in an in vitro model led to the determination of the optimal PK/PD parameters to prevent drug resistance [26].…”

Section: Discussionmentioning

confidence: 99%

The PK/PD Integration and Resistance of Tilmicosin against Mycoplasma hyopneumoniae

Huang

Zheng

et al. 2020

Pathogens

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Mycoplasma hyopneumoniae is the major pathogen causing enzootic pneumonia in pigs. M. hyopneumoniae infection can lead to considerable economic losses in the pig-breeding industry. Here, this study established a first-order absorption, one-compartment model to study the relationship between the pharmacokinetics/pharmacodynamics (PK/PD) index of tilmicosin against M. hyopneumoniae in vitro. We simulated different drug concentrations of timicosin in the fluid lining the lung epithelia of pigs. The minimum inhibitory concentration (MIC) of tilmicosin against M. hyopneumoniae with an inoculum of 106 CFU/mL was 1.6 μg/mL using the microdilution method. Static time–kill curves showed that if the drug concentration >1 MIC, the antibacterial effect showed different degrees of inhibition. At 32 MIC, the amount of bacteria decreased by 3.16 log10 CFU/mL, thereby achieving a mycoplasmacidal effect. The M. hyopneumoniae count was reduced from 3.61 to 5.11 log10 CFU/mL upon incubation for 96 h in a dynamic model with a dose of 40–200 mg, thereby achieving mycoplasmacidal activity. The area under the concentration-time curve over 96 h divided by the MIC (AUC0–96 h/MIC) was the best-fit PK/PD parameters for predicting the antibacterial activity of tilmicosin against M. hyopneumoniae (R2 = 0.99), suggesting that tilmicosin had concentration-dependent activity. The estimated value for AUC0–96 h/MIC for 2log10 (CFU/mL) reduction and 3log10 (CFU/mL) reduction from baseline was 70.55 h and 96.72 h. Four M. hyopneumoniae strains (M1–M4) with reduced sensitivity to tilmicosin were isolated from the four dose groups. The susceptibility of these strains to tylosin, erythromycin and lincomycin was also reduced significantly. For sequencing analyses of 23S rRNA, an acquired A2058G transition in region V was found only in resistant M. hyopneumoniae strains (M3, M4). In conclusion, in an in vitro model, the effect of tilmicosin against M. hyopneumoniae was concentration-dependent and had a therapeutic effect. These results will help to design the optimal dosing regimen for tilmicosin in M. hyopneumoniae infection, and minimize the emergence of resistant bacteria.

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“…Li et al (2016) investigated the PK/PD relationship of cefquinome against Staphylococcus aureus using an in vitro PK/PD model, whereas this model was suited for the bacteria growing rapidly. To decrease the error of efficacy assessment caused by pumping out the medium, an in vitro PK/PD model can be set to change incrementally towards a dialysis model (Nan et al, 2016). Previous studies tested the dialysis model and showed that it overcame the above-mentioned error and also maintained a constant volume.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Integration and Resistance Analysis of Tilmicosin Against Mycoplasma gallisepticum in an In Vitro Dynamic Model

Huang

Zhou

et al. 2019

Front. Pharmacol.

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Mycoplasma gallisepticum is the major pathogen causing chronic respiratory disease in chickens. In the present study, we successfully established a one-compartment open model with first-order absorption to determine the relationship between tilmicosin pharmacokinetic and pharmacodynamic (PK/PD) indices and M. gallisepticum in in vitro . The aim was to simulate the PK/PD of tilmicosin against M. gallisepticum in lung tissues. The results of static time-killing curves at constant drug concentrations [0–64 minimum inhibitory concentration (MIC)] showed that the amount of M. gallisepticum was reduced to the limit of detection after 36 h when the drug concentration exceeded 1 MIC, with a maximum kill rate of 0.53 h -1 . In dynamic time-killing studies, tilmicosin produced a maximum antimycoplasmal effect of 6.38 Log 10 CFU/ml reduction over 120 h. The area under the concentration–time curve over 24 h divided by the MIC (AUC 24h /MIC) was the best PK/PD parameter to predict the antimicrobial activity of tilmicosin against M. gallisepticum [R 2 = 0.87, compared with 0.49 for the cumulative time that the concentration exceeds the MIC (%T > MIC)]. Therefore, tilmicosin showed concentration-dependent activity. Seven M. gallisepticum strains (M1–M7) with decreased susceptibility to tilmicosin were isolated from seven dose groups. These strains of M. gallisepticum had acquired resistance to erythromycin as well as to tylosin. However, no change in susceptibility to amikacin and doxycycline was observed in these strains. Gene mutation analysis was performed on the basis of annotated single nucleotide polymorphisms using the genome of strain S6 as the reference. For strain M5, a G495T mutation occurred in domain II of the 23S rrnA gene. In strain M3, resistance was associated with a T854A mutation in domain II of the 23S rrnB gene and a G2799A mutation in domain V of 23S rrnB . To the best of our knowledge, these tilmicosin resistance-associated mutations in M. gallisepticum have not been reported. In conclusion, tilmicosin shows excellent effectiveness and concentration-dependent characteristics against M. gallisepticum strain S6 in vitro . Additionally, these results will be used to provide a reference to design the optimal dosage regimen for tilmicosin in M. gallisepticum infection and to minimize the emergence of resistant bacteria.

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The PK/PD Interactions of Doxycycline against Mycoplasma gallisepticum

Cited by 33 publications

References 39 publications

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin

Determination of the Mutant Selection Window and Evaluation of the Killing of Mycoplasma gallisepticum by Danofloxacin, Doxycycline, Tilmicosin, Tylvalosin and Valnemulin

The PK/PD Integration and Resistance of Tilmicosin against Mycoplasma hyopneumoniae

Pharmacokinetic and Pharmacodynamic Integration and Resistance Analysis of Tilmicosin Against Mycoplasma gallisepticum in an In Vitro Dynamic Model

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