Degradation kinetics and formation of regulated and emerging disinfection by-products during chlorination of two expectorants ambroxol and bromhexine.

Ambroxol hydrochloride (AMB) and bromhexine hydrochloride (BRO) are classic expectorants and bronchosecretolytic pharmaceuticals. In 2022, both AMB and BRO were recommended by medical emergency department of China to alleviate cough and expectoration for symptoms caused by COVID-19. The reaction characteristics and mechanism of AMB/BRO with chlorine disinfectant in the disinfection process were investigated in this study. The reaction of chlorine with AMB/BRO were well described by a second-order kinetics model, first-order in both AMB/BRO and chlorine. The second order rate reaction constant of AMB and BRO with chlorine at pH 7.0 were 1.15 × 102 M-1s-1 and 2.03 × 102 M-1s-1, respectively. During chlorination, a new class of aromatic nitrogenous disinfection by-products (DBPs) including 2-chloro-4, 6-dibromoaniline and 2, 4, 6-tribromoaniline were identified as the intermediate aromatic DBPs by gas chromatography-mass spectrometry. The effect of chlorine dosage, pH, and contact time on the formation of 2-chloro-4, 6-dibromoaniline and 2, 4, 6-tribromoaniline were evaluated. In addition, it was found that bromine in AMB/BRO were vital bromine source to greatly promote the formation of classic brominated DBPs, with the highest Br-THMs yields of 23.8% and 37.8%, respectively. This study inspired that bromine in brominated organic compounds may be an important bromine source of brominated DBPs.

Murine Thigh Microdialysis to Evaluate the Pharmacokinetic/Pharmacodynamic Integration of Cefquinome Against Actinobacillus pleuropneumoniae.

This study aimed to explore the application of microdialysis in pharmacokinetic (PK)/pharmacodynamic (PD) integration of cefquinome against Actinobacillus pleuropneumoniae. After the A. pleuropneumoniae population reached 106 CFU/thigh, the mice received 0.04, 0.16, 0.63, 2.5, and 10 mg/kg cefquinome by subcutaneous injection. Plasma samples were collected by retro-orbital puncture for 4 h, and thigh dialysate was obtained by microdialysis at a flow rate of 1.5 µL/min for 6 h for the PK study. For the PD experiment, the infected mice were treated with a 4-fold-increase in the total cefquinome dose, ranging from 0.01 to 10 mg/kg/24 h, divided into one, two, three, four, and eight doses. The number of bacteria was determined and an inhibitory sigmoid maximum effect (Emax) model was used to analyse the relationships between PK/PD parameters and efficacy. The mean penetration of cefquinome from plasma to the thigh was 0.591. The PK data for PK/PD integration were obtained by extrapolation. The fittest PK/PD parameter for efficacy evaluation was %fT>MIC (the percentage of time that free drug concentrations exceed the MIC). The magnitudes of %fT>MIC to achieve net bacterial stasis, 1-log10 CFU reduction, 2-log10 CFU reduction, and 3-log10 CFU reduction were 19.56, 28.65, 41.59, and 67.07 % in plasma and 21.74, 36.11, 52.96, and 82.68% in murine thigh, respectively. Microdialysis was first applied to evaluate the PK/PD integration of cefquinome against A. pleuropneumoniae. These results would provide valuable references when we apply microdialysis to study the PK/PD integration model and use cefquinome to treat animal diseases caused by A. pleuropneumoniae.

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

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 Log10 CFU/ml reduction over 120 h. The area under the concentration-time curve over 24 h divided by the MIC (AUC24h/MIC) was the best PK/PD parameter to predict the antimicrobial activity of tilmicosin against M. gallisepticum [R2 = 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.