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In vitro Dynamic Pharmacokinetic/Pharmacodynamic (PK/PD) study and COPD of Marbofloxacin against Haemophilus parasuis.

Sun J, Xiao X, Huang RJ, Yang T, Chen Y, Fang X, Huang T, Zhou YF, Liu YH - BMC Vet. Res. (2015)

Bottom Line: The PK/PD surrogate markers Cmax/MIC, Cmax/MPC (the maximum concentration divided by MIC or mutant prevention concentration (MPC)) and AUC 24h/MIC, AUC 24h/MPC (the area under the curve during the first 24 h divided by MIC or MPC) simulated the antimicrobial effect of marbofloxacin successfully with the R(2) of 0.9928 and 0.9911, respectively.The target values of 3-log10-unit and 4-log10-unit reduction for AUC 24h/MPC were 33 and 42, while the same efficacy for AUC 24h/MIC were 88 and 110.The PK/PD surrogate markers AUC 24h/MIC, Cmax/MIC and AUC 24h/MPC, Cmax/MPC properly described the effects of marbofloxacin.

View Article: PubMed Central - PubMed

Affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, 510642, China. jiansun@scau.edu.cn.

ABSTRACT

Background: Haemophilus parasuis (H. parasuis) can invade the body and cause systemic infection under stress conditions. Marbofloxacin has been recommended for the treatment of swine infections. However, few studies have investigated the PK/PD characteristics and PK/PD cutoff (COPD) of this drug against H. parasuis.

Results: MICs of marbofloxacin against 198 H. parasuis isolates were determined. The MIC50 and MIC90 were 2 and 8 mg/L, respectively. An in vitro dynamic PK/PD model was established to study the PK/PD relationship of marbofloxacin against H. parasuis. The PK/PD surrogate markers Cmax/MIC, Cmax/MPC (the maximum concentration divided by MIC or mutant prevention concentration (MPC)) and AUC 24h/MIC, AUC 24h/MPC (the area under the curve during the first 24 h divided by MIC or MPC) simulated the antimicrobial effect of marbofloxacin successfully with the R(2) of 0.9928 and 0.9911, respectively. The target values of 3-log10-unit and 4-log10-unit reduction for AUC 24h/MPC were 33 and 42, while the same efficacy for AUC 24h/MIC were 88 and 110. The COPD deduced from Monte Carlo simulation (MCS) for marbofloxacin against H. parasuis was 0.5 mg/L. The recommended dose of marbofloxacin against H. parasuis with MIC ≤ 2 mg/L was 16 mg/kg body weight (BW).

Conclusions: The PK/PD surrogate markers AUC 24h/MIC, Cmax/MIC and AUC 24h/MPC, Cmax/MPC properly described the effects of marbofloxacin. Marbofloxacin can achieve the best efficacy at dosage of 16 mg/kg BW for strains with MIC values ≤ 2 mg/L, therefore, it is obligatory to know the sensitivity of the pathogen and to treat animals as early as possible. The very first COPD provide fundamental data for marbofloxacin breakpoint determination.

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Sigmoid Emax model relationships between antibacterial effect [E, log10 (cfu/mL)] and AUC24h/MIC of marbofloxacin in the in vitro PK/PD model against H. parasuis with an inoculum size of 1 × 107 cfu/mL
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Fig4: Sigmoid Emax model relationships between antibacterial effect [E, log10 (cfu/mL)] and AUC24h/MIC of marbofloxacin in the in vitro PK/PD model against H. parasuis with an inoculum size of 1 × 107 cfu/mL

Mentions: The pharmacokinetics of marbofloxacin in pigs was well simulated by this model with the relative deviation below 7 %. Time killing curves were shown in Fig. 2. The marbofloxacin inhibited H. parasuis moderately when the AUC24h/MIC was less than 13.8. The bacteria decreased rapidly within 12 h, but re-grew to 106 cfu/mL at 24 h with the AUC24h/MIC of 46. When the AUC24h/MIC was 55 and 73, H. parasuis could not be detected at 12 h, however, re-growth was observed at 24 h. When AUC24h/MIC was 92 and 110, marbofloxacin killed H. parasuis without regrowth in 24 h (4-log-unit and 5-log-unit decrease, respectively). The relationship between in vitro antimicrobial efficacy and PK/PD surrogate markers (AUC24h/MIC or Cmax/MIC) was described using the sigmoid Emax model. Both of the PK/PD surrogate markers simulated the in vitro antimicrobial effect of marbofloxacin successfully with the R2 of 0.9928 and 0.9911 respectively (Figs 3, 4). The estimated Log Emax, Log E0, EC50, and slope were shown in Tables 1 and 2 respectively. The target values of 3-log10-unit and 4-log10-unit decreases for Cmax/MIC were 6.5 and 8 while for AUC24h/MIC were 88 and 110, respectively. The same effects for surrogates Cmax/MPC and AUC24h/MPC were 2.5, 3 and 33, 42 respectively. They also simulated the in vitro antimicrobial effect of marbofloxacin successfully with the R2 of 0.9928 and 0.9911 respectively.Fig. 2


In vitro Dynamic Pharmacokinetic/Pharmacodynamic (PK/PD) study and COPD of Marbofloxacin against Haemophilus parasuis.

Sun J, Xiao X, Huang RJ, Yang T, Chen Y, Fang X, Huang T, Zhou YF, Liu YH - BMC Vet. Res. (2015)

Sigmoid Emax model relationships between antibacterial effect [E, log10 (cfu/mL)] and AUC24h/MIC of marbofloxacin in the in vitro PK/PD model against H. parasuis with an inoculum size of 1 × 107 cfu/mL
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4666160&req=5

Fig4: Sigmoid Emax model relationships between antibacterial effect [E, log10 (cfu/mL)] and AUC24h/MIC of marbofloxacin in the in vitro PK/PD model against H. parasuis with an inoculum size of 1 × 107 cfu/mL
Mentions: The pharmacokinetics of marbofloxacin in pigs was well simulated by this model with the relative deviation below 7 %. Time killing curves were shown in Fig. 2. The marbofloxacin inhibited H. parasuis moderately when the AUC24h/MIC was less than 13.8. The bacteria decreased rapidly within 12 h, but re-grew to 106 cfu/mL at 24 h with the AUC24h/MIC of 46. When the AUC24h/MIC was 55 and 73, H. parasuis could not be detected at 12 h, however, re-growth was observed at 24 h. When AUC24h/MIC was 92 and 110, marbofloxacin killed H. parasuis without regrowth in 24 h (4-log-unit and 5-log-unit decrease, respectively). The relationship between in vitro antimicrobial efficacy and PK/PD surrogate markers (AUC24h/MIC or Cmax/MIC) was described using the sigmoid Emax model. Both of the PK/PD surrogate markers simulated the in vitro antimicrobial effect of marbofloxacin successfully with the R2 of 0.9928 and 0.9911 respectively (Figs 3, 4). The estimated Log Emax, Log E0, EC50, and slope were shown in Tables 1 and 2 respectively. The target values of 3-log10-unit and 4-log10-unit decreases for Cmax/MIC were 6.5 and 8 while for AUC24h/MIC were 88 and 110, respectively. The same effects for surrogates Cmax/MPC and AUC24h/MPC were 2.5, 3 and 33, 42 respectively. They also simulated the in vitro antimicrobial effect of marbofloxacin successfully with the R2 of 0.9928 and 0.9911 respectively.Fig. 2

Bottom Line: The PK/PD surrogate markers Cmax/MIC, Cmax/MPC (the maximum concentration divided by MIC or mutant prevention concentration (MPC)) and AUC 24h/MIC, AUC 24h/MPC (the area under the curve during the first 24 h divided by MIC or MPC) simulated the antimicrobial effect of marbofloxacin successfully with the R(2) of 0.9928 and 0.9911, respectively.The target values of 3-log10-unit and 4-log10-unit reduction for AUC 24h/MPC were 33 and 42, while the same efficacy for AUC 24h/MIC were 88 and 110.The PK/PD surrogate markers AUC 24h/MIC, Cmax/MIC and AUC 24h/MPC, Cmax/MPC properly described the effects of marbofloxacin.

View Article: PubMed Central - PubMed

Affiliation: National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, 510642, China. jiansun@scau.edu.cn.

ABSTRACT

Background: Haemophilus parasuis (H. parasuis) can invade the body and cause systemic infection under stress conditions. Marbofloxacin has been recommended for the treatment of swine infections. However, few studies have investigated the PK/PD characteristics and PK/PD cutoff (COPD) of this drug against H. parasuis.

Results: MICs of marbofloxacin against 198 H. parasuis isolates were determined. The MIC50 and MIC90 were 2 and 8 mg/L, respectively. An in vitro dynamic PK/PD model was established to study the PK/PD relationship of marbofloxacin against H. parasuis. The PK/PD surrogate markers Cmax/MIC, Cmax/MPC (the maximum concentration divided by MIC or mutant prevention concentration (MPC)) and AUC 24h/MIC, AUC 24h/MPC (the area under the curve during the first 24 h divided by MIC or MPC) simulated the antimicrobial effect of marbofloxacin successfully with the R(2) of 0.9928 and 0.9911, respectively. The target values of 3-log10-unit and 4-log10-unit reduction for AUC 24h/MPC were 33 and 42, while the same efficacy for AUC 24h/MIC were 88 and 110. The COPD deduced from Monte Carlo simulation (MCS) for marbofloxacin against H. parasuis was 0.5 mg/L. The recommended dose of marbofloxacin against H. parasuis with MIC ≤ 2 mg/L was 16 mg/kg body weight (BW).

Conclusions: The PK/PD surrogate markers AUC 24h/MIC, Cmax/MIC and AUC 24h/MPC, Cmax/MPC properly described the effects of marbofloxacin. Marbofloxacin can achieve the best efficacy at dosage of 16 mg/kg BW for strains with MIC values ≤ 2 mg/L, therefore, it is obligatory to know the sensitivity of the pathogen and to treat animals as early as possible. The very first COPD provide fundamental data for marbofloxacin breakpoint determination.

Show MeSH
Related in: MedlinePlus