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In vivo evaluation of mutant selection window of cefquinome against Escherichia coli in piglet tissue-cage model.

Zhang B, Gu X, Li Y, Li X, Gu M, Zhang N, Shen X, Ding H - BMC Vet. Res. (2014)

Bottom Line: The resistance of cephalosporins is significantly serious in veterinary clinic.Maintenance of antimicrobial concentrations above the MPC for > 50% of administration interval is a straightforward way to restrict the acquisition of resistance in this tissue cage model.This situation was achieved with daily intramuscular doses of 1 mg cefquinome/kg body weight.

View Article: PubMed Central - PubMed

Affiliation: National Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China. 874364610@qq.com.

ABSTRACT

Background: The resistance of cephalosporins is significantly serious in veterinary clinic. In order to inhibit the bacterial resistance production, the mutant selection window (MSW) hypothesis with Escherichia coli (E. coli) ATCC 25922 exposed to cefquinome in an animal tissue-cage model was investigated.

Results: Localized infection with E. coli was established in piglets, and the infected animals were administrated intramuscularly with various doses and intervals of cefquinome to provide antibiotic concentrations below the MIC99, between the MIC99 and the mutant prevention concentration (MPC), and above the MPC. E. coli lost susceptibility when drug concentrations fluctuated between the lower and upper boundaries of the window, which defined in vitro as the MIC99 (0.06 μg/mL) and the MPC (0.16 μg/mL) respectively. For PK/PD parameters, there were no mutant selection enrichment when T>MIC99 was ≤ 25% or T>MPC was ≥ 50% of administration interval. When T>MIC99 was > 25% and T>MPC was <50% of administration interval, resistance selection was observed. When AUC24 h/MIC99 and AUC24 h/MPC were considered, the mutant selection window extended from 32.84 h to 125.64 h and from 12.83 h to 49.09 h, respectively.

Conclusions: These findings demonstrate that the MSW exists in vivo for time-dependent antimicrobial agents, and its boundaries fit well with those determined in vitro. Maintenance of antimicrobial concentrations above the MPC for > 50% of administration interval is a straightforward way to restrict the acquisition of resistance in this tissue cage model. This situation was achieved with daily intramuscular doses of 1 mg cefquinome/kg body weight.

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Effect of actual cefquinome concentration on loss of susceptibility and mutant enrichment. Tissue-cage implantation and Escherichia coli ATCC 25922 infection were done as described in Meterials and Methods. Piglets having above 1 × 108 CFU/mL E.coli in tissue-cage fluid 2 days after infection were treated with various intramuscular doses of cefquinome once daily and twice daily for 5 times beginning 3 days after infection. The dosage, administration at hour or day 0 of the x-axis, protocol for each panel was as follows: A1, 4 received 0.1 mg/kg; A2, 3 received 1.0 mg/kg; A3, 4 received 0.2 mg/kg and 2 received 0.4 mg/kg; A4, 4 received 0.8 mg/kg and 1 received 1.0 mg/kg; A5, 3 received 0.4 mg/kg; A6, 2 received 0.2 mg/kg and 3 received 0.4 mg/kg; A7, 1 received 0.2 mg/kg and 4 received 0.4 mg/kg; A8, 3 received 0.2 mg/kg. Cefquinome concentration in tissue-cage fluid was monitored at the indicated times after the administration of each dose (panels A1-A8). The boundaries of the mutant selection window (the MIC99 and MPC) were determined with the E.coli inoculum by agar plate assays. Tissue-cage fluid was sampled for bacteria at 24 h and 12 h intervals for 7 times starting immediately before the administration of the first dose of cefquinome. Loss of susceptibility (panels B1-B8) was monitored as an increase in MIC averaged for all piglets in the group. The fraction of resistant mutants (panels C1-C8) in each group of piglets was determined daily as the number of colonies grown on cefquinome-containing agar (MIC) relative to the number that grew on drug-free agar.
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Fig2: Effect of actual cefquinome concentration on loss of susceptibility and mutant enrichment. Tissue-cage implantation and Escherichia coli ATCC 25922 infection were done as described in Meterials and Methods. Piglets having above 1 × 108 CFU/mL E.coli in tissue-cage fluid 2 days after infection were treated with various intramuscular doses of cefquinome once daily and twice daily for 5 times beginning 3 days after infection. The dosage, administration at hour or day 0 of the x-axis, protocol for each panel was as follows: A1, 4 received 0.1 mg/kg; A2, 3 received 1.0 mg/kg; A3, 4 received 0.2 mg/kg and 2 received 0.4 mg/kg; A4, 4 received 0.8 mg/kg and 1 received 1.0 mg/kg; A5, 3 received 0.4 mg/kg; A6, 2 received 0.2 mg/kg and 3 received 0.4 mg/kg; A7, 1 received 0.2 mg/kg and 4 received 0.4 mg/kg; A8, 3 received 0.2 mg/kg. Cefquinome concentration in tissue-cage fluid was monitored at the indicated times after the administration of each dose (panels A1-A8). The boundaries of the mutant selection window (the MIC99 and MPC) were determined with the E.coli inoculum by agar plate assays. Tissue-cage fluid was sampled for bacteria at 24 h and 12 h intervals for 7 times starting immediately before the administration of the first dose of cefquinome. Loss of susceptibility (panels B1-B8) was monitored as an increase in MIC averaged for all piglets in the group. The fraction of resistant mutants (panels C1-C8) in each group of piglets was determined daily as the number of colonies grown on cefquinome-containing agar (MIC) relative to the number that grew on drug-free agar.

Mentions: The values of MIC, MIC99, and MPC were 0.064 μg/mL, 0.06 μg/mL, and 0.16 μg/mL in present study, respectively. Cefquinome concentrations, determined in samples of tissue-cage fluid collected at various time points over several days, are shown in Figure 2 (panels A1-A8). There were totally 34 tissue cages analyzed and another 2 tissue cages were excluded because of bacterial pollution. And the cefquinome concentrations shown for each of the 8 groups were the means of the concentrations from all animals/tissue cage fluids selected for those groups. The boundaries of the mutant selection window were determined to be 0.06 μg/mL (MIC99) and 0.16 μg/mL (MPC) by agar plate assays, which were the average values determined in the five independent experiments. There are 8 groups (A1-A8) to display the different classifications (lower, higher, partially inside, totally inside) of cefquinome concentrations based on the MSW boundary.Figure 2


In vivo evaluation of mutant selection window of cefquinome against Escherichia coli in piglet tissue-cage model.

Zhang B, Gu X, Li Y, Li X, Gu M, Zhang N, Shen X, Ding H - BMC Vet. Res. (2014)

Effect of actual cefquinome concentration on loss of susceptibility and mutant enrichment. Tissue-cage implantation and Escherichia coli ATCC 25922 infection were done as described in Meterials and Methods. Piglets having above 1 × 108 CFU/mL E.coli in tissue-cage fluid 2 days after infection were treated with various intramuscular doses of cefquinome once daily and twice daily for 5 times beginning 3 days after infection. The dosage, administration at hour or day 0 of the x-axis, protocol for each panel was as follows: A1, 4 received 0.1 mg/kg; A2, 3 received 1.0 mg/kg; A3, 4 received 0.2 mg/kg and 2 received 0.4 mg/kg; A4, 4 received 0.8 mg/kg and 1 received 1.0 mg/kg; A5, 3 received 0.4 mg/kg; A6, 2 received 0.2 mg/kg and 3 received 0.4 mg/kg; A7, 1 received 0.2 mg/kg and 4 received 0.4 mg/kg; A8, 3 received 0.2 mg/kg. Cefquinome concentration in tissue-cage fluid was monitored at the indicated times after the administration of each dose (panels A1-A8). The boundaries of the mutant selection window (the MIC99 and MPC) were determined with the E.coli inoculum by agar plate assays. Tissue-cage fluid was sampled for bacteria at 24 h and 12 h intervals for 7 times starting immediately before the administration of the first dose of cefquinome. Loss of susceptibility (panels B1-B8) was monitored as an increase in MIC averaged for all piglets in the group. The fraction of resistant mutants (panels C1-C8) in each group of piglets was determined daily as the number of colonies grown on cefquinome-containing agar (MIC) relative to the number that grew on drug-free agar.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4279896&req=5

Fig2: Effect of actual cefquinome concentration on loss of susceptibility and mutant enrichment. Tissue-cage implantation and Escherichia coli ATCC 25922 infection were done as described in Meterials and Methods. Piglets having above 1 × 108 CFU/mL E.coli in tissue-cage fluid 2 days after infection were treated with various intramuscular doses of cefquinome once daily and twice daily for 5 times beginning 3 days after infection. The dosage, administration at hour or day 0 of the x-axis, protocol for each panel was as follows: A1, 4 received 0.1 mg/kg; A2, 3 received 1.0 mg/kg; A3, 4 received 0.2 mg/kg and 2 received 0.4 mg/kg; A4, 4 received 0.8 mg/kg and 1 received 1.0 mg/kg; A5, 3 received 0.4 mg/kg; A6, 2 received 0.2 mg/kg and 3 received 0.4 mg/kg; A7, 1 received 0.2 mg/kg and 4 received 0.4 mg/kg; A8, 3 received 0.2 mg/kg. Cefquinome concentration in tissue-cage fluid was monitored at the indicated times after the administration of each dose (panels A1-A8). The boundaries of the mutant selection window (the MIC99 and MPC) were determined with the E.coli inoculum by agar plate assays. Tissue-cage fluid was sampled for bacteria at 24 h and 12 h intervals for 7 times starting immediately before the administration of the first dose of cefquinome. Loss of susceptibility (panels B1-B8) was monitored as an increase in MIC averaged for all piglets in the group. The fraction of resistant mutants (panels C1-C8) in each group of piglets was determined daily as the number of colonies grown on cefquinome-containing agar (MIC) relative to the number that grew on drug-free agar.
Mentions: The values of MIC, MIC99, and MPC were 0.064 μg/mL, 0.06 μg/mL, and 0.16 μg/mL in present study, respectively. Cefquinome concentrations, determined in samples of tissue-cage fluid collected at various time points over several days, are shown in Figure 2 (panels A1-A8). There were totally 34 tissue cages analyzed and another 2 tissue cages were excluded because of bacterial pollution. And the cefquinome concentrations shown for each of the 8 groups were the means of the concentrations from all animals/tissue cage fluids selected for those groups. The boundaries of the mutant selection window were determined to be 0.06 μg/mL (MIC99) and 0.16 μg/mL (MPC) by agar plate assays, which were the average values determined in the five independent experiments. There are 8 groups (A1-A8) to display the different classifications (lower, higher, partially inside, totally inside) of cefquinome concentrations based on the MSW boundary.Figure 2

Bottom Line: The resistance of cephalosporins is significantly serious in veterinary clinic.Maintenance of antimicrobial concentrations above the MPC for > 50% of administration interval is a straightforward way to restrict the acquisition of resistance in this tissue cage model.This situation was achieved with daily intramuscular doses of 1 mg cefquinome/kg body weight.

View Article: PubMed Central - PubMed

Affiliation: National Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China. 874364610@qq.com.

ABSTRACT

Background: The resistance of cephalosporins is significantly serious in veterinary clinic. In order to inhibit the bacterial resistance production, the mutant selection window (MSW) hypothesis with Escherichia coli (E. coli) ATCC 25922 exposed to cefquinome in an animal tissue-cage model was investigated.

Results: Localized infection with E. coli was established in piglets, and the infected animals were administrated intramuscularly with various doses and intervals of cefquinome to provide antibiotic concentrations below the MIC99, between the MIC99 and the mutant prevention concentration (MPC), and above the MPC. E. coli lost susceptibility when drug concentrations fluctuated between the lower and upper boundaries of the window, which defined in vitro as the MIC99 (0.06 μg/mL) and the MPC (0.16 μg/mL) respectively. For PK/PD parameters, there were no mutant selection enrichment when T>MIC99 was ≤ 25% or T>MPC was ≥ 50% of administration interval. When T>MIC99 was > 25% and T>MPC was <50% of administration interval, resistance selection was observed. When AUC24 h/MIC99 and AUC24 h/MPC were considered, the mutant selection window extended from 32.84 h to 125.64 h and from 12.83 h to 49.09 h, respectively.

Conclusions: These findings demonstrate that the MSW exists in vivo for time-dependent antimicrobial agents, and its boundaries fit well with those determined in vitro. Maintenance of antimicrobial concentrations above the MPC for > 50% of administration interval is a straightforward way to restrict the acquisition of resistance in this tissue cage model. This situation was achieved with daily intramuscular doses of 1 mg cefquinome/kg body weight.

Show MeSH
Related in: MedlinePlus