Determination of Antibiotic Effect in an In Vitro Pharmacodynamic Model: Comparison with an Established Animal Model of Infection
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| Published in | Antimicrobial Agents and Chemotherapy Vol. 46; no. 11; pp. 3574 - 3579 |
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American Society for Microbiology
01.11.2002
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Animal infection models have historically been used to study pharmacodynamic relationships. Similar results could theoretically be produced by using an in vitro pharmacodynamic model as an alternative to animal models. We compared the antibiotic effects of ticarcillin administered in various doses and dosing regimens against Pseudomonas aeruginosa ATCC 27853 under conditions analogous to those previously employed in a neutropenic-mouse thigh infection model (B. Vogelman et al., J. Infect. Dis. 158: 831-847, 1988). Ticarcillin dosages of either 96, 192, or 384 mg/day were administered at 1-, 2-, 3-, 4-, 8-, 12-, or 24-h intervals into a two-compartment model in order to duplicate the concentration-time profiles of the animal model. Colony counts were enumerated at 0 and 24 h. Linear regression and sigmoidal maximum-effect (Emax) model fitting were used to assess the relationship between the percentage of time that the concentration remained above the MIC (% T >MIC) or above four times the MIC (% T >4×MIC) and the change in the log 10 CFU per milliliter (Δlog 10 CFU/ml) in the central and peripheral compartments. Statistical analysis of the Δlog 10 CFU/ml values was performed for matched regimens of the in vitro and animal models based on the % T >MICs. The slopes of the regression equations of % T >MICs relative to Δlog 10 CFU/ml values were similar for the in vitro and animal models, but the y intercept was greater with the in vitro model. The Δlog 10 CFU/ml values of the 0- to 24-h colony counts at equivalent % T >MICs in the two models were not statistically different ( P = 0.087). Overall, the peripheral compartment of the in vitro model was a better predictor of effect than the central compartment. This study, which compares pharmacodynamic principles between an in vitro and an animal model, demonstrated similar relationships between % T >MICs and effects. Animal infection models have historically been used to study pharmacodynamic relationships. Similar results could theoretically be produced by using an in vitro pharmacodynamic model as an alternative to animal models. We compared the antibiotic effects of ticarcillin administered in various doses and dosing regimens against Pseudomonas aeruginosa ATCC 27853 under conditions analogous to those previously employed in a neutropenic-mouse thigh infection model (B. Vogelman et al., J. Infect. Dis. 158:831-847, 1988). Ticarcillin dosages of either 96, 192, or 384 mg/day were administered at 1-, 2-, 3-, 4-, 8- , 12-, or 24-h intervals into a two-compartment model in order to duplicate the concentration-time profiles of the animal model. Colony counts were enumerated at 0 and 24 h. Linear regression and sigmoidal maximum-effect (Emax) model fitting were used to assess the relationship between the percentage of time that the concentration remained above the MIC (%T>MIC) or above four times the MIC (%T>4x MIC) and the change in the log sub(10) CFU per milliliter ([Delta]log sub(10) CFU/ml) in the central and peripheral compartments. Statistical analysis of the [Delta]log sub(10) CFU/ml values was performed for matched regimens of the in vitro and animal models based on the %T>MICs. The slopes of the regression equations of %T>MICs relative to [Delta]log sub(10) CFU/ml values were similar for the in vitro and animal models, but the y intercept was greater with the in vitro model. The [Delta]log sub(10) CFU/ml values of the 0- to 24-h colony counts at equivalent %T>MICs in the two models were not statistically different (P = 0.087). Overall, the peripheral compartment of the in vitro model was a better predictor of effect than the central compartment. This study, which compares pharmacodynamic principles between an in vitro and an animal model, demonstrated similar relationships between %T>MICs and effects. Animal infection models have historically been used to study pharmacodynamic relationships. Similar results could theoretically be produced by using an in vitro pharmacodynamic model as an alternative to animal models. We compared the antibiotic effects of ticarcillin administered in various doses and dosing regimens against Pseudomonas aeruginosa ATCC 27853 under conditions analogous to those previously employed in a neutropenic-mouse thigh infection model (B. Vogelman et al., J. Infect. Dis. 158:831-847, 1988). Ticarcillin dosages of either 96, 192, or 384 mg/day were administered at 1-, 2-, 3-, 4-, 8-, 12-, or 24-h intervals into a two-compartment model in order to duplicate the concentration-time profiles of the animal model. Colony counts were enumerated at 0 and 24 h. Linear regression and sigmoidal maximum-effect (Emax) model fitting were used to assess the relationship between the percentage of time that the concentration remained above the MIC (%T>MIC) or above four times the MIC (%T>4×MIC) and the change in the log10 CFU per milliliter (Δlog10 CFU/ml) in the central and peripheral compartments. Statistical analysis of the Δlog10 CFU/ml values was performed for matched regimens of the in vitro and animal models based on the %T>MICs. The slopes of the regression equations of %T>MICs relative to Δlog10 CFU/ml values were similar for the in vitro and animal models, but the y intercept was greater with the in vitro model. The Δlog10 CFU/ml values of the 0- to 24-h colony counts at equivalent %T>MICs in the two models were not statistically different (P = 0.087). Overall, the peripheral compartment of the in vitro model was a better predictor of effect than the central compartment. This study, which compares pharmacodynamic principles between an in vitro and an animal model, demonstrated similar relationships between %T>MICs and effects. Animal infection models have historically been used to study pharmacodynamic relationships. Similar results could theoretically be produced by using an in vitro pharmacodynamic model as an alternative to animal models. We compared the antibiotic effects of ticarcillin administered in various doses and dosing regimens against Pseudomonas aeruginosa ATCC 27853 under conditions analogous to those previously employed in a neutropenic-mouse thigh infection model (B. Vogelman et al., J. Infect. Dis. 158:831-847, 1988). Ticarcillin dosages of either 96, 192, or 384 mg/day were administered at 1-, 2-, 3-, 4-, 8-, 12-, or 24-h intervals into a two-compartment model in order to duplicate the concentration-time profiles of the animal model. Colony counts were enumerated at 0 and 24 h. Linear regression and sigmoidal maximum-effect (Emax) model fitting were used to assess the relationship between the percentage of time that the concentration remained above the MIC (%T>MIC) or above four times the MIC (%T>4xMIC) and the change in the log(10) CFU per milliliter (Deltalog(10) CFU/ml) in the central and peripheral compartments. Statistical analysis of the Deltalog(10) CFU/ml values was performed for matched regimens of the in vitro and animal models based on the %T>MICs. The slopes of the regression equations of %T>MICs relative to Deltalog(10) CFU/ml values were similar for the in vitro and animal models, but the y intercept was greater with the in vitro model. The Deltalog(10) CFU/ml values of the 0- to 24-h colony counts at equivalent %T>MICs in the two models were not statistically different (P = 0.087). Overall, the peripheral compartment of the in vitro model was a better predictor of effect than the central compartment. This study, which compares pharmacodynamic principles between an in vitro and an animal model, demonstrated similar relationships between %T>MICs and effects. ABSTRACT Animal infection models have historically been used to study pharmacodynamic relationships. Similar results could theoretically be produced by using an in vitro pharmacodynamic model as an alternative to animal models. We compared the antibiotic effects of ticarcillin administered in various doses and dosing regimens against Pseudomonas aeruginosa ATCC 27853 under conditions analogous to those previously employed in a neutropenic-mouse thigh infection model (B. Vogelman et al., J. Infect. Dis. 158: 831-847, 1988). Ticarcillin dosages of either 96, 192, or 384 mg/day were administered at 1-, 2-, 3-, 4-, 8-, 12-, or 24-h intervals into a two-compartment model in order to duplicate the concentration-time profiles of the animal model. Colony counts were enumerated at 0 and 24 h. Linear regression and sigmoidal maximum-effect (Emax) model fitting were used to assess the relationship between the percentage of time that the concentration remained above the MIC (% T >MIC) or above four times the MIC (% T >4×MIC) and the change in the log 10 CFU per milliliter (Δlog 10 CFU/ml) in the central and peripheral compartments. Statistical analysis of the Δlog 10 CFU/ml values was performed for matched regimens of the in vitro and animal models based on the % T >MICs. The slopes of the regression equations of % T >MICs relative to Δlog 10 CFU/ml values were similar for the in vitro and animal models, but the y intercept was greater with the in vitro model. The Δlog 10 CFU/ml values of the 0- to 24-h colony counts at equivalent % T >MICs in the two models were not statistically different ( P = 0.087). Overall, the peripheral compartment of the in vitro model was a better predictor of effect than the central compartment. This study, which compares pharmacodynamic principles between an in vitro and an animal model, demonstrated similar relationships between % T >MICs and effects. |
| Author | Charles R. Bonapace Roger L. White John A. Bosso Lawrence V. Friedrich |
| AuthorAffiliation | Anti-Infective Research Laboratory, College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425 |
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| Cites_doi | 10.1128/AAC.36.12.2577 10.1128/AAC.39.3.650 10.1016/S0022-3476(86)80754-5 10.1086/516284 10.1128/AAC.35.3.399 10.1128/AAC.15.4.587 10.1093/infdis/159.2.281 10.1093/jac/37.4.645 10.1001/archinte.1989.00390100083020 10.1128/AAC.23.1.49 10.1093/infdis/158.4.831 10.1016/0732-8893(95)00053-D 10.1007/BF01117450 10.1093/infdis/146.3.423 10.1128/AAC.35.5.837 10.1093/infdis/146.5.691 10.1016/S0002-9343(84)80073-X |
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| Keywords | Pseudomonadales Animal model Intravenous administration β-Lactams Rodentia Ticarcillin In vitro Biological activity Penicillin derivatives In vivo Vertebrata Antibiotic Mammalia Mouse Minimum inhibitory concentration Bacteria Pseudomonadaceae Pseudomonas aeruginosa Antibacterial agent Pharmacokinetics |
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| Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Corresponding author. Mailing address: Anti-Infective Research Laboratory, Medical University of South Carolina, College of Pharmacy, 280 Calhoun St., P.O. Box 250142, Charleston, SC 29425. Phone: (843) 792-8501. Fax: (843) 792-1712. E-mail: bossoja@musc.edu. |
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| References | e_1_3_2_9_2 e_1_3_2_15_2 e_1_3_2_16_2 e_1_3_2_7_2 e_1_3_2_17_2 e_1_3_2_6_2 e_1_3_2_18_2 (e_1_3_2_2_2) 1987; 31 e_1_3_2_20_2 e_1_3_2_21_2 e_1_3_2_5_2 e_1_3_2_11_2 e_1_3_2_22_2 e_1_3_2_4_2 e_1_3_2_12_2 e_1_3_2_23_2 e_1_3_2_3_2 (e_1_3_2_14_2) 1996; 37 (e_1_3_2_13_2) 1991; 74 (e_1_3_2_19_2) 1982; 146 (e_1_3_2_8_2) 1985; 15 (e_1_3_2_10_2) 1985; 15 |
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Reddit... Animal infection models have historically been used to study pharmacodynamic relationships. Similar results could theoretically be produced by using an in... ABSTRACT Animal infection models have historically been used to study pharmacodynamic relationships. Similar results could theoretically be produced by using... |
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| SubjectTerms | Animals Anti-Bacterial Agents Anti-Bacterial Agents - pharmacokinetics Anti-Bacterial Agents - pharmacology Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Bacillus subtilis - drug effects Bacterial Infections Bacterial Infections - drug therapy Bacterial Infections - microbiology Biological and medical sciences Colony Count, Microbial Experimental Therapeutics Linear Models Medical sciences Mice Microbial Sensitivity Tests Models, Biological Neutropenia - complications Neutropenia - microbiology Pharmacology. Drug treatments Pseudomonas aeruginosa - drug effects Pseudomonas Infections - drug therapy Pseudomonas Infections - microbiology Time Factors |
| Title | Determination of Antibiotic Effect in an In Vitro Pharmacodynamic Model: Comparison with an Established Animal Model of Infection |
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