In-vivo assessment of in-vitro killing patterns of Pseudomonas aeruginosa

Gerber, Andreas; Feller-Segessenmann, C

doi:10.1093/jac/15.suppl_a.201

Cited by 37 publications

(26 citation statements)

References 5 publications

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“…We have previously shown that the bactericidal effect of gentamicin and netilmicin on Pseudomonas is fast and drug-concentration dependent in vitro as well as in our animal model [12]. The dose-response curve of gentamicin on Pseudomonas had no ceiling [12,13]. In contrast, the bactericidal effect of various fl-lactam drugs against P aeruginosa clearly had an upper limitation that was close to the MIC, i.e., the bactericidal activity of 13-lactams was not dose dependent in concentrations above the MIC [14].…”

Section: Discussionmentioning

confidence: 53%

“…This finding in turn most likely relates to the mechanism of action and more specifically to the shape of the dose-response curve of the drugs. We have previously shown that the bactericidal effect of gentamicin and netilmicin on Pseudomonas is fast and drug-concentration dependent in vitro as well as in our animal model [12]. The dose-response curve of gentamicin on Pseudomonas had no ceiling [12,13].…”

Section: Discussionmentioning

confidence: 58%

See 1 more Smart Citation

Antibiotic Therapy of Infections Due to Pseudomonas aeruginosa in Normal and Granulocytopenic Mice: Comparison of Murine and Human Pharmacokinetics

Gerber¹,

Brugger²,

Feller³

et al. 1986

Journal of Infectious Diseases

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112

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An effort was made to elucidate the limits of drug-activity tests in small animals. Human plasma kinetics of gentamicin, netilmicin, ticarcillin, ceftazidime, and ceftriaxone were approximated in normal and in granulocytopenic mice infected with various strains of Pseudomonas aeruginosa in the thigh muscle or intraperitoneally. The effect of such dosing on bacterial time-kill curves and on survival was compared with the effect of identical amounts of drug given as a single-bolus injection. With fl-lactams, a highly significant superiority of fractionated dosing (simulated human kinetics) over bolus injections (murine plasma kinetics) was demonstrated, whereas with aminoglycosides it was a singlebolus injection that tended to be more active. Thus, when tested in conventional smallanimal models, aminoglycoside activity may be overestimated, whereas fl-lactam activity may be underestimated in respect to humans. These differences found in vivo most probably reflect the different pharmacodynamics between aminoglycosides and f3-lactam drugs (time-kill curves, dose-response curves, and postantibiotic effect) similar to those previously observed in vitro.In a first approach, the in vivo activity and toxicity of any new drug is routinely studied in experimental models by using small animals such as mice, rats, guinea pigs, or rabbits. Moreover, some measure of the activity and toxicity of a single dose has become a mandatory requirement for any new drug to be licensed. Although conclusions from such studies are not directly transferable to man, they are at least looked on as a basis for investigations to be performed in more expensive animal models or humans. However, major biologic differences have to be considered between small experimental animals and man, one of which is metabolic activity in general. This difference becomes most evident in a compari- The present study was based on the hypothesis that the difference between small animals and man regarding drug kinetics cannot be overcome by just injecting larger amounts (per kilogram of body weight) of that substance into small animals. Rather, some kind of "human-adapted" pharmacokinetics of the study drug should be approximated in small animals.In a tentative pioneering effort we used an experimental thigh infection -as well as the standard mouse peritonitis model -to elucidate the impact of murine vs. human half-life of J3-lactam drugs and aminoglycosides on activity against Pseudomonas aeruginosa. In one group of mice the study drug was given as a single-bolus injection that was followed 90

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 58%

Antibiotic Therapy of Infections Due to Pseudomonas aeruginosa in Normal and Granulocytopenic Mice: Comparison of Murine and Human Pharmacokinetics

Gerber¹,

Brugger²,

Feller³

et al. 1986

Journal of Infectious Diseases

Self Cite

112

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show abstract

“…Gerber and Feller-Segessenmann used the granulocytopenic mouse thigh infection model subsequently and in this examination found that outcome for the animal could be correlated directly with peak concentrations of aminoglycoside in serum (16). However, because the pharmacokinetics of aminoglycosides in small animals reveal an extremely short half-life, there would be a significant covariance between the peak concentration achieved in serum and the total area under the curve.…”

Section: Aminoglycoside Antibioticsmentioning

confidence: 99%

Role of pharmacokinetics in the outcome of infections

Drusano

1988

Antimicrob Agents Chemother

324

155

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“…Although we are unable to completely explain these findings, they may relate to inherent differences between the in vitro and animal models. The lower degree of antibiotic effect detected in the in vitro model may be explained by the higher growth rate of P. aeruginosa in MuellerHinton broth than in neutropenic-and nonneutropenic-mouse thigh models (6,7). On the average, the ⌬log 10 CFU for 12 h of growth was approximately 1.7-fold and 5.6-fold greater in the in vitro model than in a neutropenic-and nonneutropenicmouse thigh model, respectively.…”

Section: Discussionmentioning

confidence: 91%

Determination of Antibiotic Effect in an In Vitro Pharmacodynamic Model: Comparison with an Established Animal Model of Infection

Bonapace

Friedrich

Bosso

et al. 2002

Antimicrob Agents Chemother

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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 ( Knowledge of an antibiotic's pharmacodynamic and pharmacokinetic properties is necessary for the selection of the most appropriate dose and dosage regimen. While pharmacokinetics describes the time course of drug concentrations in relation to the dose or dosage regimen, pharmacodynamics describes the concentration-drug effect relationship and is time independent. Integration of the two allows a description of a drug's effect over time. While certain pharmacokinetic-pharmacodynamic relationships have been described for antibiotic classes based on both animal models and human data (e.g., time-dependent killing of bacteria with ␤-lactams and concentration-dependent killing of bacteria with aminoglycosides), it is difficult to assess individual agents relative to others from within and outside their chemical classes and thus to assess their relative activities and determine whether these characteristics vary with different bacteria. It would be practical and desirable to elucidate an antibiotic's concentration-effect-time course properties and characteristics in an in vitro model that precludes or minimizes the use of experimental animals or human trials early in the drug's development. While a number of in vitro pharmacodynamic models have been devised and described in the literature, none have been systematically compared to animal models to validate their use. The specific aims of the present study were designed to address this need by using a pharmacodynamic model developed in our laboratory.Despite theories regarding the potential advantages of one in vitro model over others or over animal models, it is nonetheless unclear what relevance experimental results generated in these models has to human pharmacokinetics and pharmacodynamics and the treatment of clinical infection. It therefore appears logical, as a first step in addressing this issue, that results obtained from the in vitro model be compared with those obtained from an animal model under identical experimental conditions (i.e., the same antibiotic, equivalent doses and dosage regimens, the same test organism, and the same pharmacokinetic parameters). Thus, the objective of this study was to compare the antibacterial effect measured in an in vitro model with the published results of an established model, namely, thigh infections in neutropenic mice (21).(This work has been presented in part at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., 26 to 29 September 1999.) MATERIALS AND METHODSAntibiotics. The antibiotic used in this study was pharmaceuti...

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In-vivo assessment of in-vitro killing patterns of Pseudomonas aeruginosa

Cited by 37 publications

References 5 publications

Antibiotic Therapy of Infections Due to Pseudomonas aeruginosa in Normal and Granulocytopenic Mice: Comparison of Murine and Human Pharmacokinetics

Antibiotic Therapy of Infections Due to Pseudomonas aeruginosa in Normal and Granulocytopenic Mice: Comparison of Murine and Human Pharmacokinetics

Role of pharmacokinetics in the outcome of infections

Determination of Antibiotic Effect in an In Vitro Pharmacodynamic Model: Comparison with an Established Animal Model of Infection

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