Pharmacokinetic and Pharmacodynamic Parameters for Antimicrobial Effects of Cefotaxime and Amoxicillin in an In Vitro Kinetic Model

Antibiotic dosing regimens may vary in their capacity to select mutants. Our hypothesis was that selection of a more resistant bacterial subpopulation would increase with the time within a selective window (SW), i.e., when drug concentrations fall between the MICs of two strains. An in vitro kinetic model was used to study the selection of two Escherichia coli strains with different susceptibilities to cefotaxime. The bacterial mixtures were exposed to cefotaxime for 24 h and SWs of 1, 2, 4, 8, and 12 h. A mathematical model was developed that described the selection of preexisting and newborn mutants and the post-MIC effect (PME) as functions of pharmacokinetic parameters. Our main conclusions were as follows: (i) the selection between preexisting mutants increased with the time within the SW; (ii) the emergence and selection of newborn mutants increased with the time within the SW (with a short time, only 4% of the preexisting mutants were replaced by newborn mutants, compared to the longest times, where 100% were replaced); and (iii) PME increased with the area under the concentration-time curve (AUC) and was slightly more pronounced with a long elimination half-life (T 1/2 ) than with a short T 1/2 situation, when AUC is fixed. We showed that, in a dynamic competition between strains with different levels of resistance, the appearance of newborn high-level resistant mutants from the parental strains and the PME can strongly affect the outcome of the selection and that pharmacodynamic models can be used to predict the outcome of resistance development.

Section: Methodsmentioning

confidence: 99%

Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-ResistantEscherichia coli

Olofsson

Geli

Andersson

et al. 2005

“…The pharmacodynamic function can then be used in combination with pharmacokinetic data to investigate the efficacy of antibiotic treatment. Frequently the pharmacodynamic relationship is reduced to a single parameter, the MIC (3,14,15,20,21,27,37,[39][40][41]46,56), even though antibiotics with the same MIC can have very different pharmacodynamic functions (1,44).…”

mentioning

confidence: 99%

Pharmacodynamic Functions: a Multiparameter Approach to the Design of Antibiotic Treatment Regimens

Regoes

Wiuff

Zappala

et al. 2004

313

432

There is a complex quantitative relationship between the concentrations of antibiotics and the growth and death rates of bacteria. Despite this complexity, in most cases only a single pharmacodynamic parameter, the MIC of the drug, is employed for the rational development of antibiotic treatment regimens. In this report, we use a mathematical model based on a Hill function-which we call the pharmacodynamic function and which is related to previously published E max models-to describe the relationship between the bacterial net growth rates and the concentrations of antibiotics of five different classes: ampicillin, ciprofloxacin, tetracycline, streptomycin, and rifampin. Using Escherichia coli O18:K1:H7, we illustrate how precise estimates of the four parameters of the pharmacodynamic function can be obtained from in vitro time-kill data. We show that, in addition to their respective MICs, these antibiotics differ in the values of the other pharmacodynamic parameters. Using a computer simulation of antibiotic treatment in vivo, we demonstrate that, as a consequence of differences in pharmacodynamic parameters, such as the steepness of the Hill function and the minimum bacterial net growth rate attained at high antibiotic concentrations, there can be profound differences in the microbiological efficacy of antibiotics with identical MICs. We discuss the clinical implications and limitations of these results.Fundamental to the rational design (35, 55) of effective antibiotic treatment protocols are accurate measures of the absorption, distribution, and decay of the drug in treated patients (pharmacokinetics) and the functional relationship between the concentration of the antibiotic and the rate of growth or death of the target bacteria (pharmacodynamics). Typically the pharmacodynamics of antibiotics are studied in vitro by exposing exponentially growing bacteria to a range of drug concentrations and monitoring the changes in density of viable cells over time and thereby generating time-kill curves (7, 9, 16, 17, 23, 25, 31, 50-52, 54, 58, 61). From these data, the growth or death rates of the bacteria at different concentrations of antibiotics can be estimated and the functional relationship between bacterial growth (or death) and the concentration of the antibiotic can thereby be determined. We refer to this relationship as the pharmacodynamic function. The pharmacodynamic function can then be used in combination with pharmacokinetic data to investigate the efficacy of antibiotic treatment. Frequently the pharmacodynamic relationship is reduced to a single parameter, the MIC (3,14,15,20,21,27,37,[39][40][41]46,56), even though antibiotics with the same MIC can have very different pharmacodynamic functions (1,44).In this study, we examined the pharmacodynamic relationship between antibiotic concentration and bacterial growth and death rates. We generated time-kill curves for Escherichia coli exposed to antibiotics of five different classes: rifampin, ampicillin, ciprofloxacin, streptomycin, and tetracycline. These...

“…50% was required to obtain maximal efficacy of amoxicillin against a penicillin-susceptible and a penicillin-intermediate (MIC ϭ 0.25 mg/liter) strain of S. pneumoniae. For a strain with an MIC of 2 mg/liter, a TϾMIC of 60% was needed, but the C max was also important (20). The importance of local resistance epidemiology and the pharmacodynamic properties of antibiotics for the determination of dosing strategies has also been demonstrated in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…A previously described model (20,22) was used in these experiments. It consists of a 100-ml spinner flask with a 0.45-m-pore-size filter membrane and a prefilter fitted in between the upper and bottom parts.…”

Section: Antibioticmentioning

confidence: 99%

Suboptimal Antibiotic Dosage as a Risk Factor for Selection of Penicillin-Resistant Streptococcus pneumoniae : In Vitro Kinetic Model

Odenholt

Gustafsson

Löwdin

et al. 2003

Streptococcus pneumoniae is the most significant bacterial cause of community-acquired respiratory tract infections (23). During the last decade, the spread of penicillin nonsusceptible pneumococci with increased MICs has created clinically significant treatment problems, especially in infections against which therapeutic concentrations are difficult to achieve, such as meningitis (1,(15)(16)(17)(18)28). Clinical and animal studies indicate, however, that by optimizing the dosing regimen, it may still be possible in many cases to use penicillin for treatment of S. pneumoniae with decreased susceptibility (3-5, 8-10, 12-14, 25). Dosing regimens should, however, be optimized not only to obtain a maximal antibacterial effect but also to reduce the risk for the emergence of resistance (2,19,24). Little is known about the selective properties of different antibiotic regimens in a mixed culture of bacteria with different antibiotic susceptibilities. The normal nasopharyngeal flora of patients may be simultaneously colonized with different types of S. pneumoniae having a variable resistance pattern. A certain dosage regimen could select more resistant strains even if these at the time constitute a minority for the original population (11,21,26,27). The aim of the present investigation was to use an in vitro kinetic model to study the selective effects of different concentrations of benzylpenicillin on a culture containing a mixture of 90% penicillin-susceptible, 9% penicillin-intermediate, and 1% penicillin-resistant S. pneumoniae strains.(This study was presented in part at the 40th InterscienceConference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, on 17 to 20 September 2000.) MATERIALS AND METHODS Antibiotic.Benzylpenicillin was provided by AstraZeneca, Södertälje, Sweden. The antibiotic was obtained as a reference powder with known potency and dissolved in distilled water prior to each experiment.Bacterial strains. Three clinical strains of S. pneumoniae belonging to serotype 6B obtained from the Department of Microbiology, University Hospital, Reykjavik, Iceland, were used in the study: S. pneumoniae A 2000 (PSP), S. pneumoniae 9506 (PIP), and S. pneumoniae BCC-67 (PRP).Determination of MICs. The MICs for the three strains of S. pneumoniae were determined in fluid media by a macrodilution technique in duplicate on different occasions according to the National Committee for Clinical Laboratory Standards. Twofold serial dilutions of benzylpenicillin were added to broth and inoculated with a final inoculum of 10 5 CFU of the test strain per ml and incubated at 37°C in 5% CO 2 for 20 h. The MIC was defined as the lowest concentration of the antibiotic allowing no visible growth. The MICs of erythromycin were determined with E-test (Biodisk, Solna, Sweden).The MICs of penicillin were 0.031, 0.25, and 8 mg/liter, respectively. The PSP strain was erythromycin resistant (MIC Ͼ 128 mg/liter), whereas the two other strains were susceptible to erythromycin (MIC Ͻ 0.03 mg/liter).Concentrations of benzylpenicill...