Influence of Inoculum Size on the Selection of Resistant Mutants of
            <i>Escherichia coli</i>
            in Relation to Mutant Prevention Concentrations of Marbofloxacin

Ferran, Aude; Dupouy, Véronique; Toutain, Pierre‐Louis; Bousquet‐mélou, Alain

doi:10.1128/aac.00156-07

Cited by 34 publications

(40 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The time the fluoroquinolone concentrations were within the MSW has previously been shown to be associated with a promotion of resistant bacterial-subpopulation enrichment in vitro (1,9,10,15) and in vivo (16). However, we did not observe in our experiment such a relationship between T MSW and R-8ϫMIC subpopulation enrichment (Fig.…”

Section: Discussioncontrasting

confidence: 55%

“…Previous in vitro studies of E. coli, Staphylococcus aureus, and Pseudomonas aeruginosa (15,26) and an in vivo study of E. coli in immunocompromised mice (16) showed an impact of inoculum size on the enrichment of resistant mutants. The present study confirms these results and clearly shows this impact in immunocompetent animals.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been suggested that selective amplification of spontaneous drug-resistant mutants is more pronounced within the range of antimicrobial plasma concentrations between the MIC of the wild bacterial population and the MPC, defined as the mutant selection window (MSW) (6,23,36,37). The concept of the MSW has been characterized in vitro (15,18) and in vivo (16), and the MSW has been shown to be an association between the time a pathogen population is subjected to antimicrobial exposure within the MSW (T MSW ) and the mutant enrichment. On the other hand, this concept has been challenged and debated in the literature (31,35).…”

mentioning

confidence: 99%

“…We previously observed in vitro and in vivo, in neutropenic mice, that both the time that the antimicrobial concentrations are within the MSW and the bacterial inoculum size at the start of the antimicrobial treatment play an important role in the enrichment of the resistant mutant subpopulation (15,16). The aim of the present study was to use a rat model of Klebsiella pneumoniae lung infection to investigate (i) whether different bacterial inoculum sizes at the infection site at the beginning of antimicrobial treatment could influence the selection of resistant mutants in immunocompetent animals and (ii) what PK/PD indices are best associated with the prevention of resistant-mutant enrichment after different dosage regimens of marbofloxacin, a fluoroquinolone of veterinary interest.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of Klebsiella pneumoniae in a Rat Lung Infection Model

Kesteman

Ferran

Perrin-Guyomard

et al. 2009

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

We tested the hypothesis that the bacterial load at the infection site could impact considerably on the pharmacokinetic/pharmacodynamic (PK/PD) parameters of fluoroquinolones. Using a rat lung infection model, we measured the influence of different marbofloxacin dosage regimens on selection of resistant bacteria after infection with a low (10 5 CFU) or a high (10 9 CFU) inoculum of Klebsiella pneumoniae. For daily fractionated doses of marbofloxacin, prevention of resistance occurred for an area-under-the-concentrationtime-curve (AUC)/MIC ratio of 189 h for the low inoculum, whereas for the high inoculum, resistantsubpopulation enrichment occurred for AUC/MIC ratios up to 756 h. For the high-inoculum-infected rats, the AUC/MIC ratio, C max /MIC ratio, and time within the mutant selection window (T MSW ) were not found to be effective predictors of resistance prevention upon comparison of fractionated and single administrations. An index corresponding to the ratio of the time that the drug concentrations were above the mutant prevention concentration (MPC) over the time that the drug concentrations were within the MSW (T >MPC /T MSW ) was the best predictor of the emergence of resistance: a T >MPC /T MSW ratio of 0.54 was associated with prevention of resistance for both fractionated and single administrations. These results suggest that the enrichment of resistant bacteria depends heavily on the inoculum size at the start of an antimicrobial treatment and that classical PK/PD parameters cannot adequately describe the impact of different dosage regimens on enrichment of resistant bacteria. We propose an original index, the T >MPC /T MSW ratio, which reflects the ratio of the time that the less susceptible bacterial subpopulation is killed over the time that it is selected, as a potentially powerful indicator of prevention of enrichment of resistant bacteria. This ratio is valid only if plasma concentrations achieve the MPC.

show abstract

Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of Klebsiella pneumoniae in a Rat Lung Infection Model

Kesteman

Ferran

Perrin-Guyomard

et al. 2009

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…We previously observed in vitro that the emergence of resistance was more frequent when both the T MSW and the bacterial inoculum size increased (15), and the aim of this study was to test, in vivo, the ability of T MSW and also of the area under the concentration-time curve of 0 to 24 h divided by the MIC (AUC 0-24 /MIC) and C max /MIC indices to predict the selection of resistant bacteria in a low and a high inoculum. We assessed the selection of a preexisting resistant subpopulation of Escherichia coli in mouse thighs infected with the two bacterial inoculum sizes after different exposures to marbofloxacin, a fluoroquinolone extensively used in veterinary medicine.…”

mentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Analysis of the Influence of Inoculum Size on the Selection of Resistance in Escherichia coli by a Quinolone in a Mouse Thigh Bacterial Infection Model

Ferran

Kesteman

Toutain

et al. 2009

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Maintaining quinolone concentrations outside the mutant selection window (MSW) between the MIC and mutant prevention concentration (MPC) was suggested by in vitro and in vivo studies to prevent the selection of resistant mutants. However, selection also may depend on the presence of resistant bacterial mutants at the start of treatment, which is highly dependent on the initial inoculum size. In this study, a mouse thigh bacterial infection model was used to test the influence of different exposures to marbofloxacin on the selection of resistant bacteria after infection with a low (10 5 CFU) or high (10 8 CFU) initial inoculum of Escherichia coli. The inoculum size was shown to influence the exposure to marbofloxacin and the values of pharmacokinetic/ pharmacodynamic indices. When the abilities of the indices time within the MSW (T MSW ), area under the concentration-time curve of 0 to 24 h divided by the MIC, and the maximum concentration of drug in plasma divided by the MIC to predict the selection of resistant bacteria were compared, only T MSW appeared to be a good predictor of the prevention of resistance for values less than 30%. When the T MSW was higher than 34%, the selection of resistant bacteria occurred less often in thighs initially infected with the low inoculum (11/24; 46%) than in those infected with the high inoculum (30/36; 80%), suggesting that the selection of resistant mutants depends on both the T MSW and inoculum size. The relevance of these results merits further investigation to test different strategies of antibiotic therapy depending on the expected bacterial burden at the infectious site.Resistances to fluoroquinolones can occur spontaneously in bacterial populations at a frequency of about 10 Ϫ6 to 10 Ϫ8 (5) by following a stepwise process that involves mutations in genes coding for the targets DNA gyrase and topoisomerase IV (23, 29). Consequently, if the bacterial load at the infectious site exceeds the inverse of the mutation frequency, it can be presumed that a small resistant subpopulation already coexists with a larger susceptible population before any antimicrobial treatment is administered. Traditionally, in vitro antimicrobial studies and animal infection models have been used to assess the reduction in the total bacterial population at an infectious site while often ignoring the impact of drug pressure on the amplification of the drug-resistant subpopulation (2,8). Thus, the values of pharmacokinetic/pharmacodynamic (PK/PD) indices determined from these experiments were selected previously to predict the bacteria killing and not the selection of resistant bacteria.

show abstract

The Pharmacodynamics of Antimicrobial Agents

Martinez¹,

Toutain²,

Turnidge³

2013

Antimicrobial Therapy in Veterinary Medicine

View full text Add to dashboard Cite

Influence of Inoculum Size on the Selection of Resistant Mutants of Escherichia coli in Relation to Mutant Prevention Concentrations of Marbofloxacin

Cited by 34 publications

References 12 publications

Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of Klebsiella pneumoniae in a Rat Lung Infection Model

Influence of Inoculum Size and Marbofloxacin Plasma Exposure on the Amplification of Resistant Subpopulations of Klebsiella pneumoniae in a Rat Lung Infection Model

Pharmacokinetic/Pharmacodynamic Analysis of the Influence of Inoculum Size on the Selection of Resistance in Escherichia coli by a Quinolone in a Mouse Thigh Bacterial Infection Model

The Pharmacodynamics of Antimicrobial Agents

Contact Info

Product

Resources

About