Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves

Brentnall, C; Cheng, Zhangrui; McKellar, Quintin; Lees, P.

doi:10.1136/vr.100935

Cited by 18 publications

(36 citation statements)

References 25 publications

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“…Whilst serum is not identical to extravascular infection site fluids, it is likely to be closer in chemical composition to the biophase than broths, and indeed in immunological constituents also [22, 23]. A comparison of broth MICs with potency determined in biological fluids is therefore relevant to PK/PD breakpoint estimation.…”

Section: Introductionmentioning

confidence: 99%

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling

2017

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BackgroundBacterial pneumonia in pigs occurs widely and requires antimicrobial therapy. It is commonly caused by the pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida. Marbofloxacin is an antimicrobial drug of the fluoroquinolone class, licensed for use against these organisms in the pig. In recent years there have been major developments in dosage schedule design, based on integration and modelling of pharmacokinetic (PK) and pharmacodynamic (PD) data, with the objective of optimising efficacy and minimising the emergence of resistance. From in vitro time-kill curves in pig serum, PK/PD breakpoint Area under the curve (AUC) 24h /minimum inhibitory concentration (MIC) values were determined and used in conjunction with published PK, serum protein binding data and MIC distributions to predict dosages based on Monte Carlo simulation (MCS).ResultsFor three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count, mean AUC24h/MIC values were 20.9, 45.2 and 71.7 h, respectively, for P. multocida and 32.4, 48.7 and 55.5 h for A. pleuropneumoniae. Based on these breakpoint values, doses for each pathogen were predicted for several clinical scenarios: (1) bacteriostatic and bactericidal levels of kill; (2) 50 and 90% target attainment rates (TAR); and (3) single dosing and daily dosing at steady state. MCS for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 0.44 and 0.95 mg/kg (P. multocida) and 0.28 and 0.66 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 0.28 and 0.59 mg/kg (P. multocida) and 0.22 and 0.39 mg/kg (A. pleuropneumoniae) were required for pigs aged 12 weeks. Doses were also predicted for pigs aged 16 and 27 weeks.ConclusionsPK/PD modelling with MCS approaches to dose determination demonstrates the possibility of tailoring clinical dose rates to a range of bacterial kill end-points.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-017-1128-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling

2017

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“…Moreover, MICs differed and had to be determined on a matrix-by-matrix, species-by-species, compound-by-compound basis. Likewise, Brentnall et al [10, 14] reported for oxytetracycline, after correction for serum protein binding, for a calf isolate of Mannheimia haemolytica , a MIC in serum 6 times greater than the broth MIC. In marked contrast, Toutain et al [6] reported, after correction for serum protein binding, MICs some 80-fold smaller in calf serum compared to broth for tulathromycin for M. haemolytica and P. multocida isolates from calves.…”

Section: Discussionmentioning

confidence: 99%

“…Whilst serum is not identical to extravascular infection site fluids, it is likely to be closer to the biophase than broths in chemical composition and indeed in respect of immunological components also [9, 10]. A comparison of broth MICs with potency determined in biological fluids is therefore relevant to PK/PD breakpoint estimation, when the aim is optimal dose prediction for clinical use.…”

Section: Introductionmentioning

confidence: 99%

“…A comparison of broth MICs with potency determined in biological fluids is therefore relevant to PK/PD breakpoint estimation, when the aim is optimal dose prediction for clinical use. For some drugs and pathogens, calculation of a scaling factor to bridge between broth and serum MICs may be warranted [4, 6, 10]. …”

Section: Introductionmentioning

confidence: 99%

“…Based on methods previously described [11, 12] five overlapping sets of doubling dilutions were used in this study to decrease inaccuracy from up to 100% to no more than 20% for a small number of individual isolates. Hence, the quantitative determination potency with improved accuracy and in biological fluids may be appropriate for some drug classes and some microorganisms, when calculating PK/PD indices [6, 10, 12–16]. …”

Section: Introductionmentioning

confidence: 99%

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Impact of growth matrix on pharmacodynamics of antimicrobial drugs for pig pneumonia pathogens

Dorey

Lees

2017

BMC Vet Res

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BackgroundThe most widely used measure of potency of antimicrobial drugs is Minimum Inhibitory Concentration (MIC). MIC is usually determined under standardised conditions in broths formulated to optimise bacterial growth on a species-by-species basis. This ensures comparability of data between laboratories. However, differences in values of MIC may arise between broths of differing chemical composition and for some drug classes major differences occur between broths and biological fluids such as serum and inflammatory exudate. Such differences must be taken into account, when breakpoint PK/PD indices are derived and used to predict dosages for clinical use. There is therefore interest in comparing MIC values in several broths and, in particular, in comparing broth values with those generated in serum. For the pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, MICs were determined for three drugs, florfenicol, oxytetracycline and marbofloxacin, in five broths [Mueller Hinton Broth (MHB), cation-adjusted Mueller Hinton Broth (CAMHB), Columbia Broth supplemented with NAD (CB), Brain Heart Infusion Broth (BHI) and Tryptic Soy Broth (TSB)] and in pig serum.ResultsFor each drug, similar MIC values were obtained in all broths, with one exception, marbofloxacin having similar MICs for three broths and 4–5-fold higher MICs for two broths. In contrast, for both organisms, quantitative differences between broth and pig serum MICs were obtained after correction of MICs for drug binding to serum protein (fu serum MIC). Potency was greater (fu serum MIC lower) in serum than in broths for marbofloxacin and florfenicol for both organisms. For oxytetracycline fu serum:broth MIC ratios were 6.30:1 (P. multocida) and 0.35:1 (A. pleuropneumoniae), so that potency of this drug was reduced for the former species and increased for the latter species. The chemical composition of pig serum and broths was compared; major matrix differences in 14 constituents did not account for MIC differences. Bacterial growth rates were compared in broths and pig serum in the absence of drugs; it was concluded that broth/serum MIC differences might be due to differing growth rates in some but not all instances.ConclusionsFor all organisms and all drugs investigated in this study, it is suggested that broth MICs should be adjusted by an appropriate scaling factor when used to determine pharmacokinetic/pharmacodynamic breakpoints for dosage prediction.

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The Pharmacodynamics of Antimicrobial Agents

Martinez¹,

Toutain²,

Turnidge³

2013

Antimicrobial Therapy in Veterinary Medicine

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Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves

Cited by 18 publications

References 25 publications

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling

Impact of growth matrix on pharmacodynamics of antimicrobial drugs for pig pneumonia pathogens

The Pharmacodynamics of Antimicrobial Agents

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