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In Vitro Pharmacokinetics/Pharmacodynamics Evaluation of Marbofloxacin Against Staphylococcus Pseudintermedius

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In Vitro Pharmacokinetics/Pharmacodynamics Evaluation of Marbofloxacin Against Staphylococcus Pseudintermedius Original Paper Veterinarni Medicina, 65, 2020 (03): 116–122 https://doi.org/10.17221/82/2019-VETMED In vitro pharmacokinetics/pharmacodynamics evaluation of marbofloxacin against Staphylococcus pseudintermedius Yixian Quah, Naila Boby, Seung-Chun Park* Laboratory of Veterinary Clinical Pharmacology, Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea *Corresponding author: [email protected] Citation: Quah Y, Boby N, Park SC (2020): In vitro pharmacokinetics/pharmacodynamics evaluation of marbofloxacin against Staphylococcus pseudintermedius. Vet Med-Czech 65, 116–122. Abstract: This study aimed at determining the in vitro antibacterial activity of a clinically achievable marbofloxa- cin (MAR) concentration against the clinical isolate S. pseudintermedius in an in vitro dynamic model simulat- ing the in vivo pharmacokinetics of dogs. The in vitro PK/PD (pharmacokinetic/pharmacodynamic) model that mimics the single daily doses of MAR (half-life, 8 h) was simulated. An inoculum (108 cfu/ml) of clinical isolate S. pseudintermedius (MIC = 0.0625 μg/ml) was exposed to monoexponentially decreasing concentrations of MAR with simulated AUC24 h/MIC varied from 34.81 h to 696.15 h. Every two hours, the multiple sample colony forming units were determined. The result of this study demonstrated that the clinically achieved MAR concentrations at AUC24 h/MIC ratios of 348.08 and 696.15 h produced a pronounced reduction in the bacterial counts and pre- vented the re-growth of the clinical isolate S. pseudintermedius. However, further study, considering the strains with different susceptibility levels, is recommended. Keywords: dogs; clinical isolates; simulation; antimicrobial resistance S. pseudintermedius is a coagulase positive Staph- et al. 2010). Clinically, fluoroquinolones such as ylococcus species which is most commonly associ- MAR should only be used as second-line antibi- ated with canine pyoderma and causes an oppor- otics for canine pyoderma to limit the emergence tunistic infection in dogs (Morris et al. 2017) and of resistance, which is probably due to the common occasionally in humans (Van Hoovels et al. 2006). use of these drugs (Beco et al. 2013). The in vitro and in vivo activities of marbofloxa- Since antimicrobial resistance is mainly associ- cin (MAR), a fluoroquinolone, against S. pseudin- ated with suboptimal dose at the site of infection termedius have been proven in previous studies (Martinez et al. 2012), an appropriate dose that can (Awji et al. 2012). However, the emerging resis- minimise the selection of a resistant mutant and tances of S. pseudintermedius for multiple classes maximise the efficacy needs to be achieved. Thus, of antimicrobial agents including fluoroquinolones employment of pharmacokinetic/pharmacodynamic (Awji et al. 2012) could impede the successful treat- (PK/PD) models have been suggested to select an ap- ment outcome in canine pyoderma, especially those propriate dose regimen and to describe the pharma- caused by prolonged antibiotic treatment (Yoon codynamics information of antimicrobials (Gloede Supported by Kyungpook National University Development Project Research Fund, 2018. 116 Veterinarni Medicina, 65, 2020 (03): 116–122 Original Paper https://doi.org/10.17221/82/2019-VETMED et al. 2010). The AUC/MIC, Cmax/MIC and T > MIC In vitro dynamic model simulating in vivo are important PK/PD indices used to predict the ef- pharmacokinetics ficacy of antimicrobials (Tam and Nikolaou 2011). A previous in vitro static study integrated with A previously described dynamic model (Zinner published pharmacokinetics parameters sug- et al. 2003) was used in this study. A series of mo- gested that higher doses of MAR within the clini- noexponential profiles that mimic the single daily cally recommended ranges minimise the selection doses of MAR (half-life, 8 h) administered for three of resistant mutants (Awji et al. 2012). However, consecutive days were simulated. The simulated the impacts of the periodic exposure of S. pseudin- half-life was obtained from the pharmacokinetic termedius to MAR at clinically achievable concen- analysis of our study (data not shown) which is trations have not been evaluated. In this study, we closer to the value reported previously by Heinen investigated the activity of MAR against S. pseudin- (2002). The model consisted of two connected termedius in an in vitro PK/PD model, using previ- flasks, one containing the fresh Mueller Hinton ously suggested doses that minimise the selection Broth (MHB) and the other, the central unit with of resistant mutants. a magnetic stirrer, MHB plus either the bacterial culture alone (control) or with the antimicrobial (killing/re-growth experiment). Peristaltic pumps MATERIAL AND METHODS circulated the fresh MHB to the flasks and from the central unit at 8.6 ml/h. An overnight culture Antimicrobial agent and bacterial strains of S. pseudintermedius was inoculated to the cen- tral unit. After a 2-h incubation, the resulting In order to obtain the desirable MSW (mu- exponentially growing bacterial cultures reached tant selection window) for this study, six clinical 108 colony-forming units per millilitre (cfu/ml) isolates of S. pseudintermedius with the mini- as reported previously (Gebru et al. 2012). Then mum inhibitory concentration (MIC) of MAR the MAR was injected into the central unit. Five at 0.0625 μg/ml were selected as the representa- ratios of an area under the concentration time curve tive strains from the 52 clinical isolates collected (AUC) over a 24 h dosing interval (AUC24 h/MIC) from the dogs which visited the veterinary teaching including the clinically achievable values at the con- hospital of Kyungpook National University reported ventional dosing regimen of MAR were simulated in a previous study (Awji et al. 2012). Staphylococcus and the mean ratios of the simulated AUC24 h/MIC aureus ATCC 29213 was used as the quality con- varied from 34.8 h to 696.2 h (Figure 1). These val- trol strain in this study for Staphylococcus spp. ac- ues corresponded to the peak concentrations (Cmax) cording to the Clinical and Laboratory Standards that equalled the MIC, which fell between the MIC Institute (CLSI 2008). A pure standard of MAR and MPC (within MSW) or exceeded the MPC. (Sigma Aldrich, St. Louis, MO, USA) was used All the experiments were performed in duplicate. to prepare the stock and working solutions. The actual bacterial exposure to MAR was further confirmed by the HPLC (high-performance liquid chromatography) analysis described previously Determination of MIC and MPC (Frazier et al. 2000). The MICs of MAR against S. pseudintermedius and S. aureus (ATCC 29213) were determined Quantification of the time-kill curves and using the broth microdilution method accord- antimicrobial effect ing to the guideline for CLSI (2008). The mutant prevention concentration (MPC) was determined The multiple sampling of the bacteria contain- as described elsewhere (Firsov et al. 2003). To esti- ing media from the central compartment was mate the MPC, the logarithms of the bacterial num- performed throughout the observation period. bers were plotted against the MAR concentrations. The colony-forming unit (cfu) was determined The MPC was taken as the lower concentration that for each sample at each sampling time point and completely inhibited growth. All the experiments the duration of the experiments was defined in each were performed in triplicate. case as the time until the antibiotic-exposed bacte- 117 Original Paper Veterinarni Medicina, 65, 2020 (03): 116–122 https://doi.org/10.17221/82/2019-VETMED ↓ ↓ ↓ 10.00 34.81 (50.91%) 1.00 69.61 (84.11%) Figure 1. The in vitro sim- MPC 139.23 (82.50%) ulated pharmacokinetic profile of MAR (data 348.08 (38.36%) for 0–72 h). The legends 0.10 indicate the AUC24 h/MIC MIC 696.15 (4.79%) values and percentage of the dosing interval MAR concentration (μg/ml) during which the MAR concentration fell within 0.01 0 24 48 72 the MSW. The arrows indicate the MAR dosing Time (h) ria reached the number of bacteria observed in the x − logAUC24 h/MIC ratio; 9 absence of the antibacterial (≥ 10 cfu/ml). The low- x0 − logAUC24 h/MIC ratio that corresponds 2 er limit of accurate detection was 2 × 10 cfu/ml. to Ymax/2; To reveal changes in the susceptibility, the MAR dx − parameter width. MICs of the bacterial cultures sampled from the model were determined at 24, 48, and 72 h after the treatment begins. Quantification of the resistance and its The final MIC (MICfinal) was then related to the relationship to AUC24 h/MIC ratio initial MIC (MICinitial). The cumulative effect of each simulated treatment of MAR on the sus- The changes in susceptibility of S. pseudinterme- ceptible S. pseudintermedius subpopulations was dius for MAR was evaluated at 24, 48 and 72 h time expressed by its intensity (IE) as described by the points after beginning the treatment and a Gaussian area between the control growth and the bacte- type function was used to relate the increased MIC rial killing re-growth curves from the zero point, to the simulated AUC24 h/MIC or AUC24 h/MPC: the moment of the drug input into the model, up 2/b to the time when viable counts on the re-growth Y = Y0 + a exp[−(x − xc) ] (2) curve are close to the maximum values observed without the drug (Firsov et al. 2002). where: Y − MICfinal/MICinitial ratio; x − logAUC24 h/MIC or AUC24 h/MPC; Relationship of the antimicrobial effect xc − logAUC24 h/MIC or AUC24 h/MPC that to the AUC24 h/MIC ratio corresponds to the maximal value of MICfinal/MICinitial; The IE versus logAUC24 h/MIC data were fitted a, b − parameters. by the Boltzmann function: Y = (Ymin – Ymax)/{1 + exp[(x – x0)/dx)]} + Ymax (1) Statistical analysis where: Statistical analyses were performed using Y − IE; GraphPad InStat (GraphPad Software Inc., San Ymax, Ymin − maximum and minimum values of IE; Diego, CA, USA).
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