Pharmacokinetics of marbofloxacin after a single oral dose to loggerhead sea turtles (Caretta caretta)

The single-dose disposition kinetics of marbofloxacin (MBX) were determined in clinically healthy loggerhead sea turtles (n = 5) after oral (PO) administration of 2 mg kg⁻¹ bodyweight. Marbofloxacin plasma concentrations were determined by DAD–HPLC (LOD/LOQ 0.015/0.05 μg ml⁻¹). Data were subjected to non-compartmental analysis. Following PO administration, marbofloxacin achieved maximum plasma concentrations of 11.66 ± 2.53 mg L⁻¹ at 15.00 ± 3.00 h. The absence of general adverse reactions in the turtles of the study, and the favourable pharmacokinetic properties (long half-life and high maximum plasma concentration) of MBX administered PO at the single-dose of 2 mg kg⁻¹ suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.     

PK-PD integration and modeling of marbofloxacin in sheep

The fluoroquinolone antimicrobial drug, marbofloxacin, was administered intravenously (IV) and intramuscularly (IM) to sheep at a dose rate of 2 mg kg⁻¹ in a 2-period cross-over study. Using a tissue cage model of inflammation, the pharmacokinetic properties of marbofloxacin were established for serum, inflamed tissue cage fluid (exudate) and non-inflamed tissue cage fluid (transudate). For serum, after IV dosing, mean values for pharmacokinetic parameters were: clearance 0.48 L kg⁻¹ h⁻¹; elimination half-life 3.96 h and volumes of distribution 2.77 and 1.96 L kg⁻¹, respectively, for V_darea and V_ss. After IM dosing mean values for pharmacokinetic variables were: absorption half-time 0.112 h, time of maximum concentration 0.57 h, terminal half-life (T½el) 3.65 h and bioavailability 106%. For exudate, mean T½el values were 12.38 and 13.25 h, respectively, after IV and IM dosing and for transudate means were 13.39 h (IV) and 12.55 h (IM).The in vitro minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) and ex vivo time-kill curves for marbofloxacin in serum, exudate and transudate were established against a pathogenic strain of Mannheimia haemolytica. Integration of in vivo pharmacokinetic data with MIC determined in vitro provided mean values of area under curve (AUC)/MIC ratio for serum, exudate and transudate of 120.2, 156.0 and 156.6 h after IV dosing and 135.5, 165.3 and 146.2 h after IM dosing, respectively. After IM administration maximum concentration (C_max)/MIC ratios were 21.1, 6.76 and 5.91, respectively, for serum, exudate and transudate. The ex vivo growth inhibition data after IM administration were fitted to the sigmoid E_max (Hill) equation to provide values for serum of AUC_24 h/MIC producing, bactericidal activity (22.51 h) and virtual eradication of bacteria (35.31 h). It is proposed that these findings might be used with MIC₅₀ or MIC₉₀ data to provide a rational approach to the design of dosage schedules which optimise efficacy in respect of bacteriological as well as clinical cures.     

Antibiotic susceptibility of bacteria isolated from infections in cats and dogs throughout Europe (2002–2009)

A monitoring program of the pre-treatment susceptibility of clinical isolates of bacteria from diseased dogs and cats was active between the years 2002 and 2009. Susceptibility of each isolated strain to a panel of nine antibiotics (amoxicillin/clavulanic acid, ampicillin, penicillin, clindamycin, doxycycline, enrofloxacin, marbofloxacin, trimethoprim and trimethoprim/sulfamethoxazole) was assessed. The Minimum Inhibitory Concentration (MIC) of marbofloxacin was also determined by a standardized microdilution technique following CLSI recommendations. In total, 1857 bacterial strains were collected throughout Europe from cases of otitis, respiratory, urinary and dermatological infections. Although bacterial susceptibility varied for each of the antibiotics within the panel, patterns of susceptibility were similar to those described in the literature for comparable time periods and geographical areas. With a clinical resistance varying from 0 to 14.48% against the isolated strains, marbofloxacin susceptibility was very high and remains an effective antibiotic for the treatment of otitis, urinary, respiratory and dermatological infections in companion animals.     

Comparative pharmacokinetics of marbofloxacin in healthy and Mannheimia haemolytica infected calves

The pharmacokinetics of marbofloxacin were investigated in healthy (n=8) and Mannheimia haemolytica naturally infected (n=8) Simmental ruminant calves following intravenous (i.v.) and intramuscular (i.m.) administration of 2 mg kg(-1) body weight. The concentration of marbofloxacin in plasma was measured using high performance liquid chromatography with ultraviolet detection. Following i.v. administration of the drug, the elimination half-life (t(1/2 beta)) and mean residence time (MRT) were significantly longer in diseased calves (8.2h; 11.13 h) than in healthy ones (4.6 h; 6.1 h), respectively. The value of total body clearance (CL(B)) was larger in healthy calves (3 ml min(-1) kg(-1)) than in diseased ones (1.3 ml min(-1) kg(-1)). After single intramuscular (i.m.) administration of the drug, the elimination half-life, mean residence time (MRT) and maximum plasma concentration (C(max)) were higher in diseased calves (8.0, 12 h, 2.32 microg ml(-1)) than in healthy ones (4.7, 7.4 h, 1.4 microg ml(-1)), respectively. The plasma concentrations and AUC following administration of the drug by both routes were significantly higher in diseased calves than in healthy ones. Protein binding of Marbofloxacin was not significantly different in healthy and diseased calves. The mean value for MIC of marbofloxacin for M. haemolytica was 0.1+/-0.06 microg ml(-1). The C(max)/MIC and AUC(24)/MIC ratios were significantly higher in diseased calves (13.0-64.4 and 125-618 h) than in healthy calves (8-38.33 and 66.34-328 h). The obtained results for surrogate markers of antimicrobial activity (C(max)/MIC, AUC/MIC and T > or = MIC) indicate the excellent pharmacodynamic characteristics of the drug in diseased calves with M. haemolytica, which can be expected to optimize the clinical efficacy and minimize the development of resistance.     

Canine visceral leishmaniasis: comparison of in vitro leishmanicidal activity of marbofloxacin, meglumine antimoniate and sodium stibogluconate

The control of canine leishmaniasis largely depends on the success of treatment. Drugs currently available to treat this disease are toxic and partially effective. The curative effect of marbofloxacin, a third-generation fluoroquinolone developed for veterinarian individual treatment, was evaluated in vitro in the presence of Leishmania infantum promastigotes and dog-monocyte-derived macrophages; meglumine antimoniate and sodium stibogluconate were used as comparative treatments. We observed that the killing of Leishmania promastigotes and intracellular amastigotes by marbofloxacin was dose-dependent. We demonstrated that successful treatment of canine infected macrophages for 48 h was possible with 500 microg/ml of marbofloxacin. Leishmanicidal activity acted through a TNF-alpha and nitric oxide pathway and correlated with the generation of nitric oxide (NO(2)) production by monocytes derived macrophages from infected (23+/-5 microM) or healthy (21+/-6 microM) dogs, in comparison with NO(2) concentration in infected/non-treated macrophages (< 3 microM, P<0.01). This significant induced parasiticidal effect correlated with extensive elimination of amastigotes by macrophages derived from infected (11+/-5) and healthy dogs (6+/-2), when compared to infected/non-treated macrophages (530+/-105 and 472+/-86 amastigotes, respectively, P< 0.01). Marbofloxacin was shown to be non-toxic at 500 microg/ml in vitro and no cell apoptosis was observed. The molecule was able to induce a parasitic process after significant elimination of amastigotes in leishmania-infected dog macrophages. We propose that marbofloxacin, compared to standard chemotherapeutic agents (meglumine antimoniate and sodium stibogluconate), could be an effective and pragmatic oral route alternative to treat canine leishmaniasis.     

Disposition of marbofloxacin in vulture (Gyps fulvus) after intravenous administration of a single dose

The pharmacokinetics properties of marbofloxacin were studied in adult Eurassian Griffon vulture after single-dose intravenous (IV) administration of 2 mg/kg. Drug concentration in plasma was determined by high-performance liquid chromatography and the data obtained were subjected to compartmental and non-compartmental kinetic analysis. Marbofloxacin presented a volume of distribution at steady-state (Vdss) of 1.51 ± 0.22 L and total plasma clearance (Cl) of 0.109 ± 0.023 L/h kg. The permanence of this drug was long in vultures (T_1/2λ = 12.51 ± 2.52 h; MRT_∞ = 13.54 ± 2.29 h). The optimal dose of marbofloxacin estimated is 2.73 mg/kg per day for the treatment of infections in vultures with MIC₉₀ = 0.2 μg/mL.     

马波沙星的致突变性和致畸性研究

选用Wistar大鼠和昆明系小鼠对马波沙星的遗传毒性进行研究。试验结果显示，马波沙星在抑菌剂量之下对鼠伤寒沙门氏菌不产生致突变作用；马波沙星不引起小鼠骨髓有微核多染红细胞率增加；马波沙星不引起雄性小鼠生殖细胞染色体畸变而造成的早期胚胎死亡；20mg／kg b．w．和100mg／kg b．w．剂量马波沙星对母鼠的生殖机能和胎鼠的生长发育无明显影响，对胎鼠不产生致畸作用，500mg／kg b．w．剂量马波沙星对胎鼠体长和骨骼发育有一定影响，但不存在剂量反应关系。上述结果表明，马波沙星无明显的致突变性和致畸性。     

曙红Y与马波沙星相互作用的分光光度法研究及应用

采用分光光度法研究了曙红Y与马波沙星的相互作用,并应用于样品测定。在10 mL容量瓶中依次加入1.00 mL曙红Y溶液、适量马波沙星标准溶液或待测液、1.0 mL 0.01%聚乙烯吡咯烷酮溶液,加0.1mol/L盐酸0.6 mL,用水稀释至刻度,摇匀,以水为参比立即进行光谱扫描或固定波长为536 nm进行吸光度测定。在约0.01mol/L盐酸中,曙红Y与马波沙星主要通过静电引力形成复合物。复合物最大吸收峰位于536 nm,比曙红Y本身红移20 nm。方法的线性范围为10.2～50.8 mg·L~(-1),检出限为3 mg·L~(-1)。回归方程为:A=0.0057c(mg·L~(-1))+0.4349,相关系数为0.9947。     

禽多杀性巴氏杆菌感染对麻保沙星在鸡体内药动学特征的影响研究

按每kg体重30万个CFU在鸡胸部肌肉注射接种禽多杀性巴氏杆菌（C48-1），人工诱发鸡急性多杀性巴氏杆菌病。选用90只51-61日龄健康未经多杀性巴氏杆菌苗免疫的岭南黄鸡，18只用作病理模型研究，其余72只随机分为6组，进行静注、肌注及内服麻保沙星（2.5mg/kg）在健康和禽多杀性巴氏杆菌感染鸡的药物动力学研究。用反相高效液相色谱法测定血浆中麻保沙星的浓度。用MCPKP药物动力学程序处理血浆药物浓度-时间数据。麻保沙星在鸡体内的药动学特征是吸收迅速且安全、分布广泛、消除缓慢。急性禽多杀性巴氏杆菌感染除显著延长了肌注及内服麻保沙星的消除并衰期、血药有效浓度维持时间和降低肌注给药的峰浓度外，对其他药动学参数无显著性差异的影响。     

麻保沙星对鸡实验性葡萄球菌病的药效学研究

本研究首先测定了麻保沙星对金黄色葡萄球菌的体外抑菌作用，然后对人工感染金黄色葡萄球菌的病鸡进行临床疗效试验。人工发病6小时后，分别以2.5、5、10mg/kg体重的剂量内服和肌注麻保沙星（每组30只鸡），一天1次，连续给药3天。结果表明，麻保沙星对金黄色葡萄球菌的最小抑菌浓度为0.2μg/ml；对鸡实验性葡萄球菌病，麻保沙星（5、10mg/kg)有显著疗效，治愈率为80％－90％。