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Modulation of efficacies and pharmacokinetics of antibiotics by granulocyte colony-stimulating factor in neutropenic mice with multidrug-resistant Enterococcus faecalis infection

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JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 2000年第3期46卷 429-436页

作者： Onyeji, CO Nicolau, DP Nightingale, CH Bow, L Hartford Hosp Dept Pharm Res Hartford CT 06102 USA Hartford Hosp Div Infect Dis Hartford CT 06102 USA Hartford Hosp Off Res Adm Hartford CT 06102 USA Obafemi Awolowo Univ Fac Pharm Ife Nigeria

It has been demonstrated previously that, in non-neutropenic animals, interferon-gamma markedly enhances the efficacies of gentamicin and vancomycin against Enterococcus faecalis resistant to these antibiotics. The aim of our study was to determining whether granulocyte colony-stimulating factor (G-CSF) can be beneficial as an adjunct to gentamicin and vancomycin in the treatment of the same infection in neutropenic mice. After induction of neutropenia by cyclophosphamide, mice were inoculated ip with the organism. The infected animals received sc administrations of G-CSF, antibiotic or a combination of both agents at determined dosing regimens. Infected animals treated with G-CSF alone showed a dose-dependent increase in survival. The inoculum size used in establishing infection affected the effectiveness of the cytokine. Survival was significantly (P < 0.01) better in the infected animals given gentamicin and vancomycin plus G-CSF than in those given antibiotics or G-CSF alone. The possibility of pharmacokinetic interaction between G-CSF and each of the antibiotics was examined. The cytokine significantly increased the plasma clearance of gentamicin, with a resultant decrease in the area under the concentration-time curve (AUC), while the disposition of vancomycin was not affected. This study suggests that G-CSF may be a useful adjunct to gentamicin and vancomycin for the treatment of multidrug-resistant E. faecalis infection in neutropenic patients.

关键词：抗菌药/药代动力学抗菌药/药理学抗菌药/治疗应用抗药性多药药物疗法联合粪肠球菌/药物作用庆大霉素类/药代动力学庆大霉素类/药理学庆大霉素类/治疗应用革兰氏阳性菌感染/药物疗法革兰氏阳性菌感染/微生物学粒细胞集落刺激因子/治疗应用中性粒细胞减少/化学诱导中性粒细胞减少/药物疗法万古霉素/药代动力学万古霉素/药理学万古霉素/治疗应用万古霉素抗药性动物女(雌)性人类小鼠

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In vitro release of vancomycin and tobramycin from impregnated human and bovine bone grafts

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JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 2000年第3期46卷 423-428页

作者： Winkler, H Janata, O Berger, C Wein, W Georgopoulos, A Danube Hosp Dept Orthopaed A-1220 Vienna Austria Danube Hosp Cent Bone Bank Vienna A-1220 Vienna Austria Danube Hosp Dept Infect Control A-1220 Vienna Austria Univ Vienna Dept Clin Pharmacol A-1090 Vienna Austria Univ Vienna Clin Dept Infect & Chemotherapy A-1090 Vienna Austria

In order to combine the effects of bone repair and eradication of infection, with both Gram-positive and Gram-negative pathogens, the behaviour of a compound of bone graft and antibiotics was investigated. Samples of human and bovine bone, cancellous and cortical, were processed and incubated with vancomycin and tobramycin, respectively. The compound was placed in 5% human albumin and the surrounding liquid was exchanged completely every 24 h. Concentrations of antibiotics in the fluid were measured over less than or equal to 28 days using high pressure liquid chromatography and a bioassay. All tested combinations eluted mainly in the initial phase with a logarithmic decrease over the testing period. The concentration of antibiotics in the albumin was well above the MIC for common pathogens throughout the investigation in all tested specimens. The highest initial concentrations were measured in the compound of bovine bone together with vancomycin (24395.8 +/- 1138.9 mg/L), decreasing to 9.02 +/- 1.3 mg/L after 11 exchanges. Human and bovine bone did not have significantly different properties. The storage capability of cortical bone was generally lower than that of cancellous bone. Tobramycin concentrations were significantly lower in the initial phase;however, it eluted move steadily and over a longer period, so that from day 6 onwards, its concentration was greater than that of vancomycin. After 28 days, the tobramycin concentration was 18.09 +/- 2.46 mg/L (bovine cancellous bone). In conclusion, bone, if processed adequately, is an excellent carrier for vancomycin and tobramycin. Cortical bone is as suitable as cancellous bone. The pharmacokinetics of human and bovine bone are comparable. Using an antibiotic-graft compound, eradication of pathogens and grafting of bony defects may be accomplished in a one-stage procedure.

关键词：抗菌药/投药和剂量抗菌药/药代动力学骨移植骨和骨组织/药物作用骨和骨组织/代谢冷冻干燥法妥布拉霉素/投药和剂量妥布拉霉素/药代动力学万古霉素/投药和剂量万古霉素/药代动力学动物牛人类

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Relationships between aminoglycoside and vancomycin pharmacokinetics in patients with hematopoietic stem-cell transplants

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AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY 1999年第2期56卷 161-164页

作者： Leader, WG Andria, M Kessel, KK W Virginia Univ Sch Pharm Dept Clin Pharm Morgantown WV 26506 USA W Virginia Univ Hosp Morgantown WV USA Univ Utah Coll Pharm Salt Lake City UT 84112 USA

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The effect of topical povidone-iodine, intraocular vancomycin, or both on aqueous humor cultures at the time of cataract surgery

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AMERICAN JOURNAL OF OPHTHALMOLOGY 2001年第3期131卷 293-300页

作者： Soto, AM Mendívil, MP Hosp Ramon & Cajal Dept Ophthalmol E-28034 Madrid Spain

PURPOSE: To investigate whether the use of topical povidone-iodine before surgery, the addition of vancomycin to the irrigating solutions during phacoemulsification, or both reduces the frequency of positive intraocular cultures at the end of surgery, METHODS: A two-part, clinical study was performed, In the preliminary study, intracameral antibiotic concentrations were measured immediately after surgery (in 11 eyes) and 2 hours after surgery (in 11 eyes) in patients treated with vancomycin, In the primary study, 400 patients were divided into four groups composed of 100 eyes each. The first and the second groups received vancomycin (20 mug/ml) in the irrigating fluid, The third and the fourth groups received irrigating fluid only without antibiotics. The first and third groups received a topical 5% povidone-iodine solution 10 and 5 minutes before surgery;a topical placebo solution was used in the second and the fourth groups. All patients in the primary study underwent anterior chamber aspiration after surgery, and culturing was performed 2 hours later. Identification and quantification of positive cultures in thioglycolate broth and chocolate agar were performed. RESULTS: In the preliminary study, the half-life of intraocular vancomycin was less than 2 hours, In the primary study, intraocular aspirates yielded positive cultures in two (2%), five (5%), 11 (11%), and 13 (13%) specimens from the first, second, third, and fourth groups, respectively. CONCLUSIONS: We found a lower rate of positive cultures in the group that received vancomycin in the irrigating fluid;2 hours of contact between the antibiotic solution and bacteria produced results that reached statistical significance (P = 0.032), (Am J Ophthalmol 2001;131:293-300, (C) 2001 by Elsevier Science Inc, All rights reserved.).

关键词：抗生素预防眼房水/微生物学细菌/分离和提纯生物利用度双盲法药物疗法联合眼内炎/微生物学眼内炎/预防和控制眼感染细菌性/微生物学眼感染细菌性/预防和控制半衰期超声乳化白内障吸除术聚维酮碘/投药和剂量聚维酮碘/药代动力学聚维酮碘/治疗应用万古霉素/投药和剂量万古霉素/药代动力学万古霉素/治疗应用女(雌)性人类男(雄)性中年人

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Adsorption and release of antibiotics from morselized cancellous bone - In vitro studies of 8 antibiotics

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ACTA ORTHOPAEDICA SCANDINAVICA 1999年第3期70卷 298-304页

作者： Witso, E Persen, L Loseth, K Bergh, K Univ Trondheim Hosp Dept Orthopaed Surg NO-7006 Trondheim Norway Univ Trondheim Hosp Dept Microbiol NO-7006 Trondheim Norway

We studied the basic release patterns of antibiotics from cancellous bone in vitro. Antibiotic-impregnated bone was compressed into a wire-mesh cylinder and the release of antibiotic was assessed by two different in vitro methods: agar diffusion and broth elution. The zones of inhibition were measured on seeded agar and the amounts of antibiotics released in elution tubes were assessed by a bioassay. The study continued for 21 days with daily transfer of the cylinders. The results indicated that benzylpenicillin, dicloxacillin, cephalotin, netilmicin, clindamycin, vancomycin, ciprofloxacin and rifampicin were adsorbed to cancellous bone in vitro. Compared to broth elution, agar diffusion showed a prolonged period of release, owing to the small amounts of antibiotic leaking out of the cylinder into the agar. The betalactams had antibacterial activity in broth for a shorter time than the other antibiotics. The release patterns of the betalactams were similar, in spite of their differences in thermal stability. Only rifampicin showed a concentration higher than MIC for longer than 21 days.

关键词：吸附抗菌药/药代动力学生物学鉴定法骨移植/方法头孢菌素类/药代动力学环丙沙星/药代动力学克林霉素/药代动力学集落计数微生物药物载体药物评价临床前药物稳定性奈替米星/药代动力学青霉素G/药代动力学利福平/药代动力学温度时间因素移植同种万古霉素/药代动力学人类

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High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures

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JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 2000年第3期45卷 329-335页

作者： Pea, F Porreca, L Baraldo, M Furlanut, M Univ Udine Inst Clin Pharmacol & Toxicol DPMSC I-33100 Udine Italy SM Misericordia Udine Hosp Div Cardiothorac Surg Udine Italy

The aim of this study was to evaluate retrospectively the importance of a Bayesian pharmacokinetic approach for predicting vancomycin concentrations to individualize its dosing regimen in 18 critically ill patients admitted to intensive care units following cardiothoracic surgery. The possible influence of some coadministered drugs with important haemodynamic effects (dopamine, dobutamine, frusemide) on vancomycin pharmacokinetics was assessed. Vancomycin serum concentrations were measured by fluorescence polarization immunoassay. Vancomycin dosage regimens predicted by the Bayesian method (D-a) were compared retrospectively with Moellering's nomogram-based dosages (D-M) to assess possible major differences in vancomycin dosing. D-a values were similar to D-M in 10 patients (D-a approximate to D-M group) (20.52 +/- 8.40 mg/kg/day versus 18.81 +/- 7.24 mg/kg;P = 0.15), whereas much higher dosages were required in the other eight patients (D-a much greater than D-M group) (26.78+/- 3.01 mg/kg/day versus 18.95 +/- 3.41 mg/kg/day;P < 0.0001) despite no major difference in attained vancomycin steady-state trough concentration (C-min (ss)) (9.22 +/- 1.33 mg/L versus 8.99 +/- 1.26 mg/L;= 0.75) or estimated creatinine clearance (1.23 +/- 0.49 mL/min/kg versus 1.21 +/- 0.24 mL/min/kg;P = 0.95) being found between the two groups. The ratio between D-a and D-M was significantly higher in the D-a much greater than D-M group than in the D-a approximate to D-M group (1.44 +/- 0.18 versus 1.10 +/- 0.21;P < 0.01). In four D-a much greater than D-M patients the withdrawal of cotreatment with haemodynamically active drugs was followed by a sudden substantial increase in the vancomycin C-min ss (13.30 +/- 1.13 mg/L versus 8.79 +/- 0.87 mg/L;P < 0.01), despite no major change in bodyweight or estimated creatinine clearance being observed. We postulate that these drugs with important haemodynamic effects may enhance vancomycin clearance by inducing an improvement in cardiac output and/o

关键词：贝叶斯定理心脏外科手术强心药/治疗应用心血管药物/治疗应用肌酸酐/血液利尿药/治疗应用多巴酚丁胺/治疗应用多巴胺/治疗应用药物相互作用呋塞米/治疗应用重症监护重症监护病房手术后医护回顾性研究万古霉素/投药和剂量万古霉素/药代动力学万古霉素/治疗应用女(雌)性人类男(雄)性中年人

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No influence of large volume blood loss on serum vancomycin concentrations during orthopedic procedures

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ACTA ORTHOPAEDICA SCANDINAVICA 1999年第1期70卷 47-50页

作者： Klekamp, JW DiPersio, D Haas, DW Vanderbilt Univ Med Ctr Div Infect Dis Dept Orthopaed & Rehabil Nashville TN USA Vanderbilt Univ Med Ctr Div Infect Dis Dept Pharmaceut Serv Nashville TN USA Vanderbilt Univ Med Ctr Div Infect Dis Dept Med Microbiol & Immunol Nashville TN USA

We prospectively studied orthopedic patients with either targe or small blood loss who also received vancomycin prophylaxis to determine the effect of intraoperative volume shifts on serum vancomycin concentrations. There were 6 index patients in the large blood loss group (greater than 2 L), and 7 in the control group (less than 2 L). Mean estimated blood loss for index and controls was 4.4 L and 1.0 L, respectively. Mean intraoperative fluid resuscitation, excluding blood products, was 12.4 Land 5.1 L, respectively. There was a modest inverse correlation between blood loss and intraoperative serum half-life of vancomycin. Although controls maintained slightly higher intraoperative vancomycin concentrations at each time-point, there was no statistically significant difference between the groups with regard to absolute concentrations or rate of decline. After 8 hours, the serum vancomycin concentration exceeded the MIC-90 for Staphylococcus aureus by approximately eightfold in all but one case patient. This was a morbidly obese patient with massive blood toss. Thus, blood loss during orthopedic procedures has minimal effects on intraoperative kinetics of vancomycin. Redosing is rarely indicated, although a preoperative 1.5 gram-dose should be considered for patients weighing more than 90 kg.

关键词：抗菌药/血液抗菌药/药代动力学抗菌药/治疗应用抗生素预防失血手术/统计学和数值数据血量体重药物监测补液疗法/方法微生物敏感性试验前瞻性研究复苏术/方法时间因素万古霉素/血液万古霉素/药代动力学万古霉素/治疗应用成年人人类中年人

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Binding interactions of vancomycin tracers with a bacterial cell wall peptidoglycan analogue

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 2000年第14期10卷 1613-1615页

作者： Adamczyk, M Grote, J Moore, JA Rege, SD Yu, ZG Abbott Labs Dept Chem Div Diagnost Abbott Pk IL 60064 USA

Binding interactions between several vancomycin tracers and (N,N'-diacetyl)KDADA in solution were evaluated in a competition format using a surface plasmon resonance instrument. Tracers derivatized from the carboxy terminus or the N-vancosaminyl sugar moiety of vancomycin bind the peptide with an affinity similar to that of underivatized vancomycin. In contrast, N-methylleucyl derivatized vancomycin tracers bind the peptide with a reduced affinity relative to vancomycin. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：抗菌药/化学合成抗菌药/化学抗菌药/药代动力学细菌结合部位细胞壁药物设计动力学分子结构肽聚糖/化学蛋白质构象构效关系万古霉素/类似物和衍生物万古霉素/化学合成万古霉素/化学万古霉素/药代动力学

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