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PubMed2006

Determination of the extent of protein binding of antibiotics by means of an automated continuous ultrafiltration method.

The extent of the protein binding of a drug is an important pharmacokinetic parameter. In this study, the determination of the protein binding of the antibiotics gatifloxacin, moxifloxacin, linezolid and telithromycin to bovine serum albumin (BSA) and human serum albumin (HSA) was performed by means of an automated continuous ultrafiltration method. The continuous ultrafiltration has several advantages compared to classical methods like equilibrium dialysis or discontinuous ultrafiltration. The method is appropriate for a fast determination of the extent of the protein binding of a drug. In one single experiment the calculation of the protein binding over a wide range of different drug/protein ratios is possible. Comparing the results obtained with the continuous ultrafiltration with binding data reported in literature shows good correlation and proves the reliability of the method.

Acetamides↗
PubMed2005

Evaluation of ion mobility spectroscopy for determining charge-solvated versus salt-bridge structures of protonated trimers.

The cross sections of five different protonated trimers consisting of two base molecules and trifluoroacetic acid were measured by using ion mobility spectrometry. The gas-phase basicities of these five base molecules span an 8-kcal/mol range. These cross sections are compared with those determined from candidate low-energy salt-bridge and charge-solvated structures identified by using molecular mechanics calculations using three different force fields: AMBER*, MMFF, and CHARMm. With AMBER*, the charge-solvated structures are all globular and the salt-bridge structures are all linear, whereas with CHARMm, these two forms of the protonated trimers can adopt either shape. Globular structures have smaller cross sections than linear structures. Conclusions about the structure of these protonated trimers are highly dependent on the force field used to generate low-energy candidate structures. With AMBER*, all of the trimers are consistent with salt-bridge structures, whereas with MMFF the measured cross sections are more consistent with charge-solvated structures, although the assignments are ambiguous for two of the protonated trimers. Conclusions based on structures generated by using CHARMm suggest a change in structure from charge-solvated to salt-bridge structures with increasing gas-phase basicity of the constituent bases, a result that is most consistent with structural conclusions based on blackbody infrared radiative dissociation experiments for these protonated trimers and theoretical calculations on the uncharged base-acid pairs.

Aza Compounds↗
PubMed2004

Simultaneous determination of levofloxacin, gatifloxacin and moxifloxacin in serum by liquid chromatography with column switching.

Liquid chromatography with a column-switching technique was developed for simultaneous direct quantification of levofloxacin, gatifloxacin and moxifloxacin in human serum. Serum samples were injected on a LiChroCART 4-4 pre-column (PC) filled with a LiChrospher 100 RP-18, 5 microm where fluoroquinolones (FQs) were purified and concentrated. The FQs were back-flushed from the PC and then separated on a Supelcosil ABZ+ Plus (150 mm x 4.6 mm i.d.) analytical column with a mobile phase containing 10 mM phosphate buffer (pH 2.5), acetonitrile (88:12, v/v) and 2mM tetrabutyl ammonium bromide. The effects of ion-pair reagents, buffer type, pH and acetonitrile concentrations in the mobile phase on the separation of the three FQs were investigated. Fluorescence detection provided sufficient sensitivity to achieve a quantification limit of 125 ng/ml for levofloxacin and moxifloxacin; 162.5 ng/ml for gatifloxacin with a 5 microl sample size. The on-line process of extraction avoids time-consuming treatment of the samples before injection and run time is shortened. The recovery, selectivity, linearity, precision and accuracy of the method are convenient for pharmacokinetic studies or routine assays.

Anti-Infective Agents↗
PubMed2006

Quantitative analysis of Variolin analog (PM01218) in mouse and rat plasma by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

PM01218 is a novel marine-derived alkaloid and has shown potent growth inhibitory activity against several human cancer cell lines. A rapid and sensitive high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to quantify PM01218 in mouse and rat plasma. The lower limit of quantitation (LLOQ) was 0.05 ng/mL. The calibration curve was linear from 0.05 to 100 ng/mL (R(2)>0.999). The assay was specifically based on the multiple reaction monitoring (MRM) transitions at m/z 278.4-->184.2, no endogenous material interfaced with the analysis of PM01218 and its internal standard from blank mouse and rat plasma. The mean intra- and inter-day assay accuracy remained below 15 and 8%, respectively, for all calibration standards and QC samples. The intra- and inter-day assay precision was less than 12.8 and 8.5% for all QC levels, respectively. The utility of the assay was demonstrated by pharmacokinetics studies of i.v. (bolus) PM01218 on SD rats.

Animals↗
PubMed2006

Optimization and validation of the direct HPLC method for the determination of moxifloxacin in plasma.

Moxifloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo-[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid hydrochloride) is new, fourth generation fluoroquinolone with broaden spectrum of antibacterial activity. In the present work simple and rapid RP-HPLC method for the direct determination of moxifloxacin in human plasma is described. Separation of moxifloxacin from plasma components was achieved on Supelco LC-Hisep shielded hydrophobic phase column. The mobile phase consisted of acetonitrile and 0.25mol/dm(3) Na(3)PO(4) (pH 3) in a volume percent ratio (5:95, v/v) and was delivered at a rate of 1mL/min. Fluorescence detection was employed with excitation at 290nm and emission at 500nm. Ofloxacin was used as internal standard and sodium dodecylsulfate solution was used as a displacing agent. Sample preparation was simplified and involved only addition of displacing agent and internal standard and dilution with water. The separation conditions were optimized by the response surface method in two factor space, i.e. the dependence of the retention time on volume percent of acetonitrile and on pH of aqueous phase was optimized. The method was fully validated and validation parameters were: linearity range 3-1300microg/L; correlation coefficient, 0.99986; mean recovery, 92.5%; limit of quantification, 3.0microg/L and limit of detection, 1.0microg/L. Method was applied for the determination of moxifloxacin in human plasma after single or repeated oral doses of 400mg Avelox tablets. The proposed method proved to be rapid and accurate and can be successfully used in pharmacokinetic studies and routine clinical practice.

Anti-Bacterial Agents↗
PubMed2004

Comparative penetration of moxifloxacin and gatifloxacin in rabbit aqueous humor after topical dosing.

PURPOSE: To evaluate the aqueous penetration of the fourth-generation fluoroquinolones moxifloxacin and gatifloxacin. SETTING: University of Arizona, Tucson, Arizona, USA. METHODS: Forty eyes of 20 New Zealand white rabbits were divided into 2 experimental groups. In Experiment I rabbits (20 eyes), a commercial preparation of topical gatifloxacin 0.3% was administered to 9 eyes and moxifloxacin 0.5% to 9 eyes; 2 eyes served as a control. Eyes were dosed according to a keratitis protocol; ie, every 15 minutes for 4 hours. The aqueous humor was sampled 10 minutes after the last dose. Experiment II rabbits (20 eyes) were dosed according to a cataract prophylaxis protocol; ie, 4 times a day for 10 days. The aqueous humor was sampled 1 hour after the last dose of antibiotic in 12 eyes and 24 hours after the last dose in 8 eyes. High-performance liquid chromatography was used to determine the fluoroquinolone concentration. RESULTS: In the keratitis dosing protocol, the mean concentration of moxifloxacin in the aqueous (n=9) was 11.057 microg/mL (range 7.66 to 18.87 microg/mL), which was significantly higher than the mean concentration of gatifloxacin (n=8) (7.570 microg/mL [range 4.75 to 10.86 microg/mL]) (P=.030). In the cataract prophylaxis dosing protocol, the mean aqueous concentration of moxifloxacin (n=6) was 1.745 microg/mL (range 0.92 to 3.87 mg/mL). The mean concentration of gatifloxacin (n=6) was 1.207 microg/mL (range 0.44 to 2.44 microg/mL). The difference was not statistically significant (P=.359). CONCLUSIONS: Higher mean levels (x1.46) of aqueous penetration were achieved with moxifloxacin than with gatifloxacin in the keratitis-dosing model. There was no statistically significant difference between the 2 drugs in the cataract prophylaxis dosing model. Both antibiotics had aqueous levels in excess of the minimum inhibitory concentration for most pathogenic organisms in both models.

Administration, Topical↗
PubMed2005

In-use study of potential bacterial contamination of ophthalmic moxifloxacin.

PURPOSE: To determine the contamination rate of topical moxifloxacin 0.5% (Vigamox) after clinical use for preoperative and postoperative prophylaxis for cataract surgery. SETTING: Bascom Palmer Eye Institute, Miami, Florida, USA. METHODS: A total of 61 bottles of moxifloxacin were collected in a 2-month time period after use preoperatively by patients (n = 21, mean 2.2 days), postoperatively by patients (n = 16, mean 7.2 days), or by nurses in the operating room (n = 24). For each bottle, cultures of the cap, tip, external thread, and solution were inoculated onto chocolate agar plates and incubated at 35 degrees for 7 days. A total of 13 bottles of benzalkonium chloride (BAC)-preserved gatifloxacin ophthalmic solution (Zymar) were also cultured in a similar manner for comparison. RESULTS: No organisms were found by cultures of the cap, tip, or solution from any bottle in the study. One colony of coagulase-negative Staphylococcus was recovered from the thread of 1 Vigamox bottle. This bottle had negative cultures from its cap, tip, and solution. CONCLUSIONS: The only contaminant found in this study was cultured from the bottle thread. This is a location with a high rate of skin contact and minimal solution contact. The remaining cultures from this bottle were negative, showing the solution's ability to self-preserve. These data demonstrate that BAC-free Vigamox can be treated no differently than BAC-preserved solutions by patients and medical staff, without concern for solution contamination.

Aza Compounds↗
PubMed2005

Nocardia keratitis after laser in situ keratomileusis: clinicopathologic correlation.

A case of Nocardia asteroides keratitis occurring 3 weeks after laser in situ keratomileusis (LASIK) in a nontraumatized eye is reported. The patient presented with decreased vision, inflammation, and stromal melting of the LASIK flap, discrete infiltrates, and an anterior chamber cellular reaction. Cultures for acid-fast bacteria grew Nocardia asteroides after 5 days. Infection progressed despite treatment with topical antibiotics and eventually required penetrating keratoplasty (PKP). Postoperatively, the patient was placed on moxifloxacin, a fourth-generation flouroquinolone. The patient experienced a recurrence of Nocardia keratitis at the graft-host interface 2 months after the PKP. This eventually resolved with a combination of topical moxifloxacin and imipenem therapy.

Administration, Topical↗
PubMed2005

Determination of aqueous and vitreous concentration of moxifloxacin 0.5% after delivery via a dissolvable corneal collagen shield device.

PURPOSE: To determine the penetration of moxifloxacin 0.5% in the human aqueous and vitreous when delivered by a presoaked collagen shield. SETTING: University-based clinical practice. METHODS: Moxifloxacin 0.5% was administered before vitrectomy surgery in 10 patients using a 24-hour dissolvable cross-linked corneal collagen shield delivery device. Aqueous and vitreous samples were obtained after the shield was placed for 4 hours in the first 5 patients and for 24 hours in the second 5 patients. Assays were performed using high-performance liquid chromatography. RESULTS: Delivery of moxifloxacin via a collagen shield revealed a mean aqueous concentration of 0.30 microg/mL +/- 0.17 (SD) 4 hours after placement (n = 5). Vitreous levels at 4 hours and aqueous and vitreous levels at 24 hours were negligible using this route of administration. Peak aqueous moxifloxacin levels occurred soon after shield placement. This is when high concentrations of moxifloxacin are most needed to clear the aqueous of bacteria. The minimum inhibitory concentration at which 90% of the isolates were inhibited for organisms commonly responsible for endophthalmitis was exceeded in the 4-hour aqueous group. Negligible concentrations were detected at 24 hours. CONCLUSIONS: Although aqueous moxifloxacin levels achieved through the use of a collagen shield delivery device are lower than via topical drops, there are several advantages to this route of delivery that make it appealing in the immediate postoperative period. Future studies will be needed to define precisely the role of fourth-generation fluoroquinolones and presoaked collagen shields in the prophylaxis or management of intraocular infections.

Aged↗
PubMed2005

Effect of gatifloxacin 0.3% and moxifloxacin 0.5% ophthalmic solutions on human corneal epithelium following 2 dosing regimens.

PURPOSE: To determine whether gatifloxacin 0.3% ophthalmic solution or moxifloxacin 0.5% ophthalmic solutions are toxic to the corneal epithelium when used with 1 of 2 dosing regimens in healthy human eyes. SETTING: Price Vision Group, Indianapolis, Indiana, USA. METHODS: In this double-masked randomized fellow-eye comparison study, gatifloxacin 0.3% was instilled in 1 eye and moxifloxacin 0.5% in the other eye either 4 times a day for 7 days or hourly for 10 hours. Before and after dosing, all eyes were examined with a slitlamp and the cell layers in the central cornea were evaluated by confocal microscopy. Subject discomfort with study drop instillation was also assessed. RESULTS: There was no statistically significant increase in the incidence or severity of superficial punctuate keratitis following use of gatifloxacin 0.3% or moxifloxacin 0.5% when instilled 4 times a day for 7 days or hourly for 10 hours. Hourly use of gatifloxacin 0.3% for 10 hours resulted in a mild but statistically significant increase in conjunctival hyperemia (P = .029). Use of moxifloxacin 0.5% resulted in a small but statistically significant deterioration of the corneal epithelial surface as assessed by confocal microscopy (P = .045). The incidence of subject discomfort with study drop instillation was comparable for the 2 antibiotics (P = .67). CONCLUSION: Use of ophthalmic solutions of gatifloxacin 0.3% or moxifloxacin 0.5% did not result in clinically significant epithelial toxicity in healthy human corneas after dosing regimens of 4 times a day for 7 days or hourly for 10 hours dosing regimens.

Adult↗
PubMed2006

Fourth-generation fluoroquinolone-resistant bacterial keratitis after refractive surgery.

We report the first 2 cases of bacterial keratitis resistant to fourth-generation fluoroquinolones after laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). The first patient had Pseudomonas aeruginosa keratitis after PRK despite treatment with moxifloxacin. The second patient was on gatifloxacin post-LASIK when she had methicillin-resistant Staphylococcus aureus (MRSA) keratitis diagnosed. In both cases, culture susceptibilities showed isolates resistant to moxifloxacin and gatifloxacin, and treatment with topical aminoglycosides and surgical intervention was necessary to effect a cure. These cases show the potential limitations in the coverage of these antibiotics.

Adult↗
PubMed2006

Hydrophilic acrylic intraocular lens as a drug-delivery system: Pilot study.

PURPOSE: To evaluate the ability of a hydrophilic acrylic intraocular lens (IOL) to serve as a drug-delivery system for commercially available gatifloxacin and moxifloxacin. SETTING: David J. Apple, MD, Laboratories for Ophthalmic Devices Research, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. METHODS: Hydrophilic acrylic IOLs (C-flex, Rayner Ltd.), presoaked for 24 hours in commercially available solutions of gatifloxacin (Zymar) or moxifloxacin (Vigamox), were implanted in the capsular bag of 6 rabbits for a total of 12 eyes (6 in each group). Aqueous humor samples were taken 2, 4, and 6 hours after implantation. One rabbit served as a control and had nonpresoaked C-flex IOLs implanted. At the end of the operation, 1 drop of Vigamox was applied to the right eye and 1 drop of Zymar was applied to the left eye of the control rabbit. RESULTS: High concentrations of both antibiotics were found in all the samples of the eyes implanted with the presoaked IOLs. The concentrations of the antibiotics decreased over time, but even the 6-hour sample concentrations were markedly higher than the concentrations found in the control rabbit after 4 hours. CONCLUSION: The results suggest that the Rayner C-flex IOL can be effective as a drug-delivery system for fourth-generation fluoroquinolones.

Acrylic Resins↗
PubMed2006

Hydrophilic acrylic intraocular lens as a drug-delivery system for fourth-generation fluoroquinolones.

PURPOSE: To evaluate the ability and safety of a hydrophilic acrylic intraocular lens (IOL) as a drug-delivery system for commercially available gatifloxacin and moxifloxacin. SETTING: David J. Apple, MD, Laboratories for Ophthalmic Research, John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, USA. METHODS: Thirty rabbits were divided into 2 similar groups. In Group A (15 rabbits, 30 eyes), hydrophilic acrylic IOLs (C-flex, Rayner Intraocular Lenses, Ltd.) presoaked for 24 hours in commercially available solutions of gatifloxacin 3 mg/mL or moxifloxacin 5 mg/mL were implanted after evacuation of the crystalline lens. Group B (15 rabbits, 30 eyes) had topical preoperative and postoperative cataract prophylaxis with gatifloxacin 3 mg/mL or moxifloxacin 5 mg/mL; IOLs that were not presoaked were also implanted after evacuation of the crystalline lenses. In both groups, aqueous humor samples were taken 4, 8, or 12 hours after IOL implantation (5 eyes at each time point) to determine the antibiotic concentrations. Clinical examinations were performed 24 hours postoperatively. RESULTS: The antibiotic concentrations in Group A (presoaked IOLs) were statistically significantly higher than those in Group B (topical) for both antibiotics in all postoperative samples except moxifloxacin at 12 hours. In both groups, there was no statistically significant difference between the concentrations of the 2 antibiotics. No eye showed signs of clinical toxicity. CONCLUSION: Results show the C-flex IOL is a safe and effective drug-delivery system for fourth-generation fluoroquinolones.

Acrylic Resins↗
PubMed2006

Bilateral simultaneous Achromobacter xylosoxidans keratitis following penetrating keratoplasty.

We report a case of severe bilateral simultaneous Achromobacter xylosoxidans keratitis following penetrating keratoplasty (PKP) in a patient with graft-versus-host disease. The predisposing factors, clinical features, treatment options, and final visual outcome are reviewed. To our knowledge, this is the first report of bilateral A xylosoxidans keratitis following PKP.

Achromobacter denitrificans↗
PubMed2007

Aqueous humor penetration of gatifloxacin and moxifloxacin eyedrops given by different methods before cataract surgery.

PURPOSE: To determine whether the penetration into the aqueous humor of 2 new fourth-generation fluoroquinolone antibiotics, gatifloxacin (Zymar) and moxifloxacin (Vigamox) eyedrops, was affected by different methods of administration before cataract surgery. SETTING: Pasqua Hospital, Regina, Saskatchewan, Canada. METHODS: This prospective randomized study comprised 193 patients. The patients were divided into 2 main groups. One group received gatifloxacin eyedrops and the other, moxifloxacin eyedrops. Each group was subdivided into 4 subgroups. All patients received the drops 4 times a day starting 2 days preoperatively. The first subgroup did not receive any more antibiotics. The second subgroup received the antibiotic drops 3 times, starting approximately 2 hours preoperatively. The third subgroup received a wick soaked in a dilating mixture containing the antibiotic. The fourth subgroup received the wick and the antibiotic drops at the time of preparation for surgery. At the beginning of surgery, 0.1 mL of aqueous humor was aspirated, frozen, and sent under ice by courier to the Provincial Laboratory for analysis by high-performance liquid chromatography. RESULTS: The study included 124 women and 69 men. The mean concentrations in the aqueous humor were 0.19, 0.82, 0.22, and 0.30 microg/mL in the 4 gatifloxacin subgroups, respectively, and 0.38, 2.16, 0.88, and 0.97 microg/mL in the 4 moxifloxacin subgroups, respectively. Analysis of variance showed the differences between the 2 antibiotics to be statistically significant. CONCLUSIONS: Moxifloxacin penetrated the aqueous humor better than gatifloxacin regardless of the method of administration. Both antibiotics penetrated the aqueous humor well when given in drop form. They reached and exceeded the minimum inhibitory concentration levels for the most common ocular pathogens causing endophthalmitis. Only moxifloxacin reached these levels when the wick was used.

Adult↗
PubMed2007

Safety of prophylactic intracameral moxifloxacin 0.5% ophthalmic solution in cataract surgery patients.

PURPOSE: To determine the safety of prophylactic intracameral moxifloxacin 0.5% ophthalmic solution (Vigamox) in patients having cataract surgery. SETTING: American Eye Center, Manila, Philippines. METHODS: Preoperative and 1-month postoperative anterior chamber reaction, corneal endothelial cell density, and corneal thickness were assessed in 65 eyes that had cataract surgery with intracameral moxifloxacin. All eyes received 0.1 mL intracameral moxifloxacin 0.5% ophthalmic solution containing 500 mug of moxifloxacin as the last step of phacoemulsification. Different ophthalmologists conducted the postoperative evaluation in an observer-masked fashion. A P value less than 0.05 was considered significant. RESULTS: All 65 eyes completed the study. The mean age was 69.5 years +/- 9.13 (SD) (range 48 to 84 years). All eyes had a postoperative best corrected visual acuity of 20/30 or better. All eyes had trace to +2 cells and flare anterior chamber reaction only on the first day after surgery. The mean endothelial cell count was 2491.52 cells/mm(2) preoperatively and 2421.58 cells/mm(2) postoperatively. The mean difference was 70 cells/mm(2), which not statistically significant (P = .737). The increase of 17.80 microm in postoperative pachymetry 1 month after surgery was not statistically significant (P>.65). CONCLUSION: Intracameral Vigamox 0.5 mg/mL appeared to be nontoxic in terms of visual rehabilitation, anterior chamber reaction, pachymetry, and corneal endothelial cell density.

Aged↗
PubMed2004

Safety and efficacy of sequential i.v. to p.o. moxifloxacin versus conventional combination therapies for the treatment of community-acquired pneumonia in patients requiring initial i.v. therapy.

To compare the efficacy of sequential i.v. to p.o. moxifloxacin with ceftriaxone +/- azithromycin +/- metronidazole for the treatment of patients with community acquired pneumonia (CAP), a multi-centered, prospective, randomized, open label study was performed. CAP patients were randomized to moxifloxacin (400 mg/d-at least one i.v. dose) or ceftriaxone (at least one dose of 2 g i.v. q.d. followed by cefuroxime 500 mg p.o. b.i.d.) +/- azithromycin, +/- metronidazole (cephalosporin/macrolide control: CMC). The primary endpoint was clinical response at test-of-cure (TOC) visit. Bacteriological response at TOC was the secondary endpoint. Clinical cure was found in 83.3% (90/108) of moxifloxacin patients and 79.6% (90/113) of control patients. Microbiological responses were 81.8% (18/22) for moxifloxacin and 60.7% (17/28) for CMC patients. Drug-related adverse events occurred in 18.0% of moxifloxacin and 16% of CMC patients. It is concluded that i.v. to p.o. moxifloxacin is as effective as CMC for treatment of CAP and is a reliable alternative antimicrobial therapy.

Adult↗