Intravitreal vancomycin and gentamicin concentrations in patients with postoperative endophthalmitis

BACKGROUND/AIMS: To study the intravitreal antibiotic concentrations and the efficacy of an intravitreal dosing regimen to treat patients with postoperative bacterial endophthalmitis. This regimen, based on pharmacokinetic/pharmacodynamic considerations, relies on a repeat antibiotic injection of a lower dose than is generally used. METHODS: In consecutive patients with suspected postoperative endophthalmitis a vitreous biopsy for bacterial culture was taken before 0.2 mg vancomycin and 0.05 mg gentamicin were injected intravitreally. After 3 or 4 days a second biopsy was taken for bacteriological culture and to measure intravitreal vancomycin and gentamicin concentrations, followed by a repeat injection of 0.2 mg vancomycin. RESULTS: 17 patients entered the study. In 11 patients the initial bacterial culture was positive, predominantly coagulase negative staphylococci. All second vitreous biopsies were sterile. Intravitreal vancomycin levels varied between 2.6 and 18.0 microg/ml (mean 10.3 (SD 4.1) microg/ml) after 3 days and between 3.1 and 16.6 microg/ml (mean 7.5 (6.2) microg/ml) after 4 days which is well above the minimal inhibitory concentration for most micro-organisms. Concentrations of intravitreal gentamicin varied between 0.90 and 3.3 microg/ml (mean 1.6 (0.72) microg/ml) after 3 days and between 1.2 and 2.6 microg/ml (mean 1.9 (0.99) microg/ml) after 4 days. CONCLUSION: This dosing regimen resulted both in adequate intravitreal vancomycin and gentamicin levels for over a week as well as in negative second cultures. This study also provides new information on intravitreal vancomycin and gentamicin concentration over time in patients with postoperative endophthalmitis.     

Human corneal stromal tissue concentration after consecutive doses of topically applied 3.3% vancomycin

AIMS: To evaluate vancomycin penetration into human corneal stromal tissue in patients treated with topical vancomycin eyedrops before penetrating keratoplasty (PKP). METHODS: Twenty four patients who underwent PKP, seven patients with keratoconus (group 1) and 17 patients with corneal scar or corneal decompensation (group 2). All patients received topical application of vancomycin eyedrops (concentration: 33 mg/ml) 10, 3, 2, 1 hour, and 15 minutes before the operation. Corneal cumulative vancomycin levels were assessed by bioassay. RESULTS: Mean vancomycin corneal stromal tissue concentration was 46.7 (SE 4.11) microg/g tissue. This value was four to 20-fold in excess of the MIC90 of vancomycin in Staphylococcus aureus (2-10 microg/ml). CONCLUSIONS: Vancomycin reached high corneal tissue concentrations that significantly exceeded the MIC90 (2-10 microg/ml) for most key Gram positive corneal pathogens. The ratio of vancomycin stromal concentration to protein concentration was statistically higher in group 2 (non-keratoconus).     

Differential aqueous and vitreous concentrations of moxifloxacin and ofloxacin after topical administration one hour before vitrectomy

PURPOSE: To investigate the penetration of ofloxacin and moxifloxacin into the aqueous and vitreous after topical administration one hour before vitrectomy surgery. DESIGN: Prospective, randomized, double-blind case series study. METHODS: Twenty-seven patients undergoing vitrectomy were randomized to receive either topical ofloxacin 0.3% or moxifloxacin 0.5% every 10 minutes for one hour before surgery. Aqueous and vitreous samples were obtained and analyzed using high-performance liquidation chromatography. RESULTS: The moxifloxacin aqueous (1.576 +/- 0.745 microg/ml) and vitreous (0.225 +/- 0.013 microg/ml) levels were significantly higher than the ofloxacin aqueous (0.816 +/- 0.504 microg/ml) (P = .0009) and vitreous (0.225 +/- 0.013 microg/ml) [P = .0054] levels, respectively. The mean moxifloxacin aqueous and vitreous levels exceeded the minimum inhibitory concentration for 90% of isolates (MIC(90)) for a wide variety of bacteria implicated in endophthalmitis. In contrast, the aqueous level of ofloxacin exceeded the MIC(90) of only a few organisms. CONCLUSIONS: Moxifloxacin applied every 10 minutes during the hour before vitrectomy penetrated the eye significantly better than ofloxacin.     

葛根素经全身用药在兔眼房水和玻璃体中的药代动力学

目的:测定腹腔注射单次剂量的葛根素后不同时间点新西兰白兔眼房水、玻璃体中葛根素的浓度变化,探讨葛根素在兔眼房水和玻璃体中的药动学变化。方法:新西兰白兎随机分组,每只白兔腹腔注射葛根素80mg/kg,在用药前(0h)和用药后0.5、1、2、3、4、6、8、12、16、24h取房水液、玻璃体液,采用反相高效液相色谱法(RP-HPLC)进行测定。3P87软件拟合药动学参数。结果:腹腔注射葛根素后,其浓度在正常新西兰白兔房水、玻璃体呈开放式二房室模型。理论值:高峰浓度(Cmax)分别为1.61、0.09μg/ml,达峰时间(tmax)为1.68、1.81h,半衰期t1/2α为1.36、1.05h,t1/2β为19.72、15.18h,清除率(CL)分别为2.17、12.43L/h。实测值30min分别为(0.78±0.29)μg/ml、(0.06±0.02)μg/ml,2h达高峰,分别为(2.32±0.15)μg/ml、(0.12±0.04)μg/ml,随后逐渐下降,6h后房水中葛根素含量降至0.57μg/ml,玻璃体为0.05μg/ml,16h后,葛根素在房水和玻璃体中的浓度降至0.03μg/ml或以下。结论:本方法灵敏、特异、准确和快速,可用于房水、玻璃体中葛根素浓度的测定;葛根素通过腹腔注射能透过血-眼屏障进入房水、玻璃体,进入房水的葛根素药量较大,进入玻璃体的药量有限。     

Penetration of topical and oral ciprofloxacin into the aqueous and vitreous humor in inflamed eyes.

PURPOSE: To assess the aqueous and vitreous penetration of ciprofloxacin after topical and combined topical and oral administration and investigate the effects of inflammation on drug penetration. METHODS: A standardized penetrating injury was made in the right eyes of 16 rabbits. Intraocular inflammation was induced by intravitreal injection of a suspension of Staphylococcus aureus in these eyes. The animals were divided into two groups according to treatment methodology: topical and topical-oral. The intact left eyes of the animals were maintained as controls. In the topical treatment group, two drops of ciprofloxacin 0.3% were instilled to both eyes every 30 minutes for 4 hours. In the topical-oral treatment group, animals were given two oral 40 mg/kg doses of ciprofloxacin at 12-hour intervals. After the last oral dose, the protocol of the topical group was applied to these eyes. Half an hour after the last drop, 100-microL samples were taken from aqueous and vitreous humor of all eyes. Drug concentrations were measured using high-pressure liquid chromatography. RESULTS: Mean aqueous levels of ciprofloxacin in control eyes were 2.31 microg/mL (range, 1.02-6.27 microg/mL) in the topical group and 5.88 microg/mL (1.52-17.81) in the topical-oral group. Mean aqueous levels in inflamed eyes were 7.36 microg/mL (2.34-17.15) in the topical group and 14.43 microg/mL (2.18-18.66) in the topical-oral group. Mean vitreous levels in control eyes were 0.77 microg/mL (0.09-1.93) in the topical group and 1.01 microg/mL (0.49-1.57) in the topical-oral group. Mean vitreous levels in inflamed eyes were 0.95 microg/mL (0.18-1.27) in the topical group and 1.98 microg/mL (0.51-3.34) in the topical-oral group. There was no significant difference among the groups (P > 0.05). Mean aqueous levels in all eyes and mean vitreous levels in the combined topical and oral group of inflamed eyes were above the 90% minimum inhibitory concentration for most of the common microorganisms causing endophthalmitis. CONCLUSION: There is an increase in both aqueous and vitreous humor concentrations with inflammation and with oral and topical administrations, as opposed to topical only, of ciprofloxacin. Using oral as well as topical treatment may be a beneficial method of antibiotic prophylaxis in ocular trauma once a patient has received intravenous or intravitreal therapy.     

The effect of long-term use and inflammation on the ocular penetration of topical ofloxacin.

PURPOSE. To study the penetration of ofloxacin into the aqueous and vitreous humors after long-term topical administration and to investigate the effects of inflammation on drug penetration in rabbits. METHODS. A standardized model of intraocular infection after penetrating injury was achieved in the right eyes of 16 rabbits. The animals were randomly and equally divided into two groups. The intact left eyes of the groups were maintained as the control. Ofloxacin eyedrops (0.3%) were instilled into all eyes at a frequency of 2 drops every hour for 7 hours in the first group and for 14 hours in the second group. Half an hour after the last drop, samples of the aqueous and vitreous humors were taken and ofloxacin concentrations were measured by using HPLC. RESULTS. The mean aqueous humor concentrations of ofloxacin in control eyes after 7 and 14 hours of instillation were: 1.45 +/- 0.93 microg/ml and 2.48 +/- 0.33 microg/ml, respectively; those in infected eyes 2.35 +/- 1. 84 microg/ml and 3.49 +/- 1.47 microg/ml, respectively. However the differences among the groups were not significant (p > 0.05). The vitreous ofloxacin concentrations in the control eyes were similar after 7 and 14 hours of instillation (0.23 +/- 0.14 microg/ml, 0.27 +/- 0.10 microg/ml, respectively). In infected eyes, the mean vitreous ofloxacin concentration after 14 hour of instillation was significantly higher than that in control eyes (p < 0.05; 0.4 +/- 0. 09 microg/ml, 0.29 +/- 0.11 microg/ml, respectively). The mean vitreous ofloxacin concentration in infected eyes after 14 hours instillation was not significantly higher than that after 7 hours instillation. CONCLUSIONS. Topical ofloxacin instillation for 7 or 14 hours yields aqueous concentrations above the MIC(90) for common ocular pathogens. Prolonged application and the presence of inflammation increased the penetration of ofloxacin into the vitreous humor.     

Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy

PURPOSE: To determine the levels of pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in the vitreous of patients with diabetic retinopathy (DR). DESIGN: Experimental study of PEDF and VEGF levels in vitreous samples collected during vitrectomy. METHODS: The levels of PEDF and VEGF were measured by enzyme-linked immunosorbent assay in the vitreous of 46 eyes of 43 patients who underwent vitrectomy with diabetic retinopathy (DR) (32 eyes of 29 patients) and an idiopathic macular hole (MH) (14 eyes of 14 patients). RESULTS: The vitreal concentration of PEDF was significantly lower at 1.11 +/- 0.14 microg/ml (mean +/- standard error) in eyes with DR than in eyes with MH at 1.71 +/- 0.22 microg/ml (P =.021). The VEGF level was 1799 +/- 478 pg/ml in eyes with DR and not detectable in MH. The PEDF level in proliferative DR (PDR) (0.94 +/- 0.12 microg/ml) was lower than that in nonproliferative DR (NPDR) (2.25 +/- 0.32 microg/ml), and that in active DR (0.85 +/- 0.14 microg/ml) was significantly lower than that in inactive DR (1.59 +/- 0.24 microg/ml; P =.01). The VEGF level was 2025 +/- 533 pg/ml in PDR and 215 +/- 201 pg/ml in NPDR and that in active DR (2543 +/- 673 pg/ml) was significantly higher than that in inactive DR (395 +/- 188 pg/ml; P =.0098). CONCLUSIONS: These results suggest that lower levels of PEDF and higher levels of VEGF may be related to the angiogenesis in DR that leads to active PDR.     

Penetration of topically applied ciprofloxacin and ofloxacin into the aqueous humor and vitreous

PURPOSE: To determine the intraocular penetration of topical drops of 2 antibiotics, ciprofloxacin 0.3% and ofloxacin 0.3%, into the aqueous humor and vitreous and to relate these levels to the miminum inhibitory concentration (MIC(90)) for organisms associated with ocular bacterial infections. SETTING: Department of Ophthalmology, Ankara Hospital, and Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey. METHODS: This prospective randomized clinical trial comprised 18 patients having cataract surgery, all with an intact corneal epithelium. The patients were randomly assigned to receive topical ciprofloxacin 0.3% (n = 10) or topical ofloxacin 0.3% (n = 8) 1 drop every 15 minutes 5 times and every 30 minutes 3 times before surgery. Aqueous and vitreous samples (if vitreous loss occurred during the cataract surgery) were collected 30 minutes after the administration of the last dose. Drug concentrations were determined by high-performance liquid chromatography (HPLC) fluorescence. RESULTS: All patients had detectable drug concentrations in the aqueous humor and vitreous measurable by HPLC. The mean aqueous humor concentration of ciprofloxacin was 1.13 microg/mL +/- 1.90 (SD) and the mean vitreous concentration, 0.23 +/- 0.06 microg/mL. Topical administration of ciprofloxacin yielded 4.9 times more drug concentration in the anterior chamber than in the vitreous. The mean aqueous concentration of ofloxacin was 2.06 +/- 1.06 microg/mL and the mean vitreous concentration, 0.46 +/- 0.10 microg/mL. Topical administration of ofloxacin yielded 4.7 times more drug concentration in the anterior chamber than in the vitreous. Aqueous humor concentrations of ofloxacin and ciprofloxacin were not statistically significantly different (P =.353). Intravitreal concentrations of ofloxacin were statistically significantly higher than those of ciprofloxacin (P =.001). CONCLUSIONS: Topical ofloxacin 0.3% penetrated better than topical ciprofloxacin 0.3% into the anterior chamber and vitreous in noninflamed eyes. Both drugs were above the MIC(90) for most ocular pathogens in the anterior chamber. The mean concentration in the vitreous of topically applied ofloxacin 0.3% was statistically significantly higher than that of ciprofloxacin 0.3%, but it was not sufficiently above the MIC(90) for most ocular pathogens in terms of empirical endopthalmitis therapy.     

An in vitro study of ceftazidime and vancomycin concentrations in various fluid media: implications for use in treating endophthalmitis

PURPOSE: To investigate the precipitation process of a mixture of vancomycin and ceftazidime by equilibrium dialysis and determine its subsequent effect on the level of free antibiotics for treatment of endophthalmitis. METHODS: Concentrations of vancomycin and ceftazidime in an equilibrium dialysis chamber were measured during the equilibrium process by high-performance liquid chromatography. Normal saline (NS), balanced salt solution (BSS), and vitreous were used separately as the medium of dialysis. RESULTS: Precipitation of ceftazidime occurred at 37 degrees C but not at room temperature and did not affect the pH of the medium. It formed precipitate on its own or when mixed with vancomycin in all the three media of NS, BSS, and vitreous. More precipitation was formed if ceftazidime was initially prepared in BSS than in NS. After 168 hours in the dialysis chambers, ceftazidime prepared in NS precipitated to 54% of that in vitreous, compared with 88% if prepared in BSS. At 48 hours, ceftazidime prepared in NS decreased from an initial concentration of 137.5 to 73.4 microg/mL in vitreous medium and to 6.3 microg/mL if prepared in BSS. Precipitation of vancomycin was negligible. CONCLUSIONS: Based on this in vitro investigation, ceftazidime precipitates in vitreous at body temperature, regardless of the presence of vancomycin. NS is preferred to BSS as a preparation medium for antibiotics for intravitreal injection, because the extent of ceftazidime precipitation is less. However, due to precipitation, the concentration of free ceftazidime in vitreous may not be sufficiently high for antibacterial activity against most common organisms.     

Aqueous and vitreous penetration of levofloxacin after oral administration

OBJECTIVE: To investigate the penetration of levofloxacin, an optical S-(-)isomer of ofloxacin, into the aqueous and vitreous humor after oral administration. DESIGN: Randomized, clinical trial comparing tissue levels of levofloxacin after one or two doses 12 hours apart. PARTICIPANTS: Forty-five patients undergoing initial vitrectomy between February 1997 and June 1997 at the UIC Eye Center. METHODS: Aqueous, vitreous, and serum samples were obtained and later analyzed from 45 patients after oral administration of 1 500-mg tablet (group 1, 22 patients) or 2 500-mg tablets (group 2, 23 patients) 12 hours apart before surgery. MAIN OUTCOME MEASURES: Aqueous, vitreous, and serum concentrations of levofloxacin (micrograms/milliliter). RESULTS: Group 1 achieved mean aqueous, vitreous, and serum levels of 0.59 +/- 0.48 microg/ml, 0.32 +/- 0.34 microg/ml, and 4.34 +/- 3.59 microg/ml, respectively. Group 2 achieved mean aqueous, vitreous, and serum levels of 1.90 +/- 0.97 microg/ml, 2.39 +/- 0.70 microg/ml, and 8.02 +/- 3.14 microg/ml. CONCLUSIONS: Mean inhibitory aqueous and vitreous MIC90 levels were achieved against a majority of ocular pathogens, including Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus pneumoniae (vitreous), Bacillus cereus (vitreous), Haemophilus influenzae, Moraxella catarrhalis, and most gram-negative aerobic organisms except Pseudomonas aeruginosa after two doses given 12 hours apart. Mean MIC90 levels were obtained in the vitreous for a majority of pathogens responsible for traumatic, postoperative, or bleb-related endophthalmitis.     

Characterization of a novel intraocular drug-delivery system using crystalline lipid antiviral prodrugs of ganciclovir and cyclic cidofovir

PURPOSE: In an earlier study, a novel intraocular drug-delivery system was reported in which hexadecyloxypropyl-phospho-ganciclovir (HDP-P-GCV) was used as a prototype. The hypothesis was that many biologically effective compounds could be modified to crystalline lipid prodrugs and could be delivered directly into the vitreous in a long-lasting, slow-release form. This study was undertaken to characterize this new drug-delivery system further, by using small particles of HDP-P-GCV and hexadecyloxypropyl-cyclic cidofovir (HDP-cCDV). METHODS: HDP-P-GCV was microfluidized into 4.4-microm (median) particles, injected into rabbit vitreous. The vitreous drug level was then measured at different time points. Crystalline HDP-cCDV was synthesized, suspended in 5% dextrose, and injected into the rabbit's vitreous at 10, 55, 100, 550, or 1000 microg in 50 microL vehicle per eye, to determine the highest nontoxic dose. The dose, 100 microg, was injected into 24 rabbit eyes, to evaluate pharmacokinetics; into 14 rabbit eyes with established HSV retinitis, to evaluate its efficacy; and into 58 rabbit eyes before herpes simplex virus (HSV) infection to evaluate its intraocular antiviral duration. RESULTS: Microfluidized particles of HDP-P-GCV showed an increased drug release rate compared with the large-particle drug formulation, with area under concentration-time curve (AUC) of 219.8 +/- 114.1 (n=3) versus 108.3 +/- 47.2 (n=3) for unmodified HDP-P-GCV during the 12-week period after a 2.8-micromole intravitreal injection. There was a 103% increase of the drug released from the microfluidized formulation of HDP-P-GCV versus the unmodified formulation. Intravitreal injections of HDP-cCDV at doses of 100 microg/eye or lower were not toxic. After the 100 microg/eye injections, HPLC analysis showed a vitreous HDP-cCDV level of 0.05 microM at week 5, which declined to 0.002 microM at week 8. The concentration at week 8 (0.002 microM) remained above the IC50 for cytomegalovirus (0.0003 microM). The pretreatment study demonstrated an antiviral effect that lasted 100 days after a single intravitreal injection. CONCLUSIONS: This crystalline lipid prodrug intravitreal delivery system is an effective approach to achieving sustained, therapeutic drug levels in the eye. Small microfluidized particles of HDP-P-GCV provide more rapid dissolution and higher vitreous drug levels.     

Inverse levels of pigment epithelium-derived factor and vascular endothelial growth factor in the vitreous of eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy

PURPOSE: To determine the vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy. DESIGN: Prospective, noncomparative case series. METHODS: Pigment epithelium-derived factor and vascular endothelial growth factor concentrations were measured by enzyme-linked immunosorbent assay in 26 eyes with retinal detachment, 6 with proliferative vitreoretinopathy, and 14 with an idiopathic macular hole. RESULTS: Pigment epithelium-derived factor concentration in proliferative vitreoretinopathy (0.57 +/- 0.05 microg/ml) was lower (P =.0069), and retinal detachment (2.37 +/- 0.34 microg/ml) was higher (P =.16) than that in macular hole (1.71 +/- 0.22 microg/ml). Vascular endothelial growth factor concentration (168 +/- 139 microg/ml) in proliferative vitreoretinopathy was significantly higher than that in retinal detachment (11 +/- 11 microg/ml, P =.0084) and macular hole (not detectable, P =.0095). CONCLUSION: Lower levels of pigment epithelium-derived factor and higher levels of vascular endothelial growth factor may be related to ocular cell proliferation.     

Grepafloxacin concentration in ocular tissues after intravenous infusion in rabbits with intraocular inflammation

PURPOSE: To determine the penetration of grepafloxacin into ocular tissues during experimental ocular inflammation. METHODS: 10 albino and 10 pigmented rabbits underwent a continuous intravenous infusion of the drug 24 h after injecting Salmonella typhimurium toxin intravitreously, creating ocular inflammation. The animals were killed and grepafloxacin levels were determined in plasma and ocular tissues using high performance liquid chromatography. RESULTS: Grepafloxacin levels achieved a steady-state plasma concentration of 1.5 microg/ml. The drug diffused more towards vascularized tissues (chorioretina and iris) in both albino and pigmented rabbits with a tissue/serum ratio higher than 1. Grepafloxacin showed more affinity to pigmented tissue, rising levels of 40,000-50,000 ng/g in the chorioretina and iris in pigmented animals. After inflammation, grepafloxacin intraocular penetration increased in albino animals with levels exceeding the minimum inhibitory concentration for the most common ocular pathogens. CONCLUSION: Grepafloxacin intraocular penetration is higher in pigmented tissues. Ocular inflammation increases the drug penetration into the vitreous.     

Intravitreal penetration of cefepime after systemic administration to humans

PURPOSE: To investigate the penetration of cefepime (a fourth-generation cephalosporin) into the vitreous after single-dose intravenous administration to human subjects. METHODS: Thirty phakic patients about to undergo vitreous surgery received 1 g (group 1, 15 patients) or 2 g cefepime (group 2, 15 patients) in a single intravenous injection before surgery. The indications for vitreous surgery were retinal detachment with proliferative vitreoretinopathy (24 patients), retinal detachment associated with giant retinal tear (4 patients), macular hole (1 patient) and intraocular foreign body (1 patient). Samples of vitreous and serum were obtained at 0.5, 1, 2, 4 and 12 h after injection. Three patients were used for each sampling time and for 1 g and 2 g of cefepime. Samples were assayed for cefepime concentrations with high-performance liquid chromatography (HPLC). RESULTS: All the patients had detectable cefepime in their vitreous and serum measurable by HPLC. The level of cefepime in the vitreous peaked at 2 h and reached a minimum at 12 h after intravenous injection in both groups. A mean peak vitreous level of cefepime was 1.91 +/- 0.13 microg/ml in group 1 and 2.86 +/- 0.37 microg/ml in group 2. The level of cefepime in the vitreous at 12 h after injection was 0.89 +/- 0.14 microg/ml in group 1 and 0.97 +/- 0.30 microg/ml in group 2. CONCLUSION: The vitreous level of cefepime after intravenous injection was below the minimum inhibitory concentration (MIC(90)) against Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa, but was over the MIC(90) against Proteus mirabilis, Klebsiella spp., Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes and Enterobacter spp.     

Pigment epithelium-derived factor in the vitreous is low in diabetic retinopathy and high in rhegmatogenous retinal detachment

PURPOSE: To report the levels of pigment epithelium-derived factor in the vitreous of patients with diabetic retinopathy, rhegmatogenous retinal detachment, and idiopathic macular hole. METHODS: Using enzyme-linked immunosorbent assay, we measured the levels of pigment epithelium-derived factor in the vitreous of 34 eyes of 33 patients who underwent vitrectomy for the treatment of diabetic retinopathy (17 eyes of 16 patients), rhegmatogenous retinal detachment (10 eyes), and idiopathic macular hole (seven eyes). RESULTS: The vitreal concentration of pigment epithelium-derived factor was 1.15 +/- 0.23 microg/ml (mean +/- standard error) in eyes with diabetic retinopathy, 3.28 +/- 0.69 microg/ml in rhegmatogenous retinal detachment, and 1.71 +/- 0.39 microg/ml in idiopathic macular hole. The pigment epithelium-derived factor level in rhegmatogenous retinal detachment was significantly higher than that in diabetic retinopathy (P =.0008) and idiopathic macular hole (P =.034). For eyes with diabetic retinopathy, the pigment epithelium-derived factor level was 0.88 +/- 0.21 microg/ml in proliferative diabetic retinopathy and 2.43 +/- 0.37 microg/ml in nonproliferative diabetic retinopathy (P =.0083). Additionally, the pigment epithelium-derived factor level in active diabetic retinopathy (0.70 +/- 0.22 microg/ml) was significantly lower than the level in inactive diabetic retinopathy (1.79 +/- 0.35 microg/ml; P =.018). CONCLUSIONS: These results suggest that pigment epithelium-derived factor inhibits angiogenesis and that lower levels of pigment epithelium-derived factor may be related to the angiogenesis in diabetic retinopathy and result in active proliferative diabetic retinopathy. The results also suggest that higher levels of pigment epithelium-derived factor in the eyes with rhegmatogenous retinal detachment may act as a neuroprotective agent for the detached retina.     

An in vitro study on the compatibility and precipitation of a combination of ciprofloxacin and vancomycin in human vitreous

AIMS: To investigate the precipitation process of a mixture of vancomycin and ciprofloxacin by equilibrium dialysis and its subsequent effect on the level of available free antibiotics. METHODS: Concentrations of vancomycin and ciprofloxacin in an equilibrium dialysis chamber were measured during the equilibrium process by high performance liquid chromatography and fluorescence polarisation immunoassay. Normal saline (NS), balanced salt solution plus (BSS Plus), and vitreous were used separately as the medium of dialysis. RESULTS: Precipitation of ciprofloxacin occurred on incubation at 37 degrees C. It formed precipitate on its own or when mixed with vancomycin in all the three media of NS, BSS Plus, and vitreous. There was more precipitation at higher initial ciprofloxacin concentrations; at 25.0 mg/l about 75% free drug in BSS Plus was lost after 72 hours. The extent of precipitation was similar in both NS and BSS Plus. In the dialysis chambers, 20 mg/l ciprofloxacin dialysed against 125 mg/l vancomycin was reduced to a concentration about 5.0 mg/l after 168 hours. Precipitation of vancomycin was negligible. Ciprofloxacin precipitated in vitreous at body temperature, irrespective of the presence of vancomycin. Even after precipitation, the resultant concentration of ciprofloxacin was still higher than the MIC(90) of the drug against most Gram negative organisms. CONCLUSIONS: Based on this in vitro study, ciprofloxacin precipitated in vitreous at body temperature, irrespective of the presence of vancomycin or the medium for intravitreal injection. The resultant amount of ciprofloxacin was still higher than the MIC(90) of the drug against most Gram negative organisms after precipitation. The authors suggest ciprofloxacin in place of ceftazidime when used in combination with vancomycin for treatment of infective endophthalmitis.     

Vitreous penetration of orally administered valacyclovir

PURPOSE: To investigate the vitreous penetration of acyclovir, the active metabolite of valacyclovir, after oral administration of valacyclovir. DESIGN: Prospective, interventional case series. METHODS: Ten patients scheduled for elective pars plana vitrectomy at a single academic institution were given three oral doses of valacyclovir 1000 mg eight hours apart the day before surgery, with a fourth dose on the morning of surgery. Blood and undiluted vitreous samples were obtained during surgery and subsequently were analyzed with high-performance liquid chromatography to determine the concentrations of acyclovir present. RESULTS: Ten eyes of 10 subjects ranging in age from 46 to 83 years were included. All patients had normal renal and hepatic function as confirmed by metabolic panels obtained before surgery. Mean serum acyclovir concentration +/- standard deviation was 4.41 +/- 0.88 microg/ml (range, 3.18 to 5.92 microg/ml), mean vitreous acyclovir concentration was 1.03 +/- 0.23 microg/ml (range, 0.67 to 1.33 microg/ml), and mean vitreous-to-serum concentration ratio of acyclovir was 0.24 +/- 0.06 (range, 0.16 to 0.34). CONCLUSIONS: Orally administered valacyclovir results in substantial vitreous penetration of acyclovir. The vitreous concentrations achieved in noninflamed eyes are within the reported inhibitory ranges for most strains of herpes simplex 1, herpes simplex 2, and varicella zoster virus. This suggests that orally administered valacyclovir may be an alternative to intravenous acyclovir in the treatment of acute retinal necrosis.     

Lactoferrin increases the susceptibility of S. epidermidis biofilms to lysozyme and vancomycin.

PURPOSE: The tear cationic protein lactoferrin increases the activity of various antimicrobial agents against suspended bacterial cultures including Staphylococcus epidermidis, the predominant causative agent of intraocular lens biofilm infections. We investigated the ability of lactoferrin to enhance the activity of vancomycin and lysozyme against biofilms of a clinical S. epidermidis isolate. METHODS: Biofilms were prepared on soft contact lenses and cells released from the biofilm surface were collected from the surrounding broth. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against the intact biofilm, released cells and suspended bacteria were evaluated using vancomycin with and without lactoferrin. RESULTS: Lactoferrin induced a two-fold reduction in the MBC of vancomycin for biofilm (p < 0.01) and biofilm-released cells from 64 microg/ml to 32 microg/ml and similarly decreased the MIC for biofilm-released cells (p < 0.01) from 32 microg/ml to 16 microg/ml. With or without lactoferrin, the MIC of vancomycin for suspended cells (2 and 4 microg/ml respectively) was less (p < 0.01) than that of both the biofilm (32 and 32 microg/ml) and biofilm-released cells (16 and 32 microg/ml). Lactoferrin did not reduce the MIC of lysozyme, but, at a lysozyme concentration of 16 mg/ml, did significantly (p < 0.05) reduce the number of viable biofilm and biofilm-released cells. CONCLUSIONS: Lactoferrin displays potential as an adjunctive agent to vancomycin in the treatment of S. epidermidis biofilm infections, such as endophthalmitis, associated with intraocular lenses.     

万古霉素在正常兔眼和细菌性眼内炎兔眼内的药代动力学研究

背景万古霉素近年来常被作为金黄色葡萄球菌性眼内炎治疗的首选药物,万古霉素在眼内药代动力学的研究报道较少。目的观察万古霉素在正常兔眼和细菌性眼内炎兔眼房水、玻璃体及血清中质量浓度的变化,并进行药代动力学参数比较。方法选取健康成年兔72只,采用随机数字表法分为正常组和眼内炎组,每组36只。眼内炎组兔右眼玻璃体腔内接种2000CFU／ml金黄色葡萄球菌建立眼内炎模型,注射后72h待出现典型的眼内炎表现时,兔眼玻璃体腔内注射10g／L万古霉素注射液0．1ml,分别于注射后0．5、2、4、6、12、24、48、72、84h经兔耳缘静脉采血2ml,之后以空气栓塞法处死动物,摘除眼球,收集房水和玻璃体,利用高效液相色谱仪紫外（HPLC—UV）法检测万古霉素在血液、房水和玻璃体内的质量浓度。3p97药代动力学软件拟合药代动力学参数。结果HPLC法的准确度和精确度符合生物样品的检测要求。玻璃体腔内注射万古霉素后,其在正常兔眼内的代谢呈二室模型,拟合曲线的高峰质量浓度Cmax分别为50．16mg／L和751．42mg／L,t1/2为51．04h和53．21h;其在金黄色葡萄球菌性眼内炎兔眼中代谢呈一室模型,高峰质量浓度Cmax分别为24．94mg／L和687．66mg／L,t1/2分别为11．42h和12．91h,2组动物血药质量浓度均较低,差异无统计学意义（P〉0．05）。正常组和眼内炎组玻璃体腔内注射万古霉素后随时间延长,玻璃体中万古霉素的质量浓度逐渐下降,而房水中出现先升高后下降的趋势。与正常组相应时间点比较,眼内炎组玻璃体和房水中万古霉素的质量浓度均明显下降,差异均有统计学意义（P〈0．05,P〈0．01）。结论HPLC能满足万古霉素药代动力学分析的需要;万古霉素在正常兔眼内的质量浓度较高,清除缓慢,而在细菌性眼内炎兔眼中质量浓度较低、清除较快。     

Intraocular penetration of vancomycin eye drops after application to the medial canthus with closed lids

AIMS: To investigate the intraocular penetration of vancomycin eye drops and to compare the conventional method of drop instillation to the lower cul de sac with applying drops to the medial canthus with closed lids. METHODS: This prospective randomised trial evaluated 53 eyes of 53 patients who had undergone extracapsular cataract extraction (ECCE) with intraocular lens implantation. Vancomycin (50 mg/ml) eye drops were applied to either the lower cul de sac with open lids (conventional method), or to the medial canthus with the patient in a supine position and with closed lids. After paracentesis performed during ECCE, an aqueous humour sample was taken and vancomycin concentration was measured using the TDX vancomycin assay (fluorescence polarisation immunoassay). RESULTS: Vancomycin concentration in the anterior chamber were above the minimal inhibitory concentration for Gram positive bacteria in the two methods of drop instillation examined (2.04 (SD 1.9) microg/ml and 1.49 (1.1) microg/ml in the open and closed methods, respectively (p =0.202)). CONCLUSIONS: Vancomycin (50 mg/ml) reaches therapeutic concentration in the anterior chamber after topical drop application. Comparable concentrations were reached when drops were applied in either the lower cul de sac or to the medial canthus with closed lids. The latter method is proposed as likely to improve patient compliance.