Intraocular penetration of tri-tetracyclines after parenteral and subconjunctival administration

Summary Methacycline, doxycycline, and oxytetracycline were administered to rabbits in the form of tri-tetracycline complexes and pyrrolidinomethyloxytetracycline by i.v. or subconjuntival injection. Antibiotic levels in the aqueous humour proved to be highest after tri-methacycline when the substances were administered by the i.v. route and after administration of tri-doxycycline when they were given subconjunctivally. Administration of tri-oxytetracyclines resulted in higher aqueous humour levels than pyrrolidinomethyloxytetracycline after both i.v. and subconjunctival administration. Chemosis was never observed.

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Zusammenfassung Kaninchen wurden Methacyclin, Doxycyclin und Oxytetracyclin in der Form von Tri-tetracyclin Komplexen und Pyrrolidinomethyloxytetracyclin intravenös oder subconjunctival verabreicht. Der höchste Kammerwasserspiegel wurde nach Tri-methacyclin erreicht, wenn die Applikation intravenös erfolgte und nach Tri-doxycyclin im Falle von subconjunktivaler Verabreichung. Die intravenöse oder subconjunktivale Application von Tri-oxytetracyclin gab höhere Kammerwasserkonzentrationen als Pyrrolidinomethyloxytetracyclin. Chemosis war nie zu beobachten.

     

Aqueous humor levels of gentamicin after parenteral, subconjunctival and topical administration (aithor's transl)]

The purpose of this study was to determine the concentration of Gentamicin in blood serum and primary aqueous humor at varying periods of time after intravenous, intramuscular, subconjunctival and topical administration of Gentamicin. Therapeutic effective levels in primary aqueous humor were measured only after subconjunctival injections. The only broad spectrum antibiotics are the aminoglykosides Gentamicin, Tobramycin, Sisomicin and Amikacin. For prompt treatment of bacterial endophthalmitis without bacterial culture and antibiotic sensitivity testing therefore subconjunctival injection of Gentamicin is necessary.     

Intraocular levels of cefamandole compared with cefazolin after subconjunctival injection in rabbits.

We compared the intraocular pharmacokinetics of cefazolin with those of cefamandole, a recently marketed cephalosporin with enhanced activity against gram-negative bacilli. Following subconjunctival injection of 12.5 mg into infected eyes (S. aureus endophthalmitis) of pigmented rabbits, both drugs reached peak concentrations greater than 100 microgram/gm in cornea, sclera, and choroid-retina. The half-life was markedly shorter in sclera and choroid-retina than in cornea. Levels in the aqueous humor rose and fell more slowly than those in ocular tissues, reaching a maximum of only 5 to 10 microgram/ml. The pharmacokinetics of the two drugs were virtually identical in most intraocular sites. When cefazolin, which was less irritating than cefamandole by the subconjunctival route, was given in a dosage of 100 mg, levels in ocular tissues were increased by twofold to fourfold and in aqueous humor by 15-fold, compared to the concentrations produced by the 12.5 mg dosage. Levels in the vitreous humor were exceedingly low with both drugs; mean peak concentrations were 0.24 microgram/ml after the 12.5 mg dosage of cefamandole and less than 1.6 microgram/ml after the 100 mg dose of cefazolin.     

Intraocular ciprofloxacin levels after oral administration in silicone oil-filled eyes

PURPOSE: To evaluate penetration of oral ciprofloxacin in the retro-silicone oil space fluid (RSOF) in silicone oil (SO)-filled eyes. METHODS: One dose of 750 mg ciprofloxacin was given to two groups of five patients with vitrectomized eyes with SO endotamponade, 4 hours (group I) and 8 hours (group II) before SO removal. In 10 vitrectomized eyes with SO endotamponade (group III) and another 10 patients scheduled for vitrectomy for the first time (group IV), two 750-mg doses every 12 hours, with the last dose 12 hours before surgery, were given. Blood samples were taken at the time of collection of RSOF samples in groups I, II, and III and of the vitreous in group IV. All samples were assayed for ciprofloxacin by high-performance liquid chromatography. RESULTS: The mean drug concentration in the RSOF was 0.34 +/- 0.09, 0.37 +/- 0.04, 0.84 +/- 0.29, and 0.44 +/- 0.11 micro g/mL in groups I, II, III, and IV respectively. The mean serum concentration was 1.29 +/- 0.63, 1.08 +/- 0.14, 1.93 +/- 0.84, and 1.34 +/- 0.55 micro g/mL in groups I, II, III, and IV respectively with no statistically significant difference between groups III and IV (P = 0.081). CONCLUSIONS: Antibiotic levels in the RSOF in SO-filled eyes after oral administration of ciprofloxacin in two 750-mg doses exceeded the minimal inhibitory concentration for 90% of isolates (MIC(90)) for most bacterial species and was higher than levels reached in the vitreous in nonvitrectomized eyes (P = 0.001).     

Intraocular penetration kinetics of prednisolone after subconjunctival injection in rabbits

Prednisolone concentrations in cornea, aqueous humor, and vitreous humor and the residual amount in conjunctival tissue were assayed by high-performance liquid chromatography during a 14-hour period after subconjunctival injection of prednisolone sodium succinate in rabbits. Prednisolone was concentrated in the corneal epithelium and reached a peak within 5 min, whereas the peak level of prednisolone in stroma-endothelium was achieved 1 h after the injection. There was an apparent linear binding of prednisolone with the ocular tissue homogenates and fluids except for the vitreous humor. However, the protein binding of prednisolone with vitreous humor showed marked concentration dependency. A pharmacokinetic model involving a rapid conversion to prednisolone from its ester prodrug, first-order transfer to various tissues, and first-order elimination of unbound prednisolone from vitreous humor succeeded in predicting the observed concentration-time profiles of prednisolone in various ocular tissues and fluids after subconjunctival injection at three different doses: 0.1, 1.0, and 10.0 mg/kg. The present model predicted that absorption into precorneal area and epithelium and direct penetration into aqueous humor and vitreous humor are 1.7, 0.1, and 0.2% of the applied dose, respectively, and that almost the entire dose (98%) is absorbed into the systemic circulation, with a half-life of 38 min.     

Intraocular pressure reduction after subconjunctival mitomycin-C in absolute glaucomatous eyes

This study investigated the intraocular pressure (IOP) lowering effect of subconjunctival injection of mitomycin-C in human eyes blinded by glaucoma. Twenty eyes received injection of 1 mg of mitomycin-C and were followed up for 2 months. A statistically significant decline in IOP was observed until day 30 in all patients. The IOP-lowering effect of 1 mg of subconjunctivally injected mitomycin in patients with intractable glaucoma appears to be temporary.     

Systemic absorption of topical and subconjunctival gentamicin.

Ten patients received ocular gentamicin therapy topically or subconjunctivally. Systemic absorption was not detected after topical use but was detected after subconjuctival administration. The relative safety of ocular gentamicin therapy is discussed and the literature is reviewed.     

A study of aqueous and serum levels of ceftazidime following subconjunctival administration.

Patients undergoing cataract surgery may develop an infective endophthalmitis postoperatively which may result in the loss of an eye. This study was carried out to measure aqueous humour levels and to assess patients' tolerance of ceftazidime, a potent antipseudomonal cephalosporin, given subconjunctivally. Eighteen patients received 125 mg ceftazidime subconjunctivally before they underwent routine cataract surgery. A further two patients received 62.5 mg subconjunctivally. The results show good penetration into the aqueous humour well above the minimum inhibitory concentrations (MICs) of possible pathogens. There were no postoperative infections, no local irritation, and no systemic side effects.     

Intraocular distribution of 70-kDa dextran after subconjunctival injection in mice

PURPOSE: To investigate the intraocular distribution kinetics of 70-kDa dextran after subconjunctival injection. METHODS: The right eye of 15 mice received a single subconjunctival injection of a 1.5-microL solution of 0.25% 70-kDa tetramethylrhodamine-dextran (TMR-D). The distribution of fluorescent labeling in eye sections was examined by fluorescence microscopy at 0.25, 1, 4, 24, or 72 hours after the injection. The brightness and homogeneity of fluorescence in the sclera, choroid, and retina were scored near the injection site, on the side of the globe opposite the injection site, and adjacent to the optic nerve head. Fluorescence intensity within the sclera and choroid adjacent to the optic nerve was assessed quantitatively by imaging densitometry. RESULTS: TMR-D readily diffused transsclerally and dispersed throughout a large portion of the sclera, uvea, and cornea. Shortly after the injection, homogenous fluorescence was observed in the sclera and choroid on the same meridian as that of the injection site. This fluorescence gradually decreased in intensity with distance from the injection site. At the opposite meridian, fluorescence in the choroid was more intense than in the adjacent sclera and could be traced up to the ciliary muscle. TMR-D was also observed in the retinal and optic nerve vessels. The intensity of scleral and choroidal fluorescence adjacent to the optic nerve reached a maxima at 1 hour, and then decreased slowly, with half-lives of approximately 16 and 100 hours, respectively. Visible fluorescence was maintained at least until 72 hours in the sclera, choroid, iris, and cornea. Specific fluorescent labeling was never found in the contralateral eyes. CONCLUSIONS: Macromolecular 70-kDa dextran can be readily delivered to the mouse retina and uveal tissues by subconjunctival injection through transscleral diffusion, local hematogenous spread, and possibly movement through the uveoscleral outflow pathway. Subconjunctival injection may be a useful approach for delivering macromolecules to the retina and uvea.     

Intraocular lens implantation with subconjunctival local anesthesia

Between April 1988 and May 1989 extracapsular cataract extraction with intraocular lens implantation was performed on 66 (63 patients) with only subconjunctival local anesthesia (lidocaine/carbostesin with adrenaline 1.5 ml). Anesthesia was excellent, and movements of the globe and lids hardly interfered with the procedure. Subconjunctival anesthesia is less dangerous and more comfortable for the patient. The intraoperative hypotension of the globe is remarkable.     

Recurrent herpetic keratitis during topical acyclovir application.

Dendritic herpetic keratitis developed in a 49-year-old patient during topical acyclovir treatment. A positive herpes simplex culture was obtained. After acyclovir was replaced by trifluorothymidine and interferon, the dendritic lesion disappeared and herpes simplex culture became negative. Six months later a carcinoma of the larynx was diagnosed. The acyclovir-resistant herpetic keratitis may be associated with the carcinoma because resistant herpes simplex virus strains are predominantly described in patients suffering from immune deficiency.     

Corneal and intraocular penetration of topical and subconjunctival fusidic acid.

Corneal tissue absorption and intraocular penetration of fusidic acid were assessed in the rabbit after topical or subconjunctival application. Corneal tissue levels of fusidic acid one hour after the last topical application of the drug were well above the minimum inhibitory concentrations (MICs) for most Gram-positive and many Gram-negative organisms. Adequate levels were achieved in the aqueous at one hour following the last topical application, but no significant levels were detected in the vitreous. The corneal tissue and aqueous levels declined at 12 and 24 hours following the last drug application, however, corneal tissue levels at 24 hours were considered to be above the MICs for most Gram-positive organisms. A single subconjunctival injection of 100 mg of fusidic acid produced levels above the MICs of most organisms in the cornea, aqueous, and vitreous which persisted over 24 hours, but subconjunctival injection of fusidic acid at this concentration resulted in conjunctival necrosis and corneal decompensation. Fusidic acid penetrates well into avascular tissue and fully penetrates corneas with both intact and debrided epithelium, as evidenced by the intracameral drug levels. Good corneal penetration and absence of known topical toxicity make fusidic acid suitable for the treatment of microbial keratitis caused by susceptible organisms.     

Intraocular penetration of rifampin after oral administration

Rifampin, the most potent anti-staphylococcal drug known, was examined for its penetration into the aqueous and vitreous of rabbits after a single oral dose of 150 mg, 300 mg, or 600 mg. Maximum levels after the 150 mg dose were achieved at 4 h and were 4.2 μg/ml in the aqueous and 2.2 μg/ml in the vitreous. After the 300 mg dose, maximum levels were also achieved at 4 h, and were 5.0 μg/ml in the aqueous and 2.6 μg/ml in the vitreous. The 600 mg dose produced maximum levels at 6 h after administration, with 20.0 μg/ml in the aqueous and 15.2 μg/ml in the vitreous. These levels exceed the mimimum inhibitory concentration for many microorganisms and suggest additional investigation into possible applications of systemic rifampin in the prophylaxis and treatment of bacterial endophthalmitis. This work was supported in part by NEI grant EY04474 (Dr. D’Amico)