Aqueous and vitreous penetration of linezolid (Zyvox) after oral administration

doi:10.1016/j.ophtha.2003.09.042

Ophthalmology

Volume 111, Issue 6, June 2004, Pages 1191-1195

Poster presented at: Association for Research in Vision and Ophthalmology meeting, May, 2003; Ft. Lauderdale.

https://doi.org/10.1016/j.ophtha.2003.09.042 Get rights and content

Abstract

Objective

To investigate the penetration of linezolid, a synthetic oxazolidinone antibiotic, into the aqueous and vitreous humor after oral administration.

Design

Noncomparative interventional, prospective case series study, randomized into group 1 (dose, one 600-mg tablet) or group 2 (2 doses of 600 mg given 12 hours apart).

Participants

Patients undergoing pars plana vitrectomy between March 2001 and August 2002 at the University of Illinois at Chicago Eye Center who had not had prior vitrectomy surgery.

Methods

Aqueous, vitreous, and plasma samples were obtained and analyzed from 29 patients after oral administration of 1 dose (group 1A, 13 patients [13 eyes] sampled less than 2 hours after administration; group 1B, 9 patients [9 eyes] sampled more than 2 hours after administration) or 2 doses 12 hours apart (group 2, 7 patients [7 eyes]) before surgery.

Main outcome measures

Aqueous, vitreous, and plasma concentrations of linezolid (micrograms per milliliter).

Results

Group 1A achieved mean aqueous, vitreous, and plasma levels of 0.77±0.6 μg/mL, 0.3±0.3 μg/mL, and 5.0±3.3 μg/mL, respectively. Group 1B achieved mean aqueous, vitreous, and plasma levels of 3.8±1.2 μg/mL, 2.3±1.4 μg/mL, and 7.6±2.7 μg/mL, respectively. Group 2 achieved mean aqueous, vitreous, and plasma levels of 6.6±2.7 μg/mL, 5.7±2.7 μg/mL, and 10.3±4.1 μg/mL, respectively.

Conclusions

Mean inhibitory aqueous and vitreous minimum inhibitory concentrations for 90% of isolates (MIC₉₀) were achieved against all gram-positive bacteria, including vancomycin-resistant enterococcus, methicillin-resistant Staphylococcus aureus, and streptococcal species after 2 doses given 12 hours apart. Mean MIC₉₀ were achieved for many gram-positive pathogens after only one dose in many patients after approximately 4 hours.

Section snippets

Materials and methods

The study was approved by the University of Illinois at Chicago Institutional Review Board before initiation. Patients undergoing vitrectomy between March 2001 and August 2002 at the University of Illinois at Chicago Eye Center who had not had prior pars plana vitrectomy surgery were randomly assigned to be given 1 (group 1) or 2 (group 2) doses of 600-mg linezolid (12 hours apart) before surgery. The inclusion criteria included any patients 18 years or older. Exclusion criteria included any

Results

Group 1 contained 22 patients (22 eyes; 13 men and 9 women) with an average age of 48.9 years. Group 2 contained 7 patients (7 eyes; 2 men and 5 women) with an average age of 52.7.

Surgical indications included dislocated lens or retained lens material (3), nonclearing vitreous hemorrhage (8), retinal detachment (7), tractional retinal detachment (5), idiopathic macular hole (3), shunt revision (1), optic nerve pit (1), and chronic iridocyclitis (1). Patients tolerated the medication well, with

Discussion

Our study demonstrated that oral linezolid (600 mg every 12 hours × 2 doses) provided mean inhibitory concentrations in the aqueous and vitreous fluids against major gram-positive bacteria including VRE, MRSA, and streptococcal species. Concentrations above the mean inhibitory concentrations for 90% of isolates (MIC₉₀) were reached in the vitreous cavity against S. aureus, S. epidermidis, S. pneumonia, Bacillus cereus, and Propionibacterium acnes (Table 2).

A previous study documented good

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The first case report of endophthalmitis with VRE (Enterococcus faecium) was by Bains et al.11 In addition to intravitreal vancomycin and amikacin, they administered intravenous linezolid 600 mg BID but stopped short of administering the medication into the vitreous. The literature suggests that oral linezolid 600 mg BID is capable of crossing the blood retina barrier.12,13 We administered oral linezolid for about three weeks, but found it ineffective; clearance of the vitreous haze and opacities.
Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including Streptococcus, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). We report on a case of endophthalmitis caused by vancomycin-resistant Enterococcus feacium treated with intravitreal linezolid. It has proved efficacious in animal models but its safety in humans is not fully known.
An 84-year-old man who had phacoemulsification surgery and anterior chamber intraocular lens due to posterior capsule rent. Visual acuity (VA) following surgery was 6/24 uncorrected. The following week he developed signs of endophthalmitis, characterized by corneal infiltration and keratic precipitates, with anterior chamber and vitreous haze. Cultures yielded no growth, while repeated treatments with intravitreal vancomycin, ceftazidime, and amphotericin B did not control the infection. Vitrectomy was performed twice during the patient's course, with intravitreal amikacin injection after the second vitrectomy, but poor control of the endophthalmitis persisted. After several weeks of limited response to treatments, the diagnosis was finally made using Giemsa stain of direct smear which showed characteristic morphology of Enterococcus faecium. Linezolid, one of the oxazo-lidinones, was initially given in oral form 600 mg BID for three weeks, but did not prove efficacious. Subsequently, intravitreal linezolid 200 mcg in 0.1ml was injected, which cleared the vitreous and cornea infection within a week. However, there was a residual exudative detachment of the retina in the posterior pole, leaving the patient with a final vision of hand movement.
Vancomycin-resistant enterococcus is a rare cause of endophthalmitis. Intravitreal linezolid is an effective treatment, but the subsequent exudative retinal detachment may have been related to this novel therapy.
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Importantly, rifampicin has to be combined with an effective second anti-staphylococcal agent to prevent resistance. Mean vitreous levels of linezolid in phakic non-inflamed human eyes range from 1.2 to 3.7 mg/L after one dose [37–40], with two studies showing further accumulation after two doses (4.5 and 5.7 mg/L) [37,39]. The good penetration into the vitreous is consistent with CSF penetration [22].
Adjunctive systemic antibiotic therapy for treatment of bacterial endophthalmitis is controversial but common practice due to the severity of the disease. In the absence of guidance documents, several antibiotic regimens are being used without applying evidence-based prescribing, leading to inappropriate treatment of this serious eye condition.
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The best-documented agents achieving therapeutic levels in the vitreous are meropenem, linezolid and moxifloxacin. Vancomycin, cefazoline, ceftriaxone, ceftazidime, imipenem and trimethoprim-sulfamethoxazole reach levels justifying their use in specific situations. Available data do not support the use of ciprofloxacin, levofloxacin, aminoglycosides, aminopenicillins, piperacillin, cefepime and clarithromycin. With very limited but available promising data, the use of daptomycin and rifampicin deserves further investigation.
The choice of the adjunctive systemic antibiotic agent—in situations where it is considered relevant for treatment—must to date be made on an individual basis, considering microbiological aspects as well as operative status and inflammation of the eye. This review gives a systematic overview of antibiotic options and provides guidance to the clinician striving for optimal systemic antibiotic treatment of bacterial endophthalmitis.
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Concentrations raised to 3.9 (±1.1) μg/mL after two hours, to reach maximum concentrations between two and four hours after intake at 6.8 (±1.2) μg/mL, to decline to 3.9 (±1.6) μg/mL after 4 to 8 hours.107 Comparable concentrations were reached after ingestion of two oral doses of 600 mg at 12-hour interval with 6.6 (±2.7) μg/mL sampled 18 hours after the first dose48 and after single intravenous infusion of 600 mg linezolid 5.17 (±0.95) μg/mL retrieved 2–4.5 hours after the end of the infusion.134 Vitreal concentrations after a single oral dose of 600 mg linezolid were 1.25 μg/mL measured 2–3.5 hours after ingestion.25
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The use of oral antibiotics in the setting of BAI remains controversial, and decisions regarding their administration should be made on a case-by-case basis. Linezolid lacks cross-resistance with other antibiotic classes and is effective for organisms involved in BAI and has demonstrated good penetration into the aqueous and vitreous cavities.60,67 Oral linezolid may be a potential alternative if its efficacy in this condition is confirmed in future studies.
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Manuscript no. 230393.

The authors have no financial interest in Zyvox or any other product mentioned in the article.

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Original articleAqueous and vitreous penetration of linezolid (Zyvox) after oral administration☆

Abstract

Objective

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Section snippets

Materials and methods

Results

Discussion

Surv Ophthalmol

Ophthalmology

Am J Ophthalmol

Lancet

Ophthalmology

Ophthalmology

J Cataract Refract Surg

Intracorneal, aqueous humor, and vitreous humor penetration of topical and oral ofloxacin

Arch Ophthalmol

Ofloxacin penetration into the eye after intravenous and topical administration

Retina

Penetration of ofloxacin in human aqueous and vitreous humors following oral and topical administration

Retina

Original article
Aqueous and vitreous penetration of linezolid (Zyvox) after oral administration☆