Download The penetration of gentamicin into the vitreous humor in man.

The Penetration of Gentamicin into the
Vitreous Humor in Man
Ethan Rubinstein, Johana Goldfarb, Gad Keren, Michael Blumenthal, and Giora Treister
Twenty-two patients received gentamicin intramuscularly or subconjunctivally 35-220 min prior to
undergoing ocular surgery. There were no detectable gentamicin levels in the vitreous humor of
patients who received the drug systemically. Of the patients who received gentamicin subconjunctivally, three quarters had no detectable gentamicin levels, only three of these patients had therapeutic
concentrations in their vitreous humor. These results confirm kinetic drug studies performed in animals
in which low or absent vitreal gentamicin levels were observed following systemic and subconjunctival
administrations. It is suggested that intravitreal injection of aminoglycosides is required in the treatment of bacterial endophthalmitis. Invest Ophthalmol Vis Sci 24:637-639, 1983
Materials and Methods
The transport of aminoglycosides into the vitreous
humor in humans has not been studied extensively,
despite the frequent use of this class of agents in eye
infections.
Animal studies show low or absent concentrations
of gentamicin in the vitreous humor following administration by drop or ointment onto both normal
and infected rabbit corneas.1 Low or absent vitreal
concentrations of gentamicin and tobramycin have
also been reported following intravenous administration in normal and aphakic rabbits as well as in normal guinea pigs.2"6 However, in an experimental
model of bacterial endophthalmitis in the rabbit low
vitreal gentamicin concentrations (2 fig/m\ were
found following continuous intravenous gentamicin
infusions.7
In rabbits and guinea pigs low vitreal gentamicin
levels were found after subconjunctival administration6; significant levels were obtained when high doses
were used.4'5 In other studies therapeutic doses of gentamicin administered subconjunctivally resulted in
subtherapeutic vitreal levels in the eyes of infected
rabbits as well as in normal squirrel monkeys.6"9 In
view of the dissimilarities between the rabbit and the
human eye,10 we have investigated the penetration
of gentamicin into the human vitreous humor following intramuscular subconjunctival administration
in 22 patients undergoing vitreal surgery.
Twenty-two patients were studied. Ages ranged
from 31-78 years. All patients had serum creatinine
values below 3 mg% before receiving gentamicin.
Indications for surgery included: (1) Proliferative
diabetic retinopathy with vitreous hemorrhage and
traction retinal detachment (five cases). (2) Central
retinal vein occlusion with vitreous hemorrhage (five
cases). (3) Secondary operations for perforating eye
injuries with: vitreous hemorrhage (six cases), and
vitreous hemorrhage with tractional detachment of
the retina (three cases). (4) Secondary operations following periretinal proliferation with organized, total
retinal detachment (three cases).
Patients were randomly assigned to receive gentamicin (Miramycin, Teva, Israel) 1.6 mg/kg intramuscularly 35-90 min prior to operation or 40 mg
gentamicin subconjunctivally 60-220 min prior to
surgery. Subconjunctival administration was preceded by installation of benoxinate HCL 0.4% drops.
Informed consent was obtained in all cases. All surgical procedures were performed by one surgeon.
(GT). Local anesthesia was used in all cases.
Surgery included the creation of a fornix based
conjunctival flap. A 1-mm sclerotomy was made 4
mm from the temporal limbus, through which an
Ocutome® probe was then inserted into the vitreal
space. Vitreous humor samples, approximately 0.5
ml, were cut and sucked into containers through the
probe; irrigation of the globe was then begun. Samples
were obtained 15-20 min after beginning of the operation. At the time of vitreal sampling, a blood specimen was obtained from an antecubital vein.
Samples were handled as follows: Vitreal samples
From the Infectious Diseases Unit and the Goldschlager Eye
Institute, The Chaim Sheba Medical Center, Tel Aviv University
School of Medicine Tel Hashomer, Israel.
Submitted for publication March 3, 1982.
Reprint requests: Giora Treister, MD, Goldschlager Eye Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel.
0146-0404/83/0500/637/$0.95 © Association for Research in Vision and Ophthalmology
637
Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933339/ on 08/03/2017
638
INVESTIGATIVE OPHTHALMOLOGY G VISUAL SCIENCE / Moy 1983
Table 1. Serum and vitreous gentamicin
concentrations following a 1.6-mg/kg gentamicin
dose administered intramuscularly
Patient
Time in min between
administration and Serum cone. Vitreous cone.
sample collection
in ftg/ml
in ng/ml
30
35
90
70
45
90
75
80
11.0
70
60
8.0
10
6.4
<0.2
<0.2
<0.2
<0.2
<0.2
<0.2
<0.2
<0.2
<0.2
<0.2
mean (±SD)
64.5 (±21.5)
5.7 (±3.6)
<0.2
1
2
3
4
5
6
7
8
9
7.6
9.4
1.6
2.2
3.2
5.2
9.4
containing visible blood were discarded, and only
clear or slightly xanthochromic samples were analyzed necessitating the exclusion of four patients from
the study. Vitreal specimens were sonicated for 30
sec and were than incubated with an equal amount
of 1:1 mixture of collagenase, type U-S (100 units)
0.4% (sigma C2014, USA) and trypsin 0.25% (Gibco
Lab. USA) for 30 min at 37 C with constant agitation
(this procedure was shown by us to extract over 90%
of gentamicin added to vitreal substance obtained at
autopsy). Serum was separated promptly from whole
blood by centrifugation.
Gentamicin in serum and in the vitreous humor
were assayed by a radioimmunoassay in duplicate
(gentamicin RIA kit, New England Nuclear, USA).
Additionally, in several instances, a microbiologic
assay (using Ca++ and Mg++ supported Mueller-Hinton agar and Staphylococcus epidermidis as the test
Table 2. Serum and vitreal gentamicin
concentrations following a 40-mg gentamicin dose
administered subconjunctivally
Patient
Time in min. between
administration and Serum cone. Vitreous cone.
sample collection
in fig/ml
in fig/ml
1
2
3
4
5
6
7
8
9
10
11
12
60
60
90
60
60
45
130
120
220
110
120
80
mean (±SD)
96.2 (±48.5)
3.1
0.5
0
2.8
1.4
0.7
2.0
5.1
0.5
3.2
3.2
2.5
2.16 (±1.52)
<0.2
<0.2
3.1
<0.2
<0.2
<0.2
<0.2
<0.2
<0.2
10.5
<0.2
3.7
Vol. 24
organism) was also performed. Results obtained from
the vitreous humor were multiplied by two to correct
the dilution factor. The two assay methods used differed by no more than 8.3% for values in the therapeutic range. In both methods the sensitivity was 0.2
Results
Serum gentamicin levels ranged from 1.6-11 jig/
ml, with a mean (±SD) of 5.7 (±3.6) Mg/ml in the ten
patients who received intramuscular gentamicin.
There were no detectable levels in the vitreous humor
specimens obtained from these patients (Table 1).
The 12 patients who received subconjunctival gentamicin had mean serum gentamicin level of 2.16
(±1.52) /ig/ml. Nine of these patients had no gentamicin detected in the vitreous humor. Three had levels as follows: patient #3: 3.1 ng/ml; patient #10: 10.5
Mg/ml; and patient #12: 3.7 /ug/ml (Table 2).
None of these three patients had xanthochromic
vitreal fluid.
Discussion
Our data in humans confirm other studies in normal guinea pigs, and in normal and aphakic rabbits:
systemic administration of aminoglycosides results in
absent or subtherapeutic vitreal drug levels.2"6 Only
one study using systemic gentamicin administration
documented vitreal gentamicin concentrations of 2
/ug/ml when the drug was given in a continuous intravenous infusion to rabbits with experimental endophthalmitis.7
Following subconjunctival administration of 10
mg gentamicin to normal and aphakic rabbits vitreal
drug concentrations were reportedly in the range of
2-3 /xg/ml.4 Lower doses of gentamicin given by subconjunctival or retrobulbar injections to normal rabbits, to rabbits with experimental endophthalmitis,
and to squirrel monkeys, resulted in subtherapeutic
drug concentrations in the vitreous humor.4'89 In the
guinea pig, with experimental pseudomonas keratitis,
a large subconjunctival tobramycin dose (2 mg/kg)
resulted in a therapeutic (12.3 jig/ml) vitreal drug
level.5
In the present study, no drug was detected in the
vitreous humor in patients who received systemic
gentamicin. Similarly, it was not detected in 75% of
patients who received subconjunctival gentamicin. It
should, however, be noted that our patients had severe disturbances of their retinal vasculature that may
have affected free transport of gentamicin into the
vitreous humor. In addition, since only a single gentamicin injection was given, a kinetic steady state was
not achieved. Such a steady state may be associated
Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933339/ on 08/03/2017
No. 5
PENETRATION OF GENTAMICIN INTO HUMAN VITREOUS / Rubinstein er ol.
with higher vitreous humor gentamicin concentrations.
Three of the patients who received subconjunctival
injections had therapeutic gentamicin vitreal levels.
In none of these patients was the vitreal sample contaminated with blood that might have increased gentamicin concentrations. Since every effort was made
to inject the drug superficially we believe that the
subretinal space was not entered during the subconjunctival injection to account for these levels.
Patient #10, who had the highest vitreal gentamicin
level, had had repeated surgical procedures for an old
perforating eye injury with vitreal hemorrhage and
tractional retinal detachment; patients #3 and #12
had central retinal vein occlusion with vitreal hemorrhage due to proliferative diabetic retinopathy with
retinal detachment. These injuries may have diminished the blood-retinal-vitreal barrier." This barrier
may inhibit lipid insoluble, weak cationic molecules
like the aminoglycosides from reaching the vitreous
humor.
In patients who had no detectable vitreal humor
levels, time of sampling was somewhat earlier than
in the three patients with detectable levels. This raises
a question of whether our sampling period was too
short (Table 2).
Our data suggest that gentamicin, and probably
other aminoglycosides, cannot be used reliably in systemic or subconjunctival administrations. Studies
monitoring their concentrations in various eye tissues
and spaces under infectious conditions are needed
before recommendations can be made concerning
their use in bacterial endophthalmitis.
Intravitreal administration of aminoglycosides is
associated with: a low rate of local side effects,13 a
prolonged intravitreal half-life,15 and favorable clinical results.12"14 These factors, together with the present data, indicate that intravitreal administration of
aminoglycosides should be used in therapy of bacterial endophthalmitis.
639
Key words: gentamicin, penetration, vitreous humor, human eye
References
1. Ellerhorst B, Golden B, and Jarudi N: Ocular penetration of
topically applied gentamicin. Arch Ophthalmol 93:371, 1975.
2. Litwack KD, Pettit T, and Johnson BL Jr: Penetration of gentamicin; administered intramuscularly and subconjunctivally
into aqueous humor. Arch Ophthalmol 82:687, 1969.
3. Kuming BS and Tonkin M: Use of gentamicin sulphate in
ophthalmology. I. Absorption of gentamicin into the rabbit
aqueous. Br J Ophthalmol 58:609, 1974.
4. Peyman GA, May DR, Homer PI, and Kasbeer RT: Penetration of gentamicin into the aphakic eye. Ann Ophthalmol
9:871, 1977.
5. Davis SD, Sarff LD, and Hyndiuk RA: Antibiotic therapy of
experimental Pseudomonas keratitis in guinea pigs. Arch
Ophthalmol 95:1638, 1977.
6. Barza M, Kane A, and Baum J: The difficulty of determining
the route of intraocular penetration of gentamicin after subconjunctival injection in the rabbit. Invest Ophthalmol Vis Sci
20:509, 1981.
7. Barza M: Treatment of bacterial infections of the eye. Curr
Clin Top Infect Dis 1:158, 1980.
8. Barza M, Kane A, and Baum JL: Regional differences in ocular
concentration of gentamicin after subconjunctival and retrobulbar injection in the rabbit. Am J Ophthalmol 83:407, 1977.
9. Barza M, Kane A, and Baum J: Intraocular penetration of
gentamicin after subconjunctival and retrobulbar injection.
Am J Ophthalmol 85:541, 1978.
10. Maurice DM: Injection of drugs into the vitreous body. In
Symposium on Ocular Therapy, vol. 9, Leopold IH and Burns
RP, editors. New York, Wiley, 1976. pp. 59-72.
11. Gloor BP: The vitreous. In Adler's Physiology of the Eye,
Clinical Application, 6th ed, Moses RA, editor. St. Louis, CV
Mosby, 1975, pp. 252.
12. Peyman GA: Antibiotic administration in the treatment of
bacterial endophthalmitis. II. Intravitreal injections. Surv
Ophthalmol 21:332, 1977.
13. Forster RK, Zachary IG, Cottingham AJ Jr, Norton EWD:
Further observations on the diagnosis, cause, and treatment
of endophthalmitis. Am J Ophthalmol 81:52, 1976.
14. Baum JL: The treatment of bacterial endophthalmitis. Ophthalmology 85:350, 1978.
15. Cobo LM, Forster RK: The clearance of intravitreal gentamicin. Am J Ophthalmol 92:59, 1981.
Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933339/ on 08/03/2017