The Penetration of Oral Ciprofloxacin Into the Aqueous
Humor, Vitreous, and Subretinal Fluid of Humans
Mark R. Lesk, M.D., Helene Ammann, Ph.D., Gilles Marcil, M.D.,
Bernard Vinet, Ph.D., Laurent Lamer, M.D., and Mikael Sebag, M.D.
We examined ciprofloxacin levels in the aq-
ueous humor, vitreous, or subretinal fluid in
40 patients undergoing cataract extraction,
vitrectomy, or scleral buckling. Ciprofloxacln,
750 mg, was administered orally an average of
171/2 and 51/2 hours preoperatively. We obtained
mean ciprofloxacin levels of 0.53 ....g/ml in
aqueous humor, 0.51 ....g/ml in vitreous, and
0.71 ....g/ml in subretinal fluid. These vitreous
levels exceed the minimum inhibitory con-
centration (MIC)9o of Staphylococcus epider-
midis, Propionibacterium species, Pseudo-
monas aeruginosa, Proteus mirabilis, and
Haemophilus influenzae, as well as the MIC 70
of S. au reus and Bacillus cereus. Therefore,
ciprofloxacin may have a role in the manage-
ment and prevention of endophthalmitis.
ENDOPHTHALMITIS is one of the most serious
complications of intraocular procedures and
penetrating ocular trauma. Despite the best
available therapy, 80% of eyes with endoph-
thalmitis have a marked loss of visual acuity.'
Because systemically administered antibiot-
ics penetrate relatively poorly into the eye,
therapy of endophthalmitis includes intravitre-
ous antibiotic injections." Vitrectomy is often
indicated, as well. A few days after the intravit-
real injection, most of the injected antibiotic
has left the eye and maintenance of therapeutic
intraocular antibiotic levels depends on sys-
temically administered antibiotics.! Thus, the
Accepted for publication Jan. 29, 1993.
From the Departments of Ophthalmology (Drs. Lesk.
Marcil, Lamer, and Sebag) and Biochemistry (Drs. Am-
mann and Vinet), Notre-Dame Hospital, Montreal, Que-
bec, Canada. This study was supported by a grant from
Miles Canada Inc., Etobicoke, Ontario, Canada.
Reprint requests to Mark R. Lesk, M.D., Department of
Ophthalmology, Notre-Dame Hospital,
1560 Sherbrooke St. E., Montreal, Quebec, Canada H2L
4Ml.
©AMERICAN JOURNAL OF OPHTHALMOLOGY 115:623-628,
use of systemic antibiotics with the highest
possible intraocular penetration is indicated.
Ciprofloxacin is a fluoroquinolone antibiotic
that has demonstrated excellent penetration
into tissues (such as meninges and bone) that
are poorly accessible to many other antibiotics.
Ciprofloxacin's spectrum includes both gram-
positive and gram-negative bacteria. In adults
ciprofloxacin's toxicity is lower than that of
many other commonly used antibiotics, and it
has far less renal toxicity than the aminoglyco-
sides or vancomycin, and far fewer allergic
reactions than the cephalosporins." It can, how-
ever, occasionally cause central nervous system
excitation. Ciprofloxacin can be administered
orally. We evaluated the intraocular penetra-
tion of ciprofloxacin to determine its potential
use in the treatment of endophthalmitis.
Subjects and Methods
Forty patients scheduled for cataract extrac-
tion, vitrectomy, scleral buckle, or combined
operations were entered into the study. In-
formed consent was obtained. Exclusion crite-
ria were vitreous hemorrhage present for less
than one month; age less than 18 years; preg-
nancy; allergy to quinolones; central nervous
system or renal disease; and concomitant ad-
ministration of theophylline, warfarin, noncor-
ticosteroidal anti-inflammatory drugs, or cyclo-
sporine. Two patients were each entered into
the study on two separate occasions, and four
others had samples taken from two intraocular
compartments, for a total of 46 intraocular
samples. Indications for vitrectomy are shown
in Table 1. Patients were administered two oral
doses of ciprofloxacin (750 mg) 12 hours apart.
According to the study protocol, the second
dose was to be administered two to 12 hours
preoperatively.
Aqueous humor samples were obtained at the
MAY, 1993 623
624 AMERICAN JOURNAL OF OPHTHALMOLOGY May, 1993

TABLE 1 detection limit of ciprofloxacin was 0.01 ~g/ml,

VITRECTOMY INDICATIONS with linearity from 0.01 j.Lg/ml to 3.60 j.Lg/ml
and reproducibility of greater than 95%.
NO. OF PATIENTS Statistical analysis was done by using the
WHOSE SAMPLES Kruskal-Wallis one-way analysis of variance
WERE OBTAINED
and Mann-Whitney U-Wilcoxon rank sum W-
TWO TO 12 HOURS
NO. OF AFTER SECOND DOSE
tests.
GROUP INDICATION PATIENTS OF CIPROFLOXACIN

V1 Proliferative 6·
vitreoretinopathy
V1 Diabetic tractional
retinal detachments 2
V2 Diabetic vitreous
hemorrhage 4 4
V2 Nondiabetic vitreous
hemorrhage 3·
V3 Epiretinal membrane 4·
V3 Macular hole 2·
V4 Dislocated pseudophakos
or cataract fragment 3·
Total 24
• All patients were nondiabetic.
beginning of cataract extraction. Using a sy-
ringe attached to a 27-gauge needle, we per-
formed a paracentesis through a partial-thick-
ness sclerocorneal cataract incision, and 0.2 ml
of aqueous humor was withdrawn. After initial
entry into the eye, vitreous samples (0.2 ml)
were obtained from pars plana vitrectomy pa-
tients before starting the intraocular infusion,
by using a vitrector attached to a syringe. Sub-
retinal fluid was obtained at the sclerotomy
drainage site at the end of scleral buckle proce-
dure by aspirating the draining fluid with a
syringe attached to a 20-gauge plastic intrave-
nous catheter. Venous blood was obtained at
the beginning of each procedure.
Samples were diluted in a solution contain-
ing n-ethyl-ciprofloxacin as an internal stan-
dard. Vitreous samples were homogenized by
passage through a 25-gauge needle. Serum pro-
teins were precipitated before ciprofloxacin de-
termination by the addition of one volume of
acetonitrile to the diluted serum.' Ciprofloxacin
levels were determined by using high-perfor-
mance liquid chromatography on a PKB-100
column (Supelco, Bellefonte, Pennsylvania).
Elution was performed at room temperature (21
C) with phosphate-buffered saline solution (50
mmol Zl, pH 3.0) containing 20-mmol/l tetra-
butylammonium bromide and 12% acetoni-
trile." By using a fluorescence detector (excita-
tion at 280 nm, emission at 455 nm), the
6
Results
The average age of our patients was 62 years.
Twenty-three patients were women and 17
were men. Thirty-nine of the 46 samples were
3 obtained between two and 12 hours after the
3 second dose of ciprofloxacin. The remaining
2 seven samples are shown in Figures 1 and 2, but
are excluded from the statistical analysis and
1
20 from further discussion because they did not
conform to the study protocol.
Ciprofloxacin levels were measured in the
anterior chamber of 11 eyes from two to four
hours after the second oral dose. The mean
level was 0.53 ± 0.24 ~g/ml (range, 0.20 to
1.00 j.Lg/ml) (Fig. 1). Vitreous ciprofloxacin
levels were measured in 20 eyes including one
eye on two occasions with an average level of
0.51 ± 0.35 j.Lg/ml (range, 0.20 to 1.40 ~g/ml).
We also noted that vitreous ciprofloxacin levels
tended to increase during the first four hours
after the second dose; thus, vitreous levels
between four and 12 hours (12 eyes) averaged
0.59 ± 0.42 j.Lg/ml (Fig. 2). Subretinal fluid was
sampled in eight eyes, with average ciprofloxa-
cin levels of 0.71 ± 0.24 j.Lg/ml (range, 0.40 to
1.10 ~g/ml) (Fig. 1) (Table 2).
Serum ciprofloxacin levels averaged 3.70 ±
2.22 ~g/ml (range, 0.74 to 8.61 ~g/ml) be-
tween two and 12 hours. Averaged intraocular
values were 15.0% of averaged serum values,
but it was often difficult to correlate individual
serum levels directly with intraocular ciproflox-
acin levels in the same patient. Kinetics of
serum ciprofloxacin concentration demonstrat-
ed peak values at 2% hours and much less
interpatient variation around a given time point
than did intraocular values (data not shown).
The difference between aqueous, vitreous,
and subretinal fluid values was not statistically
significant; however, the difference between
vitreous and subretinal fluid values tended to-
ward significance (P = .06). The difference in
mean ciprofloxacin levels between groups V2
and V3 approached statistical significance (P =
Vol. 115, No.5 Ciprofloxacin Penetration in Vitreous and Subretinal Fluid 625

'"

-
=.
0
A
5
55
0
E : 5
C>
:;>'<D
0
Fig. 1 (Lesk and associates). In-
traocular ciprofloxacin levels vs
~ AA
z 0
<3 '"
.
'\A

-c time after second oral dose. A indi-

x
0
..J
0 5 cates aqueous humor; 5 indicates
LL
0 A
5
subretinal fluid. Note that the ver-
rr: :;J
c, A tical axis is plotted as a logarithmic
<3 scale.
N
0 A

o-L.-----r----.-----.-----.----~--~--~--~------.J
10 12 16

TIME (HOURS)

.08) (Table 2). The difference between diabetic acin of the bacterial species that most frequent-
(five eyes) and nondiabetic (15 eyes) vitreous ly cause endophthalmitis. With the exception of
ciprofloxadn levels was not significant (P = .9). Streptococcus organisms, most strains of these
bacteria are sensitive to the mean ciprofloxacin
levels we obtained in aqueous humor, vitreous,
and subretinal fluid (Table 3).
Discussion We compared our findings to those found in
similar studies performed with the antibiotics
On the basis of three published sources'" and most commonly used systemically for the treat-
the Cipro Product Monograph (Etobicoke, On- ment of endophthalmitis. The average intraoc-
tario, Canada, Miles Canada Inc., 1991), we ular levels of cefazolin, vancomycin, and genta-
summarized the in vitro sensitivity to ciproflox- micin in uninflamed or minimally inflamed

'"
V2 V2

-
0
VI
Fig. 2 (Lesk and associates). Vit-
'"
reous ciprofloxacin levels, vs time
0
E V1
C>
:;>. <D
VI after second oral dose, grouped by
surgical indication. VI indicates
V2

. '<h
Z
<3 '"
0
«
x
V4 diabetic tractional retinal detach-
ment or proliferative vitreoretinop-
V1
0 0
..J
VI
athy; V2 indicates vitreous hem-
LL
V3
0 V2
cr: :; VI
a,
orrhage; V3 indicates macular hole
V3 V2
V3V3
U VI

V3 or epiretinal membrane; V4 indi-

V1
cates dislocated cataract fragment
N
0
V4

or pseudophakos.
V4
V3

;;
10 12 14 16

TIME (HOURS)
626 AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE 2
INTRAOCULAR CIPROFLOXACIN LEVELS
CIPROFLOXACIN LEVEL (PG/MLI
MEAN ±
SOURCE STANDARD DEVIATION
Aqueous humor (n = 11) 0.53 :t 0.24
Vitreous (n = 20) 0.51 :t 0.35
V1 (n = 7) 0.49 :t 0.28
0.71 :t 0.47
V2 (n = 7)
V3 (n = 5) 0.28 :t 0.04
V4 (n = 1) 0.44
0.71 :t 0.25
Subretinal fluid (n = 8)
human eyes after intravenous administration
are 1.2 ~g/ml, < 0.78 ~g/ml, and < 0.18
ILg/ml, respectively.P" We compared these val-
ues to recent mean inhibitory concentrations
(MIC) of the bacteria most commonly found in
endophthalmitis.P:'! and compiled the results
(Table 4). In uninflamed or minimally inflamed
eyes, oral ciprofloxacin reaches therapeutic vit-
reous levels for all organisms but Streptococcus
species. Ciprofloxacin is the only one of these
antibiotics the vitreous level of which exceeds
the MIC 90 for Staphylococcus epidermidis and
gram-negative organisms. It is also the only one
of these antibiotics reaching intraocular levels
active against Bacillus cereus. Clindamycin is
the current drug of choice in treating and pre-
venting B. cereus endophthalmitis; however, we
are unable to find published vitreous clindamy-
cin levels and thus cannot compare its efficacy
to that of ciprofloxacin.
Ciprofloxacin vitreous levels have good activ-
ity, similar to that of cefazolin, against S. aureus
and Propionibacterium species. Whereas cipro-
floxacin appears to be superior to systemic
cefazolin against S. epidermidis, cefazolin is the
only one of these antibiotics the vitreous level
of which exceeds the MIC 90 of St. pneumoniae
and St. pyogenes.
In uninflamed eyes, intravenously adminis-
tered vancomycin and gentamicin are unlikely
to reach vitreous levels that exceed even the
MIC so of any of these organisms, including St.
[aecalis (Table 4). However, they are together
considered to be the drugs of choice in treating
St. [aecalis endophthalmitis. Their efficacy may
depend on their synergism, on enhanced pene-
tration into highly inflamed eyes, and on direct
intravitreous injections. Vitreous ciprofloxacin
levels have a mild degree of activity against St.
faecalis (MIC 3o) ' Ciprofloxacin is not recom-
May, 1993
mended for treatment of streptococcal infec-
tions.
The most common causes of endophthalmitis
after penetrating trauma are S. epidermidis,
streptococci, Pseudomonas species, Proteus mir-
RANGE
abilis, and B. cereus,' Prophylactic systemic an-
tibiotics are often urgently administered for
0.20-1.00 traumatized eyes that are relatively unin-
0.20-1.40 flamed. Ciprofloxacin appears to be the only
0.20-0.97 systemic antibiotic among those that we com-
0.29-1.40 pared that has adequate action against these
0.22-0.33 organisms, with the exception of the strepto-
cocci, which would be better covered by cefazo-
0.40-1.10 lin. Intravenous cefazolin covers nonenteric
streptococci as well as S. aureus. Systemic ad-
ministration of ciprofloxacin in association
with cefazolin would appear to be a promising
choice for prophylactic systemic therapy before
and after surgical intervention in these cases.
Intravitreous injection of antibiotics covering
enterococci may complement this systemic
therapy.
After cataract extraction, bacterial endoph-
thalmitis may manifest in three forms. Early,
fulminant endophthalmitis developing two to
four days postoperatively is most likely to be
caused by streptococci or gram-negative organ-
isms. Moderately severe endophthalmitis de-
veloping five to seven days postoperatively is
most likely to be caused by S. epidermidis.
Tardive, chronic endophthalmitis developing
several months postoperatively may be caused
by P. acnes or S. epidermidis. Ciprofloxacin's
vitreous levels are active against all these or-
ganisms, with the exception of the streptococci.
The values in Table 3 apply to uninflamed
eyes. Vitreous antibiotic levels would likely be
TABLE 3
SENSITIVITY OF COMMON INTRAOCULAR PATHOGENS
TO CIPROFLOXACIN
MIC so
BACTERIA (!'G!ML)
S. aureus 0.57
S. epidermidis 0.40
St. pneumoniae 2.0
St. pyogenes 1.34
St. faecalis 1.53
Propionibacterium sp. 0.70
B. cereus 1.0
P. aeruginosa 0.50
P. mirabilis 0.06
H. influenzae 0.01
Vol. 115, No.5 Ciprofloxacin Penetration in Vitreous and Subretinal Fluid 627

TABLE 4 cin, could possibly replace systemic gentami-

PERCENT OF BACTERIAL STRAINS INHIBITED BY cin, especially when vancomycin is required.
MEAN ANTIBIOTIC LEVELS REPORTED FOR The exception may be enterococci infections.
UNINFLAMED HUMAN EYES Penetration of oral ciprofloxacin into aqueous
humor has been studied previously.v-" Keren
ANTIBIOTIC AND REPORTED MEAN INTRAOCULAR LEVEL and associates" recently demonstrated vitreous
CIPROFLOXACIN CEFAZOLIN VANCOMYCIN GENTAMICIN
ciprofloxacin levels similar to ours in seven
0.51 p.G/ML 1.2 p.GJML <0.78 p.GJML· 0.18ItG/ML t
patients who received two doses of ciprofloxa-
BACTERIA (VITREOUS) (VITREOUS) (AQUEOUS) (AQUEOUS)
cin. El Baba and associates" demonstrated vit-
reous ciprofloxacin levels of 0.28 ~g/ml after a
S. aureus 80 85 <40 0 single oral dose. We attribute our higher vitre-
S. epidermidis 95 25 <16 0 ous levels to the fact that our measurements
St. pneumonia 27 100 <90 0 were made after two doses of antibiotic. Our
St. pyogenes 30 100 <18 0 data (Figs. 1 and 2), together with those of
St. faecalis 30 0 0 0 Keren and associates," suggest that intraocular
Pro acnes 88* 99 <100 0 ciprofloxacin levels are maintained for at least
B. cereus 70 5 <20 0 12 hours after the second oral dose. Ciprofloxa-
P. aeruginosa 90 0 0 0 cin is usually administered every 12 hours.
P. mirabilis 100 0 0 0 Thus, we would expect patients treated with
H. Influenzae 100 0 0 0 this antibiotic to maintain continuous thera-
peutic levels of ciprofloxacin in the vitreous
"No vancomycin was detected. Limit of detection was 0.78
after their second dose.
p,g/ml. No data available for vitreous vancomycin levels.
Recent studies in rabbits suggest that intravit-
tVitreous levels reported as < 0.2 p.g/ml (not detected).
really injected ciprofloxacin is well tolerated in
*Available data are for Propionibacterium species.
therapeutic doses." Direct intravitreal injection
would produce vitreous ciprofloxacin levels ex-
ceeding the MIC lOo of all frequently encoun-
higher in inflamed eyes. This has been found tered organisms and would complement oral
experimentally in rabbits" and probably ex- ciprofloxacin.
plains why combined systemic and local cefazo- Oral ciprofloxacin achieves therapeutic levels
lin and gentamicin have been reported to treat in human eyes. It may be a promising alterna-
S. epidermidis endophthalmitis successfully tive to conventional antibiotic therapy. Studies
without requiring intravitreal antibiotics." In are warranted on the effectiveness of oral cipro-
our study, eyes with marked breakdown of the floxacin alone or with other antibiotics in the
blood-ocular barrier (groups VI and V2) had prophylaxis and treatment of endophthalmitis.
higher vitreous ciprofloxacin levels than those
eyes with presumably intact vascular barriers
(group V3), although this difference did not ACKNOWLEDGMENTS
reach statistical significance. Roch Roy, Ph.D., and Michel Lamoureux,
We measured the penetration of ciprofloxacin M.Sc., University of Montreal, Montreal, Que-
into subretinal fluid, as well as into vitreous bec, Canada, performed statistical analysis.
and aqueous humor. Our results demonstrate
that ciprofloxacin penetrates well into this
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