 |
|
Penetration of Ofloxacin and Ciprofloxacin Into the Aqueous Humor of Eyes With Functioning Filtering Blebs
A Randomized Trial
Louis B. Cantor, MD;
Eric Donnenfeld, MD;
L. Jay Katz, MD;
Winnie L. Gee, MS;
Charles D. Finley, MD;
Vipul K. Lakhani, MD;
Joni Hoop, CCRC;
Kelly Flarty, MS
Arch Ophthalmol. 2001;119:1254-1257.
ABSTRACT
| |
Objective To determine concentrations of ofloxacin and ciprofloxacin hydrochloride
in aqueous humor after topical or combined topical and oral administration
in eyes with filtering blebs.
Design A prospective, investigator-masked, randomized, controlled comparative
study involving 36 eyes of 34 patients with functioning filtering blebs who
were to undergo cataract surgery. Treatment groups received either topical
ofloxacin or topical ciprofloxacin (instillation of 0.3% ophthalmic solution
every 30 minutes for 4 hours before surgery), or a combined topical plus oral
regimen (ciprofloxacin hydrochloride, four 100-mg tablets, or ofloxacin, one
400-mg tablet, administered 24-26, 12-14, and 2 hours preceding surgery).
The main outcome measure was antibiotic concentration measured by chromatographic
separation and mass spectrometry of aqueous samples obtained during surgery.
Results Topical antibiotic treatment yielded mean concentrations of ofloxacin,
0.75 µg/mL, and ciprofloxacin, 0.21 µg/mL, in aqueous. With combined
topical and oral therapy, significantly more ofloxacin was measured than ciprofloxacin
(3.84 µg/mL vs 0.35 µg/mL [P<.001]).
The combination regimen produced significantly greater ofloxacin levels than
did topical therapy alone (P = .007).
Conclusions Ofloxacin penetrates better than ciprofloxacin into the aqueous of eyes
with filtering blebs, particularly after combined topical and oral administration,
by which ofloxacin reaches more than a 10-fold greater concentration than
does ciprofloxacin. Combined topical and oral therapy with ofloxacin may be
beneficial in the treatment of bleb-associated infections.
INTRODUCTION
THE PRIMARY organisms involved in bleb-associated infections are Staphylococcus aureus, Staphylococcus
epidermidis, Streptococcus species, and Haemophilus infuenzae.1
Conventional medical treatment of bleb infections typically has used vancomycin
and cefazolin, both of which have poor aqueous penetration and are not available
in a commercial form for topical administration. In contrast, fluoroquinolones
such as ofloxacin and ciprofloxacin are commercially available for topical
administration. Fluoroquinolones are highly soluble and have a broad spectrum
of activity. They offer the potential for broad coverage against infection
if sufficient quantities of antibiotic penetrate the eye to achieve high levels
in aqueous humor. Moreover, fluoroquinolones can be given as an oral agent
on an outpatient basis. Previous work2 suggests
that combining oral and topical administration of fluoroquinolones may greatly
increase the aqueous concentration of these drugs.
These properties make fluoroquinolones attractive candidates for treatment
of ocular infections. The purpose of this study was to evaluate the potential
usefulness of the fluoroquinolones ofloxacin and ciprofloxacin for the treatment
of bleb-associated infections. Because antibiotics achieving the highest concentrations
in aqueous have the greatest potential for the management of infection in
eyes that have undergone glaucoma filtration surgery, we sought to determine
whether ofloxacin or ciprofloxacin penetrated better into eyes with filtering
blebs and whether a combined topical plus oral treatment regimen produced
higher antibiotic concentrations in aqueous than did topical administration
alone.
METHODS
STUDY POPULATION
The study involved 36 eyes with functioning filtering blebs from 34
patients who were to undergo cataract surgery by 3 of us (L.B.C., E.D., and
L.J.K.) at our respective hospitals. Patients who were scheduled to have cataract
surgery in an eye with a functioning filtering bleb were enrolled in the study.
Key exclusion criteria included the following: an ongoing ocular inflammatory
disease, bleb leakage, any suspected infection, and known contraindications
to use of the study medications. Enrolled patients ranged in age from 37 to
86 years and included 18 men and 16 women. All aspects of the study complied
with the Declaration of Helsinki, and protocol and informed consent forms
were reviewed and approved by an institutional review board.
MASKING, INTERVENTION, AND TIMING
Thirty-six eyes were randomly assigned to 1 of 4 treatment groups of
8 or 10 eyes each (Figure 1). Treatment
group assignment was determined by random allocation of shuffled 3 x
5-inch index cards, which were kept at Indiana University, Indianapolis. The
code for the treatment group assignments was forwarded with the aqueous humor
specimens to the University of California, San Francisco, laboratories, where
the analysis for antibiotic levels was performed. Treatment groups received
either topical ofloxacin, topical and oral ofloxacin, topical ciprofloxacin,
or topical and oral ciprofloxacin. The surgeon investigators were masked with
regard to the antibiotic regimen received by the patients, and aqueous samples
were identified by coded labels to mask the investigators involved in analysis
of the samples. Topical doses of ofloxacin (Ocuflox; Allergan, Inc, Irvine,
Calif) or ciprofloxacin hydrochloride (Ciloxan; Alcon Laboratories, Inc, Fort
Worth, Tex) were administered by instillation of 1 drop of a 0.3% ophthalmic
solution every half hour, beginning 4 hours before surgery, with the last
dose administered 30 minutes before surgery. Oral doses of ofloxacin (Floxin,
one 400-mg tablet; Ortho-McNeil Pharmaceutical, Raritan, NJ) and ciprofloxacin
hydrochloride (Cipro, four 100-mg tablets; Bayer Corporation, West Haven,
Conn) were administered 24 to 26, 12 to 14, and 2 hours before surgery.
|
|
|
|
Figure 1. Flow diagram of the study randomization
and procedure. No patients withdrew from the study.
|
|
|
Preoperative evaluation was performed in the usual manner for eyes being
considered for cataract surgery. However, special attention was given to the
appearance of the filtering bleb, and its size and vascularity were noted.
In addition, a Seidel test was used to detect any bleb or transconjunctival
leakage. Eyes with bleb leaks were excluded.
Aqueous samples (0.1-0.2 mL) were withdrawn during surgery, stored at -80°C,
and sent to the University of California, San Francisco, for analysis.
DRUG CONCENTRATIONS
The antibiotic content of all aqueous samples was measured following
chromatographic separation and mass spectrometric detection using a protocol
adapted from Ren et al3 and validated for use
with human aqueous humor samples.4 Aqueous
humor samples (10 µL) were diluted with a combination of 20 µL
of acetonitrile, 50 µL of triamterene internal standard solution, and
150 µL of 45% acetonitrile. Aliquots (20 µL) were then separated
by high-performance liquid chromatography (PE Sciex-API III System; PE Sciex,
Concord, Ontario) equipped with a butyl column (4.6 x 50.0 mm, 5-µm
particle size) using a combination of 50% acetonitrile, 0.06% trifluoroacetic
acid, 5mM ammonium acetate, and 0.0006% ammonium phosphate as the mobile phase.
Mass spectrometric detection with sample inlet by heated nebulizer, positive
ionization by atmospheric pressure chemical ionization, and mass scanning
by multiple reaction monitoring were used. Antibiotic concentrations in samples
were calculated with the use of standard curves that were prepared by spiking
rabbit aqueous humor with a constant amount of internal standard and known
amounts of ofloxacin or ciprofloxacin. Rabbit aqueous humor was used in the
standard curves because of the unavailability of human aqueous humor. The
limit of detection for both ofloxacin and ciprofloxacin was 0.01 µg/mL.
STATISTICAL ANALYSIS
Antibiotic concentrations were analyzed with the use of descriptive
statistics (mean ± SD). Three samples from ciprofloxacin-treated patients
contained no quantifiable antibiotic; these were assigned a value of 0.0099
µg/mL. Results were similar when a value of 0 µg/mL was assigned
to these samples. Data from each eye were analyzed separately for the 2 patients
who had both eyes included in the study. A 2-way analysis of variance was
used to test for the effects of type of antibiotic and drug regimen on antibiotic
concentrations in aqueous. The t test was used for
post hoc comparisons between individual treatment groups. Differences were
considered statistically significant at P<.05.
RESULTS
Topical administration alone yielded antibiotic concentration (mean
± SD) in aqueous humor of 0.75 ± 0.48-µg/mL ofloxacin
compared with 0.21 ± 0.20 µg/mL ciprofloxacin, a significant
difference (P = .005; Figure 2). Combined topical plus oral administration yielded antibiotic
concentrations in aqueous of 3.84 ± 2.72-µg/mL ofloxacin compared
with 0.35 ± 0.30-µg/mL ciprofloxacin. Again, ofloxacin concentrations
were significantly higher than were ciprofloxacin concentrations (P<.001). We also compared antibiotic concentrations produced by
topical vs combined topical and oral administration for each drug. For ofloxacin,
the combined dosing regimen of topical and oral administration produced greater
antibiotic concentration in aqueous than did topical instillation alone (P = .007). However, ciprofloxacin concentrations in aqueous
were not significantly enhanced by the addition of oral dosing to topical
administration (P = .14).
|
|
|
|
Figure 2. Antibiotic concentrations in aqueous
humor of eyes with filtering blebs after different dosing regimens. Eyes received
0.3% antibiotic topically every 30 minutes for 4 hours preceding surgery.
Some patients also received oral antibiotic, 1200 mg, in divided doses in
the 26 hours before surgery. Values are given as mean ± SD (n = 8 or
10 for each group). Asterisk indicates
P = .005 vs ciprofloxacin;
dagger, P<.001 vs ciprofloxacin; and
double dagger, P = .007
vs topical administration.
|
|
|
COMMENT
The risk of bleb infection and subsequent vision-threatening endophthalmitis
in eyes with antimetabolite filtering blebs may be as high as 1% per year.5 Although infection can be a major health risk in postoperative
patients with glaucoma, few studies have addressed ocular drug penetration
for treatment of these conditions in patients with filtering blebs. This study
shows that ofloxacin is found at significantly greater concentration than
ciprofloxacin in the aqueous humor of eyes with functioning filtering blebs
after cataract surgery, whether administered topically or as a combined regimen
of topical and oral administration. Ofloxacin was 3.5-fold more concentrated
in aqueous than was ciprofloxacin when applied topically and 10-fold more
concentrated when oral therapy was added to the topical therapy. These differences
may have clinical significance, particularly for the combined therapy of topical
and oral administration, because ofloxacin levels well exceeded the MIC90 (minimum inhibitory concentration required to inhibit growth of 90%
of the bacterial isolates tested) for S aureus and S epidermidis, whereas ciprofloxacin levels were less than
the MIC90 for these organisms.6
This may make ofloxacin a prudent choice for the management of bleb-associated
infections.
Antibiotic concentrations measured in this study are in agreement with
those of previous researchers who measured aqueous levels of fluoroquinolones
applied either as topical drops6-8
or as collagen shields.9 However, patients
in the earlier studies did not have a history of trabeculectomy. Fluoroquinolone
concentrations in the aqueous are similar in patients with or without trabeculectomy,
which suggests that the presence of the filtering bleb (in the absence of
corneal and conjunctival leakage) does not affect antibiotic penetration.
An important result of our study is that treatment with a combination
of topical and oral ofloxacin resulted in a more than 5-fold greater ofloxacin
concentration than did treatment with topical drug alone. Bleb-associated
endophthalmitis is often caused by S epidermidis
or by gram-negative bacteria that are sensitive to ofloxacin,10
and oral dosing has been demonstrated to result in concentrations of ofloxacin
in aqueous humor sufficient for activity against some of these organisms.11 Furthermore, both oral and topical ofloxacin have
been shown to penetrate the vitreous.2 This
penetration of antibiotic to the posterior eye may reduce the risk of bleb
infection progressing to endophthalmitis. Ofloxacin levels seen in this study
with combined oral and topical treatment exceed the MIC90 of common
gram-positive ocular pathogens, including S aureus, S epidermidis, and Streptococcus pneumoniae. In addition, these ofloxacin levels were in a range similar to the
MIC90 of the problematic gram-negative Pseudomonas
aeruginosa and well exceeded the MIC90 of other gram-negative
pathogens like H influenzae, Proteus
mirabilis, and Escherichia coli (Table 1). A combined topical and oral dosing
regimen of ofloxacin, therefore, may have great potential for effective treatment
of blebitis and bleb-related endophthalmitis after glaucoma filtration surgery.14 Further studies are needed to explore these possibilities.
|
|
|
|
Minimum Inhibitory Concentrations (MIC90) of Ofloxacin Against
Selected Ocular Pathogens In Vitro*
|
|
|
AUTHOR INFORMATION
Accepted for publication May 10, 2001.
This study was supported by an unrestricted grant from Research to Prevent
Blindness, Inc, New York, NY, and by a grant from the Glaucoma Research and
Education Foundation, Indianapolis.
Presented in part as a poster at the 103rd Annual Meeting of the American
Academy of Ophthalmology and the XXII Congress of the Pan-American Association
of Ophthalmology, held jointly in Orlando, Fla, October 24-27, 1999.
Corresponding author and reprints: Louis B. Cantor, MD, Department
of Ophthalmology, Indiana University School of Medicine, 702 Rotary Cir, Room
141, Indianapolis, IN 46202 (e-mail: lcantor{at}iupui.edu).
From the Department of Ophthalmology, Indiana University School of
Medicine, Indianapolis (Drs Cantor, Finley, and Lakhani, and Ms Hoop); Department
of External Disease/Cornea, Manhattan Eye, Ear and Throat Hospital (Dr Donnenfeld),
and Cornea Department, North Shore University Hospital (Dr Donnenfeld), New
York, NY; Wills Eye Hospital (Dr Katz and Ms Flarty) and Department of Ophthalmology,
Jefferson Medical College (Dr Katz), Philadelphia, Pa; and the Department
of Biopharmaceutical Sciences, University of California, San Francisco (Ms
Gee). The authors have no financial interest in the drugs used in this study.
REFERENCES
| |
1. Waheed S, Ritterband DC, Greenfield DS, Liebmann JM, Seedor JA, Ritch R. New patterns of infecting organisms in late bleb-related endophthalmitis:
a ten year review. Eye. 1998;12:910-915.
2. Donnenfeld ED, Perry HD, Snyder RW, Moadel K, Elsky M, Jones H. Intracorneal, aqueous humor, and vitreous humor penetration of topical
and oral ofloxacin. Arch Ophthalmol. 1997;115:173-176.
ABSTRACT
3. Ren Q, Li X, Horng H, Shi R. Quantitation of ketorolac and ofloxacin in rabbit plasma by LC/MS/MS. Poster presented at: annual meeting of the American Association of
Pharmaceutical Scientists (AAPS); October 29–November 2, 2000; Indianapolis,
Ind.
4. Ren Q, Li X, Horng H, Shi R. Quantitation of ketorolac and ofloxacin in rabbit plasma by LC/MS/MS
[abstract]. In: Program and abstracts of the annual meeting of the American Association
of Pharmaceutical Scientists (AAPS); October 29–November 2, 2000; Indianapolis,
Ind. Available at:
http://www.aapspharmaceutica.com/scientificjournals/pharmsci/am_abstracts/2000/2215.html. Accessed July 6, 2001.
5. Greenfield DS, Suner IJ, Miller MP, Kangas TA, Palmberg PF, Flynn HW Jr. Endophthalmitis after filtering surgery with mitomycin. Arch Ophthalmol. 1996;114:943-949.
ABSTRACT
6. Beck R, van Keyserlingk J, Fischer U, Guthoff R, Drewelow B. Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous
humor using different topical application modes. Graefes Arch Clin Exp Ophthalmol. 1999;237:89-92.
FULL TEXT
|
ISI
| PUBMED
7. Cekic O, Batman C, Totan Y, et al. Penetration of ofloxacin and ciprofloxacin in aqueous humor after topical
administration. Ophthalmic Surg Lasers. 1999;30:465-468.
ISI
| PUBMED
8. von Keyserlingk J, Beck R, Fischer U, Hehl EM, Guthoff R, Drewelow B. Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous
humour of patients by different topical application routes. Eur J Clin Pharmacol. 1997;53:251-255.
PUBMED
9. Taravella MJ, Balentine J, Young DA, Stepp P. Collagen shield delivery of ofloxacin to the human eye. J Cataract Refract Surg. 1999;25:562-565.
PUBMED
10. Ciulla TA, Beck AD, Topping TM, Baker AS. Blebitis, early endophthalmitis, and late endophthalmitis after glaucoma-filtering
surgery. Ophthalmology. 1997;104:986-995.
ISI
| PUBMED
11. Hanioglu-Kargi S, Basci N, Soysal H, Bozkurt A, Gursel E, Kayaalp O. The penetration of ofloxacin into human aqueous humor given by various
routes. Eur J Ophthalmol. 1998;8:33-36.
ISI
| PUBMED
12. Osato MS, Jensen HG, Trousdale MD, et al. The comparative in vitro activity of ofloxacin and selected ophthalmic
antimicrobial agents against ocular bacterial isolates. Am J Ophthalmol. 1989;108:380-386. [published correction appears
in Am J Ophthalmol. 1991;112:478-479]
PUBMED
13. Wiedemann B, Grimm H. Susceptibility to antibiotics: species incidence and trends. In: Lorian VL, ed. Antibiotics in Laboratory Medicine. 4th ed. Baltimore, Md: Williams & Wilkins; 1996:900-1168.
14. Ayyala RS, Bellows AR, Thomas JV, Hutchinson BT. Bleb infections: clinically different courses of "blebitis" and endopthalmitis. J Ophthalmic Nurs Technol. 1997;16:292-300.
PUBMED
RELATED ARTICLE
Archives of Ophthalmology Reader's Choice: Continuing Medical Education
Arch Ophthalmol. 2001;119(9):1399-1400.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Ocular penetration of levofloxacin, ofloxacin and ciprofloxacin in eyes with functioning filtering blebs: investigator masked, randomised clinical trial
Cantor et al.
Br. J. Ophthalmol. 2008;92:345-347.
ABSTRACT
| FULL TEXT
193-nm Excimer Laser-Induced Fluorescence Detection of Fluoroquinolones in Rabbit Corneas
Chuck et al.
Arch Ophthalmol 2004;122:1693-1699.
ABSTRACT
| FULL TEXT
|
