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Adv Ther (2009) 26(4):447-454.
ORIGINAL RESEARCH Rate of Bacterial Eradication by Ophthalmic Solutions
of Fourth-Generation Fluoroquinolones
Michelle C. Callegan ∙ Billy D. Novosad ∙ Raniyah T. Ramadan ∙ Brandt Wiskur ∙ Andrea L. Moyer Received: February 25, 2009 / Published online: April 16, 2009 / Printed: May 8, 2009 Springer Healthcare Communications 2009 Laboratories, Inc., Fort Worth, TX, USA) is pre-servative-free. Recent studies have demonstrated Introduction: Antibacterial activity of ophthal-
that the presence of BAK dramatically affects the mic fourth-generation fluoroquinolones has tra- antibacterial activity of the ophthalmic formu- ditionally been evaluated by comparing only lation of gatifloxacin. This study was designed their active ingredients, gatifloxacin and moxi- to compare the kill rates of ophthalmic solu- floxacin. However, ophthalmic formulations of tions of fourth-generation fluoroquinolones fourth-generation fluoroquinolones differ in against isolates of common ocular bacterial terms of the inclusion of preservatives. While pathogens. Methods: Approximately 5.6 log
gatifloxacin ophthalmic solution 0.3% (Zymar®; colony-forming units (CFU)/mL of Haemophilus Allergan, Inc., Irvine, CA, USA) contains 0.005% influenzae (n=1), Streptococcus pneumoniae (n=1), benzalkonium chloride (BAK), moxifloxacin Staphylococcus aureus (n=2), methicillin-resistant ophthalmic solution 0.5% (Vigamox®; Alcon Staphylococcus aureus (MRSA) (n=4), methicillin-resistant Staphylococcus epidermidis (MRSE) (n=4), and fluoroquinolone-resistant S. epidermidis (n=1) Michelle C. Callegan ( ) Molecular Pathogenesis of Eye Infections Research were incubated with ophthalmic solutions of Center, Dean A. McGee Eye Institute, Oklahoma City, either gatifloxacin or moxifloxacin. Viable bac- Department of Ophthalmology, Oklahoma Center teria were quantified at specific time points up for Neuroscience, and Department of Microbiology to 60 minutes. Results: Gatifloxacin 0.3% com-
and Immunology, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd. DMEI 418, pletely eradicated H. influenzae and Strep. pneu- Oklahoma City, Oklahoma 73104, USA. moniae in 5 minutes, one of two S. aureus isolates in 15 minutes, and the other S. aureus isolate in Billy D. Novosad ∙ Andrea L. Moyer 60 minutes. Gatifloxacin 0.3% completely killed Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, all MRSA, MRSE, and fluoroquinolone-resistant S. Oklahoma City, Oklahoma, USA epidermidis isolates in 15 minutes. Moxifloxacin Raniyah T. Ramadan ∙ Brandt Wiskur 0.5% completely eradicated Strep. pneumoniae Oklahoma Center for Neuroscience, University of and one of four MRSA isolates in 60 minutes. Oklahoma Health Sciences Center, Oklahoma City, All other isolates incubated with moxifloxacin Adv Ther (2009) 26(4):447-454.
0.5% retained viable bacteria ranging from 1.8 isolated from suspected cases of bacterial kera- to 4.4 log CFU/mL. Conclusions: The ophthal-
titis and endophthalmitis.8,10 However, there are mic solution of gatifloxacin 0.3% eradicated bac- few studies that compare the rate of bacterial teria that frequently cause postoperative ocular eradication by fourth-generation fluoroquinolo- infections substantially faster than did the oph- nes as ophthalmic formulations.
thalmic solution of moxifloxacin 0.5%.
Ophthalmic formulations of fourth-gener- ation fluoroquinolones differ in terms of the Keywords: gatifloxacin ophthalmic solution
inclusion of preservatives. While gatifloxacin 0.3%; moxifloxacin ophthalmic solution 0.3% contains 0.005% benzalkonium chlo- 0.5%; ocular surgery prophylaxis; speed of ride (BAK), moxifloxacin 0.5% is preservative- bactericidal activity free.11,12 The presence of BAK, however, appears to dramatically affect the antibacterial activity of the ophthalmic formulation of gatifloxacin. An in-vitro study demonstrated that BAK lowered Bacterial keratitis and endophthalmitis are the minimum inhibitory concentrations (MICs) serious vision-threatening complications of cat- of gatifloxacin against methicillin-resistant aract and refractive surgery.1,2 The causative bac- Staphylococcus aureus (MRSA) by approximately teria are commonly Staphylococcus, Streptococcus, 2- to 500-fold compared with the MICs of gati- and Haemophilus species, which usually origi- floxacin alone.13 Gatifloxacin plus BAK was also nate from the patient's ocular surface and peri- significantly more effective than gatifloxacin ocular skin.3,4 Perioperative topical antibiotics alone or BAK alone in eradicating gatifloxacin- are generally used to reduce bacterial counts in resistant MRSA in vivo.14 the tear film until the epithelium is healed after The key to successful eradication of bacte- surgery.5,6 Rapid and timely eradication of bacte- ria and infection control is proper use of pro- ria on the ocular surface before and after surgery phylactic agents that reduce bacterial numbers is crucial to a successful prophylaxis of postop- rapidly. Therefore, this study was designed to erative ocular infections.
compare the kill rates of ophthalmic formula- Gatifloxacin ophthalmic solution 0.3% tions of fourth-generation fluoroquinolones (Zymar®; Allergan, Inc., Irvine, CA, USA) against bacteria that frequently cause postoper- and moxifloxacin ophthalmic solution 0.5% ative ocular infections.
(Vigamox®; Alcon Laboratories, Inc., Fort Worth, TX, USA) are topical fourth-generation fluoro- MATERIALS AND METHODS quinolones that are often used to prevent and treat ocular infections.7 Several studies have Isolates of Haemophilus influenzae (n=1), evaluated the antibacterial activity of ophthal- Streptococcus pneumoniae (n=1), Staphylococcus mic fourth-generation fluoroquinolones by com- aureus (n=2), MRSA (n=4), methicillin-resistant paring only their active ingredients, gatifloxacin Staphylococcus epidermidis (MRSE) (n=4), and fluo- and moxifloxacin. Both fluoroquinolones had a roquinolone-resistant S. epidermidis (n=1) were broad spectrum of activity and penetrated well obtained from the collection of bacterial kerati- into ocular tissues.8,9 In general, gatifloxacin and tis and endophthalmitis isolates maintained at moxifloxacin were also equally effective against the Dean A. McGee Eye Institute in Oklahoma Gram-positive and Gram-negative organisms City, Oklahoma, USA. Gatifloxacin ophthalmic Adv Ther (2009) 26(4):447-454.
solution 0.3% and moxifloxacin ophthalmic Figure 1. Viability curves of ocular (A) H. influenzae and solution 0.5% were used as study drugs. As per (B) Strep. pneumoniae incubated with gatifloxacin 0.3% their commercial formulations, gatifloxacin or moxifloxacin 0.5%. Suspensions of H. influenzae (n=1) or Strep. pneumoniae (n=1) were incubated with 0.3% contained BAK (0.005%) and moxifloxacin gatifloxacin 0.3% or moxifloxacin 0.5%, and viability was 0.5% was preservative-free.
analyzed in triplicate at 0, 5, 10, 15, 30, and 60 minutes. H. influenzae was grown from stock cultures on a chocolate agar while all other bacterial iso- lates were grown on a blood agar (5% in brain heart infusion agar). Following overnight incu- H. influenzae bation at 37°C, bacteria were suspended in sterile saline to achieve an optical density of 0.13-0.15 at 650 nm. Subsequently, 20 µL of each bacte- rial suspension with a density of 5.65-5.72 log colony-forming units (CFU)/mL was inoculated with 4 mL of study drugs and incubated at 37°C in a water bath.
To assess bacterial viability, aliquots were removed from the suspensions of H. influen- zae and Strep. pneumoniae at 0, 5, 10, 15, 30, and 60 minutes, and from the suspensions of S. aureus, MRSA, MRSE, and fluoroquinolone-resist-ant S. epidermidis at 0, 15, 30, and 60 minutes. Strep. pneumoniae Aliquots were diluted 1:10 in Dey Engley neutral- izing broth supplemented with 5% magnesium chloride and 3.5% Tween 80, and incubated for 10 minutes at room temperature. Aliquots were then serially diluted, filtered through a 0.45 µm Supor® filter membrane (Pall Co., Ann Arbor, MI, USA), and washed with 300 mL of sterile saline supplemented with 3.5% Tween 80. The filters 10 20 30 40 50 60 were transferred to chocolate or blood agar plates supplemented with 5% magnesium chloride and 3.5% Tween 80 and were incubated at 37°C in a by gatifloxacin 0.3% at 5 minutes while humidified CO chamber. Bacterial colonies were 3.6 log CFU/mL of bacteria were recovered counted after a minimum of 72 hours. All exper- from the suspensions incubated with moxi- iments were carried out in triplicate.
floxacin 0.5% at 60 minutes (Figure 1A). Viable Strep. pneumoniae were reduced to 0 log CFU/mL by gatifloxacin 0.3% at 5 minutes and by moxi-floxacin 0.5% at 60 minutes (Figure 1B). Of the The initial average load of the bacterial suspen- two S. aureus isolates tested, one was completely sions tested was 5.68±0.04 log CFU/mL. Viable eradicated by gatifloxacin 0.3% at 15 minutes H. influenzae were reduced to 0 log CFU/mL while the other S. aureus isolate was completely Adv Ther (2009) 26(4):447-454.
Figure 2. Viability curves of ocular S. aureus isolates incubated Figure 4. Viability curves of ocular (A) MRSE isolates and with gatifloxacin 0.3% or moxifloxacin 0.5%. Suspensions (B) fluoroquinolone-resistant S. epidermidis incubated of S. aureus (n=2) were incubated with gatifloxacin 0.3% or with gatifloxacin 0.3% or moxifloxacin 0.5%. Suspensions moxifloxacin 0.5%, and viability was analyzed in triplicate at of MRSE (n=4) or fluoroquinolone-resistant 0, 15, 30, and 60 minutes. CFU=colony-forming units.
S. epidermidis (n=1) were incubated with gatifloxacin 0.3% or moxifloxacin 0.5%, and viability was analyzed in triplicate at 0, 15, 30, and 60 minutes. The lines representing the viability of four MRSE isolates incubated with gatifloxacin 0.3% are superimposed as the complete kill against all four isolates was achieved at 15 minutes. CFU=colony-forming units; MRSE=methicillin-resistant S. epidermidis.
10 20 30 40 50 60 Figure 3. Viability curves of ocular MRSA isolates incubated with gatifloxacin 0.3% or moxifloxacin 0.5%. Suspensions of MRSA (n=4) were incubated with gatifloxacin 0.3% or moxifloxacin 0.5%, and viability was analyzed in triplicate at 0, 15, 30, and 60 minutes. The lines representing the viability of four MRSA isolates incubated with gatifloxacin 0.3% are 10 20 30 40 50 60 superimposed as the complete kill against all four isolates was achieved at 15 minutes. CFU=colony-forming units; Fluoroquinolone-resistant S. epidermidis 10 20 30 40 50 60 10 20 30 40 50 60 eradicated at 60 minutes (Figure 2). None of the MRSA isolates was reduced to 0 log CFU/mL by S. aureus isolates were completely killed by moxi- moxifloxacin 0.5% at 60 minutes (Figure 3). Viable floxacin 0.5%. At 60 minutes, viable bacteria bacteria ranging from 2.3 to 2.9 log CFU/mL ranging from 2.8 to 3.8 log CFU/mL were recov- were recovered from the remaining three MRSA ered from S. aureus suspensions incubated with suspensions incubated with moxifloxacin 0.5%. moxifloxacin 0.5%.
Similar to MRSA, all viable MRSE and fluoroqui- Bacterial counts of all MRSA isolates were nolone-resistant S. epidermidis were reduced to reduced to 0 log CFU/mL by gatifloxacin 0.3% at 0 log CFU/mL by gatifloxacin 0.3% at 15 min- 15 minutes. The bacterial count of one of these utes. No MRSE or fluoroquinolone-resistant Adv Ther (2009) 26(4):447-454.
S. epidermidis isolates were completely killed by pneumoniae and one MRSA isolate, which were moxifloxacin 0.5% at 60 minutes (Figure 4). Viable eradicated by moxifloxacin 0.5% at 60 minutes. bacteria ranging from 1.8 to 4.4 log CFU/mL Although the time at which moxifloxacin 0.5% were recovered from suspensions of MRSE achieved a complete kill was not determined in and fluoroquinolone-resistant S. epidermidis this study, it has been reported that it may take after 60 minutes of incubation with moxiflox- moxifloxacin as long as 4 hours to completely eradicate S. aureus.19 The underlying reason for the differential rate of bacterial eradication by ophthalmic formulations of gatifloxacin and moxifloxacin Endophthalmitis is a devastating complica- is not known. Recent evidence demonstrat- tion that may occur following intraocular sur- ing that BAK enhances the antibacterial activ- gery. It is known that clear cornea incisions ity of gatifloxacin against MRSA both in vitro may allow inflow of tear film into the ante- and in vivo supports the notion that BAK may rior chamber and that wounds may leak on the have contributed to the faster rate of bacte- first postoperative day.15 Several studies have rial eradication by gatifloxacin 0.3% in our shown that most postoperative infections are study.13,14 The contribution of BAK may also caused by pathogens originating from the ocu- explain the in-vivo efficacy of gatifloxacin lar surface.4,16,17 The primary goal of prophylaxis ophthalmic solution against S. aureus isolates against postoperative infections is to reduce that were resistant to the gatifloxacin molecule the bacterial load on the ocular surface and, thereby, to minimize bacterial penetration into Bacterial resistance to second- and third- the deeper ocular tissues and prevent infection. generation fluoroquinolones is of growing An ideal prophylactic antibiotic would have concern.22,23 Resistance to antibiotics may broad-spectrum antimicrobial coverage and a enhance the risk of persistent postopera- rapid kill rate.18 tive infections and seriously jeopardize the Fourth-generation fluoroquinolones share outcome of a prophylactic therapy. Fourth- a similar spectrum of coverage.8 Our findings, generation fluoroquinolones have a poten- however, demonstrate that gatifloxacin 0.3% tially lower propensity to induce resistance eradicated bacteria that commonly cause ocu- as two mutations are necessary to render bac- lar infections considerably faster than moxi- teria insusceptible to fourth-generation fluo- floxacin 0.5%. Gatifloxacin 0.3% reduced the roquinolones, whereas only a single enzyme viable cell counts of almost all susceptible mutation may be sufficient for bacteria to and resistant isolates to 0 log CFU/mL at the become resistant to the older fluoroquinolo- first study time point, 5 or 15 minutes, with nes.24-27 In general, use of the most effective the exception of one S. aureus isolate, which antibiotic with the least propensity to induce was eradicated after 60 minutes. These find- resistance is recommended as the first-line ings suggest that the actual time necessary for prophylaxis in order to minimize the devel- a complete kill may be even shorter than 5 or opment of resistance.28 In our study, among 15 minutes. In contrast, bacterial eradication fourth-generation fluoroquinolones, gati- with moxifloxacin 0.5% was incomplete for floxacin 0.3% eradicated MRSA and MRSE almost all isolates, with the exception of Strep. faster than moxifloxacin 0.5%, suggesting Adv Ther (2009) 26(4):447-454.
that the ophthalmic formulation of gati- floxacin may be a more effective prophylac-tic option against postoperative infections The ophthalmic solution of gatifloxacin erad- caused by resistant bacteria.
icated bacteria that frequently cause postopera- Postoperative ocular infections are seri- tive ocular infections substantially faster than ous complications that may result in the loss did the ophthalmic solution of moxifloxacin. of vision despite therapeutic interventions.29 Further clinical studies are warranted to evaluate Effective prophylactic strategies are key to the implication of our findings in the prophy- preventing ocular infections. Several clinical laxis against ocular infections in patients under- studies suggest that gatifloxacin 0.3% may be going ocular surgery.
more efficacious than moxifloxacin 0.5% in eradicating bacteria in vivo. In patients under- going cataract surgery, gatifloxacin 0.3% sig-nificantly eliminated conjunctival bacterial This study was supported by a research grant flora after both 1-hour and 1-day administra- from Allergan, Inc. The authors have no finan- tions whereas moxifloxacin 0.5% was effective cial or proprietary interest in any material or only after 1-day administration.30,31 Recent method mentioned in this study.
studies found that the incidence of endoph-thalmitis presenting during the prophylactic treatment was lower in patients who received gatifloxacin 0.3% than those who received 1. Miller JJ, Scott IU, Flynn HW Jr., Smiddy WE, New- ton J, Miller D. Acute-onset endophthalmitis after moxifloxacin 0.5%.32,33 Our findings suggest cataract surgery (2000-2004): incidence, clinical that the superior outcome of prophylaxis with settings, and visual acuity outcomes after treat-ment. Am J Ophthalmol. 2005;139:983-987.
the ophthalmic formulation of gatifloxacin may be, at least in part, due to its faster rate 2. Solomon R, Donnenfeld ED, Azar DT, et al. In- of bacterial eradication.
fectious keratitis after laser in situ keratomileu-sis: results of an ASCRS survey. J Cataract Refract In-vitro kill studies are associated with a number of limitations. Under in-vitro condi- 3. Pushker N, Dada T, Sony P, Ray M, Agarwal T, Vaj- tions, bacteria are exposed to a constant con- payee RB. Microbial keratitis after laser in situ centration of an antibiotic only once, whereas keratomileusis. J Refract Surg. 2002;18:280-286.
under in-vivo conditions there are multiple 4. Speaker MG, Milch FA, Shah MK, Eisner W, Kre- daily exposures to a changing concentration iswirth BN. Role of external bacterial flora in the of an antibiotic. It remains to be determined pathogenesis of acute postoperative endophthalmi-tis. Ophthalmology. 1991;98:639-649.
whether the in-vitro kill studies appropriately model the multiple daily dosing of antibiot- 5. Liesegang TJ. Use of antimicrobials to prevent post- ics. However, the changes in the tear levels operative infection in patients with cataracts. Curr Opin Ophthalmol. 2001;12:68-74.
of ophthalmic solutions of fourth-generation fluoroquinolones are not expected to affect 6. Donnenfeld ED, O'Brien TP, Solomon R, Perry HD, Speaker MG, Wittpenn J. Infectious keratitis the relative differences observed between the after photorefractive keratectomy. Ophthalmol- ophthalmic formulations tested in this study, as the tear levels of both formulations are 7. Schlech BA, Blondeau J. Future of ophthalmic subjected to similar changes.
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ophthalmic solution 0.5% (VIGAMOX). Surv Oph- 18. Tipperman R. Pharmacologic considerations for cat- thalmol. 2005;50(suppl. 1):S64-S67.
aract surgery. Curr Opin Ophthalmol. 2004;15:51-55.
8. Callegan MC, Ramirez R, Kane ST, Cochran DC, Jensen H. Antibacterial activity of the fourth- 19. Kowalski RP, Kowalski BR, Romanowski EG, Mah generation fluoroquinolones gatifloxacin and FS, Thompson PP, Gordon YJ. The in vitro impact moxifloxacin against ocular pathogens. Adv of moxifloxacin and gatifloxacin concentration (0.5% vs 0.3%) and the addition of benzalkonium chloride on antibacterial efficacy. Am J Ophthal- 9. Solomon R, Donnenfeld ED, Perry HD, et al. Pen- etration of topically applied gatifloxacin 0.3%, moxifloxacin 0.5%, and ciprofloxacin 0.3% into the 20. Romanowski EG, Mah FS, Yates KA, Kowalski aqueous humor. Ophthalmology. 2005;112:466- RP, Gordon YJ. The successful treatment of gat- ifloxacin-resistant Staphylococcus aureus kera-titis with Zymar (gatifloxacin 0.3%) in a NZW 10. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. rabbit model. Am J Ophthalmol. 2005;139:867- Gatifloxacin and moxifloxacin: an in vitro suscep- tibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am 21. Tungsiripat T, Sarayba MA, Kaufman MB, et al. J Ophthalmol. 2003;136:500-505.
Fluoroquinolone therapy in multiple-drug resistant staphylococcal keratitis after lamellar keratectomy 11. Zymar® [package insert]. Irvine, CA: Allergan, in a rabbit model. Am J Ophthalmol. 2003;136:76- 12. Vigamox® [package insert]. Fort Worth, TX: Alcon 22. Goldstein MH, Kowalski RP, Gordon YJ. Emerging Laboratories, Inc.; 2006.
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14. Romanowski EG, Mah FS, Kowalski RP, Yates KA, 24. Hooper DC. Mechanisms of action and resistance Gordon YJ. Benzalkonium chloride enhances the of older and newer fluoroquinolones. Clin Infect antibacterial efficacy of gatifloxacin in an experi- Dis. 2000;31(suppl. 2):S24-S28.
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25. Huelves L, Sevillano D, Martinez-Marin C, et al. Correlation between in vitro and in vivo activity of 15. Herretes S, Stark WJ, Pirouzmanesh A, Reyes JM, levofloxacin and moxifloxacin against pneumococ- McDonnell PJ, Behrens A. Inflow of ocular surface cal strains with different susceptibilities to fluoro- fluid into the anterior chamber after phacoemulsifi- quinolones. Int J Antimicrob Agents. 2006;27:294- cation through sutureless corneal cataract wounds. Am J Ophthalmol. 2005;140:737-740.
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