REVIEW ARTICLE
Besifloxacin in the management of bacterial infections of the ocular surface Jean Deschênes, MD, FRCSC,* Joseph Blondeau, PhD†,‡,§ ABSTRACT ● RÉSUMÉ Acute bacterial conjunctivitis is a common infection of the ocular surface. Increasing rates of bacterial resistance have prompted the development of new antibiotics with improved activity against the bacterial species most often found in this disease. Besifloxacin is the first topical chlorofluoroquinolone developed solely for ophthalmic use. Studies have attested to its in vitro potency against a broad range of bacteria, as well as its efficacy in clinical studies of bacterial conjunctivitis when dosed 2 or 3 times a day. This review provides an up-to-date summary of studies on causative pathogens in acute bacterial conjunctivitis; recent geographic trends in bacterial resistance among ocular pathogens, including that of methicillin-resistant Staphylococcus aureus; the efficacy of besifloxacin in preclinical and clinical studies; its safety; and the role of besifloxacin in combating resistant strains. Further, this review provides a brief update on bacterial keratitis, causative pathogens, the development of resistance among those pathogens, and the potential role of besifloxacin in the treatment of bacterial keratitis. La conjonctivite bactérienne aiguë est une infection courante de la surface oculaire. Face à la résistance croissante des bactéries, on a mis au point de nouveaux antibiotiques plus efficaces contre les espèces bactériennes le plus souvent à l’origine de l’infection. La bésifloxacine est la première chloro-fluoroquinolone topique conçue exclusivement pour usage ophtalmique. Des études ont attesté son action in vitro contre un large éventail de bactéries, et des études cliniques sur la conjonctivite bactérienne ont aussi démontré son efficacité lorsqu’elle était administrée de 2 à 3 fois par jour. Cette revue fournit une synthèse à jour sur : des études ayant porté sur des agents pathogènes responsables de la conjonctivite bactérienne aiguë; les tendances géographiques récentes de la résistance d’agents pathogènes oculaires, dont le staphylocoque doré résistant à la méthicilline; l’efficacité de la bésifloxacine mesurée dans des études précliniques et cliniques; son innocuité; et le rôle de la bésifloxacine dans la lutte contre des souches résistantes. La revue fait aussi brièvement le point sur la kératite bactérienne, les agents pathogènes qui en sont responsables, le développement de la résistance de ces agents et le rôle que pourrait jouer la bésifloxacine dans le traitement de la kératite bactérienne.
Besifloxacin ophthalmic suspension 0.6% (Besivance®; Bausch & Lomb, Rochester, N.Y.) is a chlorofluoroquinolone developed solely for ophthalmic use with demonstrated safety and efficacy in the treatment of acute bacterial conjunctivitis.1 In this review, we discuss aspects of bacterial conjunctivitis pertinent to treatment with a focus on the role of besifloxacin. We examine the clinical and epidemiologic features of acute bacterial conjunctivitis, common pathogens implicated in its cause, and the role of antibacterial treatment. Further, in vitro and clinical studies of besifloxacin demonstrating effectiveness against typical and drug-resistant bacterial strains are evaluated. Finally, we explore the potential role of besifloxacin in the treatment of bacterial keratitis.
Acute bacterial conjunctivitis is associated with gluing of the eyelids in the morning and an absence of itch.2
Disease results when bacteria on the ocular surface, often commensal, overcome the host’s defense mechanisms.3,4 Conjunctivitis accounts for 1% of all primary care consultations in U.K. health centres.5 In 2005, the incidence rate of bacterial conjunctivitis in the United States was estimated at 1.35%.6 It is more common in preschool children compared with older children and adults.7 In adults, Staphylococcus aureus is the most common species in bacterial conjunctivitis, followed by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella species.8 In children, the most common bacteria are H. influenzae, S. pneumoniae, S. aureus, and Moraxella catarrhalis.8 However, variable incidences of infection with other pathogens have been reported, based on geographic region and period of sample collection. A study across 32 centres in the United States between October 2009 and October 2010 found that among 496 bacterial conjunctivitis isolates from children and adults, the most common species were H. influenzae (21.4%), followed by Staphylococcus
From the *McGill University, Montreal, QC; †Departments of Pathology and Laboratory Medicine ; ‡Microbiology and Immunology; §Ophthalmology, Royal University Hospital and University of Saskatchewan, Saskatoon, SK.
Correspondence to Jean Deschênes, FRCSC, McGill University, Uveitis, Cornea & External Disease, McGill University Eye Centre, 5252 Boulevard de Maisonneuve Ouest, Montréal, QC H4A 3S5; jean. [email protected]
BACTERIAL CONJUNCTIVITIS: PRESENTATION, INCIDENCE, AND CAUSATIVE PATHOGENS
Data from the Antibiotic Resistance Monitoring in Ocular micRorganisms Canada Surveillance study were presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology in Orlando, Fla., May 4–8, 2014. Originally received Aug. 26, 2014. Final revision Nov. 24, 2014. Accepted Dec. 22, 2014
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Can J Ophthalmol 2015;50:184–191 0008-4182/15/$-see front matter & 2015 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.12.013
Besifloxacin for ocular bacterial infections—Deschênes and Blondeau epidermidis (13.7%), S. aureus (13.3%), Streptococcus mitis group (12.7%), and S. pneumoniae (7.1%).4 In a separate study investigating 1324 bacterial isolates from patients with bacterial conjunctivitis in the United States and Asia,9 the most common species were H. influenzae (26.0%), S. pneumoniae (22.8%), S. aureus (14.4%), and S. epidermidis (8.4%). Similar results were reported from studies in New York and South Florida,10,11 but results differed in Spain, where S. epidermidis represented 41.2% and S. aureus represented 13.2% of the species isolated.12 In this study, evaluating 1044 patients with conjunctivitis, 56.6% of ocular surface pathogens were staphylococcal species, 21.4% were streptococcal species, and 12.1% were Haemophilus species.12 This variation in causative organisms often necessitates the use of broad-spectrum antibiotics for empiric therapy.
TREATMENT
OF
BACTERIAL CONJUNCTIVITIS
Most cases of acute bacterial conjunctivitis are selflimiting13; however, topical antibacterial treatment offers several benefits. These include shorter disease duration; prevention of spread of infection; reduction in adverse events (AEs), including those threatening vision; and reduced disease recurrence.14,15 The socioeconomic impact of these benefits are significant, with decreased absenteeism from school and work. Moreover, the presence of red eyes may constitute a social and psychological burden16 driving demand for medical treatment. A Cochrane review of randomized controlled trials (RCTs) of antibiotics versus placebo showed that topical broad-spectrum antibiotic use was associated with significantly improved clinical and microbiologic remission rates, and that more patients experience remission significantly faster, usually within 2 to 5 days, with empiric treatment.17 Nevertheless, treatment of suspected bacterial conjunctivitis with topical antibiotics is not universally accepted. Authors of a study in pediatric patients suggest that an ocular antibiotic may be unnecessary on first presentation to primary care.18 Some have advocated the delayed use of topical antibiotics for patients in primary care because of the perception of marginal benefits with antibiotic use at days five to seven, high spontaneous remission rates, and low risks of adverse outcomes in untreated patients.19 As reliance on culture delays treatment, physicians who treat suspected bacterial conjunctivitis do so empirically with broad-spectrum topical antibiotics.20,21 Compared with other classes of antibiotics, topical fluoroquinolones are preferred for treating bacterial conjunctivitis, because they offer safety and broad-spectrum efficacy against disease-specific bacteria.15 Earlier second-generation fluoroquinolones include ciprofloxacin and ofloxacin; these were followed by the third-generation fluoroquinolone, levofloxacin; the fourth-generation fluoroquinolones, gatifloxacin and moxifloxacin; and most recently, besifloxacin, the first topical chlorofluoroquinolone.22 In the following section,
we discuss antibiotic resistance and the development of newer fluoroquinolones to combat drug-resistant strains.
INCREASING DRUG RESISTANCE Antibiotic resistance may occur because of various factors, including extended and prophylactic use, overuse for systemic infections, agricultural use, use of subtherapeutic dosages, and misuse for nonbacterial infections. Additional factors include globalization and migration with resultant cross-transmission of resistance, health care policies that affect specific usage factors, and biological characteristics of specific bacterial species predisposing them to the development of resistance.15 Fluoroquinolones are used in a variety of infections. Similar to other fluoroquinolones, besifloxacin acts by inhibiting bacterial DNA gyrase and topoisomerase IV, enzymes that catalyze negative supercoiling of DNA and participate in decatenation, respectively. However, besifloxacin has relatively balanced activity against these 2 enzymes,23 resulting in increased in vitro activity against gram-positive bacteria while retaining activity against gram-negative bacteria when compared with older fluoroquinolones. This balanced, dual action may also partially account for the lower rate of resistance development to besifloxacin compared with older fluoroquinolones that preferentially target either one of these enzymes, because dual mutations are required for development of high-level resistance to besifloxacin.15 A mutant-selection study showed that the proportion of isolates acquiring resistance to besifloxacin was nearly 2 orders of magnitude lower than those developing resistance to ciprofloxacin23; further, because besifloxacin is not used for systemic indications, there is no possibility of developing resistance subsequent to systemic use. However, cross-resistance from bacteria developing resistance to other fluoroquinolones is still possible. The initial use of newer, balanced fluoroquinolones such as besifloxacin likely decreases the development of resistance by averting selection of single-point mutants.24 These factors assume added significance when it comes to trends reported for bacterial resistance. In South Florida, a significant increase has been reported in ciprofloxacin resistance among gram-positive ocular isolates collected between 1994 and 1995 (11.7%) and between 2002 and 2003 (35.6%).11 A large study of isolates from patients with bacterial conjunctivitis in New York found similar significant increases in methicillin-resistant S. aureus (MRSA) over 11.5 years.10 The ocular Tracking Resistance in U.S. Today (TRUST) study found high rates of resistance among MRSA against various antibiotics, including gatifloxacin (81.8%) and moxifloxacin (75.8%).25 In the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) surveillance study, a large proportion of S. aureus and coagulase-negative staphylococci (CoNS) isolates were resistant to oxacillin/methicillin, CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Besifloxacin for ocular bacterial infections—Deschênes and Blondeau Table 1—Multidrug resistance among 592 ocular bacterial isolates from the Antibiotic Resistance Monitoring in Ocular micRorganisms 2009 surveillance study26 Bacterial Isolate
Drug Classes
Staphylococcus aureus Coagulase-negative staphylococci Streptococcus pneumoniae Haemophilus influenzae Pseudomonas aeruginosa
AG, BL, FQ, GP, LA, ML AG, BL, FQ, GP, LA, ML BL, CE, CH, FQ, ML CE, CH, FQ, ML AG, BL, CE, FQ
Susceptible to All, n (%)
Resistant to 1 Class, n (%)
Resistant to 2 Classes, n (%)
Resistant to 3 Classes, n (%)
Resistant to 4 Classes, n (%)
Resistant to 5 Classes, n (%)
Total, n (%)
72 (36.0)
35 (17.5)
26 (13.0)
19 (9.5)
25 (12.5)
23 (11.5)
200 (100)
31 (21.5)
29 (20.1)
27 (18.8)
31 (21.5)
17 (11.8)
9 (6.3)
144 (100)
54 (72.0)
14 (18.7)
4 (5.3)
3 (4.0)
0
0
75 (100)
71 (97.3)
2 (2.7)
0
0
0
NA
73 (100)
79 (79.0)
12 (12.0)
3 (3.0)
4 (4.0)
2 (2.0)
NA
100 (100)
AG, aminoglycoside; BL, β-lactam; FQ, fluoroquinolone; GP, glycopeptide; LA, lincosamide; ML, macrolide; CE, cephalosporin; CH, chloramphenicol; NA, Clinical and Laboratory Standards Institute interpretive breakpoints currently not available/applicable. Intermediate isolates were counted as being resistant for the purpose of this analysis.
azithromycin, and/or earlier-generation fluoroquinolones (Table 1).26 Recently, the ARMOR study was extended to Canada and showed similarly high levels of drug resistance among S. aureus and CoNS (Fig. 1).27 Staphylococci were highly resistant to azithromycin (45%–51%), oxacillin/ methicillin (14%–42%), and ciprofloxacin (29%–33%). Among S. pneumoniae isolates, 32% were resistant to azithromycin, 16% were nonsusceptible to imipenem, although all were susceptible to fluoroquinolones.27 These and other data emphasize the need for newer therapies aimed at managing drug-resistant isolates.
BESIFLOXACIN Besifloxacin was approved by the U.S. Food and Drug Administration28 and by Health Canada29 in 2009 for the treatment of bacterial conjunctivitis in adults and children. It has also been approved for the treatment of bacterial conjunctivitis in various countries in South America and Asia.28 To our knowledge, besifloxacin is the only fluoroquinolone developed specifically for a topical ocular indication (i.e., no systemic formulation), thereby limiting its overall exposure and contribution to bacterial resistance. A 3-aminohexahydro-1H-azepine ring at the C-7 position and a chlorine group at the C-8 position make besifloxacin structurally different from other fluoroquinolones.23 This combination of substituents results in unique interactions with DNA gyrase and topoisomerase IV, and accounts for higher in vitro potency compared with earlier fluoroquinolones.30 Further, the C-8 chlorine substitution is thought to improve activity against organisms with DNA gyrase mutations.31 Figure 2 depicts the chemical structures of several fluoroquinolones. In addition to point mutations in the bacterial genes encoding DNA gyrase and topoisomerase IV, efflux pumps may also mediate fluoroquinolone resistance. However, besifloxacin appears to be less affected by efflux pump–mediated resistance than earlier fluoroquinolones.32 Besifloxacin ophthalmic suspension contains 0.01% benzalkonium chloride (BAK) as a preservative.33 In vitro
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studies have shown that BAK enhances the antimicrobial potency and mutant prevention concentration of fluoroquinolones.34 In vitro time-kill experiments against 4 common bacterial species showed bactericidal activity within 5 minutes in the presence of BAK and either gatifloxacin, moxifloxacin, or besifloxacin.35 In the absence of BAK, faster bactericidal activity occurred with besifloxacin (45 minutes) compared with moxifloxacin and gatifloxacin (Z120 minutes). Besifloxacin kill rates against fluoroquinolone-susceptible and -resistant strains were at least 2- to 4-fold faster.35 Besifloxacin contains DuraSite® (InSite Vision, Alameda, CA), a mucoadhesive polymer with viscoelastic properties designed for drug retention on the ocular surface and accounting for the long residence time of besifloxacin (4.7 hours).36 The total exposure to besifloxacin in tears, based on its area under the 24-hour drug concentration versus time curve (AUC(0–24)), was 1232 μg/g h,37 suggesting that tid or bid dosing would be effective in the treatment of bacterial conjunctivitis. Efficacy of besifloxacin
The in vitro efficacy of besifloxacin has been studied extensively. A study examining the in vitro activity of various antibiotics, including besifloxacin, against 2690 bacterial isolates showed that besifloxacin had higher potency against gram-positive pathogens and anaerobes, and was equivalent to comparator fluoroquinolones against most gram-negative pathogens.38 A study evaluating the bactericidal activity of besifloxacin against staphylococci, S. pneumoniae, and H. influenzae showed it to have minimum bactericidal concentration/ minimum inhibitory concentration (MBC/MIC) ratios r4 for nearly all isolates tested and speed of kill faster than those of other fluoroquinolones, including against strains with multiple mutations in the genes encoding DNA gyrase and topoisomerase IV.39 Recently, an integrated analysis of susceptibility data of 1324 isolates from bacterial conjunctivitis studies showed that besifloxacin had greater in vitro potency than other antibiotics, especially against
In vitro studies.
Besifloxacin for ocular bacterial infections—Deschênes and Blondeau
Fig. 1 — Chemical structures of the fluoroquinolone molecule and topical ophthalmic fluoroquinolones used for ocular infections.
gram-positive organisms.9 Another study evaluating the in vitro efficacy of different antibiotics against ciprofloxacinand methicillin-susceptible/resistant staphylococci showed that besifloxacin had the lowest MIC90 (MIC required to inhibit the growth of 90% of isolates within a given species), 8-fold lower than moxifloxacin and 32-fold lower than ciprofloxacin.40 Several clinical trials have evaluated the efficacy and safety of besifloxacin for the treatment of
Clinical trials.
acute bacterial conjunctivitis. A prospective, randomized trial showed that more patients receiving besifloxacin tid had clinical resolution of the baseline infection at day 8 than vehicle (73.3% vs 43.1%, respectively; p o 0.001). Rates of bacterial eradication were also significantly greater with besifloxacin (88.3% vs 60.3%; p o 0.001). 41 In an active comparator trial in 1161 patients, besifloxacin was not inferior to moxifloxacin for clinical resolution on days five (58.3% vs 59.4%, respectively) and eight (84.5% vs CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Besifloxacin for ocular bacterial infections—Deschênes and Blondeau
Fig. 2 — Multidrug resistance among staphylococci from the first Antibiotic Resistance Monitoring in Ocular micRorganisms Canada 2012 to 2013 surveillance study.
84.0%, respectively) and for microbial eradication on days five (93.3% vs 91.1%, respectively) and eight (87.3% vs 84.7%, respectively).42 Both drugs were well tolerated, with similar overall incidence of ocular AEs. However, eye irritation was reported more frequently for moxifloxacin-treated eyes (p ¼ 0.0201).42 A randomized study including 390 patients showed significantly greater clinical resolution and microbial eradication with besifloxacin than with vehicle at the second visit (day 5 ⫾ 1: 45.2% vs 33.0%, p ¼ 0.0084; and 91.5% vs 59.7%, p o 0.0001, respectively) and the third visit (day 8 or 9: 84.4% vs 69.1%, p ¼ 0.0011; and 88.4% vs 71.7%, p o 0.0001, respectively).21 A clinical trial involving 31 centres in the United States showed that rates of clinical resolution and bacterial eradication were significantly greater in the besifloxacin group (dosed bid for 3 days) compared with vehicle at days four or five (69.8% vs 37.5%, p o 0.001; and 86.8% vs 57.1%; p o 0.001, respectively).43 Similarly, rates of bacterial eradication and clinical resolution were significantly higher for besifloxacin than vehicle (85.2% vs 54.6%, p o 0.001; and 65.9% vs 44.0%, p o 0.001, respectively) at day four or five.44 A post hoc analysis of 4 RCTs showed that besifloxacin treatment led to high rates of clinical resolution and bacterial eradication of Pseudomonas aeruginosa by the first follow-up visit.45 Results in pediatric patients were consistent with results for the overall population in these studies. In a post hoc analysis of patients aged 1 to 17 years, both clinical resolution and microbial eradication rates were significantly greater for besifloxacin than vehicle at visits 2 and 3 (p r 0.048).46 No significant differences were observed between besifloxacin and moxifloxacin in clinical resolution and microbial eradication. Besifloxacin was found to be well tolerated in this pediatric subgroup.46
relevant safety signals based on ophthalmoscopy, or biomicroscopy findings, in comparison with vehicle or moxifloxacin.47 The most commonly reported ocular AEs were blurred vision (2.1%), eye pain (1.8%), eye irritation (1.4%), nonspecific conjunctivitis (1.2%), and eye pruritus (1.1%). Blurred vision, eye irritation, and nonspecific conjunctivitis occurred in significantly fewer besifloxacintreated patients than vehicle-treated patients (p r 0.05). Results from a large, randomized, clinical safety trial further support the safety of besifloxacin.48 Besifloxacin administered tid for 7 days was safe and well-tolerated, with similar rates of treatment-emergent AEs as for vehicle. Similarly, besifloxacin dosed bid was found to be safe in comparison with vehicle.44 Efficacy of besifloxacin against methicillin-resistant S. aureus and methicillin-resistant S. epidermidis
MRSA infections of the eye, including in acute conjunctivitis, are of particular concern to ophthalmologists or general practitioners.49 A pharmacokinetic/pharmacodynamic study in healthy volunteers showed that compared with gatifloxacin and moxifloxacin, besifloxacin had the greatest AUC:MIC90 ratio with regard to MRSA and methicillin-resistant S. epidermidis (MRSE) in tears.36 Furthermore, topoisomerase mutations associated with high-level resistance to earlier fluoroquinolones in S. aureus had a lesser effect on besifloxacin antibacterial activity.30 The U.S. ARMOR study showed that MIC50/MIC90 values (in mg/mL) for 144 CoNS isolates from ocular infections, including 68 (47.2%) methicillin-susceptible CoNS isolates and 76 (52.8%) methicillin-resistant CoNS (MRCoNS) isolates, were 0.06/2 for besifloxacin, 0.5/64 for ciprofloxacin, 0.12/16 for moxifloxacin, 64/4512 for azithromycin, 0.06/416 for clindamycin, 0.5/44 for oxacillin, 0.12/32 for tobramycin, and 1/2 for vancomycin.26 Results of the Canadian ARMOR study show that besifloxacin had the lowest MIC90 values among the fluoroquinolones (1 mg/mL for S. aureus, 0.5 mg/mL for CoNS), equal to or more potent than that of vancomycin.27 Compared with other fluoroquinolones, besifloxacin had 4- to Z128-fold higher potency against ciprofloxacinresistant MRSA and MRSE; its MIC50 values (0.5 μg/mL) were the lowest for the ciprofloxacin-resistant isolates, regardless of methicillin susceptibility.9 In a post hoc analysis of clinical outcomes for patients with conjunctival infections caused by MRSA or MRSE across 4 RCTs, the bacterial eradication rate was 87.8% by the second follow-up visit for patients treated with besifloxacin (n ¼ 49).50 The majority of MRSA and MRSE isolates from these patients demonstrated concurrent in vitro resistance to ciprofloxacin.50
Safety of besifloxacin
In an integrated analysis of 1192 patients from 3 clinical studies, besifloxacin tid was found to be safe and well tolerated, with no significant effect on visual acuity,
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Besifloxacin in bacterial keratitis
Bacterial keratitis, an infection of the cornea, has potential for serious complications, including corneal
Besifloxacin for ocular bacterial infections—Deschênes and Blondeau scarring and permanent visual impairment or vision loss, if treatment is delayed.51,52 Common keratitis-causing pathogens include S. aureus, CoNS, P. aeruginosa, S. pneumonia, and Serratia species.22,53 In the United Kingdom, an increase in gram-negative bacterial keratitis in association with contact lens wear was observed in a 10year retrospective study.54 Similarly, a retrospective case series in the greater Toronto area over an 11-year period revealed a decrease in gram-positive and an increase in gram-negative pathogens.55 The most common pathogen was CoNS, and the most common gram-negative bacterium was P. aeruginosa.55 The American Academy of Ophthalmology issued guidelines recommending topical broad-spectrum antibiotics for empirical treatment of bacterial keratitis.52 With regard to the treatment of bacterial corneal ulcers, topical fluoroquinolones are considered the drug of choice in the absence of microbiological evaluation.56 A meta-analysis on the treatment of keratitis showed that when compared with combined fortified antibiotics such as aminoglycosides and cephalosporins, fluoroquinolones offer similar efficacy and a better tolerance profile.51 However, as with bacterial conjunctivitis, increasing resistance to early-generation fluoroquinolones has been reported.54,57,58 A U.K.-based study reported continued susceptibility of gram-negative bacteria to ciprofloxacin and gentamicin, but an increase in resistance to ciprofloxacin among gram-positive bacteria.54 A randomized trial examining resistance patterns of bacterial strains in 229 patients with bacterial keratitis showed none were resistant to moxifloxacin, 17.5% were resistant to chloramphenicol, 14.8% to cephazolin, 2.8% to ciprofloxacin, 2.5% to ofloxacin, and 1.6% to tobramycin.59 A Toronto study showed that methicillin resistance was present in 1.3% of S. aureus and 43.1% of CoNS isolates from patients with keratitis. Further, the study reported a trend toward increasing resistance to methicillin from 28% during the first 4 years of the study to 38.8% for the last 3 years (p ¼ 0.133).55 Besifloxacin was effective in the treatment of bacterial keratitis in preclinical studies. In a rabbit model of keratitis, besifloxacin was significantly more effective than gatifloxacin and moxifloxacin in reducing MRSA colony-forming units.60,61 Similar results were obtained when besifloxacin was used to treat keratitis induced by P. aeruginosa.62 In humans, a gradually tapered regimen including besifloxacin was effective in the treatment of a patient with corneal ulcer, presumably because of P. aeruginosa infection.63 A large, retrospective, case surveillance study showed that besifloxacin was as safe as moxifloxacin in the treatment of bacterial keratitis, with similar low incidences of corneal scarring and neovascularization, and similar rates (96% with besifloxacin) of physician-assessed bacterial eradication.64 Along with the efficacy demonstrated by besifloxacin against S. aureus, CoNS, P. aeruginosa, and Serratia species in
patients with conjunctivitis,50 these results suggest a potential role for besifloxacin in the treatment of bacterial keratitis. However, randomized, controlled clinical trials of besifloxacin in the treatment of bacterial keratitis are needed.
CONCLUSIONS Besifloxacin, with its broad-spectrum activity and potency to inhibit and kill bacteria, is likely to be associated with a lower rate of resistance development compared with other topical antibiotics and is, therefore, an excellent choice for the treatment of acute bacterial conjunctivitis. Although besifloxacin shows potential for use in the treatment of bacterial keratitis, further randomized, controlled trials are needed.
Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article.
Acknowledgments: Writing services were provided by Cactus Communications and funded by Bausch & Lomb. The authors retained full control of the manuscript content. REFERENCES 1. Carter NJ, Scott LJ. Besifloxacin ophthalmic suspension 0.6%. Drugs. 2010;70:83-97. 2. Rietveld RP, ter Riet G, Bindels PJ, Sloos JH, van Weert HC. Predicting bacterial cause in infectious conjunctivitis: cohort study on informativeness of combinations of signs and symptoms. BMJ. 2004;329:206-10. 3. American Optometric Association. Care of the patient with conjunctivitis. Optometric clinical practice guideline. Available from: http:// www.aoa.org/documents/CPG-11.pdf. Accessed January 20, 2013. 4. Haas W, Gearinger LS, Hesje CK, Sanfilippo CM, Morris TW. Microbiological etiology and susceptibility of bacterial conjunctivitis isolates from clinical trials with ophthalmic, twice-daily besifloxacin. Adv Ther. 2012;29:442-55. 5. McDonnell PJ. How do general practitioners manage eye disease in the community? Br J Ophthalmol. 1988;72:733-6. 6. Smith AF, Waycaster C. Estimate of the direct and indirect annual cost of bacterial conjunctivitis in the United States. BMC Ophthalmol. 2009;9:13-24. 7. Gold RS. Treatment of bacterial conjunctivitis in children. Pediatr Ann. 2011;40:95-105. 8. O’Brien TP. Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. Adv Ther. 2012; 29:473-90. 9. Haas W, Gearinger LS, Usner DW, Decory HH, Morris TW. Integrated analysis of three bacterial conjunctivitis trials of besifloxacin ophthalmic suspension, 0.6%: etiology of bacterial conjunctivitis and antibacterial susceptibility profile. Clin Ophthalmol. 2011;5:1369-79. 10. Adebayo A, Parikh JG, McCormick SA, et al. Shifting trends in in vitro antibiotic susceptibilities for common bacterial conjunctival isolates in the last decade at the New York Eye and Ear Infirmary. Graefes Arch Clin Exp Ophthalmol. 2011;249:111-9. 11. Cavuoto K, Zutshi D, Karp CL, Miller D, Feuer W. Update on bacterial conjunctivitis in South Florida. Ophthalmology. 2008;115: 51-6. 12. Carreras B. Bacteriological analysis in the management of conjunctivitis. Comparison of antibiotic resistance between 1982 and 2008. Arch Soc Esp Oftalmol. 2012;87:107-11. CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Besifloxacin for ocular bacterial infections—Deschênes and Blondeau 13. Rose P. Management strategies for acute infective conjunctivitis in primary care: a systematic review. Expert Opin Pharmacother. 2007; 8:1903-21. 14. Hovding G. Acute bacterial conjunctivitis. Acta Ophthalmol. 2008;86:5-17. 15. Karpecki P, Paterno MR, Comstock TL. Limitations of current antibiotics for the treatment of bacterial conjunctivitis. Optom Vis Sci. 2010;87:908-19. 16. Provine RR, Cabrera MO, Brocato NW, Krosnowski KA. When the whites of the eyes are red: a uniquely human cue. Ethology. 2011; 117:395-9. 17. Sheikh A, Hurwitz B, van Schayck CP, McLean S, Nurmatov U. Antibiotics versus placebo for acute bacterial conjunctivitis. Cochrane Database Syst Rev. 2012;9:CD001211. 18. Rose PW, Harnden A, Brueggemann AB, et al. Chloramphenicol treatment for acute infective conjunctivitis in children in primary care: a randomised double-blind placebo-controlled trial. Lancet. 2005;366:37-43. 19. Visscher KL, Hutnik CM, Thomas M. Evidence-based treatment of acute infective conjunctivitis: breaking the cycle of antibiotic prescribing. Can Fam Physician. 2009;55:1071-5. 20. Tarabishy AB, Jeng BH. Bacterial conjunctivitis: a review for internists. Cleve Clin J Med. 2008;75:507-12. 21. Tepedino ME, Heller WH, Usner DW, et al. Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis. Curr Med Res Opin. 2009; 25:1159-69. 22. Wong RL, Gangwani RA, Yu LW, Lai JS. New treatments for bacterial keratitis. J Ophthalmol. 2012;2012:831502. 23. Cambau E, Matrat S, Pan XS, et al. Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae, Staphylococcus aureus and Escherichia coli. J Antimicrob Chemother. 2009;63:443-50. 24. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol. 2004;49(Suppl. 2):S79-83. 25. Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008;145:951-8. 26. Haas W, Pillar CM, Torres M, Morris TW, Sahm DF. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study. Am J Ophthalmol. 2011; 152:567-74.e3. 27. Blondeau RL, Sanfilippo CM, Morris TW, Deane J, Sahm DF. In vitro Antibiotic Susceptibility Profile of Ocular Pathogens—Results from the First ARMOR Canada Surveillance Study. Association for Research in Vision and Ophthalmology Annual Meeting, Orlando, Fla., May 4–8, 2014; Poster 2840-B0073. 28. Bausch and Lomb Incorporated. Besivance (besifloxacin ophthalmic suspension) 0.6%: US prescribing information. Available from: http://www.bausch.ca/our-products/rx-pharmaceuticals/besiv ance#.VONP4PmUdf0. Accessed March 20, 2014. 29. Bausch and Lomb Incorporated. Besifloxacin ophthalmic suspension 0.6% (Besivance): Canadian product monograph. Vaughan, Ont.: Bausch & Lomb Incorporated; 2009. Available from: http://www. visioninstitute.optometry.net/UserFiles/users/499/File/BESIVANCE %20-%20B&L.pdf. Accessed April 25, 2014. 30. Sanfilippo CM, Hesje CK, Haas W, Morris TW. Topoisomerase mutations that are associated with high-level resistance to earlier fluoroquinolones in Staphylococcus aureus have less effect on the antibacterial activity of besifloxacin. Chemotherapy. 2011;57: 363-71. 31. Ward KW, Lepage JF, Driot JY. Nonclinical pharmacodynamics, pharmacokinetics, and safety of BOL-303224-A, a novel fluoroquinolone antimicrobial agent for topical ophthalmic use. J Ocul Pharmacol Ther. 2007;23:243-56. 32. Shinabarger DL, Zurenko GE, Hesje CK, Sanfilippo CM, Morris TW, Haas W. Evaluation of the effect of bacterial efflux pumps on the antibacterial activity of the novel fluoroquinolone besifloxacin. J Chemother. 2011;23:80-6. 33. McDonald M, Blondeau JM. Emerging antibiotic resistance in ocular infections and the role of fluoroquinolones. J Cataract Refract Surg. 2010;36:1588-98.
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34. Hesje CK, Borsos SD, Blondeau JM. Benzalkonium chloride enhances antibacterial activity of gatifloxacin and reduces its propensity to select for fluoroquinolone-resistant strains. J Ocul Pharmacol Ther. 2009;25:329-34. 35. Haas W, Pillar CM, Hesje CK, Sanfilippo CM, Morris TW. In vitro time-kill experiments with besifloxacin, moxifloxacin and gatifloxacin in the absence and presence of benzalkonium chloride. J Antimicrob Chemother. 2011;66:840-4. 36. Torkildsen G, Proksch JW, Shapiro A, Lynch SK, Comstock TL. Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration. Clin Ophthalmol. 2010;4:331-41. 37. Proksch JW, Granvil CP, Siou-Mermet R, Comstock TL, Paterno MR, Ward KW. Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans. J Ocul Pharmacol Ther. 2009;25:335-44. 38. Haas W, Pillar CM, Zurenko GE, Lee JC, Brunner LS, Morris TW. Besifloxacin, a novel fluoroquinolone, has broad-spectrum in vitro activity against aerobic and anaerobic bacteria. Antimicrob Agents Chemother. 2009;53:3552-60. 39. Haas W, Pillar CM, Hesje CK, Sanfilippo CM, Morris TW. Bactericidal activity of besifloxacin against staphylococci, Streptococcus pneumoniae and Haemophilus influenzae. J Antimicrob Chemother. 2010;65:1441-7. 40. Miller D, Chang JS, Flynn HW, Alfonso EC. Comparative in vitro susceptibility of besifloxacin and seven comparators against ciprofloxacin- and methicillin-susceptible/nonsusceptible staphylococci. J Ocul Pharmacol Ther. 2013;29:339-44. 41. Karpecki P, Depaolis M, Hunter JA, et al. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial conjunctivitis: a multicenter, prospective, randomized, double-masked, vehiclecontrolled, 5-day efficacy and safety study. Clin Ther. 2009;31: 514-526. 42. McDonald MB, Protzko EE, Brunner LS, et al. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis. Ophthalmology. 2009;116:1615-23. e1. 43. Silverstein BE, Allaire C, Bateman KM, Gearinger LS, Morris TW, Comstock TL. Efficacy and tolerability of besifloxacin ophthalmic suspension 0.6% administered twice daily for 3 days in the treatment of bacterial conjunctivitis: a multicenter, randomized, doublemasked, vehicle-controlled, parallel-group study in adults and children. Clin Ther. 2011;33:13-26. 44. DeLeon J, Silverstein BE, Allaire C, et al. Besifloxacin ophthalmic suspension 0.6% administered twice daily for 3 days in the treatment of bacterial conjunctivitis in adults and children. Clin Drug Investig. 2012;32:303-17. 45. Silverstein BE, Morris TW, Gearinger LS, Decory HH, Comstock TL. Besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis patients with Pseudomonas aeruginosa infections. Clin Ophthalmol. 2012;6:1987-96. 46. Comstock TL, Paterno MR, Usner DW, Pichichero ME. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% in children and adolescents with bacterial conjunctivitis: a post hoc, subgroup analysis of three randomized, double-masked, parallel-group, multicenter clinical trials. Paediatr Drugs. 2010;12:105-12. 47. Comstock TL, Paterno MR, Decory HH, Usner DW. Safety and tolerability of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis: data from six clinical and phase I safety studies. Clin Drug Investig. 2010;30:675-85. 48. Malhotra R, Ackerman S, Gearinger LS, Morris TW, Allaire C. The safety of besifloxacin ophthalmic suspension 0.6 % used three times daily for 7 days in the treatment of bacterial conjunctivitis. Drugs R D. 2013;13:243-52. 49. Hesje CK, Sanfilippo CM, Haas W, Morris TW. Molecular epidemiology of methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolated from the eye. Curr Eye Res. 2011; 36:94-102. 50. Comstock TL, Morris TW, Gearinger LS, DeCory HH. Clinical outcomes with besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis due to potentially consequential pathogens. Clin Optom. 2014;6:25-35. 51. Hanet MS, Jamart J, Chaves AP. Fluoroquinolones or fortified antibiotics for treating bacterial keratitis: systematic review and
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52.
53. 54. 55. 56. 57. 58.
meta-analysis of comparative studies. Can J Ophthalmol. 2012;47: 493-9. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Patterns Guidelines. Bacterial Keratitis. San Francisco, Calif.: American Academy of Ophthalmology; 2013. Available from: www.aao.org/ppp. Accessed March 10, 2014. Thomas PA, Geraldine P. Infectious keratitis. Curr Opin Infect Dis. 2007;20:129-41. Shalchi Z, Gurbaxani A, Baker M, Nash J. Antibiotic resistance in microbial keratitis: ten-year experience of corneal scrapes in the United Kingdom. Ophthalmology. 2011;118:2161-5. Lichtinger A, Yeung SN, Kim P, et al. Shifting trends in bacterial keratitis in Toronto: an 11-year review. Ophthalmology. 2012;119: 1785-90. Miller D. Pharmacological treatment for infectious corneal ulcers. Expert Opin Pharmacother. 2013;14:543-60. Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. 1999;106:1313-8. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology. 2000;107:1497-502.
59. Constantinou M, Daniell M, Snibson GR, Vu HT, Taylor HR. Clinical efficacy of moxifloxacin in the treatment of bacterial keratitis: a randomized clinical trial. Ophthalmology. 2007;114:1622-9. 60. Sanders ME, Moore QC 3rd, Norcross EW, Shafiee A, Marquart ME. Efficacy of besifloxacin in an early treatment model of methicillin-resistant Staphylococcus aureus keratitis. J Ocul Pharmacol Ther. 2010;26:193-8. 61. Sanders ME, Norcross EW, Moore QC 3rd, Shafiee A, Marquart ME. Efficacy of besifloxacin in a rabbit model of methicillinresistant Staphylococcus aureus keratitis. Cornea. 2009;28: 1055-60. 62. Sanders ME, Moore QC 3rd, Norcross EW, et al. Comparison of besifloxacin, gatifloxacin, and moxifloxacin against strains of pseudomonas aeruginosa with different quinolone susceptibility patterns in a rabbit model of keratitis. Cornea. 2011;30:83-90. 63. Michaud L. Efficacy of besifloxacin in the treatment of corneal ulcer. Clin Refract Optom. 2011;22:90-3. 64. Schechter BA, Parekh JG, Trattler W. Besifloxacin ophthalmic suspension, 0.6% in the treatment of bacterial keratitis: a retrospective surveillance study. J Ocul Pharmacol Ther. 2015;31(2): 114-21.
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Besifloxacin in the management of bacterial infections of the ocular surface Jean Deschênes, MD, FRCSC,* Joseph Blondeau, PhD†,‡,§ ABSTRACT ● RÉSUMÉ Acute bacterial conjunctivitis is a common infection of the ocular surface. Increasing rates of bacterial resistance have prompted the development of new antibiotics with improved activity against the bacterial species most often found in this disease. Besifloxacin is the first topical chlorofluoroquinolone developed solely for ophthalmic use. Studies have attested to its in vitro potency against a broad range of bacteria, as well as its efficacy in clinical studies of bacterial conjunctivitis when dosed 2 or 3 times a day. This review provides an up-to-date summary of studies on causative pathogens in acute bacterial conjunctivitis; recent geographic trends in bacterial resistance among ocular pathogens, including that of methicillin-resistant Staphylococcus aureus; the efficacy of besifloxacin in preclinical and clinical studies; its safety; and the role of besifloxacin in combating resistant strains. Further, this review provides a brief update on bacterial keratitis, causative pathogens, the development of resistance among those pathogens, and the potential role of besifloxacin in the treatment of bacterial keratitis. La conjonctivite bactérienne aiguë est une infection courante de la surface oculaire. Face à la résistance croissante des bactéries, on a mis au point de nouveaux antibiotiques plus efficaces contre les espèces bactériennes le plus souvent à l’origine de l’infection. La bésifloxacine est la première chloro-fluoroquinolone topique conçue exclusivement pour usage ophtalmique. Des études ont attesté son action in vitro contre un large éventail de bactéries, et des études cliniques sur la conjonctivite bactérienne ont aussi démontré son efficacité lorsqu’elle était administrée de 2 à 3 fois par jour. Cette revue fournit une synthèse à jour sur : des études ayant porté sur des agents pathogènes responsables de la conjonctivite bactérienne aiguë; les tendances géographiques récentes de la résistance d’agents pathogènes oculaires, dont le staphylocoque doré résistant à la méthicilline; l’efficacité de la bésifloxacine mesurée dans des études précliniques et cliniques; son innocuité; et le rôle de la bésifloxacine dans la lutte contre des souches résistantes. La revue fait aussi brièvement le point sur la kératite bactérienne, les agents pathogènes qui en sont responsables, le développement de la résistance de ces agents et le rôle que pourrait jouer la bésifloxacine dans le traitement de la kératite bactérienne.
Besifloxacin ophthalmic suspension 0.6% (Besivance®; Bausch & Lomb, Rochester, N.Y.) is a chlorofluoroquinolone developed solely for ophthalmic use with demonstrated safety and efficacy in the treatment of acute bacterial conjunctivitis.1 In this review, we discuss aspects of bacterial conjunctivitis pertinent to treatment with a focus on the role of besifloxacin. We examine the clinical and epidemiologic features of acute bacterial conjunctivitis, common pathogens implicated in its cause, and the role of antibacterial treatment. Further, in vitro and clinical studies of besifloxacin demonstrating effectiveness against typical and drug-resistant bacterial strains are evaluated. Finally, we explore the potential role of besifloxacin in the treatment of bacterial keratitis.
Acute bacterial conjunctivitis is associated with gluing of the eyelids in the morning and an absence of itch.2
Disease results when bacteria on the ocular surface, often commensal, overcome the host’s defense mechanisms.3,4 Conjunctivitis accounts for 1% of all primary care consultations in U.K. health centres.5 In 2005, the incidence rate of bacterial conjunctivitis in the United States was estimated at 1.35%.6 It is more common in preschool children compared with older children and adults.7 In adults, Staphylococcus aureus is the most common species in bacterial conjunctivitis, followed by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella species.8 In children, the most common bacteria are H. influenzae, S. pneumoniae, S. aureus, and Moraxella catarrhalis.8 However, variable incidences of infection with other pathogens have been reported, based on geographic region and period of sample collection. A study across 32 centres in the United States between October 2009 and October 2010 found that among 496 bacterial conjunctivitis isolates from children and adults, the most common species were H. influenzae (21.4%), followed by Staphylococcus
From the *McGill University, Montreal, QC; †Departments of Pathology and Laboratory Medicine ; ‡Microbiology and Immunology; §Ophthalmology, Royal University Hospital and University of Saskatchewan, Saskatoon, SK.
Correspondence to Jean Deschênes, FRCSC, McGill University, Uveitis, Cornea & External Disease, McGill University Eye Centre, 5252 Boulevard de Maisonneuve Ouest, Montréal, QC H4A 3S5; jean. [email protected]
BACTERIAL CONJUNCTIVITIS: PRESENTATION, INCIDENCE, AND CAUSATIVE PATHOGENS
Data from the Antibiotic Resistance Monitoring in Ocular micRorganisms Canada Surveillance study were presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology in Orlando, Fla., May 4–8, 2014. Originally received Aug. 26, 2014. Final revision Nov. 24, 2014. Accepted Dec. 22, 2014
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Can J Ophthalmol 2015;50:184–191 0008-4182/15/$-see front matter & 2015 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.12.013
Besifloxacin for ocular bacterial infections—Deschênes and Blondeau epidermidis (13.7%), S. aureus (13.3%), Streptococcus mitis group (12.7%), and S. pneumoniae (7.1%).4 In a separate study investigating 1324 bacterial isolates from patients with bacterial conjunctivitis in the United States and Asia,9 the most common species were H. influenzae (26.0%), S. pneumoniae (22.8%), S. aureus (14.4%), and S. epidermidis (8.4%). Similar results were reported from studies in New York and South Florida,10,11 but results differed in Spain, where S. epidermidis represented 41.2% and S. aureus represented 13.2% of the species isolated.12 In this study, evaluating 1044 patients with conjunctivitis, 56.6% of ocular surface pathogens were staphylococcal species, 21.4% were streptococcal species, and 12.1% were Haemophilus species.12 This variation in causative organisms often necessitates the use of broad-spectrum antibiotics for empiric therapy.
TREATMENT
OF
BACTERIAL CONJUNCTIVITIS
Most cases of acute bacterial conjunctivitis are selflimiting13; however, topical antibacterial treatment offers several benefits. These include shorter disease duration; prevention of spread of infection; reduction in adverse events (AEs), including those threatening vision; and reduced disease recurrence.14,15 The socioeconomic impact of these benefits are significant, with decreased absenteeism from school and work. Moreover, the presence of red eyes may constitute a social and psychological burden16 driving demand for medical treatment. A Cochrane review of randomized controlled trials (RCTs) of antibiotics versus placebo showed that topical broad-spectrum antibiotic use was associated with significantly improved clinical and microbiologic remission rates, and that more patients experience remission significantly faster, usually within 2 to 5 days, with empiric treatment.17 Nevertheless, treatment of suspected bacterial conjunctivitis with topical antibiotics is not universally accepted. Authors of a study in pediatric patients suggest that an ocular antibiotic may be unnecessary on first presentation to primary care.18 Some have advocated the delayed use of topical antibiotics for patients in primary care because of the perception of marginal benefits with antibiotic use at days five to seven, high spontaneous remission rates, and low risks of adverse outcomes in untreated patients.19 As reliance on culture delays treatment, physicians who treat suspected bacterial conjunctivitis do so empirically with broad-spectrum topical antibiotics.20,21 Compared with other classes of antibiotics, topical fluoroquinolones are preferred for treating bacterial conjunctivitis, because they offer safety and broad-spectrum efficacy against disease-specific bacteria.15 Earlier second-generation fluoroquinolones include ciprofloxacin and ofloxacin; these were followed by the third-generation fluoroquinolone, levofloxacin; the fourth-generation fluoroquinolones, gatifloxacin and moxifloxacin; and most recently, besifloxacin, the first topical chlorofluoroquinolone.22 In the following section,
we discuss antibiotic resistance and the development of newer fluoroquinolones to combat drug-resistant strains.
INCREASING DRUG RESISTANCE Antibiotic resistance may occur because of various factors, including extended and prophylactic use, overuse for systemic infections, agricultural use, use of subtherapeutic dosages, and misuse for nonbacterial infections. Additional factors include globalization and migration with resultant cross-transmission of resistance, health care policies that affect specific usage factors, and biological characteristics of specific bacterial species predisposing them to the development of resistance.15 Fluoroquinolones are used in a variety of infections. Similar to other fluoroquinolones, besifloxacin acts by inhibiting bacterial DNA gyrase and topoisomerase IV, enzymes that catalyze negative supercoiling of DNA and participate in decatenation, respectively. However, besifloxacin has relatively balanced activity against these 2 enzymes,23 resulting in increased in vitro activity against gram-positive bacteria while retaining activity against gram-negative bacteria when compared with older fluoroquinolones. This balanced, dual action may also partially account for the lower rate of resistance development to besifloxacin compared with older fluoroquinolones that preferentially target either one of these enzymes, because dual mutations are required for development of high-level resistance to besifloxacin.15 A mutant-selection study showed that the proportion of isolates acquiring resistance to besifloxacin was nearly 2 orders of magnitude lower than those developing resistance to ciprofloxacin23; further, because besifloxacin is not used for systemic indications, there is no possibility of developing resistance subsequent to systemic use. However, cross-resistance from bacteria developing resistance to other fluoroquinolones is still possible. The initial use of newer, balanced fluoroquinolones such as besifloxacin likely decreases the development of resistance by averting selection of single-point mutants.24 These factors assume added significance when it comes to trends reported for bacterial resistance. In South Florida, a significant increase has been reported in ciprofloxacin resistance among gram-positive ocular isolates collected between 1994 and 1995 (11.7%) and between 2002 and 2003 (35.6%).11 A large study of isolates from patients with bacterial conjunctivitis in New York found similar significant increases in methicillin-resistant S. aureus (MRSA) over 11.5 years.10 The ocular Tracking Resistance in U.S. Today (TRUST) study found high rates of resistance among MRSA against various antibiotics, including gatifloxacin (81.8%) and moxifloxacin (75.8%).25 In the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) surveillance study, a large proportion of S. aureus and coagulase-negative staphylococci (CoNS) isolates were resistant to oxacillin/methicillin, CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Besifloxacin for ocular bacterial infections—Deschênes and Blondeau Table 1—Multidrug resistance among 592 ocular bacterial isolates from the Antibiotic Resistance Monitoring in Ocular micRorganisms 2009 surveillance study26 Bacterial Isolate
Drug Classes
Staphylococcus aureus Coagulase-negative staphylococci Streptococcus pneumoniae Haemophilus influenzae Pseudomonas aeruginosa
AG, BL, FQ, GP, LA, ML AG, BL, FQ, GP, LA, ML BL, CE, CH, FQ, ML CE, CH, FQ, ML AG, BL, CE, FQ
Susceptible to All, n (%)
Resistant to 1 Class, n (%)
Resistant to 2 Classes, n (%)
Resistant to 3 Classes, n (%)
Resistant to 4 Classes, n (%)
Resistant to 5 Classes, n (%)
Total, n (%)
72 (36.0)
35 (17.5)
26 (13.0)
19 (9.5)
25 (12.5)
23 (11.5)
200 (100)
31 (21.5)
29 (20.1)
27 (18.8)
31 (21.5)
17 (11.8)
9 (6.3)
144 (100)
54 (72.0)
14 (18.7)
4 (5.3)
3 (4.0)
0
0
75 (100)
71 (97.3)
2 (2.7)
0
0
0
NA
73 (100)
79 (79.0)
12 (12.0)
3 (3.0)
4 (4.0)
2 (2.0)
NA
100 (100)
AG, aminoglycoside; BL, β-lactam; FQ, fluoroquinolone; GP, glycopeptide; LA, lincosamide; ML, macrolide; CE, cephalosporin; CH, chloramphenicol; NA, Clinical and Laboratory Standards Institute interpretive breakpoints currently not available/applicable. Intermediate isolates were counted as being resistant for the purpose of this analysis.
azithromycin, and/or earlier-generation fluoroquinolones (Table 1).26 Recently, the ARMOR study was extended to Canada and showed similarly high levels of drug resistance among S. aureus and CoNS (Fig. 1).27 Staphylococci were highly resistant to azithromycin (45%–51%), oxacillin/ methicillin (14%–42%), and ciprofloxacin (29%–33%). Among S. pneumoniae isolates, 32% were resistant to azithromycin, 16% were nonsusceptible to imipenem, although all were susceptible to fluoroquinolones.27 These and other data emphasize the need for newer therapies aimed at managing drug-resistant isolates.
BESIFLOXACIN Besifloxacin was approved by the U.S. Food and Drug Administration28 and by Health Canada29 in 2009 for the treatment of bacterial conjunctivitis in adults and children. It has also been approved for the treatment of bacterial conjunctivitis in various countries in South America and Asia.28 To our knowledge, besifloxacin is the only fluoroquinolone developed specifically for a topical ocular indication (i.e., no systemic formulation), thereby limiting its overall exposure and contribution to bacterial resistance. A 3-aminohexahydro-1H-azepine ring at the C-7 position and a chlorine group at the C-8 position make besifloxacin structurally different from other fluoroquinolones.23 This combination of substituents results in unique interactions with DNA gyrase and topoisomerase IV, and accounts for higher in vitro potency compared with earlier fluoroquinolones.30 Further, the C-8 chlorine substitution is thought to improve activity against organisms with DNA gyrase mutations.31 Figure 2 depicts the chemical structures of several fluoroquinolones. In addition to point mutations in the bacterial genes encoding DNA gyrase and topoisomerase IV, efflux pumps may also mediate fluoroquinolone resistance. However, besifloxacin appears to be less affected by efflux pump–mediated resistance than earlier fluoroquinolones.32 Besifloxacin ophthalmic suspension contains 0.01% benzalkonium chloride (BAK) as a preservative.33 In vitro
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studies have shown that BAK enhances the antimicrobial potency and mutant prevention concentration of fluoroquinolones.34 In vitro time-kill experiments against 4 common bacterial species showed bactericidal activity within 5 minutes in the presence of BAK and either gatifloxacin, moxifloxacin, or besifloxacin.35 In the absence of BAK, faster bactericidal activity occurred with besifloxacin (45 minutes) compared with moxifloxacin and gatifloxacin (Z120 minutes). Besifloxacin kill rates against fluoroquinolone-susceptible and -resistant strains were at least 2- to 4-fold faster.35 Besifloxacin contains DuraSite® (InSite Vision, Alameda, CA), a mucoadhesive polymer with viscoelastic properties designed for drug retention on the ocular surface and accounting for the long residence time of besifloxacin (4.7 hours).36 The total exposure to besifloxacin in tears, based on its area under the 24-hour drug concentration versus time curve (AUC(0–24)), was 1232 μg/g h,37 suggesting that tid or bid dosing would be effective in the treatment of bacterial conjunctivitis. Efficacy of besifloxacin
The in vitro efficacy of besifloxacin has been studied extensively. A study examining the in vitro activity of various antibiotics, including besifloxacin, against 2690 bacterial isolates showed that besifloxacin had higher potency against gram-positive pathogens and anaerobes, and was equivalent to comparator fluoroquinolones against most gram-negative pathogens.38 A study evaluating the bactericidal activity of besifloxacin against staphylococci, S. pneumoniae, and H. influenzae showed it to have minimum bactericidal concentration/ minimum inhibitory concentration (MBC/MIC) ratios r4 for nearly all isolates tested and speed of kill faster than those of other fluoroquinolones, including against strains with multiple mutations in the genes encoding DNA gyrase and topoisomerase IV.39 Recently, an integrated analysis of susceptibility data of 1324 isolates from bacterial conjunctivitis studies showed that besifloxacin had greater in vitro potency than other antibiotics, especially against
In vitro studies.
Besifloxacin for ocular bacterial infections—Deschênes and Blondeau
Fig. 1 — Chemical structures of the fluoroquinolone molecule and topical ophthalmic fluoroquinolones used for ocular infections.
gram-positive organisms.9 Another study evaluating the in vitro efficacy of different antibiotics against ciprofloxacinand methicillin-susceptible/resistant staphylococci showed that besifloxacin had the lowest MIC90 (MIC required to inhibit the growth of 90% of isolates within a given species), 8-fold lower than moxifloxacin and 32-fold lower than ciprofloxacin.40 Several clinical trials have evaluated the efficacy and safety of besifloxacin for the treatment of
Clinical trials.
acute bacterial conjunctivitis. A prospective, randomized trial showed that more patients receiving besifloxacin tid had clinical resolution of the baseline infection at day 8 than vehicle (73.3% vs 43.1%, respectively; p o 0.001). Rates of bacterial eradication were also significantly greater with besifloxacin (88.3% vs 60.3%; p o 0.001). 41 In an active comparator trial in 1161 patients, besifloxacin was not inferior to moxifloxacin for clinical resolution on days five (58.3% vs 59.4%, respectively) and eight (84.5% vs CAN J OPHTHALMOL — VOL. 50, NO. 3, JUNE 2015
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Fig. 2 — Multidrug resistance among staphylococci from the first Antibiotic Resistance Monitoring in Ocular micRorganisms Canada 2012 to 2013 surveillance study.
84.0%, respectively) and for microbial eradication on days five (93.3% vs 91.1%, respectively) and eight (87.3% vs 84.7%, respectively).42 Both drugs were well tolerated, with similar overall incidence of ocular AEs. However, eye irritation was reported more frequently for moxifloxacin-treated eyes (p ¼ 0.0201).42 A randomized study including 390 patients showed significantly greater clinical resolution and microbial eradication with besifloxacin than with vehicle at the second visit (day 5 ⫾ 1: 45.2% vs 33.0%, p ¼ 0.0084; and 91.5% vs 59.7%, p o 0.0001, respectively) and the third visit (day 8 or 9: 84.4% vs 69.1%, p ¼ 0.0011; and 88.4% vs 71.7%, p o 0.0001, respectively).21 A clinical trial involving 31 centres in the United States showed that rates of clinical resolution and bacterial eradication were significantly greater in the besifloxacin group (dosed bid for 3 days) compared with vehicle at days four or five (69.8% vs 37.5%, p o 0.001; and 86.8% vs 57.1%; p o 0.001, respectively).43 Similarly, rates of bacterial eradication and clinical resolution were significantly higher for besifloxacin than vehicle (85.2% vs 54.6%, p o 0.001; and 65.9% vs 44.0%, p o 0.001, respectively) at day four or five.44 A post hoc analysis of 4 RCTs showed that besifloxacin treatment led to high rates of clinical resolution and bacterial eradication of Pseudomonas aeruginosa by the first follow-up visit.45 Results in pediatric patients were consistent with results for the overall population in these studies. In a post hoc analysis of patients aged 1 to 17 years, both clinical resolution and microbial eradication rates were significantly greater for besifloxacin than vehicle at visits 2 and 3 (p r 0.048).46 No significant differences were observed between besifloxacin and moxifloxacin in clinical resolution and microbial eradication. Besifloxacin was found to be well tolerated in this pediatric subgroup.46
relevant safety signals based on ophthalmoscopy, or biomicroscopy findings, in comparison with vehicle or moxifloxacin.47 The most commonly reported ocular AEs were blurred vision (2.1%), eye pain (1.8%), eye irritation (1.4%), nonspecific conjunctivitis (1.2%), and eye pruritus (1.1%). Blurred vision, eye irritation, and nonspecific conjunctivitis occurred in significantly fewer besifloxacintreated patients than vehicle-treated patients (p r 0.05). Results from a large, randomized, clinical safety trial further support the safety of besifloxacin.48 Besifloxacin administered tid for 7 days was safe and well-tolerated, with similar rates of treatment-emergent AEs as for vehicle. Similarly, besifloxacin dosed bid was found to be safe in comparison with vehicle.44 Efficacy of besifloxacin against methicillin-resistant S. aureus and methicillin-resistant S. epidermidis
MRSA infections of the eye, including in acute conjunctivitis, are of particular concern to ophthalmologists or general practitioners.49 A pharmacokinetic/pharmacodynamic study in healthy volunteers showed that compared with gatifloxacin and moxifloxacin, besifloxacin had the greatest AUC:MIC90 ratio with regard to MRSA and methicillin-resistant S. epidermidis (MRSE) in tears.36 Furthermore, topoisomerase mutations associated with high-level resistance to earlier fluoroquinolones in S. aureus had a lesser effect on besifloxacin antibacterial activity.30 The U.S. ARMOR study showed that MIC50/MIC90 values (in mg/mL) for 144 CoNS isolates from ocular infections, including 68 (47.2%) methicillin-susceptible CoNS isolates and 76 (52.8%) methicillin-resistant CoNS (MRCoNS) isolates, were 0.06/2 for besifloxacin, 0.5/64 for ciprofloxacin, 0.12/16 for moxifloxacin, 64/4512 for azithromycin, 0.06/416 for clindamycin, 0.5/44 for oxacillin, 0.12/32 for tobramycin, and 1/2 for vancomycin.26 Results of the Canadian ARMOR study show that besifloxacin had the lowest MIC90 values among the fluoroquinolones (1 mg/mL for S. aureus, 0.5 mg/mL for CoNS), equal to or more potent than that of vancomycin.27 Compared with other fluoroquinolones, besifloxacin had 4- to Z128-fold higher potency against ciprofloxacinresistant MRSA and MRSE; its MIC50 values (0.5 μg/mL) were the lowest for the ciprofloxacin-resistant isolates, regardless of methicillin susceptibility.9 In a post hoc analysis of clinical outcomes for patients with conjunctival infections caused by MRSA or MRSE across 4 RCTs, the bacterial eradication rate was 87.8% by the second follow-up visit for patients treated with besifloxacin (n ¼ 49).50 The majority of MRSA and MRSE isolates from these patients demonstrated concurrent in vitro resistance to ciprofloxacin.50
Safety of besifloxacin
In an integrated analysis of 1192 patients from 3 clinical studies, besifloxacin tid was found to be safe and well tolerated, with no significant effect on visual acuity,
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Besifloxacin in bacterial keratitis
Bacterial keratitis, an infection of the cornea, has potential for serious complications, including corneal
Besifloxacin for ocular bacterial infections—Deschênes and Blondeau scarring and permanent visual impairment or vision loss, if treatment is delayed.51,52 Common keratitis-causing pathogens include S. aureus, CoNS, P. aeruginosa, S. pneumonia, and Serratia species.22,53 In the United Kingdom, an increase in gram-negative bacterial keratitis in association with contact lens wear was observed in a 10year retrospective study.54 Similarly, a retrospective case series in the greater Toronto area over an 11-year period revealed a decrease in gram-positive and an increase in gram-negative pathogens.55 The most common pathogen was CoNS, and the most common gram-negative bacterium was P. aeruginosa.55 The American Academy of Ophthalmology issued guidelines recommending topical broad-spectrum antibiotics for empirical treatment of bacterial keratitis.52 With regard to the treatment of bacterial corneal ulcers, topical fluoroquinolones are considered the drug of choice in the absence of microbiological evaluation.56 A meta-analysis on the treatment of keratitis showed that when compared with combined fortified antibiotics such as aminoglycosides and cephalosporins, fluoroquinolones offer similar efficacy and a better tolerance profile.51 However, as with bacterial conjunctivitis, increasing resistance to early-generation fluoroquinolones has been reported.54,57,58 A U.K.-based study reported continued susceptibility of gram-negative bacteria to ciprofloxacin and gentamicin, but an increase in resistance to ciprofloxacin among gram-positive bacteria.54 A randomized trial examining resistance patterns of bacterial strains in 229 patients with bacterial keratitis showed none were resistant to moxifloxacin, 17.5% were resistant to chloramphenicol, 14.8% to cephazolin, 2.8% to ciprofloxacin, 2.5% to ofloxacin, and 1.6% to tobramycin.59 A Toronto study showed that methicillin resistance was present in 1.3% of S. aureus and 43.1% of CoNS isolates from patients with keratitis. Further, the study reported a trend toward increasing resistance to methicillin from 28% during the first 4 years of the study to 38.8% for the last 3 years (p ¼ 0.133).55 Besifloxacin was effective in the treatment of bacterial keratitis in preclinical studies. In a rabbit model of keratitis, besifloxacin was significantly more effective than gatifloxacin and moxifloxacin in reducing MRSA colony-forming units.60,61 Similar results were obtained when besifloxacin was used to treat keratitis induced by P. aeruginosa.62 In humans, a gradually tapered regimen including besifloxacin was effective in the treatment of a patient with corneal ulcer, presumably because of P. aeruginosa infection.63 A large, retrospective, case surveillance study showed that besifloxacin was as safe as moxifloxacin in the treatment of bacterial keratitis, with similar low incidences of corneal scarring and neovascularization, and similar rates (96% with besifloxacin) of physician-assessed bacterial eradication.64 Along with the efficacy demonstrated by besifloxacin against S. aureus, CoNS, P. aeruginosa, and Serratia species in
patients with conjunctivitis,50 these results suggest a potential role for besifloxacin in the treatment of bacterial keratitis. However, randomized, controlled clinical trials of besifloxacin in the treatment of bacterial keratitis are needed.
CONCLUSIONS Besifloxacin, with its broad-spectrum activity and potency to inhibit and kill bacteria, is likely to be associated with a lower rate of resistance development compared with other topical antibiotics and is, therefore, an excellent choice for the treatment of acute bacterial conjunctivitis. Although besifloxacin shows potential for use in the treatment of bacterial keratitis, further randomized, controlled trials are needed.
Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article.
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