A Powerful Option for the Treatment of Bacterial Conjunctivitis

Thursday, August 1, 2013
A Powerful Option for the Treatment of Bacterial Conjunctivitis

By: Penny A. Asbell, MD, FACS , MBA

ABSTRACT Appropriate treatment of bacterial conjunctivitis serves to shorten the clinical course of disease, reduce symptoms, abbreviate the period of contagion, and reduce time lost from school or work.1,2 Furthermore, treatment with an effective agent can reduce the slight risk for more serious complications.2 Introduced in 2009, besifloxacin ophthalmic suspension 0.6% (BESIVANCE®) is broad-spectrum, topical fluoroquinolone with high potency and balanced affinity for bacterial DNA gyrase and topoisomerase IV.3-5 BESIVANCE® is indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following bacteria: Aerococcus viridans*, CDC coryneform group G, Corynebacterium pseudodiphtheriticum*, Corynebacterium striatum*, Haemophilus influenzae, Moraxella catarrhalis*, Moraxella lacunata*, Pseudomonas aeruginosa*, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis*, Staphylococcus lugdunensis*, Staphylococcus warneri*, Streptococcus mitis group, Streptococcus oralis, Streptococcus pneumoniae, Streptococcus salivarius*.

*Efficacy for this organism was studied in fewer than 10 infections.

In vitro studies have found that common bacterial conjunctivitis pathogens, including antibiotic-resistant strains, are susceptible to BESIVANCE®; and in clinical trials BESIVANCE® has demonstrated safety and robust efficacy against typical bacterial conjunctivitis pathogens.6,7 Use of a mucoadhesive polymer in the BESIVANCE® formulation increases residence time of the antimicrobial on the ocular surface and contributes to its pharmacokinetic/pharmacodynamic profile.8 Formulated for use only as a topical antibiotic, besifloxacin has not been used in internal medicine or agriculture, which may decrease selection pressure for resistance to the drug.9

Important Risk Information for BESIVANCE®

  • BESIVANCE® is for topical ophthalmic use only, and should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.
  • As with other anti-infectives, prolonged use of BESIVANCE® may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy.
  • Patients should not wear contact lenses if they have signs or symptoms of bacterial conjunctivitis or during the course of therapy with BESIVANCE®.
  • The most common adverse event reported in 2% of patients treated with BESIVANCE® was conjunctival redness. Other adverse events reported in patients receiving BESIVANCE® occurring in approximately 1–2% of patients included: blurred vision, eye pain, eye irritation, eye pruritus and headache.
  • BESIVANCE® is not intended to be administered systemically. Quinolones administered systemically have been associated with hypersensitivity reactions, even following a single dose. Patients should be advised to discontinue use immediately and contact their physician at the first sign of a rash or allergic reaction.
  • Safety and effectiveness in infants below one year of age have not been established.

Introduction

Each year, more than 4 million Americans suffer from bacterial conjunctivitis, and many of them seek medical attention.10 An estimated 1% to 4% of primary care consultations are for acute red eye, and there is evidence that the majority of those cases are caused by bacterial conjunctivitis.10,11

Prospective studies utilizing conjunctival culture found that most cases of acute conjunctivitis in children were bacterial in origin.1,11 Interestingly, physicians have been found to underestimate the prevalence of bacterial conjunctivitis in relation to other causes of an acute red eye.1

Patients with acute bacterial conjunctivitis characteristically experience tearing, ocular surface irritation, marked redness, and the presence of mucopurulent discharge that can be copious and lead to matting of the lash cilia. To prevent spreading the infection to others, patients are frequently required to stay home from work or school. While the prognosis is generally favorable—60% of cases resolve spontaneously within 2 weeks—bacterial conjunctivitis carries a small (but not zero) risk of progressing to keratitis, particularly in patients carrying large numbers of bacteria and/or an epithelial defect.11 Furthermore, infection with a difficult-to-treat pathogen such as Pseudomonas aeruginosa carries a higher risk for adverse outcomes (Figure 1).2

Figure 1

(a) Eye with confirmed bacterial conjunctivitis due to P. aeruginosa. (b) The same eye after 1 week of therapy with BESIVANCE® TID.

Microbiology

Since bacterial conjunctivitis is typically treated without culturing the eye, selection of an appropriate treatment requires knowledge of the most likely etiologic agents and their susceptibilities. Pathogens commonly implicated in bacterial conjunctivitis include typical commensal flora of the skin and nasopharynx, including such gram-positive organisms as Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pneumonia; and gram negatives Moraxella catarrhalis and Haemophilus influenzae. 9P. aeruginosa is a common cause of infection among contact lens wearers.2

An important challenge in the management of bacterial conjunctivitis is antimicrobial resistance.

Resistance

Clinicians who treat external ocular disease have been somewhat protected from problems associated with antibiotic resistance due to the unique pharmacokinetics of topically administered ophthalmic drugs—which can typically achieve concentrations at the site of infection far greater than systemic drugs.

However, even among ocular infections, rates of resistance to commonly used antibiotics are increasing rapidly; and resistant pathogens have been linked to treatment failure.9 It is therefore important that ophthalmologists keep abreast of the changing status of antibiotic resistance.

The study designated Ocular TRUST (for Tracking Resistance in the US Today) reported nationwide antibiotic susceptibility patterns of three key ocular pathogens—S. aureus, S. pneumoniae, and H. influenza - to multiple classes of ophthalmic antibiotics.12 Ocular TRUST found that, despite widespread use of fluoroquinolones in medicine and veterinary settings, and consequently high resistance selection pressure, the fluoroquinolones remained the most consistently effective class of antibiotic against S. pneumoniae, H. influenzae, and methicillin-susceptible S. aureus (MSSA) ocular isolates.12

Of particular concern, however, is the emergence of multidrug resistant gram-positive pathogens, including methicillin-resistant S. aureus (MRSA) and methicillin resistant S. epidermidis (MRSE). According to the Ocular TRUST study and others, MRSA is becoming increasingly resistant to multiple antibiotics.12 Ocular isolates from the 2009 ARMOR (Antibiotic Resistance Monitoring in Ocular microoRganisms) showed similar patterns of multidrug resistance among MRSA.13 ARMOR also revealed high rates of resistance among ocular MRSE isolates, and high levels of multidrug resistance among staphylococci and Pseudomonas strains.13

Potency

Antibiotic potency is typically quantified in terms of the minimum inhibitory concentration (MIC), the lowest concentration of a drug able to inhibit the growth of a bacterial isolate.14 To describe the potency of a drug against a bacterial species, we use the MIC50 and MIC90, the concentrations of antibiotic necessary to inhibit the growth of 50% and 90%, respectively, of different bacterial isolates of the same species. While low MIC values indicate that low concentrations of drug will be required to effect bacterial inhibition, the clinical significance of in vitro data has not been established.14

To date, besifloxacin has demonstrated excellent in vitro potency against gram-positive ocular pathogens. For example, three large clinical studies of BESIVANCE® for the treatment of bacterial conjunctivitis demonstrated low MICs against all clinical isolates (MIC50 = 0.06 and MIC90 = 0.25 mg/mL).6 In these studies, a total of 1324 bacterial pathogens representing more than 70 species were isolated.6

Besifloxacin also demonstrated strong activity against MRSA, including ciprofloxacin-resistant strains.6 Indeed, clinical research has demonstrated rapid microbial eradication by besifloxacin in cases of bacterial conjunctivitis culture-positive for MRSA and MRSE—even where the cultured isolates were found to be concurrently resistant to ciprofloxacin.15 Microbial eradication does not always correlate with clinical outcomes in antiinfective trials. In this study, the MIC90 values for besifloxacin were found to be 2 mg/mL against ciprofloxacin-resistant MRSA isolates, and 4 mg/mL against ciprofloxacin-resistant MRSE isolates.15

A 42-year-old man requested an emergency ophthalmology visit due to symptoms of “pink eye” that were affecting his ability to work. The patient reported a 2-day history of redness, irritation, and a thickened discharge from his right eye. Upon awakening, his eyelid was matted shut. His left eye felt normal and seemed to be unaffected. He reported no contact with anyone who had pink eye at home or work. He wore glasses for distance; otherwise he had no significant ocular or medical history. Examination of his right eye revealed a best corrected visual acuity of 20/30. Slit lamp examination showed trace lid swelling, 2+ conjunctival injection, and mucopurulent discharge. The eye tested negative for the presence of adenovirus. The cornea and anterior segment appeared normal. The left eye was correctable to 20/20, and slit lamp exam was normal. The patient was diagnosed with acute bacterial conjunctivitis in the right eye. BESIVANCE® (besifloxacin ophthalmic solution) 0.6% was prescribed and the patient instructed to instill one drop in the affected eye 3 times a day (4 to 12 hours apart) for 7 days. Seen 3 days later, the patient was significantly improved. He was instructed to continue BESIVANCE® to the end of the initial 7-day period and then discontinue.

The Besifloxacin Molecule

The besifloxacin molecule represents an evolution of the topical ocular fluoroquinolone family. Fluoroquinolones work by binding two enzymes critical for DNA bacterial replication: DNA gyrase (topoisomerase II) and topoisomerase IV.5 The original quinolones predominantly targeted DNA gyrase, which gave them good activity against replication of gram-negative organisms.5 Subsequent generations have had better activity against topoisomerase IV, which expands the spectrum of coverage against gram-positive organisms.5

BESIVANCE® has two halogen atoms on the quinolone backbone: a fluorine (common to all fluoroquinolones) and a chlorine at carbon 8. This imparts a balanced and increased affinity for both DNA gyrase and topoisomerase IV, enhancing besifloxacin’s overall potency.3,4 Targeting both enzymes relatively equally also means that two mutations would be required for the development of substantial resistance.5

Treating Bacterial Conjunctivitis

Since suspected bacterial conjunctivitis cases are not routinely cultured, empirical therapy should be broad-spectrum, covering as many as possible of the common gram-positive and gram-negative pathogens known to cause bacterial conjunctivitis. In addition, treatment efficacy may be enhanced by the use of a potent antibiotic that resides for a significant period on the ocular surface.

BESIVANCE® satisfies each of these criteria and several others. Its broad spectrum of coverage includes gram-positive and gram-negative pathogens that commonly cause bacterial conjunctivitis. BESIVANCE® has demonstrated potency against worrisome pathogens such as MRSA, MRSE, and P. aeruginosa.6 BESIVANCE® (besifloxacin ophthalmic suspension) 0.6% is also formulated with a mucoadhesive polymer.8 Studies have shown that this suspension allows for prolonged surface contact with the eye compared to antibiotics formulated in aqueous solutions.16

Finally, Besivance ® has an established safety profile and is a potent agent for the treatment of bacterial conjunctivitis.

Penny A. Asbell, MD, FACS, MBA, is professor of ophthalmology, director of cornea and refractive services, and cornea fellowship director in the department of ophthalmology of the Mount Sinai School of Medicine in New York, NY.

BESIVANCE is a registered trademark of Bausch & Lomb Incorporated. All other product/brand names are trademarks of their respective owners.

Click here to view the BESIVANCE® full prescribing information

References
  1. Patel PB, Diaz MCG, Bennett JE, Attia MW. Clinical features of bacterial conjunctivitis in children. Acad Emerg Med 2007;14:1-5.
  2. 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.
  3. 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.
  4. Cambau E, Matrat S, Pan X, et al. Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli. J Antimicrob Chemother. 2009;63(3):443-50.
  5. Bearden DT, Danziger LH. Mechanism of action and resistance to quinolones. Pharmacotherapy. 2001;21(10)(Suppl):224S-32S.
  6. Haas W, Gearinger LS, Usner DW, et al. Integrated analysis of three bacterial conjunctivitis trials of besifloxacin ophthalmic suspension, 0.6%: etiology of bacterial conjunctivitis and antibacterial susceptibility profile. Clin Ophthalmol. 2011 Sept;5:1369-79.
  7. 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.
  8. O’Brien TP. Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. Adv Ther. 2012;29:473-90.
  9. Karpecki P, Paterno MR, Comstock TL. Limitations of current antibiotics for the treatment of bacterial conjunctivitis. Optom Vis Sci. 2010;87:908-19.
  10. Smith AF, Waycaster C. Estimate of the direct and indirect annual cost of bacterial conjunctivitis in the United States. BMC Ophthalmol. 2009;9:13. Available at: http://www.biomedcentral.com/content/pdf/1471-2415-9-13.pdf.
  11. Hovding G. Acute bacterial conjunctivitis. Acta Ophthalmol. 2008;86:5-17.
  12. Asbell PA, Colby KA, Deng S, McDonnell P, Meisler DM, Raizman MB, Sheppard JD Jr, Sahm DF. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008;145:951-8
  13. Haas W, Pillar CM, Torres M, Morris TW, Sahm DF. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular microoRganisms (ARMOR) 2009 surveillance study. Am J Ophthalmol. 2011;152:567-74.
  14. Kowalski RP, Yates KA, Romanowski EG, et al. An ophthalmologist’s guide to understanding antibiotic susceptibility and minimum inhibitory concentration data. Ophthalmology. 2005;112:1987-91.
  15. DeCory HH, Comstock TL, Gearinger LS, Morris TW. Clinical efficacy of besifloxacin ophthalmic suspension, 0.6% against MRSA and MRSE. Poster presented at the annual meeting of the Association for Research in Vision and Ophthalmology; Fort Lauderdale, FL; May 6-10, 2012.
  16. Proksch JW, Granvil CP, Siou-Mermet R, et al. Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans. J Ocul Pharmacol Ther. 2009;25:335-43.

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