A Fluoroquinolone with Broad-spectrum Antibiotic Potency

By: Paul M. Karpecki, OD, FAAO

ABSTRACT Bacterial conjunctivitis is extremely common: in the developed world, between 1% and 4% of all visits to primary care physicians are for acute conjunctivitis, most commonly bacterial.¹ When bacterial conjunctivitis is treated without culture, it is critical to use an agent with good activity against a broad spectrum of potential pathogens. Because a significant number of the organisms isolated from eyes with bacterial conjunctivitis today show high levels of antibiotic resistance, and because some of these species can be virulent, any drug used to treat bacterial conjunctivitis must be potent as well as broad-spectrum. We have such an antibiotic in BESIVANCE^® (besifloxacin ophthalmic suspension) 0.6%. BESIVANCE^® is a quinolone antimicrobial 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.

BESIVANCE^® demonstrates potent activity against indicated pathogens, with low minimum inhibitory concentrations (MICs) against many bacteria of concern to eyecare practitioners, including methicillin-resistant staphylococci and Pseudomonas aeruginosa. Halogenation is known to impact drug efficacy and is the feature that distinguishes fluoroquinolones from earlier quinolones.² BESIVANCE^® has a second halogen, a chlorine atom, on its fluoroquinolone backbone.³ BESIVANCE^® offers balanced activity against bacterial DNA gyrase and topoisomerase IV, giving it excellent efficacy against indicated gram-positive and gram-negative bacteria.³ In addition, because BESIVANCE^® is formulated in a mucoadhesive vehicle, drug can reside on the eye at effective concentrations for 12 hours or more.⁴ These factors combine to make BESIVANCE^® a strong choice for the treatment of bacterial conjunctivitis.

Important Risk Information about 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 super- infection 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 Bacterial conjunctivitis is frequently seen by eyecare practitioners, primary care physicians, and pediatricians. While the condition is typically self-limited, there are good reasons to treat it. First, treatment limits the spread of infection between individuals: the sooner treatment is initiated and the patient is no longer contagious, the sooner he or she can return to school or work. And the sooner patients return to their ordinary activities, the lighter the economic impact of the disease—although it rarely causes serious morbidity, bacterial conjunctivitis has a significant economic impact because there is so much of it.⁵

Treating bacterial conjunctivitis also reduces the small but real risk of the infection worsening. Because we do not routinely culture eyes with conjunctivitis, the treatment we select must cover a broad spectrum of potentially infectious bacteria, including resistant strains.

Antibiotic Potency

Antibiotic potency is often defined in terms of a drug’s minimum inhibitory concentration (MIC), the lowest drug concentration that inhibits organism growth.6 To determine a drug’s potency against a bacterial species requires in vitro testing of multiple isolates. For any given bacterial species, the two most commonly cited MIC metrics, MIC₅₀ and MIC₉₀, represent the lowest concentration of the drug capable of inhibiting 50% or 90%, respectively, of tested isolates.⁶

Although MIC is measured in the laboratory, it can correlate with clinical efficacy: all other things being equal, if equal doses of two drugs with different MICs are given, the drug with the lower MIC will eradicate a greater number of organisms. This is important because bacterial conjunctivitis is typically treated empirically, making it advantageous to prescribe a drug with low MIC₉₀ values against the pathogens most frequently isolated from cases of bacterial conjunctivitis: H. influenzae, S. pneumoniae, S. aureus, and S. epidermidis, according to three clinical studies in the US and Asia.⁷ Again, though MIC data can guide clinical decision making, the clinical significance of in vitro data is not known. BESIVANCE^® (besifloxacin ophthalmic suspension) 0.6% has low MIC₉₀s against gram-positive and gram-negative organisms commonly cultured from bacterial conjunctivitis, including methicillin-resistant staphylococci (Table 1).⁷

Table 1

Diagnosis

In the absence of culture or other in vitro testing, we cannot be absolutely certain whether any given case of infectious conjunctivitis is bacterial or viral in origin. But we are not without some diagnostic clues. Bacterial conjunctivitis is typically unilateral and exhibits greater conjunctival injection, hyperemia, mucopurulent discharge, and mattering of lashes, especially in the morning (Figure 1).

When confronted with a red eye, my first diagnostic move is to take a thorough history. I inquire about contact lens wear, systemic conditions or medications that might compromise immunity, recent proximity to another person with a red eye, and current or recent flu, upper respiratory infection, skin rashes, or cold sores. Checking for lymphadenopathy can help rule out adenovirus conjunctivitis; and there is now an in-office immunoassay (Adeno Detector™; Rapid Pathogen Screening) that can also detect the presence of adenovirus.⁸

It is also important to evaluate patient symptoms, confirming when symptoms began, and in the event of a bilateral presentation, if one eye was affected first and followed by the fellow eye. Pain is typically not severe in bacterial conjunctivitis, although some patients report foreign body sensation and mild stinging. Itching and burning are more typical of allergic conjunctivitis, as is a bilateral onset. Mucopurulent discharge is more typical of a bacterial conjunctivitis, and watery or mucous discharge is more common in allergic or viral conjunctivitis.

Figure 1	Figure 2
Injection and hyperemia in bacterial conjunctivitis. (Photo courtesy of Paul Karpecki, OD).	Scanning electron micrograph of biofilm formation on glass cover slips in two strains of P. aeruginosa. A. Clumps of P. aeruginosa cells just 7 hours after inoculation. B. Weakly adherent P. aeruginosa isolates 14 hours after inoculation.   C. The same isolates form mature biofilm 20 hours after inoculation. D. Biofilm formation of same weakly adherent isolates 40 hours after inoculation.17

Treatment Criteria

In selecting an agent for the treatment of bacterial conjunctivitis, I look for an antibiotic with activity against a wide range of bacteria, including both gram-positive and gram-negative pathogens. A drug’s mechanism of action and specific activity tell us a great deal. Quinolone antibiotics, including the fluoroquinolones, work by inhibiting DNA gyrase and topoisomerase IV, both of which are enzymes necessary for bacterial replication.³

In gram-negative pathogens, like P. aeruginosa and H. influenzae, quinolones are active against DNA gyrase; whereas effective inhibition of gram-positive pathogens, such as S. aureus, S. epidermidis, and S. pneumoniae, requires activity against topoisomerase IV. Early quinolones bound with much greater affinity to DNA gyrase, and so had greater efficacy against gram-negative bacteria. The addition of a fluorine atom at the C-6 position gave quinolones enhanced affinity for topoisomerase IV and, thus, increased efficacy against gram-positive bacteria.²

BESIVANCE^® is an ophthalmic fluoroquinolone with two halogen atoms: the fluorine at C-6 and a chlorine at C-8. This double halogenation is may impact potency.² In particular, BESIVANCE^® demonstrates high affinity for topoisomerase IV, which gives it potency and efficacy against gram-positive organisms like S. aureus and S. pneumoniae.3 This balanced activity against both DNA gyrase and topoisomerase IV makes BESIVANCE^® a potent, broad-spectrum choice for treating bacterial conjunctivitis when neither the causative organism nor its susceptibility is known. Effectively targeting both enzymes may also impact the emergence of resistance to BESIVANCE^®, since mutations affecting both enzymes would be required.^3,9 In vitro resistance to BESIVANCE^® develops via multiple-step mutations and occurs at a general frequency of < 3.3 × 10–10 for S. aureus and < 7 × 10–10 for S. pneumoniae.¹⁰

BESIVANCE^® (besifloxacin ophthalmic suspension) 0.6% is formulated in a mucoadhesive vehicle, giving it excellent residence time on the ocular surface.11 Maintaining above-MIC levels of drug on the eye enhances bacterial eradication. In a pharmacokinetic study, effective concentrations of BESIVANCE^® were found in tears up to 24 hours after administration, with concentrations at 12 hours exceeding the MICs of several significant pathogens.⁴

Pathogens of Greatest Concern in Bacterial Conjunctivitis

The increasing prevalence of resistant pathogens, including methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis(MRSE) is a serious concern for those of us who treat bacterial conjunctivitis. BESIVANCE® has demonstrated excellent efficacy against both MRSA and MRSE, in part due to its ability to inhibit topoisomerase IV.

The virulent P. aeruginosa, a common cause of infection in contact lens wearers, is a serious concern for the many optometrists who fit contact lenses.¹² Several things account for the prevalence and virulence of P. aeruginosa infections in this patient population. First, P. aeruginosa readily adheres to surfaces, including contact lenses and contact lens cases, eventually forming biofilms that are difficult to disrupt (Figure 2).^13,14 Secondly, these opportunistic bacteria are nearly ubiquitous in soil, water, and on surfaces that come in contact with either.¹⁵

BESIVANCE^® is indicated for the treatment of bacterial conjunctivitis caused by P. aeruginosa. Affinity for DNA gyrase gives all quinolone antibiotics the potential to inhibit gram-negative pathogens like P. aeruginosa; and knowing that the potency of BESIVANCE^® extends to this much-feared organism is important to optometrists treating bacterial conjunctivitis.

Conclusion

It is helpful to treat bacterial conjunctivitis with an agent that has broad-spectrum activity, significant potency, and staying power at the site of infection.16 BESIVANCE^® (besifloxacin ophthalmic suspension) 0.6% has low MICs against a wide range of common ocular pathogens, including MRSA and P. aeruginosa, and is formulated in a mucoadhesive vehicle, making it an excellent choice for treating bacterial conjunctivitis.

Paul M. Karpecki, OD, FAAO, is the cornea services and clinical research director at the Koffler Vision Group in Lexington, KY. He is a paid consultant for Bausch + Lomb.

BESIVANCE^® is a trademark of Bausch & Lomb Incorporated or its affiliates. All other product/brand names are trademarks of their respective owners.

References

1. Hovding G. Acute bacterial conjunctivitis. Acta Ophthalmologica. 2008;86:5-17.
2. Andersson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemother. 2003;51(suppl S1):1-11.
3. 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.
4. 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(4):335-43.
5. 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.
6. Kowalski RP, Yates KA, Romanowski EG, et al. An ophthalmologist’s guide to understanding antibiotic susceptibility and minimum inhibitory concentration data. Ophthalmology. 2005;112(11):1987-91.
7. 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 Sept;5:1369-79.
8. Sambursky R, Tauber S, Schirra F, Kozich K, Davidson R, Cohen EJ. The RPS Adeno Detector for diagnosing adenoviral conjunctivitis. Ophthalmology. 2006;113:1758-64.
9. 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.
10. BESIVANCE package insert. Tampa, FL: Bausch & Lomb Incorporated; 2012.
11. Food and Drug Administration. Clinical pharmacology review: besifloxacin hydrochloride ophthalmic suspension 0.6%. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM185720.pdf.
12. Kreger AS. Pathogenesis of Pseudomonas aeruginosa ocular diseases. Rev Infect Dis. 1983 Nov-Dec;5(5)(suppl):S931-5.
13. Rumbaugh KP, Griswold JA, Hamood AN. Quorum sensing in the in vivo virulence of Pseudomonas aeruginosa. Microbes and Infection. 2000;2:1721-31.
14. Landa AS, van der Mei HC, van Rij G, Busscher HJ. Efficacy of ophthalmic solutions to detach adhering Pseudomonas aeruginosa from contact lenses. Cornea. 1998 14(3):293-300.
15. Lyczak JB, Cannon CL, Pier GB. Establishment of Pseudomonas aeruginosa infection: lessons from a versatile opportunist. Microbes and Infection. 2000;2:1051-1060.
16. 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(5):1159-69.
17. Deligianni E, Pattison S, Berrar D, et al. Pseudomonas aeruginosa cystic fibrosis isolates of similar RAPD genotype exhibit diversity in biofilm forming ability in vitro. BMC Microbiol. 2010;10:38.

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