Ophthalmology Focus by New Media Medical

OPHTHALMOLOGY

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Eye Allergies? Explore the NEW world of Ectoin®

Treat and prevent symptoms of allergic conjunctivitis, naturally

Suitable for the whole family*

1 Ectoin® a natural extremolyte protects against harmful allergens1 2

Hyaluronic Acid a strong, naturally occurring lubricant provides long-lasting relief2

*Suitable for children, pregnant and breastfeeding women, contact lens wearers and sensitive eyes (preservative free). References: 1. Data on file - Bitop Ectoin® Scientific Information 2. Scheuer CA, et al. Retention of conditioning agent hyaluronan on hydrogel contact lenses. Contact Lens & Anterior Eye 2010,33(1S),2-6. Proprietary name: Artelac® Allergy Eye Drops. Contains: 0,24 % hyaluronic acid (as sodium hyaluronate) and 2 % Ectoin®. Preservative free. For full prescribing information, refer to the instructions for use. Further information is available on request from Bausch + Lomb. © 2017 Bausch & Lomb Incorporated. ®/™ denote trademarks of Bausch & Lomb Incorporated. Distributed by: Soflens (Pty) Ltd. Reg. No.: 1968/011787/07. 254 Hall Street, Centurion. Tel: +27 10 025 2100. www.bausch.co.za BL326/19

Allergy

OPHTHALMOLOGY FOCUS

Welcome to Medical Chronicle’s

Ophthalmology digibook, sponsored by Bausch + Lomb

Here you will find some articles on this diverse and dynamic field that have been featured in Medical Chronicle.

Happy reading!

Contents 7 common eye disorders Conditions associated with decreased vision Descending shade Compromised ocular lubrication How to manage dry eye syndrome with HA Inflamed eyes Management of conjunctivitis Rare eye diseases Beating bacterial conjunctivitis with a topical antibiotic Discovery: Important additional function of protective eye protein Glaucoma surgery Prosthetics article

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Strike at the core of ocular allergies, time and again with

0.2%

An advancement in corticosteroid therapy that treats the full spectrum of inflammatory mediators1-3 modulates and inhibits early- and late-phase inflammatory mediators for multi-symptom relief1,3 No meaningful increases in IOP elevations in short and long-term use1 References: 1. Ilyas H, et al. Long-term safety of loteprednol etabonate 0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Eye Contact Lens 2004;30(1):10-13. 2. Comstock TL, et al. Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. Int J Inflam 2012;789623:1-11. 3. Pavesio CE, et al. Treatment of ocular inflammatory conditions with loteprednol etabonate. Br J Ophthalmol 2008;92:455–459. Scheduling status: S4 Proprietary name and dosage form: Alrex Ophthalmic Suspension. Composition: Each 1 ml contains: Loteprednol etabonate 2,00 mg (0,2 % m/v) and Benzalkonium chloride (preservative) 0,01 % m/v. Pharmacological classification: A 15.2 Ophthalmic preparations with corticosteroids. Registration number: 38/15.2/0203. Bausch & Lomb Incorporated. ®/™ denote trademarks of Bausch & Lomb Incorporated. Applicant: Soflens (Pty) Ltd. Reg. no.: 1968/011787/07. 254 Hall Street, Centurion, 0157. Tel: +27 10 025 2100. www.bausch.co.za For full prescribing information, refer to the professional information as approved by the South African Health Products Regulatory Authority (SAHPRA). BL253/17 4 MEDICAL CHRONICLE

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Descending shade Worldwide, about 20% of the ageing populations have age-related macular degeneration (AMD). AMD is associated with progressive visual impairment and loss of quality of life. The National Institute of Health Care and Excellence (NICE) and the American Academy of Ophthalmology (AAO) updated their guidelines in 2019.

MD IS A complex, chronic degenerative disorder of the macula driven by a combination of genetic and lifestyle risk factors. The disorder accounts for 8.7% of blindness worldwide, specifically in people older than 60. Currently an

estimated 196 million people are affected. This number is likely to increase to 288 million by 2040. Although AMD mostly affect older people, early signs of retinal changes in people as young as 30–40 years have been reported.

These individuals appear to be asymptomatic. By the age of 80, the disease is present in more than 33% of individuals. Those affected often describe their visual disturbances as dark, grey or obstructed by a ‘descending shade’.

CAUSE According to the 2018 NICE AMD: Diagnosis and management guidance, the exact cause for AMD is not known, but factors such as age, family origin (prevalence is higher in people of white and Chinese family origin), diet and nutrition, genetics, and smoking are thought to affect the risk of developing the disorder. Other factors that should be considered include: • Presence of AMD in the other eye • Hypertension • BMI of 30kg/m2 or higher • Lack of exercise.

Vitamin See*

Strategies for reducing the risk of developing AMD in the unaffected eye or progressing to late AMD, include smoking cessation, increasing the intake of antioxidants, carotenoids and omega 3 fatty acids through dietary changes, highdose vitamin and mineral supplementation, treatment with statins, and laser treatment of drusen.

KEEP SEEING

THE FINER THINGS IN LIFE

AVA I

LE IN SACH

DIAGNOSIS AND INVESTIGATION According to the 2019 AAO guideline, wAMD is characterised by one or more of the following: • The presence of at least intermediate-size drusen (>63µm in diameter) • Retinal pigment epithelium (RPE) abnormalities such as hypopigmentation or hyperpigmentation • Presence of any of the following features: - Geographic atrophy of the RPE - Choroidal neovascularisation (exudative, wet) - Polypoidal choroidal vasculopathy (PCV) - Reticular pseudo-drusen - Retinal angiomatous proliferation

E TS

B LA

No.1 Prescribed by

✓ Lutein

✓ Zeaxanthin

✓ Omega-3

✓ Zinc

Oph

thalmologists’

Help protect eye health against age-related sight changes such as macular degeneration and cataract formation and maintain visual performance by recommending daily supplementation of Lutein & Zeaxanthin with Ocuvite1-3

SA’s no.1 eye supplement brand4 *Contributes to the maintenance of normal vision. References: 1. Rasmussen HM , et al. Nutrients for the aging eye. Clinical Interventions in Aging 2013; 8:741–748. 2. Zhao ZC, et al. Research progress about the effect and prevention of blue light on eyes. Int J Ophthalmol. 2018 Dec 18;11(12):1999-2003. 3. Hammond BR, et al. A double-blind, placebo-controlled study on the effects of lutein and zeaxanthin on photostress recovery, glare disability, and chromatic contrast. Invest Ophthalmol Vis Sci. 2014 Dec 2;55(12):8583-9. 4. Data on file. IMS TPM S1M EYE TONICS & VITAMINS. April 2020. 5. Impact Rx. Script data – April 2020. Scheduling status: S0 Proprietary name and dosage form: Ocuvite Complete soft gel capsules. Composition: Each soft gel capsule contains fish oil rich in DHA 507,7 mg: of which DHA 180 mg and total omega-3 300 mg, Lutein 5 mg, zeaxanthin 1 mg, vitamin C 90 mg, vitamin E 15 mg, zinc 7,5 mg. Scheduling status: S0 Proprietary name and dosage form: Ocuvite Complete sachets powder. Composition: Each sachet contains omega-3 DHA 150 mg, Lutein 10 mg, zeaxanthin 2 mg, vitamin C 180 mg, vitamin E 30 mg, zinc 15 mg. Scheduling status: S0 Proprietary name and dosage form: Ocuvite Lutein tablets. Composition: Each tablet contains Lutein 6mg, Zeaxanthin 0,5 mg, Vitamin E 8,8 mg, Vitamin C 60 mg, Zinc 5 mg and 20µg Selenium. Bausch & Lomb Incorporated. ®/™ denote trademarks of Bausch & Lomb Incorporated. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. For full prescribing information, refer to the Professional Information. Applicant: Soflens (Pty) Ltd. Reg. No.: 1968/011787/07. 254 Hall Street, Centurion, 0157. Tel: +27 10 025 2100. www. bausch.co.za BL479/20

320183 Ocuvite ECP Ad_SAOJ .indd 1 MEDICAL CHRONICLE

TYPES OF AMD There are two types of AMD; namely atrophic or dry AMD and neovascular or wet AMD (wAMD). Dry AMD is quite common. About 80% of people have this form of the disorder, which affects central vision. wAMD is rarer (5% to 20%) but is responsible for more than 90% of the severe central visual acuity loss. There is not yet a cure for AMD. The focus is therefore on prevention and delaying progression.

The 2019 NICE guidance recommends the following: • A fundus examination could be conducted as part of the ocular examination for people who are showing signs of changes in their vision • People who are suspected of having late wAMD should be offered an optical coherence tomography (OCT) • People who are suspected of having late

2020/07/08 18:06

OPHTHALMOLOGY FOCUS

wAMD whose clinical examination and OCT exclude neovascularisation should not be offered a fundus fluorescein angiography (FFA) • If the OCT doesn’t exclude neovascular disease, a fundus fluorescein angiography (FFA) should be offered to the patient. MANAGEMENT AND TREATMENT STRATEGIES The 2019 NICE guidance recommends that patient with wAMD should start treatment within 14 days of diagnosis. Late wAMD can deteriorate rapidly, therefore, delaying treatment initiation can potentially lead to worse outcomes in the long run. Minimising any delays in starting treatment increases the chances of preserving vision and the quality of life. The AAO also supports prompt treatment. They recommend the following: • VEGF inhibitors have demonstrated improved visual and anatomic outcomes compared with other therapies. AntiVEGF therapies have become first-line therapy for treating and stabilising most cases of wAMD. A Cochrane systematic review demonstrates the effectiveness of these agents to maintain visual acuity. Aflibercept is a pan–VEGF-A and placental growth factor (PGF) blocker approved by the American Food and Drug Administration (FDA) and has

similar efficacy as ranibizumab. In the head-to-head phase III VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) trials the currently approved 2mg dose of aflibercept was administered by intravitreal injection every four weeks and every eight weeks after three monthly loading doses. In the first year, both study arms were similar to 0.5mg ranibizumab dosed every four weeks. Intravitreal ranibizumab (0.5mg) is approved for the treatment of all subtypes of wAMD. Ranibizumab is a recombinant, humanised immunoglobulin G1 kappa isotype therapeutic antibody fragment developed for intraocular use. Ranibizumab binds to and inhibits the biologic activity of all isoforms of human VEGF-A. • A 2018 meta-analysis of 16 studies by Gao et al compared 587 patients in the monotherapy group with various antiVEGF agents against 673 patients in the combination group and found no statistically significant difference between groups in mean BCVA, the proportion of patients who gained 15 or more letters, or central retinal thickness at the end of the study. However, combination therapy did require fewer anti-VEGF injections, as noted in other studies with reducedfluence PDT demonstrating this reduction in number of injections at a statistically significant level as opposed to the standard fluence group. In addition to

intravitreal injections of VEGF inhibitors, verteporfin PDT and thermal laser photocoagulation surgery remain approved options for the treatment of subfoveal lesions. Current practice patterns support the use of anti-VEGF monotherapy for patients with newly diagnosed wAMD and suggest that these other therapies are rarely needed. • Thermal laser photocoagulation surgery is no longer recommended for subfoveal CNV treatment. • There still remains a possible role for thermal laser surgery treatment in eyes with extrafoveal and peripapillary CNV lesions. Although photocoagulation of well-demarcated extrafoveal CNV lesions resulted in a substantial reduction in the risk of severe visual loss for the first two years, recurrence or persistence occurs in approximately 50% of cases, thus reducing this benefit over the subsequent three years of follow-up. After five years of follow-up, 48% of eyes treated for extrafoveal lesions progressed to VA loss of 30 or more letters when compared with 62% of untreated eyes. The historical data are important to recognize in current practice patterns, as none of the antiVEGF or PDT trials included extrafoveal lesions. Practitioners have extrapolated and applied data from the dramatic improvements seen in the treatment of subfoveal lesions to extrafoveal

lesions. The current trend is to use anti- VEGF agents in preference to laser photocoagulation surgery. Laser surgery for extrafoveal lesions remains a less commonly used, yet reasonable, therapy. • Current therapies that have insufficient data to demonstrate clinical efficacy include radiation therapy, acupuncture, electrical stimulation, macular translocation surgery, and adjunctive use of intravitreal corticosteroids with verteporfin PDT. Therefore, at this time, these therapies are not recommended. MONITORING Monitoring late AMD in both eyes is important for identifying changes that are associated with the condition. By monitoring the progression will support treatment planning which will naturally sidestep under-treatment which could result in loss of vision or over-treatment which could harm the quality of life. Intervals between appointments should be determined by healthcare professionals.

REFERENCE National Institute for Health and Care Excellence (UK). Age-related macular degeneration: diagnosis and management. London: National Institute for Health and Care Excellence (UK); 2018 Jan. (NICE Guideline, No. 82.) Appendix B, Guideline scope. MEDICAL CHRONICLE 9

OPHTHALMOLOGY FOCUS

Eye Allergies? Explore the NEW world of Ectoin®

Treat and prevent symptoms of allergic conjunctivitis, naturally

Suitable for the whole family*

1 Ectoin® a natural extremolyte protects against harmful allergens1 2

Hyaluronic Acid a strong, naturally occurring lubricant provides long-lasting relief2

319871 Artelac Allergy Ad_160x225 FIN.indd 2

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Allergy

2019/03/28 10:05

Introducing the Next Big Advancement in the Maintenance of Normal Vision1

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CEBROLUX™ NEURO FACTOR A multivitamin and mineral supplement containing nutrients and a neuroprotective ) agent Citicoline1 (

Reference: 1. CEBROLUX™ NF powder for oral solution (package insert). South Africa: Soflens (Pty) Ltd; 2019. Scheduling status: S0 Proprietary name and dosage form: CEBROLUX™ NF powder for oral solution. Composition: Each 3g sachet contains: Citicoline (Cognizin®) 250 mg, Vitamin C 60 mg, Vitamin B3 12 mg, Vitamin E 8,2 mg, Zinc 6,25 mg, Vitamin B5 4,5 mg, Vitamin B6 1,05 mg, Vitamin B2 1,05 mg, Vitamin B1 0,83 mg, Vitamin A 600 μg, Folic acid 150 μg, Biotin 37,5 μg and Vitamin B12 1,875 μg. Bausch & Lomb Incorporated. CEBROLUXTM is a trademark of Bausch & Lomb Incorporated or its affiliates. COGNIZIN® is a registered trademark of KYOWA HAKKO BIO CO., LTD. This unregistered medicine has not been evaluated by the SAHPRA for its quality, safety or intended use. For full prescribing information, refer to the Professional Information. Applicant: Soflens (Pty) Ltd. Reg. No.: 1968/011787/07. 254 Hall Street, Centurion, 0157. Tel: +27 10 025 2100. www. bausch.co.za BL503/21

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Taking care of all types of Dry Eyes *Pertains to the unique actuator of Artelac Splash Eye Drops and the unique formulation of Artelac Intense Rebalance Eye Drops. **Hyaluronic Acid. Proprietary name: Artelac® Advanced Lipids Eye Drops. Contains 2 mg carbomer, medium chain triglycerides. Preservative: Cetrimide (10 g multi-dose only). Proprietary name: Artelac® Intense Rebalance Eye Drops. Contains 0,15 % hyaluronic acid (as sodium hyaluronate), 0,5 % polyethylene glycol 8000, vitamin B12. Preservative: Oxyd® (a gentle preservative that converts to water, oxygen and salt at the surface of the eye in the 10 ml multi-dose unit only). Proprietary name: Artelac® Splash Eye Drops. Contains 0,24 % hyaluronic acid (as sodium hyaluronate) in the 10 ml multi-dose unit and 0,2 % hyaluronic acid (as sodium hyaluronate) in the single dose units. Both the 10 ml multi-dose and single dose units are preservative free. Proprietary name: Artelac® Moisture Eye Drops. Contains 0,32 % hypromellose. Preservative: Cetrimide (10 ml multi-dose only). For full prescribing information, refer to the instructions for use. Further information is available on request from Bausch + Lomb. © 2017 Bausch & Lomb Incorporated. ®/™ denote trademarks of Bausch & Lomb Incorporated. Distributed by: Soflens (Pty) Ltd. Reg. No.: 1968/011787/07. 254 Hall Street, Centurion. Tel: +27 10 025 2100. www.bausch.co.za BL386/19

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OPHTHALMOLOGY FOCUS

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0,15 % HA** + PEG# 8000 & VIT B12 Provides lasting relief and promotes a healthy ocular surface & self healing of corneal cells2,3 Suitable for all types of contact lenses Preservative free in the eye (Oxyd®)

*Pertains to the unique actuator of Artelac Splash 10 ml and the unique formulation of Artelac Intense Rebalance Eye Drops.**Hyaluronic Acid. #Polyethylene Glycol. References: 1. Scheuer CA, et al. Retention of conditioning agent hyaluronan on hydrogel lenses. Contact Lens & Anterior Eye 2010;33(1S);2-6. 2. 2007 Report of the International Dry Eye Workshop (DEWS). Ocul Surf 2007;5(2):65-204. 3. Nosel ER. Applied nutrition for ocular conditions. Journal of Behavioural Optometry 2001;18(5):166. Proprietary name: Artelac® Intense Rebalance Eye Drops. Contains 0,15 % hyaluronic acid (as sodium hyaluronate), 0,5 % polyethylene glycol 8000, vitamin B12. Preservative: Oxyd® (a gentle preservative that converts to water, oxygen and salt at the surface of the eye in the 10 ml multi-dose unit only). Proprietary name: Artelac® Splash Eye Drops. Contains 0,24 % hyaluronic acid (as sodium hyaluronate) in the 10 ml multi-dose unit and 0,2 % hyaluronic acid (as sodium hyaluronate) in the single dose units. Both the 10 ml multi-dose and single dose units are preservative free. For full prescribing information, refer to the instructions for use. Further information is available on request from Bausch + Lomb. © 2017 Bausch & Lomb Incorporated. ®/TM denote trademarks of Bausch & Lomb Incorporated. Distributed by: Soflens (Pty) Ltd. Reg. No.: 1968/011787/07. 254 Hall Street, Centurion. Tel: +27 10 025 2100. www.bausch.co.za BL385/19.

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CPD | OPHTHALMOLOGY OPHTHALMOLOGY FOCUS

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To complete a quiz based on this CPD article, visit https://bit.ly/3jaz01d

Beating bacterial conjunctivitis with a topical antibiotic

Besifloxacin is a novel 8-chloro-fluoroquinolone agent with potent, bactericidal activity against prevalent and drug-resistant pathogens. It has demonstrated consistent safety and efficacy in three bacterial conjunctivitis clinical trials.

ESIFLOXACIN IS THE first fluoroquinolone (FQs) developed specifically for topical ophthalmic use. It has a C-8 chlorine substituent and is known as a chloro-fluoroquinolone. Acute bacterial conjunctivitis, the most common cause of conjunctivitis, is responsible for approximately 1% of all primary-care consultations. Of the topical ophthalmic antibiotics used to treat acute bacterial conjunctivitis, FQs are especially useful because they possess a broad antibacterial spectrum, are bactericidal in action, are generally well tolerated, and have been less prone to development of bacterial resistance. FQs have been successfully used in ophthalmology for nearly two decades, mostly due to a series of improvements in their antimicrobial activity and pharmacokinetic profiles. Today, treatment for bacterial ocular surface infections — including conjunctivitis, blepharitis and keratitis — is largely empirical. The FQs’ broad-spectrum antimicrobial activity and documented safety and lack of toxicity make them well suited to empirical therapy. With activity against a broad spectrum of bacterial pathogens including grampositive, gram-negative and anaerobic organisms, current-generation FQs, such as

besifloxacin, have become first-line agents for the treatment and prevention of bacterial ocular infections. (Mah, 2016). As with other antibiotics, resistance to FQs has developed. Until the early 2000s, FQ resistance was uncommon among ocular pathogens, but with the rapid increase in clinical utilisation of FQs (both systemic and topical), resistance has begun to emerge. Surveillance studies have shown an alarming trend of increasing resistance in ocular isolates over the past two decades. Most notably, pathogenic strains such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) are becoming prevalent, and many strains show multidrug resistance including resistance to both earlier and current generation FQs. Besifloxacin was developed solely for topical ophthalmic use. A 0.6% besifloxacin ophthalmic suspension was approved in the US and Canada for the treatment of bacterial conjunctivitis in 2009. The first topical chlorofluoroquinolone, besifloxacin has a unique molecular structure designed to confer increased antibacterial potency. In susceptibility assays, besifloxacin demonstrated potent in vitro activity against a wide range of pathogens, including those that are resistant to other FQs and

antibacterial classes. According to Mah et al (2016), “Perhaps the most distinctive feature of besifloxacin is its lack of a systemic formulation. Unlike all other ophthalmic FQs, besifloxacin has never been used systemically, nor has it been used in agriculture or animal husbandry. Because extensive systemic antibiotic use and antibiotic use in agriculture are two major drivers of resistance development among bacteria, it has been suggested that the limitation to ocular use may slow the development of bacterial resistance to besifloxacin, although cross-resistance from other FQs is still possible.” Besifloxacin possesses relatively balanced dual-targeting activity against bacterial topoisomerase IV and DNA gyrase (topoisomerse II), two essential enzymes involved in bacterial DNA replication, leading to increased potency and decreased likelihood of bacterial resistance developing to besifloxacin. Microbiological data suggest a relatively high potency and rapid bactericidal activity for besifloxacin against common ocular pathogens, including bacteria resistant to other FQs, especially resistant staphylococcal species. Randomised, double-masked, controlled clinical studies demonstrated the

BESIFLOXACIN KEY POINTS • First and only chloro-fluoroquinolone developed specifically for topical ophthalmic use • Potent and broad-spectrum coverage of pathogens • Fast effect • Because it is limited to ocular use, this may slow the development of bacterial resistance. clinical efficacy of besifloxacin ophthalmic suspension 0.6% administered three-times daily for five days to be superior to the vehicle alone and similar to moxifloxacin ophthalmic solution 0.5% for bacterial conjunctivitis. In addition, besifloxacin ophthalmic suspension 0.6% administered two-times daily for three days was clinically more effective than the vehicle alone for bacterial conjunctivitis, stated O’Brien (2012). Bacterial conjunctivitis is an inflammation of the transparent mucous membrane covering the globe of the eye. This common ocular surface infection is caused by a broad variety of bacteria and is usually treated with broad-spectrum topical ophthalmic antibacterials. The increasing prevalence of drug-resistant ocular isolates MEDICAL CHRONICLE June 2021 MEDICAL CHRONICLE 21

CPD | OPHTHALMOLOGY OPHTHALMOLOGY FOCUS highlights the need for the development of new agents for the treatment of bacterial infections. EFFICACY The antibacterial spectrum of besifloxacin was studied using 2690 clinical isolates representing 40 species. Overall, besifloxacin was the most potent agent tested against gram-positive pathogens and anaerobes and was generally equivalent to comparator FQs in activity against most gram-negative pathogens. (Haas 2012) Pharmacokinetic studies demonstrated that after a single topical dose of 0.6%

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Conclusions: Although mutant selection experiments indicated that gyrase is a primary target, further biochemical and genetic studies showed that besifloxacin has potent, relatively balanced activity against both essential DNA gyrase and topoisomerase IV targets in S. aureus and S. pneumoniae.

Against common and prevalent ocular pathogens in bacterial conjunctivitis1-3 • Flexible dosing • Up to 12 hours contact time2

References: 1. Haas W, et al. Besifloxacin, a novel fluoroquinolone, has broad-spectrum in vitro activity against aerobic and anaerobic bacteria. Antimicrob Agents Chemother. 2009;53(8):3552–60. 2. Torkildsen G, et al. Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration. Clin Ophthalmol. 2010;4:331–41. 3. Malhotra R, et al. 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(4):243–52. S4 Besivance eye drops, suspension, Besifloxacin 6,00 mg/ml, 47/15.1/1186. For full prescribing information, refer to the professional information as approved by the South African Health Products Regulatory Authority (SAHPRA) © 2020 Bausch & Lomb Incorporated or its affiliates. ®/™ denote trademarks of Bausch & Lomb Incorporated or its affiliates. Soflens (Pty) Ltd. Reg. no.: 1968/011787/07. 254 Hall Street, Centurion, 0157. Tel: +27 10 025 2100. www.bausch.co.za. BL525/21

320561 Besivance Advert 4 A4.indd 1

MEDICAL CHRONICLE June 2021 22 MEDICAL CHRONICLE

pathogens that were resistant to other FQs was particularly notable. In conjunction with recently reported safety, efficacy, and pharmacokinetic results from clinical trials, besifloxacin’s broad-spectrum activity profile is appropriate for empirical treatment of bacterial infections. (Haas 2012) Cambau et al (2009) investigated its mode of action and resistance in two major ocular pathogens, Streptococcus pneumoniae and Staphylococcus aureus, and in the reference species Escherichia coli. Methods: Primary and secondary targets of besifloxacin were evaluated by: Mutant selection experiments, minimum inhibitory concentration (MIC) testing of defined topoisomerase mutants; and inhibition and cleavable complex assays with purified S. pneumoniae and E. coli DNA gyrase and topoisomerase IV enzymes. Results: Enzyme assays showed similar besifloxacin activity against S. pneumoniae gyrase and topoisomerase IV, with IC(50) and CC(25) of 2.5 and 1 microM, respectively. In contrast to ciprofloxacin and moxifloxacin, besifloxacin was equally potent against both S. pneumoniae and E. coli gyrases. DNA gyrase was the primary target in all three species, with substitutions observed at positions 81, 83 and 87 in GyrA and 426 and 466 in GyrB (E. coli numbering). Topoisomerase IV was the secondary target. Notably, resistant mutants were not recovered at four-fold besifloxacin MICs for S. aureus and S. pneumoniae, and S. aureus topoisomerase mutants were only obtained after serial passage in liquid medium. Besifloxacin MICs were similarly affected by parC or gyrA mutations in S. aureus and S. pneumoniae and remained below 1 mg/L in gyrA-parC double mutants.

Benzydamine’s chemical structure makes it highly lipid soluble, with low plasma protein binding capacity. This promotes its absorption and selective binding into inflamed tissues, where it accumulates, reducing the possibility of systemic side effects

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ACTIVITY OF BESIFLOXACIN AGAINST GRAM-POSITIVE AEROBES Against Enterococcus faecalis and E. faecium, including vancomycin-resistant enterococci, besifloxacin was more potent

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than the comparator FQs, as well as azithromycin, vancomycin, and tobramycin. Besifloxacin further demonstrated excellent activity against Listeria monocytogenes, similar to that of tobramycin and penicillin and better than that observed with comparator FQs. Against 2690 isolates, representing 34 aerobic and six anaerobic bacterial species, the in vitro activity of besifloxacin was generally equivalent or superior to that of existing agents used for topical treatment of ocular infections. The consistently improved activity profile of besifloxacin against gram-positive and gram-negative

besifloxacin ophthalmic suspension, mean besifloxacin levels in human tears ranged from 610μg/ml at 10 min postadministration to 1.6μg/ml at 24 hours post-administration. Here, the in vitro activity of besifloxacin against a broad range of aerobic and anaerobic bacterial species, including problematic drug-resistant strains, was evaluated.

DOSAGE DeLeon et al (2012) found that besifloxacin ophthalmic suspension 0.6% given three times a day for five days is safe and effective 2021/05/28 08:44

OPHTHALMOLOGY FOCUS CPD | OPHTHALMOLOGY

in the treatment of patients with bacterial conjunctivitis. This study evaluated the safety and efficacy of besifloxacin ophthalmic suspension 0.6% administered twice daily for three days compared with vehicle in the treatment of bacterial conjunctivitis. Study design: This was a multicentre, double-masked, randomised, vehiclecontrolled, parallel-group study. Methods: A total of 474 patients aged ≥1 year with bacterial conjunctivitis were randomised in a 1 : 1 ratio to receive either besifloxacin ophthalmic suspension 0.6% or vehicle administered twice daily for three days. There were three study visits: day 1 (the baseline visit), day 4/5 (visit 2), and day 7 ± 1 (visit 3). The co-primary efficacy endpoints were bacterial eradication and clinical resolution at day 4/5 in designated study eyes of patients with cultureconfirmed bacterial conjunctivitis. Secondary efficacy endpoints were bacterial eradication and clinical resolution at day 7 ± 1, individual clinical outcomes of ocular discharge and bulbar conjunctival injection at all visits and microbial and clinical outcomes for overall bacterial species and individual gram-positive and gram-negative bacterial species at each follow-up visit. Safety endpoints included adverse events (AEs), changes in visual acuity and biomicroscopy findings at each visit, and changes in ophthalmoscopy findings at day 7 ± 1. Results: Bacterial eradication and clinical resolution rates were significantly higher in the besifloxacin group than in the vehicle group (115/135 [85.2%] vs 77/141 [54.6%], p < 0.001, and 89/135 [65.9%] vs 62/141 [44.0%], p < 0.001, respectively) at day 4/5. Rates of bacterial eradication continued to be significantly greater in the besifloxacin group (115/135 [85.2%] vs 91/141 [64.5%], respectively; p < 0.001) at day 7 ± 1. However, the rates of clinical resolution did not differ significantly between the groups (103/135 [76.3%] and 94/141 [66.7%], p = 0.209) at this visit. Ocular discharge and bulbar conjunctival injection at each visit were consistent with the primary outcomes. Clinical resolution and bacterial eradication with gram-positive or gram-negative organisms were consistent with the overall findings. All AEs in both

groups were of mild or moderate severity and were considered unrelated to the treatment. Conclusion: Treatment with besifloxacin ophthalmic suspension 0.6% administered twice daily for three days was effective and safe in adults and children with bacterial conjunctivitis. IMPROVING ANTIMICROBIAL ACTIVITY: WHAT WE HAVE LEARNED Peterson et al (2012) found that understanding of how molecular modifications of the core quinolone structure affect(s) antimicrobial agent activity has progressed rapidly. “Three positions (2, 3, and 4) cannot be changed without a significant loss of biological activity. Furthermore, it appears that a cyclopropyl group is optimal at position 1. Substituents at positions 5 and 8 affect planar configuration, and either a methyl or methoxy appear optimal at these sites. Hydrogen and amino groups have been investigated as useful substituents at position 6, replacing the fluorine of theFQs. Interestingly, in vitro activity enhancement observed with alterations at positions 5 and 6 is not always accompanied by improved in vivo action. For all these modifications, the substituents at positions 7 and 8 are critical for potent antimicrobial activity. Optimising overall molecular configuration enhances the number of intracellular targets for antimicrobial action (R-8) and impedes the efficiency of efflux proteins (R-7) that diminish intracellular penetration.” According to an earlier study by Peterson et al, “It is now clear from accumulated experience with modifications of the core molecule that positions 3 through 4 are quite fixed, and few if any changes would be expected to lead to improvements in antimicrobial activity. It also seems clear that a cyclopropyl at position 1, and a methoxy or methyl at position 8 are the optimal substituents, regardless of the changes made at other sites. Substituting a nitrogen for the carbon at position 8 remains a useful possibility as well. It appears that any of these three changes at the 8 position increases the number of intracellular targets on type II topoisomerases, so that two or more mutations are required before clinically relevant resistance develops. Replacing the carbon between positions 4 and 5 with a nitrogen, adding a methyl

or methoxy substituent at position 5, and replacing the fluorine at position 6 with a hydrogen or amino group all look to be useful modifications that extend the number of beneficial compounds within the quinolone class. Several modifications at position 7 appear possibly important in the future development of new compounds. Some type of bulky (5- or 6-membered rings) nitrogen heterocycle offers the best enhancement of activity. Addition of more bulk through a fused ring structure to impair the action of exporter proteins and so lower the propensity for development of quinolone resistance in microbial pathogens optimises the configuration here.” They stated that the current knowledge of structure-activity relationships has been gained through the past development of a large number of compounds within the quinolone class. “While we now have a considerable variety of clinically useful agents, it seems clear that improvements in antimicrobial activity are still possible, and that these will extend the useful life of these medically important compounds well into the future,” the authors stated. ANTIBIOTIC RESISTANCE Ocular bacterial infections include conjunctivitis, keratitis, endophthalmitis, blepharitis, orbital cellulitis and dacryocystitis. Treatment for most ocular bacterial infections is primarily empiric with broad-spectrum antibiotics, which are effective against the most common bacteria associated with these ocular infections. However, the widespread use of broadspectrum systemic antibiotics has resulted in a global increase in resistance among both gram-positive and gram-negative bacteria to a number of the older antibiotics as well as some of the newer fluoroquinolones used to treat ophthalmic infections. Strategies for the prevention of the increase in ocular pathogen resistance should be developed and implemented. In addition, new antimicrobial agents with optimised pharmacokinetic and pharmacodynamic properties that have low toxicity, high efficacy, and reduced potential for the development of resistance are needed. CONCLUSIONS New antimicrobial agents that treat ocular infections effectively and have a low potential for the development of resistance

could be a part of strategies to prevent the global increase in ocular pathogen resistance. Besifloxacin is a novel topical C8-chlorofluoroquinolone with potent, broad-spectrum antibacterial activity and a favourable pharmacokinetic profile that together supports its use in the empirical treatment of bacterial infection at the ocular surface. Besifloxacin has been established as an effective and safe treatment for bacterial conjunctivitis, while further investigations are needed to assess its safety and efficacy in bacterial keratitis, antimicrobial prophylaxis in ocular surgery, and for the treatment of bacterial lid disorders. Compared with other topical FQs, besifloxacin ophthalmic suspension offers several potential therapeutic advantages, including higher ocular surface drug concentrations, longer ocular surface exposure times, and greater efficacy against FQ-resistant ocular pathogens, including MRSA and MRSE. REFERENCES Mah, F.S., Sanfilippo, C.M. Besifloxacin: Efficacy and Safety in Treatment and Prevention of Ocular Bacterial Infections. Ophthalmol Ther 5, 1–20 (2016). https://doi. org/10.1007/s40123-016-0046-6. O’Brien TP. Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. Adv Ther. 2012 Jun;29(6):473-90. doi: 10.1007/ s12325-012-0027-7. Epub 2012 Jun 20. PMID: 22729919. 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 Aug;53(8):3552-60. doi: 10.1128/AAC.0041809. Epub 2009 Jun 8. PMID: 19506065; PMCID: PMC2715578. Cambau E, Matrat S, Pan XS, Roth Dit Bettoni R, Corbel C, Aubry A, Lascols C, Driot JY, Fisher LM. Target specificity of the new fluoroquinolone besifloxacin in Streptococcus pneumoniae, Staphylococcus aureus and Escherichia coli. J Antimicrob Chemother. 2009 Mar;63(3):443-50. doi: 10.1093/jac/dkn528. Epub 2009 Jan 15. PMID: 19147516. DeLeon J, Silverstein BE, Allaire C, Gearinger LS, Bateman KM, Morris TW, Comstock TL. 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 May 1;32(5):303-17. doi: 10.2165/11632470000000000-00000. PMID: 22420526. Lance R. Peterson, Quinolone Molecular StructureActivity Relationships: What We Have Learned about Improving Antimicrobial Activity, Clinical Infectious Diseases, Volume 33, Issue Supplement_3, September 2001, Pages S180–S186, https://doi. org/10.1086/321846. Bertino JS Jr. Impact of antibiotic resistance in the management of ocular infections: the role of current and future antibiotics. Clin Ophthalmol. 2009;3:507-21. doi: 10.2147/opth.s5778. Epub 2009 Sep 24. PMID: 19789660; PMCID: PMC2754082. MEDICAL CHRONICLE June 2021 MEDICAL CHRONICLE 23

OPHTHALMOLOGY FOCUS

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OPHTHALMOLOGY FOCUS

Glaucoma surgery

– the South African consensus This document was prepared on behalf of the South African Glaucoma Surgery Interest Group, under the auspices of the South African Glaucoma Society (SAGS). Corresponding author: Dr Bill Nortje, Ophthalmologist, Hillcrest Hospital, 471 Kassier Road, Hillcrest, 3610; email: billn@mweb.co.za

NTRODUCTION Glaucoma is a generic name for a group of diseases with marked complexity and variability. It is the only eye disease classified as a chronic disease, among the legislated 25 chronic disease conditions in South Africa.1 Glaucoma is one of the leading causes of blindness in South Africa2 and as such, deserves adequate, upto-date management guidelines. The prevalence of glaucoma in Africa is the highest in the world, at 4.16%,3 and is higher among the black population than the Caucasian population4 (around 5% to 7% in the black population and 3% to 5% in the white population of South Africa). It thus has a major impact on the visual health of our nation. Inadequate treatment can lead to blindness and a resultant socio-economic burden on the State. With proper treatment, however, the quality of vision and of life can be maintained.3,5,6 GOALS OF TREATMENT Current treatment is aimed at lowering intraocular pressure (IOP), thereby attempting to reduce glaucoma progression such as structural and functional loss of the optic nerve.7 There is no one method of treatment universal to all cases. The goal of glaucoma treatment is to maintain the patient’s visual function and related quality of life, at a sustainable cost. The cost of treatment in terms of inconvenience and side effects, as well as financial implications for the individual and society, requires careful evaluation. Quality of life is closely linked with visual function. Patients with early-to-moderate glaucoma damage have good visual function and a modest reduction in quality of life, while quality of life is considered reduced if both eyes have advanced visual function loss. TREATMENT GUIDELINES The SAGS Treatment Guidelines are intended to support the general ophthalmologist in managing patients affected by or suspected of having glaucoma. The clinical guidelines are to be considered as recommendations. Clinical care must be individualised to each patient, the treating ophthalmologist and the socio-economic milieu. The availability of randomised controlled trials makes it possible to apply scientific evidence to clinical recommendations. The majority of glaucoma disorders are

chronic, slowly progressive diseases. These conditions are usually started on medical therapy. A percentage of these cases,8,9 despite following recognised algorithms of medical treatment, continue to progress and are labelled ‘failed’ on maximum tolerated medical treatment and still present documented structural and functional progression. INDICATIONS FOR SURGERY OF CHRONIC GLAUCOMA The consensus group states that, in the chronic glaucomas, the following are the criteria for surgery:9 1. IOP above target IOP on maximum tolerated medical therapy 2. Progression of glaucoma on maximum tolerated medical therapy 3. Contraindications to medical therapy 4. Side effects of medical therapy • Local side effects • Allergy • Allergy to preservatives • Orbitopathy • Systemic side effects 5. Inability to administer pharmacotherapy (e.g. rheumatoid arthritis) GENERAL PRINCIPLES9,10 The different techniques of incisional surgery have different indications depending on the type of glaucoma. Their adoption depends on: • The target IOP chosen for the individual eye • The previous history (surgery, medications, degree of visual field loss) • The risk profile (i.e. single eye, occupation, refractive status) • Preferences and experience of the surgeon • The patient opinion, expectation and postoperative compliance. The decision to recommend glaucoma surgery should be made in light of published clinical trials. In the individual patient, a multitude of factors must be taken into account when deciding treatment, including compliance, stage of glaucoma, etc. Nevertheless, surgery should be considered whenever medical or laser treatment is unlikely to maintain sight in the glaucomatous eye. It should not be left as a last resort. Angle-closure glaucoma is usually initially approached by laser iridotomy or peripheral iridectomy. Primary congenital glaucoma is treated

with goniometry or trabeculotomy, or seton surgery with antifibrotic agents. There are numerous surgical options available. Each has its own advantages and disadvantages. Some are more effective at pressure lowering but at the expense of numerous potential complications. Some procedures are much safer and still others are faster and easier to perform. Some patients may not be anatomically suited to certain surgical approaches. There may be specific contraindications to certain approaches. Some approaches require more extensive post-operative care including a return to theatre. Some procedures require augmentation. Each patient needs an individual assessment to determine the best procedure for that situation.6 NEW APPROACHES New engineering and new concepts are producing multiple new approaches. Better understanding of the pathophysiology of glaucoma as well as many more doctors working on the concepts and treatment of glaucoma have produced many new approaches and new methodologies to treat glaucoma. The new advanced engineering capabilities have also produced the ability to produce smaller and better engineered devices to standards not possible in the past. The surgical routes are now directed at multiple sites: directly into the Schlemm canal (SC) or bypassing the trabecular meshwork into the SC, directly into the suprachoroidal space, ab interno into the sub conjunctival space, ab externo into the trabecular meshwork and several other routes. The newer drainage devices are aimed at being minimally invasive and to have a higher safety profile. Glaucoma surgery has a significant complication rate which can impact on vision as well as a variable long-term success rate. The newer devices are significantly less invasive and have less potential of vision impairment than the earlier procedures SAGS’ STANDPOINT Surgery has the potential to fulfil many features of an ideal approach to reducing IOP over drugs. It can lower the IOP to low teens, achieve long-term IOP reduction, minimise IOP fluctuations, lower the cost, and minimise local and systemic side effects. The major drawback, of traditional surgical options such as trabeculectomy and glaucoma drainage devices though, is

the potentially devastating, but rare, ocular side effects.11,12 This has resulted in the ongoing development of alternative surgical procedures, and several alternatives have emerged as effective options. The ideal procedure is one that is easy to perform, reproducible, with a low incidence of early post-operative complications and long-term, adequate IOP control. Glaucoma surgery has progressed, and recent advances have addressed the flaws in original surgical options. There is, however, no ‘one size fits all’ solution and one needs to be selective in choosing surgical procedures.12 In general, surgical options requiring smaller incisions (microsurgery) are a significant advance on traditional therapies, reducing IOP with minimal tissue destruction and anatomic structure preservation, short surgical time, simple instrumentation and fast post-operative recovery. The newer advances, with drainage devices of varying materials targeting varying outflow pathways, offer a selection of IOP-lowering opportunities, with reduced associated risks, time consumption and surgical complexity than older traditional options. The South African Glaucoma Society (SAGS) endorses the requirement that all devices must be FDA- and/or CE-approved before being allowed to be used in South Africa and covered by funders. They have all already undergone multiple trials before release for surgeons to use. They are all approved devices, and patient safety has been tested and confirmed. In summary, when considering surgery, the surgeon must take an individualised patient approach. Surgery should not be reserved as a last resort, as evidence has shown that earlier surgical intervention can confer benefit. Considerations include the target pressure, the patient’s previous history and risk profile, the drainage route – trabecular, suprachoroidal or subconjunctival – and whether the procedure is being performed in association with cataract surgery or as a solo procedure. For the full SAGS Policy Statement on Glaucoma Surgery, please revert to the SAGS website: https://www.sags.co.za/

REFERENCE SA Ophthalmology Journal Summer (March) 2018 vol 13 no 1.

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OPHTHALMOLOGY FOCUS

26 MEDICAL CHRONICLE

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