The Pharmaceutical Journal Vol 264 No 7084 p298-301
February 19, 2000 Continuing education

Fifteen antibiotics are listed in the section relating to topical ocular antimicrobials in the British National Formulary (see Table 1).¹ Eady and Cove² suggest that an ideal topical antibiotic should not be related to an oral drug and should be restricted to topical use only. It should not select for cross-resistance or, more importantly, for multiple-resistance to unrelated antibiotics and it should have a broad enough spectrum of activity to be used as a single agent. Of the currently available topical ocular antibiotics, none fulfil all of these criteria.

Table 1: Commercially available topical ophthalmic preparations containing antibiotics
Antibiotic	Formulation	Combination antibiotic preparations	Other combinations
Bacitracin		Polyfax eye ointment
Chloramphenicol	Eye-drops 0.5 per cent Unit dose eye drops 0.5 per cent Eye ointment 1 per cent
Chlortetracycline	Eye ointment 1 per cent
Ciprofloxacin	Eye-drops 0.3 per cent
Dibromopropamidine isethionate	Eye ointment 0.15 per cent
Framycetin	Eye-drops 0.5 per cent Eye ointment 0.5 per cent		Sofradex eye ointment Sofradex eye-drops
Fusidic acid	Eye-drops 1 per cent
Gentamicin	Eye-drops 0.3 per cent Unit dose eye-drops 0.3 per cent
Gramicidin		Neosporin eye-drops
Lomefloxacin	Eye-drops 0.3 per cent
Neomycin	Eye-drops 0.5 per cent (3500 units/ml) Eye ointment 0.5 per cent (3500 units/g) Single dose eye-drops 0.5 per cent	Neosporin eye-drops	Betnesol-N eye ointment Vistamethasone-N eye-drops Betnesol-N eye-drops FML-Neo eye-drops Maxitrol eye-drops and ointment Neo-Cortef eye-drops and ointment Predsol-N eye drops
Ofloxacin	Eye-drops 0.3 per cent
Polymyxin B		Neosporin eye-drops Polyfax eye ointment Polytrim eye-drops and ointment	Maxitrol eye-drops and ointment
Propamidine isethionate	Eye-drops 0.1 per cent
Trimethoprim		Polytrim eye-drops and ointment

Topical antibiotics are used to treat bacterial conjunctivitis, blepharitis, keratitis and external hordeola (styes). They are also used as adjunctive treatment in cases of endophthalmitis (inflammation within the eyeball) and prophylactically to prevent infection before and after ophthalmic surgery.
Treatment is usually empirical and topical agents should be active against the most likely pathogens, namely Staphylococcus aureus, coagulase negative staphylococci, streptococci, Haemophilus influenzae and coliforms. Infection with Pseudomonas aeruginosa is less common. However, P aeruginosa was found to be responsible for almost half the bacterial resistance to chloramphenicol encountered in a total of 334 strains isolated from bacterial infection of the eye.³

Aminoglycosides

Three aminoglycosides are used as topical ocular agents - neomycin, its isomer framycetin which is derived from Streptomyces, and gentamicin derived from Micromonospora. Of these, gentamicin has the broadest antibacterial spectrum, with activity against Pseudomonas aeruginosa, although aminoglycosides are not generally active against streptococci. Neomycin also has activity against the protozoa Acanthamoeba.

Neomycin Neomycin is the oldest of the ocular aminoglycosides. It is rarely used alone, but is widely used as prophylaxis in combination with corticosteroids following ocular surgery. Neomycin possesses antiprotozoal activity and is sometimes used in the treatment of Acanthamoeba keratitis; however, because of poor cysticidal activity,⁴ it is normally used in combination with other agents. When neomycin is combined with a diamidine, it has an additive effect.^5,6
Topical ocular application of neomycin frequently results in sensitisation to the drug, which can lead to contact dermatitis in approximately 4 per cent of patients.

Framycetin Framycetin has been in clinical use since the 1950s but there is little information in the literature about its use as a topical ocular agent. Brunette⁷reported a clinical study of the drops and ointment in 93 cases of ocular infection and 68 cases where the drug was used as prophylaxis against infection. He described framycetin as an excellent antibiotic for topical use. The study demonstrated a broad spectrum of antibacterial activity for framycetin, together with a very low rate of patient sensitivity. However, the antibiotic has been shown to be less effective than fusidic acid in a more recent open randomised trial in Tanzania.⁸ Dirdal compared fusidic acid administered four times a day for the first day, then twice daily, with framycetin given eight times daily on the first day, then four times a day, for a period of seven to 14 days. Seventy-three children under six months of age with suspected bacterial conjunctivitis were assessed and both clinical and microbiological success rates were significantly higher in the fusidic acid group.

Gentamicin In the past, gentamicin was often used for the treatment of bacterial conjunctivitis as an alternative to chloramphenicol in patients allergic to chloramphenicol. However, the availability of newer, less toxic agents,⁹ increasing resistance to the aminoglycosides,¹⁰ poor ocular penetration,^11,12 and the discontinuation of the ointment form, thought by certain authors to be a more effective drug delivery system,¹³ has reduced its use. Nevertheless, in specialist centres, gentamicin is still widely used in a fortified form (1.5 per cent), normally at a concentration of 1.5 per cent in combination with a beta-lactam antibiotic in the treatment of bacterial corneal ulcers.¹⁴

Chloramphenicol

Chloramphenicol, an antibiotic originally isolated from Streptomyces venezuelae, but now mainly produced synthetically, was introduced into clinical use in 1948. It is highly active against most Gram-negative and Gram-positive pathogens, Rickettsia and Mycoplasma. Enterobacteriaceae show variable resistance and Pseudomonas aeruginosa and mycobacteria are usually resistant.
Chloramphenicol is, in many ways, an ideal drug for topical use. It is the gold standard for the treatment of conjunctivitis against which other topical treatments are tested. Chloramphenicol's spectrum of activity covers the majority of ocular pathogens. In a study of 738 patients with acute bacterial infections of the external eye, Seal et al³ found an overall resistance rate of only 6 per cent to chloramphenicol, compared with 9 per cent to tetracycline and around 20 per cent to the aminoglycosides tested. Chloramphenicol penetrates well into the aqueous humour after topical application,¹⁵ has low ocular surface toxicity, and low rates of development of resistance.
In May, 1995, a controversial article in the British Medical Journal opened a debate about a link between use of topical chloramphenicol and blood dyscrasias. Doona and Walsh¹⁶ recommended that the use of chloramphenicol should be restricted and that framycetin and fusidic acid were safer and equally effective alternatives. A large number of ophthalmologists and haematologists countered this view and highlighted the extremely large number of prescriptions of chloramphenicol dispensed, the small number of blood dyscrasias reported and the lack of proof of causality in these cases. The evidence for and against this association has been reviewed.¹⁷
Since this review, three papers have helped clarify the situation. One group of workers investigated serum levels of chloramphenicol following topical application and two groups reported the results of observations in cases of aplastic anaemia.
Walker et al¹⁸ reported that the more common form of chloramphenicol toxicity, reversible marrow suppression, occurs in a dose-dependent manner with sustained serum levels greater than 25mg/L. The researchers measured serum levels of chloramphenicol in subjects after one to two weeks of treatment with four times daily instillation. They found that serum levels did not accumulate to detectable levels of 1mg/L and concluded that topical chloramphenicol did not present a risk of inducing dose-related bone marrow toxicity.
Lancaster et al¹⁹ used the general practice research database to describe prescribing patterns of chloramphenicol eye-drops and to estimate the risk of aplastic anaemia after their use. Three patients with serious haematological toxicity and one who developed mild, transient leucopenia that was not considered serious were identified among the 442,543 patients who received 674,148 prescriptions for chloramphenicol eye-drops. The researchers concluded that, even in the unlikely event that all three cases were caused by chloramphenicol eye-drops, these data indicated that the risk of serious haematological toxicity after treatment with ocular chloramphenicol was small. They added that chloramphenicol eye-drops were cheap and effective and that their continued use for eye infections seemed to be a safe clinical strategy.
Wilholm et al²⁰ conducted two population-based studies using virtually identical protocols, representing about 185m person years of observation in industrialised and developing countries. Among more than 400 cases of aplastic anaemia, there was no use of chloramphenicol eye-drops, although associations were found for several other previously suspected drugs.
The authors concluded that their data provided no support for the claim that chloramphenicol eye-drops increased the risk of aplastic anaemia and that the recommendation that the eye-drops should be avoided because of an increased risk of aplastic anaemia was not well founded. This opinion is echoed in the current edition of the BNF.¹

Chlortetracycline

Since the discontinuation of tetracycline eye-drops and ointment, chlortetracycline eye ointment is the only tetracycline available for topical ocular use.
Chlortetracycline ointment is licensed for the treatment of superficial eye infections, including trachoma, caused by organisms sensitive to the drug. The ointment is applied up to three times a day, or more frequently if required.
Chlortetracycline is a broad spectrum, bacteriostatic antibiotic, isolated in the 1940s from Streptomyces aureofaciens. It exhibits in vitro activity against staphylococci, streptococci and all other common Gram-positive pathogens. It also inhibits coliforms, Haemophilus species, Neisseria species and most other Gram-negative organisms, with the exception of Pseudomonas aeruginosa. Tetracyclines are actively concentrated within phagocytes and are therefore useful against intracellular pathogens such as Chlamydia.²¹ Resistance of some of the more common microbial pathogens, such as Staphylococcus aureus, has led to a decline in its use.²²
Ophthalmia neonatorum, a notifiable disease, is a purulent discharge from the eyes of an infant during the first 28 days of life. Although chloramphenicol is probably the most effective antibiotic to use first-line, chlortetracycline should be used if chlamydial infection is detected.²³
Topical tetracyclines have been shown to be as effective as the more toxic silver nitrate (formerly used as a 1 per cent solution) as prophylaxis in gonococcal and chlamydial disease.²⁴ However, despite the in vitro activity of tetracyclines, in practice topical application may not be highly effective against Chlamydia trachomatis eye infections in neonates. In one study, Rettig et al²⁵ found a higher rate of chlamydial conjunctivitis in babies treated with 1 per cent tetracycline ointment than in those treated with intramuscular penicillin.
In addition, topical tetracyclines will not eradicate systemic chlamydial infection. In practice, topical therapy is combined with oral erythromycin.
A small single-masked study by Tabbara et al²⁶ found similar rates of resolution (63 to 65 per cent) when active trachoma was treated with a seven-week course of a topical tetracycline or a single, oral dose of azithromycin.

Fusidic acid

Fusidic acid is a steroid-like antibiotic first isolated from the fermentation products of the fungus Fusidium coccineum in 1962. It has the greatest antistaphylococcal activity (both coagulase positive and negative) of any topical ocular antibiotic currently available.²⁷
Fusidic acid is formulated as a microcrystalline suspension in a carbomer gel. The drug penetrates well into the eye following topical application, giving a median level of 0.8mg/ml in the aqueous humour 12 hours after the last dose, a level comparable to, or higher than, that seen after systemic administration.²⁸ Tear fluid concentrations of fusidic acid fall from 15.7mg/ml one hour after instillation to 5.6mg/ml at 12 hours.²⁹ The high tear fluid levels of the drug maintained during the 12-hour dosing interval help to explain why several trials of fusidic acid in the treatment of conjunctivitis have shown it to be as effective as chloramphenicol. In theory, chloramphenicol has a much broader spectrum of activity than fusidic acid.
Sinclair and Leigh³⁰ compared 12-hourly application of 1 per cent fusidic acid eye-drops and three-hourly administration of 1 per cent chloramphenicol ointment in 489 domiciliary patients with acute conjunctivitis. Both treatments were equally effective clinically, with 83 per cent of the patients given fusidic acid and 84 per cent of the patients given chloramphenicol becoming asymptomatic after five days of treatment. Similar numbers of patients (9 per cent) in each group improved but were symptomatic, and there were equal numbers of failures (7 per cent) in each group. Pathogens were isolated in 25.8 per cent of patients treated with fusidic acid and in 28 per cent of the chloramphenicol group. These included S aureus, Streptococcus spp, Haemophilus spp, Neisseria sp and Moraxella sp. One isolate (of 14) of Streptococcus pneumoniae was resistant to the antibiotic in each group, three isolates (of 13) of Haemophilus parainfluenzae and one isolate of Moraxella (of 2) were resistant to fusidic acid. Adverse effects were reported by 14.8 per cent of patients using fusidic acid and 10.7 per cent of patients using chloramphenicol, but withdrawal from the chloramphenicol group was higher (4.3 per cent) than that in the fusidic acid group (0.8 per cent). The most common adverse effect in the fusidic acid group was "smarting/irritation/stinging," reported by 9.7 per cent of patients. The authors concluded that the sustained release formulation of fusidic acid enables a twice daily dosage regimen to be employed, without any loss of efficacy, and with high patient acceptability.
The patient acceptability of fusidic acid was confirmed in a study (unpublished), presented by Murray and Evans at the annual conference of the British Association of Accident and Emergency Medicine, in 1992. The researchers compared fusidic acid with chloramphenicol eye-drops in a randomised crossover trial of 41 accident and emergency patients with clinically diagnosed acute conjunctivitis. Adverse effects of local discomfort, itching and stinging with chloramphenicol were reported by 12 per cent of patients, while only one patient (2 per cent) complained of stinging with fusidic acid. Of 29 respondents questioned about ease of application, compliance and treatment preference, only two patients found chloramphenicol easier to apply than fusidic acid, and only one patient preferred chloramphenicol to fusidic acid.
Although the proprietary product Fucithalmic is only licensed for the treatment of bacterial conjunctivitis, a number of publications have reported its successful use for other unlicensed indications. These include twice daily instillation as prophylaxis following squint surgery,³¹ four times daily instillation for seven days to reduce bacterial load on the lids and conjunctiva prior to cataract surgery,²⁷ and a single dose as prophylaxis following corneal abrasion.³² Seal et al suggest that the efficacy of fusidic acid applied twice daily to the inferior fornix and eye lid margins in patients with recurrent blepharitis associated with rosacea³³ may be due not only to the antistaphylococcal action of the antibiotic but also to its immunosuppressive action which has been compared to that of cyclosporin A.³⁴

Diamidines

The antibacterial activity of diamidine compounds has been covered in a previous article.³⁵ However, these compounds have also been used in the treatment of Acanthamoeba keratitis since the mid 1980s.³⁶ Propamidine alone, or more usually in combination with other agents, has been the mainstay of medical therapy in this protozoal infection of the cornea, which is frequently associated with the use of contact lenses.³⁷ An in vitro study has shown that propamidine is more effective than pentamidine against Acanthamoeba hatchetti, equally potent against A polyphaga but less effective against A castellani. The commercial product, Brolene, had a lower minimal amoebicidal concentration against A polyphaga and A castellani than propamidine and pentamidine, but a concentration for A hatchetti was not determined. Both drugs were relatively non-toxic after short-term contact with cell cultures.³⁸
Propamidine 0.1 per cent has been successfully used in the treatment of Acanthamoeba keratitis in combination with neomycin and polyhexamethylene biguanide (PHMB),³⁹ with neomycin,⁴⁰ with polyhexamethylene biguanide,⁴¹ and with chlorhexidine.⁴² In a retrospective multicentre study of 218 patients with confirmed or presumed Acanthamoeba keratitis, Radford et al⁴³ reported that all patients had received treatment with propamidine. The drug was rarely used alone (2 per cent of cases), but was combined with: PHMB (50 per cent), neomycin and PHMB (14 per cent), neomycin (7 per cent), chlorhexidine (7 per cent), neomycin and chlorhexidine (6 per cent), PHMB and chlorhexidine (4 per cent), neomycin, PHMB and chlorhexidine (3 per cent), or PHMB and a topical antifungal (3per cent). The proportion of patients retaining good visual acuity were highest in the propamidine plus PHMB and propamidine plus chlorhexidine groups. The authors believe that the cationic antiseptics, chlorhexidine and PHMB, facilitate entry of the aromatic diamidine propamidine into the protozoan cell.

Mrs Titcomb is directorate pharmacist, ophthalmology, Birmingham and Midland eye centre, City hospital NHS Trust, Birmingham