How Antimicrobial Potency and Dosing Schedules Affect Pediatric Conjunctivitis Treatment

by: Marguerite B. McDonald, MD, FACS

Pediatric bacterial conjunctivitis is caused by a number of potential bacterial species, which vary with patient age. Topical antibacterial agents are preferred for the treatment of uncomplicated conjunctivitis because direct application of an eye drop produces a higher local concentration of antibiotic compared with that of systemic administration, while avoiding potential systemic adverse effects. The concentration of antibiotic on the eye following eye drop application exceeds the minimum inhibitory concentration required to inhibit the growth of 90% of micro-organisms (MIC₉₀) at the target tissue site.¹ The available topical agents may differ significantly in antimicrobial effectiveness or retention time on the eye.

Selecting a Topical Antibiotic

Choosing an appropriate antibiotic for bacterial conjunctivitis requires consideration of a number of factors. A topical antibiotic must provide broad coverage against ocular gram-positive and gram-negative bacteria.² The agent should be bactericidal rather than bacteriostatic, should result in a high concentration of antibiotic on the ocular surface, and should produce a rapid kill rate with a low risk of bacterial resistance. Treatment should be comfortable for patients with minimal toxicity to the eye. An appropriate topical agent should also have a convenient dosing schedule in order to enhance treatment compliance.

Currently, the most commonly used antibiotics include aminoglycosides, polymyxin B combination therapies, macrolides, and fluoroquinolones.³ Oral antibiotics are recommended for acute cases of otitis media with bacterial conjunctivitis. Sulfonamides and chloramphenicol are no longer favored in the United States because of tolerability and safety concerns, including severe stinging with the sulfonamides and the risk of aplastic anemia with chloramphenicol.⁴

Aminoglycosides require frequent administration, which can be inconvenient for patients or their families.⁴ Resistance is common among gram-positive organisms, especially streptococci, and treatment may cause hyperemia and/or keratopathy. Macrolides are bacteriostatic rather than bactericidal, and are also associated with resistance to common micro-organisms. Polymyxin B combinations are effective against Haemophilus influenzae and penicillin-susceptible Streptococcus pneumoniae, but are not reliably bactericidal, and cure rates may be as long as a week. With the polymyxin B/bacitracin combination ointment, there is a relatively high incidence of periocular contact dermatitis. Ocular allergic reactions are also common with a polymyxin B/neomycin/bacitracin combination product. Fluoroquinolones provide a broad spectrum of antibacterial activity against gram-positive and gram-negative organisms. However, resistance has become an increasingly common problem with these agents, especially among patients with S pneumoniae infections. Drug precipitates may occur with frequent ciprofloxacin dosing. Ofloxacin 0.3%, levofloxacin 0.5%, gatifloxacin 0.3%, moxifloxacin 0.5%, and besifloxacin 0.6% are all highly effective against a broad spectrum of gram-negative and gram-positive organisms. Moxifloxacin is the only fluoroquinolone that does not contain the preservative benzalkonium chloride. Besifloxacin was developed specifically for topical ophthalmic use. This agent produces potent in vitro activity against bacterial strains that are commonly resistant to other fluoroquinolones, although relatively few studies of besifloxacin have been published and the clinical significance of its in vitro antibacterial profile is unknown.

Fluoroquinolones for Topical Antibacterial Treatment of Pediatric Conjunctivitis

Fluoroquinolones were introduced in the 1990s and are a popular choice for the treatment of pediatric conjunctivitis due to their broad-spectrum coverage against both gram-positive and gram-negative organisms.⁵ The earliest fluoroquinolones (ofloxacin and ciprofloxacin) have largely been replaced by newer agents (levofloxacin, gatifloxacin, moxifloxacin, and besifloxacin) because of their greater antibacterial activity against gram-positive organisms. Several randomized, double-blind controlled clinical trials in children and adults have reported clinical cure rates ranging from 66% to 96% and microbial eradication rates of 84% to 96% after 1 week with the newer fluoroquinolones.⁶

Besifloxacin, the newest of the fluoroquinolones, was approved by the FDA for the treatment of bacterial conjunctivitis in May 2009. In clinical trials of adults and children with bacterial conjunctivitis, treatment with besifloxacin 0.6% resulted in clinical resolution rates of 45% to 73%, and bacterial eradication rates of 88% to 91%.^7,8 The efficacy and safety of besifloxacin in children and adolescents aged 1 to 17 years were recently confirmed in a post hoc analysis of data from 477 patients with culture-confirmed conjunctivitis, in which clinical cure rates and bacterial eradication rates were similar to rates observed for the overall population.⁹

Ophthalmic solutions of fluoroquinolones have been well-tolerated and are associated with less toxicity than other ophthalmic antibacterial classes. The most common adverse reactions include burning/stinging, chemosis, photophobia, and negative effects on the corneal epithelium.^10-12

Torkildsen and colleagues recently examined antibiotic concentrations in conjunctival samples from 108 healthy adult subjects who were randomized to receive a single intraocular drop of besifloxacin (0.6% suspension), gatifloxacin (0.3% solution), or moxifloxacin (0.5% solution).¹³ Conjunctival samples were obtained at either 15 minutes, 30 minutes, 2 hours, 6 hours, or 24 hours after eye drop application. The MIC₉₀ values for Staphylococcus aureus and Staphylococcus epidermidis were lower with besifloxacin than moxifloxacin or gatifloxacin for both methicillin-sensitive, ciprofloxacin-sensitive and methicillin-resistant, ciprofloxacin-resistant isolates (Table). The ratio of the area under the fluoroquinolone concentration curve over 24 hours (AUC) to MIC₉₀ (AUC:MIC₉₀ ratio) was examined individually for several types of conjunctival bacterial isolates. For patients with methicillin-resistant strains of S aureus or S epidermidis, the AUC:MIC₉₀ ratio was greater with besifloxacin than with moxifloxacin or gatifloxacin (Figure). For methicillin-sensitive, ciprofloxacin-sensitive S aureus and S epidermidis, the ratio of AUC:MIC₉₀ was higher with both besifloxacin and moxifloxacin than with gatifloxacin, but the besifloxacin and moxifloxacin groups did not differ significantly from one another.

Click here for larger version of Table.

The AUC over 24 hours was 6.65 µg·h/g with besifloxacin, 11.1 µg·h/g with moxifloxacin, and 6.10 µg·h/g with gatifloxacin. The mean residence time of fluoroquinolone in conjunctiva was 4.7 hours with besifloxacin, 3.0 hours with moxifloxacin, and 2.9 hours with gatifloxacin. This suggests that the besifloxacin was associated with the most stable behavior in conjunctival tissue when compared with other commonly used topical fluoroquinolones. The difference in mean retention time between besifloxacin and the other fluoroquinolones may reflect the properties of the different vehicles. For example, besifloxacin is formulated using a polymeric mucoadhesive delivery system that enhances drug residence time on the ocular surface, which may theoretically help to improve residence time in crying children.¹⁴

Click here for larger version of Figure.

Summary and Conclusions

Fluoroquinolones provide effective, broad-spectrum coverage against micro-organisms that are commonly associated with pediatric conjunctivitis. The typical dosing regimen is 3 times daily for 7 days, which is less onerous than other topical agents and may promote medication adherence. When compared with moxifloxacin and gatifloxacin, besifloxacin provides the greatest AUC/MIC₉₀ ratio for resistant and nonresistant bacterial strains. The AUC over the first 24 hours is considered the most accurate marker of efficacy. Besifloxacin also had a longer retention time, possibly due to the mucoadhesive delivery system. This effect might be important when treating crying children.

Discussion

Based on the results with besifloxacin, would you use this treatment in all cases of conjunctivitis?

Marguerite B. McDonald, MD, FACS: Ideally, I would use besifloxacin because of the broad spectrum of activity. We are beginning to see MRSA in children and adults, and besifloxacin is the fluoroquinolone that is most effective against MRSA. However, we are not in an ideal world, and besifloxacin is a more expensive drug with a higher copayment. Therefore, it is reasonable to implement polymyxin B/trimethoprim or gentamicin. If there were no constraints due to time or money or insurance, I would generally use the newest fluoroquinolone.

Are you concerned about the potential emergence of resistance if broader-spectrum fluoroquinolones are used more frequently in young children?

McDonald: I think most resistance really comes from overuse, and as discussed earlier, much of it can be attributed to tapering. Tapering the antibiotic at the end of treatment is not a good idea. Treatment should be administered using the full dose for the recommended amount of time, and then stopped. Using a subthreshold dose or tapering the dose at the end of treatment is a major driver of antibiotic resistance. If ophthalmologists and pediatricians would stop tapering antibiotics, it would go a long way toward reducing antibiotic resistance in pediatric conjunctivitis. Another important consideration is the recent development of a device known as the Adeno Detector (Rapid Pathogen Screening, Inc). This device makes it possible for the pediatrician or ophthalmologist to quickly determine whether an eye infection is bacterial or viral. As discussed, it is often impossible to distinguish bacterial from viral conjunctivitis, thus clinicians are frequently unsure whether the conjunctivitis is bacterial or viral. The widespread application of this device should help to reduce antibiotic prescribing in cases of viral conjunctivitis.

In your opinion, does the polymeric mucoadhesive property of besifloxacin represent a clinical advantage?

McDonald: I believe it does. The formulation is designed to hold the topical antibiotic against the eye while the drug is slowly released. The drug remains stably attached to the eye for a long period of time and is not washed out by artificial tears. At the moment, this formulation is used with besifloxacin and azithromycin. Azithromycin is approved for the treatment of bacterial conjunctivitis, but is used overwhelmingly for blepharitis because of its anti-inflammatory properties and due to the fact that the vehicle holds the drug firmly in place for many hours.

Is the effectiveness of besifloxacin improved compared with other agents? Or is it expected to be better theoretically on the basis of its residence time and in vitro activity? Besifloxacin was compared with moxifloxacin in at least 1 clinical trial of patients with eye infections, and the 2 antibiotics were not significantly different.

McDonald: The data I showed were from conjunctival biopsy specimens from healthy subjects who were not infected. The AUC:MIC₉₀ ratio from normal subjects defines what we would expect in a reference population. Theoretically, in an infected eye with excessive tearing, the mucoadhesive vehicle would make besifloxacin’s residence time longer compared with other fluoroquinolones. However, this is difficult to prove due to ethical considerations, as we would not want to biopsy the conjunctivae of patients with active infections.

Regarding effectiveness, besifloxacin has the highest inhibitory quotient (the most reliable metric for clinical efficacy) of any fluoroquinolone in terms of their activity against the most common and virulent pathogens involved in ocular infections. None of the newer fluoroquinolones (eg, moxifloxacin, gatifloxacin, besifloxacin) reach an inhibitory quotient of 10 (the value required for clinical efficacy) in the aqueous humor when administered as a single dose 1 hour prior to cataract surgery.¹⁵ Therefore, the ability to kill on the surface is the most effective way to prevent endophthalmitis and other ocular infections. Besifloxacin kills more rapidly and more thoroughly than moxifloxacin and gatifloxacin.¹⁶

Please comment on the effect of dosing schedules on patient compliance.

McDonald: The newer fluoroquinolones are all administered 3 times per day for 1 week, and the older agents tend to be administered 4 times per day or more, often with a duration of up to 10 days. When you are administering a topical therapy 4 times per day for 10 days, it can affect treatment compliance. This can be an especially serious problem for working parents, where the child is in the care of someone else throughout the day. The parents have a difficult time trying to catch up on missed doses at the end of the day.

Stan L. Block, MD, FAAP: In clinical practice, we often shorten the course of therapy and compress the number of doses if we feel that the parents’ compliance is going to be a problem. Administering eye drops 4 times per day in children is not practical, so clinicians do not prescribe them that way in many cases.

Michael E. Pichichero, MD: At this point, there are no clinical data about success rates with an approach such as this. Differing durations of therapy or dosing frequencies have not been extensively studied in patients with pediatric conjunctivitis. This management approach is based on clinical experience and whether you are observing a high rate of treatment failure with the recommended prescribing approach.

Block: Yes, it is important to note that this is entirely an off-label approach, it is not the prescribing method that is described in the labeling and has not been studied in clinical trials.

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