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Healio
May 06, 2011
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Treating Bacterial Conjunctivitis

David B. Granet, MD

The fact that conjunctivitis is not fatal and will resolve in 7 to 10 days without treatment raises the issue of whether it is necessary to treat patients with this infection. The position of the American Academy of Ophthalmology is that achieving an early cure of bacterial conjunctivitis will decrease morbidity, improve the patient’s quality of life, reduce the spread of the disease, decrease school absenteeism and parental leave, and allows for early identification of diseases that may masquerade as bacterial conjunctivitis.1

Shortening the course of conjunctivitis has a socioeconomic benefit as well.2 Bacterial conjunctivitis is a highly contagious disease. Reducing the spread of the infection reduces both the direct and indirect costs of the disease. Treating bacterial conjunctivitis with less effective, less expensive antimicrobials in order to save money is a false economy. For example, if the less expensive antibiotic has a cure rate of 50% by day 2, 50% of patients may need a second prescription, a repeat office visit, or more diagnostic testing. The cost to these parents in lost wages and increased medical costs reduces any savings using the less expensive, less effective antibiotic. If the more expensive, more efficacious antibiotic is used and 90% of patients are cured by day 2, only 10% of patients may require repeat clinic visits and/or additional testing. Moreover, identifying patients who are not responding to antibiotic therapy quickly allows physicians to investigate further to rule out other etiologies, such as uveitis and herpetic conjunctivitis, diseases with worse sequelae than bacterial conjunctivitis if not treated early.

Achieving an early cure of bacterial conjunctivitis will decrease morbidity, improve the patient’s quality of life, reduce the spread of disease, and decrease school absenteeism and parental leave.
— David B. Granet, MD
Student absenteeism affects school performance. Additionally, schools may also lose funding for every day the child must be absent. State and federal formulas to determine public school funding are based on student attendance. For example, sanctions employed to reduce student absences in Tulsa County, Oklahoma kept 800 students in school, resulting in reimbursements of approximately $3,000 per student. Reduced public school funding affects programs designed to increase school performance and enrich a child’s education.3

Antibiotics for Bacterial Conjunctivitis
There are a number of important characteristics an antibiotic should have. Antibiotics should be bactericidal with a fast rate of activity. They should also have a broad spectrum of activity, as there is usually not time to perform a culture before treating. Antibiotics should also have high bioavailability, achieving high therapeutic concentrations in the target tissues. Topical ophthalmic antibiotics can be delivered in ointments or eye drops. Ointments lead to blurred vision and therefore may only be useful in children 1 to 2 years of age.

The administration of eye drops to a child can be difficult. Reducing the frequency with which they must be applied is helpful in improving compliance. Using antibiotic formulations that do not sting or otherwise cause discomfort is also important for compliance. Depending on the specific agent, warming or cooling the drops can make them more comfortable for the child. Forcing the child’s eyes open is unnecessary, stressful, and counterproductive. With the child completely supine, drops can be administered to the corner of each eye when the child opens the eye voluntarily.

Sulfonamides
Sulfonamides are not typically used in ophthalmology. Sulfonamide ophthalmic solutions are bacteriostatic, not bactericidal, a characteristic that can lead to resistance. In addition, approximately 2.5% of patients will develop an allergic reaction, most frequently a maculopapular rash.4,5 Sulfonamides have also been linked to cases of Stevens-Johnson Syndrome.6-8 Importantly, sulfonamide eye drops sting, rendering them very difficult to administer to children.

Aminoglycosides
Aminoglycosides (eg, gentamicin, tobramycin, neomycin) have limited gram-positive coverage and many resistant strains of gram-positive organisms have been observed in children. They have no activity against Streptococcus pneumoniae,9 the second most common cause of bacterial conjunctivitis.10-12 Up to 10% of the population shows sensitivity to neomycin, the highest incidence of an allergic response to a drug observed in ophthalmology. Between 6.6% and 11.8% of patients have demonstrated sensitivity to aminoglycosides by patch testing.13,14 In addition, aminoglycosides frequently cause medicamentosa, also known as toxigenic conjunctivitis.

Polymyxin B/trimethoprim
Neither trimethoprim nor polymyxin B has a broad spectrum of activity. Polymyxin B is primarily effective against gram-negative organisms. In vitro testing has shown that polymyxin B is not effective against Staphylococcus aureus, other coagulase-negative staphylococci (CoNS), and S pneumoniae.15 Trimethoprim is active against these pathogens and is the only ophthalmic antibiotic that remains active against methicillin-resistant strains.15 Trimethoprim’s activity is, however, bacteriostatic rather than bactericidal.

Azithromycin
Azithromycin is a derivative of erythromycin first patented in 1981 and is one of the most commonly used antibiotics in the world. In more recent years it became available as an ophthalmic solution. The effect of azithromycin on conjunctivitis was examined in a prospective, randomized, vehicle-controlled, parallel-group, multicenter study. Two hundred seventy-nine patients aged 1 to 96 years diagnosed with acute bacterial conjunctivitis were randomized to receive either the 1% azithromycin in vehicle or the vehicle alone. Eyes were dosed twice daily on days 1 and 2 and once per day on days 3, 4, and 5. Conjunctival cultures were obtained at baseline, visit 2 (day 3 or 4), and visit 3 (day 7 or 8). At visit 3, the clinical resolution of symptoms was improved for the azithromycin group compared to the vehicle group. Bacterial eradication for the azithromycin group reached 88.5% at visit 3. The differences between the 2 groups were statistically significant.16 Therefore, the 1% azithromycin solution decreased the course of the disease by 1 or 2 days in a broad population.

The 1% azithromycin was compared to 0.3% tobramycin ophthalmic solution in a prospective, randomized, active-controlled, double-masked phase 3 trial conducted at 47 US sites between August 6, 2004 and October 6, 2005. Cultures were taken prior to treatment in 743 eligible participants older than 1 year. Patients were randomized to the 1% azithromycin group or the 0.3% tobramycin group. Because tobramycin is dosed 4 times per day and azithromycin 2 times per day for the first 2 days and once per day for the following 3 days, masking was achieved by administering vehicle to the azithromycin group to bring dosing to 4 times per day.17

Cultures for 316 of the 743 participants were positive. Resolution of symptoms was achieved for 127 patients (79.9%) in the 1% azithromycin group and 123 patients (78.3%) in the 0.3% tobramycin group. The difference was not statistically significant. Bacterial eradication on day 7 was achieved for 140 patients (88.1%) in the 1% azithromycin group and 148 patients (94.3%) in the 0.3% tobramycin group.17

The investigators concluded that using 1% azithromycin ophthalmic solution instead of 0.3% tobramycin ophthalmic solution would achieve the same result while reducing the number of doses required by 65%. Reducing the number of doses tends to increase compliance.17 However, using the 1% azithromycin as directed is not equivalent to using 1% azithromycin plus a total of 13 drops of vehicle. The efficacy of 1% azithromycin plus washout drops may be statistically and/or clinically different from the efficacy of the 1% azithromycin solution without the additional vehicle drops.

Fluoroquinolones
Fluoroquinolones block bacterial DNA synthesis by inhibiting the topoisomerase enzymes — DNA gyrase (topoisomerase II) for gram-positive organisms, and/or topoisomerase IV enzyme for gram-negative organisms.18-20 The fluoroquinolones have evolved significantly from the quinolone nalidixic acid, which was first produced in the early 1960s. Nalidixic acid was used to treat gram-negative organisms commonly associated with urinary tract infections. This quinolone had a limited spectrum of action.21 The addition of a fluorine molecule at position 6 was one of the earliest changes to the structure. This change provided > 10-fold increase in gyrase inhibition and up to 100-fold improvement in mean inhibitory concentration (MIC). The addition of a piperazine ring at the C-7 position (eg, norfloxacin) improved activity against gram-negative organisms.18 Ciprofloxacin contains, in addition to the piperazine ring, a cyclopropyl group at position N1.21 This modification increases potency and is contained in many fluoroquinolones introduced subsequently (eg, grepafloxacin, moxifloxacin, gatifloxacin, besifloxacin, garenoxacin). The ofloxacin molecule contains a tricyclic core ring instead of the bicyclic core of ciprofloxacin and earlier fluoroquinolones. This bridging ring increased gram-positive activity and increased the half-life.22,23 Levofloxacin is the levoisomer of ofloxacin. These modifications actually reduced the range of its gram-negative coverage but increased the potency against gram-positive organisms and extended its half-life.24

The newer fluoroquinolones gatifloxacin and moxifloxacin differ from older fluoroquinolones in that they have an 8-methoxy group (OCH3) attached to their basic ring structure at position 8.25 This modification led to higher binding affinity to the topoisomerase IV enzyme, which resulted in enhanced activity against gram-positive pathogens and anaerobes while also maintaining potency against gram-negative organisms. Compared to the structure of ciprofloxacin, moxifloxacin and gatifloxacin also have modifications at C-7, with gatifloxacin containing a 3-methyl piperazinyl ring and moxifloxacin a diazabicyclo group. These alterations also increase potency against gram-positive organisms. These newer fluoroquinolones therefore target both DNA gyrase and topoisomerase IV in both gram-positive and gram-negative bacteria, while the older generation drugs targeted one enzyme or the other. This is significant because for bacteria to development resistance, they must undergo 2 simultaneous mutations at both of these sites, which would be highly difficult.25,26

The MICs of gatifloxacin and moxifloxacin were compared to those of older fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) using bacterial keratitis isolates. The MICs for gatifloxacin and moxifloxacin were statistically lower than the older fluoroquinolones for all gram-positive bacteria tested. Ciprofloxacin was demonstrated to have the lowest MICs for gram-negative bacteria. While all of the newer fluoroquinolones are active against the 2 most common bacterial isolates in bacterial conjunctivitis, Haemophilus influenzae and S pneumoniae, no newer fluoroquinolone covers most of the other bacterial isolates found in bacterial conjunctivitis.27

Comparing the 2 newer fluoroquinolones, moxifloxacin was more active against most gram-positive bacteria while gatifloxacin was more active against most gram-negative bacteria.27 In vitro susceptibility patterns were also determined in this study. For most isolates, no differences in susceptibility were identified among the 5 fluoroquinolones. Gatifloxacin and moxifloxacin, however, were more effective against S aureus isolates resistant to ofloxacin, ciprofloxacin, and levofloxacin.

The kinetics of kill of moxifloxacin on 3 commonly isolated pathogens in bacterial conjunctivitis has been compared to that of nonfluoroquinolone antibiotics (ie, tobramycin, gentamicin, polymyxin B/trimethoprim, azithromycin). Moxifloxacin achieved a 99.9% kill at approximately 1 hour for S aureus, 2 hours for S pneumoniae, and 30 minutes for H influenzae. In comparison, other nonfluoroquinolone therapies took longer to achieve a bactericidal (3-log) kill and some demonstrated no change or an increase in bacterial growth. Based on these findings, it was concluded that moxifloxacin kills bacteria more rapidly than nonfluoroquinolone topical ocular antibiotics.28

Moxifloxacin was also compared to polymyxin B/trimethoprim in an in vivo masked multicenter study. Eighty-four eyes in 56 patients younger than 18 years of age with bacterial conjunctivitis were enrolled. Patients were randomized to receive either 1 drop of polymyxin B/trimethoprim 4 times daily or one drop of 0.5% moxifloxacin 3 times daily for 7 days. Ocular signs and symptoms were evaluated at baseline, 24 hours, and 48 hours after the start of treatment. Cultures were collected at baseline and at 48 hours.3 At the 48-hour visit, complete resolution of ocular signs and symptoms was observed in 81% of the patients treated with moxifloxacin and 44% of the patients treated with polymyxin B/trimethoprim (P = .001; Figure 1). No adverse events were reported. Also at this time point, only 2.3% of the patients receiving moxifloxacin were not responding to treatment, while 19.5% of patients treated with polymyxin B/trimethoprim were not responding to treatment (P = .001). These results imply that moxifloxacin is cost-effective and significantly more efficacious than polymyxin B/ trimethoprim in the speed by which it reduces the symptoms and disease transmission. Moreover, moxifloxacin can also serve as an efficient screening tool for more serious diseases. For example, herpetic conjunctivitis would be revisited as a possible diagnosis sooner in a patient treated with moxifloxacin than in a patient treated with polymyxin B/trimethoprim.3

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Besifloxacin is a recent addition to the fluoroquinolone class of antibiotics, approved in 2009. Besifloxacin contains the cyclopropyl group at the N1 position, which was associated with broad spectrum activity in other fluoroquinolones. Besifloxacin also has a chlorine substitution at the C-8 position and an amino-azepinyl group at the C-7 position. These modifications further enhance potency against both topoisomerases found in bacteria. Besifloxacin has a more balanced targeting of both topoisomerases compared to moxifloxacin and ciprofloxacin.29 This property decreases the likelihood of resistance. Furthermore, besifloxacin was developed specifically for ophthalmic use and not systemic use, which also decreases the likelihood of resistance development.30

The efficacy and safety of besifloxacin was compared to vehicle in a randomized, multicenter, double-masked, vehicle-controlled study.31 A total of 957 patients aged 1 year and older with bacterial conjunctivitis were randomized to treatment with besifloxacin ophthalmic suspension 0.6% or vehicle applied topically 3 times daily for 5 days. Three hundred ninety patients had culture-confirmed bacterial conjunctivitis. Clinical resolution and microbial eradication were significantly greater with besifloxacin ophthalmic suspension than with vehicle at visit 2 (45.2% vs. 33.0%, P = .0084; 91.5% vs. 59.7%, P < .0001) and visit 3 (84.4% vs. 69.1%, P = .0011; 88.4% vs. 71.7%, P < .0001). Results for secondary endpoints of individual clinical outcomes were consistent with primary endpoints. Fewer eyes receiving besifloxacin ophthalmic suspension experienced adverse events than those receiving vehicle (9.2% vs. 13.9%; P = .0047). These results were corroborated in another study comparing besifloxacin to vehicle.32

The efficacy and safety of besifloxacin in the treatment of bacterial conjunctivitis has also been compared to moxifloxacin in a multicenter, randomized, double-masked, parallel-group, active-controlled noninferiority study (Table 1). In this study, 1,161 patients aged 1 year and older with clinical manifestations of bacterial conjunctivitis were randomized to be treated with 0.5% moxifloxacin ophthalmic solution or 0.6% besifloxacin ophthalmic solution. Both medications were administered 3 times per day for 5 days. Patients were seen on day 1, day 5 (± 1 day), and day 8 (± 1 day).33 Bacterial conjunctivitis was confirmed by culture in 533 patients. Besifloxacin was noninferior to moxifloxacin for clinical resolution on day 5 (58.3% vs. 59.4%, respectively; 95% CI, -9.48 to 7.29) and day 8 (84.5% vs. 84.0%, respectively; 95% CI, -5.6% to 6.75%) and for microbial eradication on day 5 (93.3% vs. 91.1%, respectively; 95% CI, -2.44 to 6.74) and day 8 (87.3% vs. 84.7%, respectively; 95% CI, -3.32 to 8.53). There was no statistically significant difference between the 2 treatment groups for either efficacy endpoints on days 5 or 8 (P > .05). Besifloxacin and moxifloxacin were well-tolerated. The cumulative frequency of ocular adverse events was similar between treatments (12% and 14% with besifloxacin and moxifloxacin, respectively). However, ocular irritation occurred more often in moxifloxacin-treated eyes (0.3% for besifloxacin vs. 1.4% for moxifloxacin). 33 No data are available for earlier in the treatment course for this study.

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The safety and efficacy of besifloxacin in the treatment of conjunctivitis was further established in a post hoc analysis in a subgroup of pediatric patients aged 1 to 17 years who had participated in 1 of the 3 aforementioned clinical studies. All 3 trials were randomized, double-masked, parallel-group, multicenter trials performed in a community setting.

Two studies were vehicle-controlled and 1 study was comparator-controlled (moxifloxacin). A 0.6% besifloxacin ophthalmic suspension was administered as instructed on-label: 3 times daily with approximately 6 hours between doses.

The final analysis included 815 pediatric patients (447 with culture-confirmed bacterial conjunctivitis). Besifloxacin was found to be significantly more effective than vehicle and no significant differences were found between the efficacy of moxifloxacin and besifloxacin. Besifloxacin was also well-tolerated with similar incidences of adverse events in the besifloxacin, moxifloxacin, and vehicle groups.34

One in vitro study determined the bactericidal activity of the various antibiotics against the common bacteria isolated from patients with bacterial conjunctivitis. The antibiotics tested were besifloxacin, levofloxacin, penicillin, oxacillin, tobramycin, ceftazidime, azithromycin, ciprofloxacin, moxifloxacin, and gatifloxacin. The ratio of the minimum bactericidal concentration (MBC) to the minimum inhibitory concentration (MIC) was determined for the fluoroquinolones against S aureus, Staphylococcus epidermis, S pneumoniae, and H influenzae. More potent antibiotics exhibit lower MBC:MIC ratios. Besifloxacin had the most potent in vitro activity against all bacteria tested and was also the most potent fluoroquinolone tested against S aureus, S epidermis, and S pneumoniae. Besifloxacin, moxifloxacin, and ciprofloxacin had similarly potent activity against H influenzae. The concentrations of besifloxacin in tear fluid from prior studies were more than 20-fold higher than the highest MBC90 or MIC90.35

The most recent addition to the family of ophthalmic fluoroquinolones is a moxifloxacin hydrochloride ophthalmic solution 0.5% as base, approved in November 2010. This formulation has a dosing schedule of 2 times per day compared that of an older formulation of moxifloxacin, which is 3 times per day. As stated previously, fewer numbers of required doses increases compliance. This formulation was found to be superior to its vehicle in a randomized, nonmasked, multicenter, vehicle-controlled clinical trial of patients with conjunctivitis.36 Thus the family of ophthalmic fluoroquinolones is constantly evolving and is expected to continue to grow.

Antibiotic Resistance and the Fluoroquinolones
The newer fluoroquinolones have been developed, in part, to address growing resistance to earlier fluoroquinolones. Therefore, addressing the possibility of the emergence of bacterial strains resistant to these newer antibiotics is warranted. Research into the causes of the development of antibiotic resistance reveals that the topical ophthalmic use of antibiotics is unlikely to contribute to the problem. Systemic use of antibiotics exposes 10 million-fold more bacteria than does ophthalmic use (Table 2). In addition, topical ophthalmic use of antibiotics exposes bacteria to a 1,000-fold higher concentration of that antibiotic than does systemic use. Systemic antibiotics are also more likely to be used over a longer period of time than topical ophthalmic antibiotics. All of these factors combine to make the systemic use of antibiotics far more likely to contribute to the development of antibiotic resistance than the topical use of ophthalmic antibiotics (Table 2).37-39

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The Section on Infectious Disease of the American Academy of Pediatrics has advised against the systemic use of newer fluoroquinolones as a first-line treatment in pediatrics and commissioned a study to determine whether to make a recommendation concerning the topical use of newer fluoroquinolones in the eye and in the ear. While topical application of fluoroquinolones in the eye results in a high concentration of the drug at that site, the concentration of the drug as it overflows from the eye to the skin or nasopharyngeal sites decreases. The concern was that these distal sites may become the type of environment that selects for antibiotic-resistant strains of bacteria. In this study, 3 investigative sites enrolled children aged 8 months to 12 years diagnosed with bacterial conjunctivitis and healthy children of the same age. A total of 105 children with bacterial conjunctivitis and 57 healthy children were enrolled at sites located in Arizona, California, and Illinois between June 2006 and April 2008. The healthy children received no treatment and the children diagnosed with bacterial conjunctivitis were treated with moxifloxacin 3 times daily for 7 days.40

Microbiological swab specimens were collected from all children on day 1, day 8, and day 42. Seven swabs were collected at each visit: 1) right lower conjunctivae, 2) left lower conjunctivae, 3) right cheek, 4) left cheek, 5) right nare, 6) left nare, and 7) throat. Researchers quantified the amounts of all bacteria (S aureus, S pneumoniae, and H influenzae) cultured. Endpoint MIC testing was performed with approximately 20 antibiotics on 2,985 recovered isolates using broth microdilution methods recommended by the Clinical and Laboratory Standards Institute (CLSI).40

The primary pathogenic isolates that caused infection or re-infection of the conjunctivae were S pneumoniae and H influenzae. S aureus isolates that caused infection or re-infection were from the nares and the throat. The transient rise in Streptococcus mitis, recovered at end of therapy, was the evidence for the passage of moxifloxacin through the throat after topical ocular dosing. Moxifloxacin has never been indicated for the treatment of infections by S mitis because of its lack of efficacy. The reduction in numbers of recoverable bacteria at the end of therapy was the evidence for the passage of moxifloxacin through the nose after topical ocular dosing.40

No fluoroquinolone-resistant isolates of S pneumoniae or H influenzae were cultured from any body sites, including the infected eyes. These species did not colonize the throat. However, fluoroquinolone-resistant isolates of S aureus and Haemophilus parainfluenzae were recovered from the throats of patients before treatment. Fluoroquinolone-resistant S aureus was also cultured from some of the diseased eyes. The investigators concluded that treatment with topical ophthalmic antibiotics does not select for fluoroquinolone resistance in S aureus, S pneumoniae, or H influenzae either in the eye or in distal body sites.40 The 2010 edition of The Sanford Guide to Antimicrobial Therapy now recommends newer fluoroquinolones for the empirical therapy of non-gonococcal, non-chlamydial bacterial conjunctivitis.41

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