Pediatric Conjunctivitis: Clinical Decision-making for Optimal Treatment

Introduction Michael E. Pichichero, MD Differentiating Bacterial Conjunctivitis from Allergic and Viral Conjunctivitis Rudolph S. Wagner, MD Treating Bacterial Conjunctivitis David B. Granet, MD

Introduction
Conjunctivitis is a common condition in pediatrics. The symptoms of bacterial conjunctivitis can be cured more quickly with antibiotic therapy. Implementing treatment is worthwhile even though the infection is self-limiting because decreasing the time to resolution of symptoms improves quality of life, allowing the child to return to school after a shorter time and allowing the parents to return to work, which has a significant economic impact.

The aim of a symposium sponsored by Infectious Diseases in Children and Vindico Medical Education in November 2010 was to discuss the diagnosis and treatment of bacterial and viral conjunctivitis. Presenters discussed the incidence of bacterial, viral, and allergic conjunctivitis and how to differentiate among these etiologies. The treatment options for bacterial conjunctivitis were reviewed along with advances in antimicrobial therapies. The faculty also presented data on resistance to common ocular antibiotics and strategies to reduce or eliminate the development of new resistant strains of bacteria. Case studies highlighted the implementation of theory into practice.

The presentations and discussion at the symposium led to the development of this monograph. Readers can expect to be more knowledgeable in the diagnosis of eye diseases and the safety and efficacy of currently available therapeutics after reading the material presented. The information should result in better patient care and improved public health — goals we all share.

Michael E. Pichichero, MD
Course Chair

Differentiating Bacterial Conjunctivitis from Allergic and Viral Conjunctivitis
Rudolph S. Wagner, MD

Making a definitive diagnosis for a pediatric patient presenting with conjunctivitis can be difficult. Conjunctivitis in the pediatric patient can be mimicked by nasolacrimal duct (NLD) obstruction and caused by allergies, bacteria, and viruses. Because antimicrobial cultures take time and are not always accurate, the diagnosis and treatment of conjunctivitis are often based on the physician’s knowledge regarding the current literature on likely pathogens and clinical experience. Therefore, pediatricians must be aware of the clinical signs and symptoms that can provide a differential diagnosis of conjunctivitis, so that it can be properly treated.

Nasolacrimal Duct Obstruction

NLD obstruction is always in the differential diagnosis for conjunctivitis during the first year of life. Effort should be made to rule out NLD obstruction as the cause of the patient’s symptoms. With NLD obstruction, the child’s eyelids may be matted together or discharge may be seen along the lashes or down the child’s cheek. However, patients with NLD obstruction present with less conjunctival injection than patients with bacterial conjunctivitis. Also, if the child’s face has been cleaned to prepare the child to see the physician, signs will usually recur during the office visit.

A definitive diagnosis of NLD obstruction can be made by digital massage of the lacrimal sac. When massaged, the nasolacrimal duct will produce a reflux of mucous from the puncta. The fluorescein dye disappearance test is most helpful when the condition is unilateral. After fluorescein dye has been administered to each eye, the dye will take longer to clear from the eye with NLD obstruction.

Presentation of Allergic Conjunctivitis

The number of children presenting to the clinic with allergic conjunctivitis will vary according to the season. Allergic conjunctivitis is caused by an acute type I hypersensitivity to common allergens. Allergic conjunctivitis has a protracted course, with the severity of symptoms waxing and waning throughout the allergy season. This is another way to differentiate allergic conjunctivitis from other forms, as recurrences within a short period of time are unlikely with bacterial or viral conjunctivitis. Symptoms include itchy eyes, watery or stringy discharge, chemosis, eyelid edema, rhinitis, and an “allergic shiner.” Chemosis (swelling of the conjunctiva) can be marked and may cause the cornea to appear as if it is sitting in a depression. In addition to seasonal allergic conjunctivitis, there are vernal limbal or palpebral types. With vernal limbal conjunctivitis, there is an accumulation of eosinophils along the limbus; with vernal palpebral conjunctivitis, large papules form under the conjunctiva of the upper eyelid.

Presentation of Viral Conjunctivitis

Viral conjunctivitis is more common in older children and adults than it is in preschool-aged children. Viral conjunctivitis is highly contagious and is characterized by watery discharge. The amount of vascular injection can be variable. Viral conjunctivitis is usually caused by adenovirus, but can also be caused by other viruses such as herpes simplex virus (HSV).

HSV may be one of the most problematic causes of conjunctivitis. This virus can lead to herpetic keratitis and possibly loss of vision. Corticosteroids, sometimes used as palliative care in cases of viral conjunctivitis caused by other viruses, are contraindicated in conjunctivitis caused by HSV. The disease is almost always unilateral and monocular. Patients with herpetic conjunctivitis may complain of severe pain. The eyelids may also be involved — they can be red, edematous, and display multiple vesicles. The corneal reflex in a patient with herpetic conjunctivitis will be irregular, not be sharp and crisp. Upon close examination, dendrites or small opacities may be observed. Herpetic conjunctivitis should be in the differential whenever a patient is not responding to antibiotic therapy. Patients with conjunctivitis thought to be caused by HSV should always be referred to an ophthalmologist.

Acute hemorrhagic conjunctivitis (AHC) is most commonly caused by a picornavirus, usually Coxsackie A24 or enterovirus 70. The presentation of AHC is often dramatic. The eye will become acutely painful and possibly photophobic even before hemorrhages can be seen. The subconjunctival hemorrhages that characterize this disease begin as petechiae which then coalesce and can involve the entire subconjunctiva. While highly contagious, AHC is self-limiting and its complications are rare.

Presentation of Bacterial Conjunctivitis

Acute bacterial conjunctivitis is most frequently observed among infants, toddlers, and preschool-aged children. One in 8 children has an episode every year, and there are 5 million cases in the United States annually. Bacterial conjunctivitis is a self-limiting disease, typically lasting 7 to 10 days without antibiotic treatment. ^1-3 For example, in 1 study 83% of children diagnosed with bacterial cconjunctivitis treated with a vehicle washout drop containing no active medication had clinical cures at 7 days.¹ Viral conjunctivitis usually lasts longer than bacterial conjunctivitis. If conjunctivitis does not resolve with antibiotics after 3 to 4 days, the physician should suspect that the infection is viral.

Bacterial conjunctivitis is characterized by mucopurulent discharge with matting of the eyelids. Common clinical findings in acute bacterial conjunctivitis include burning and stinging. While bacterial conjunctivitis can present in only one eye, it is usually present in both eyes or will spread to the contralateral eye. Acute bacterial conjunctivitis can be associated with otitis media. When a patient presents with both conjunctivitis and otitis media, systemic antibiotics are indicated.^4,5 Like viral conjunctivitis, bacterial conjunctivitis is highly contagious.

Differentiating Bacterial from Viral Conjunctivitis

Bacterial conjunctivitis can be differentiated from viral conjunctivitis based on discharge (mucopurulent vs. watery), age of the affected child (preschool-aged vs. school-aged children), and whether the infection is bilateral or unilateral (Table 1).

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Ocular Pathogens in Bacterial Conjunctivitis

Studies have shown that pediatric acute conjunctivitis is most often caused by bacteria. Viruses and allergies are the second and third most common causes (Figure 1).^6,7 The younger the patient, the higher the likelihood of a bacterial etiology of the conjunctivitis.

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A variety of studies have been performed to determine the organisms responsible for conjunctivitis. In a study of 95 patients with acute conjunctivitis and 91 control children of similar age, specimens of the lid and conjunctiva were obtained for culture and conjunctival scrapings were stained with Giemsa and Gram stains. Bacterial infections were identified in 80% of patients, viral infections were identified in 13%, and allergies in 2%. No cause could be determined in 5% of patients. Of the patients with bacterial conjunctivitis, Haemophilus influenzae accounted for 58.1% of all bacterial cultures. Streptococcus pneumoniae was the second most common pathogen, accounting for 27.1% of bacteria cultures. Moraxella catarrhalis was isolated from cultures in 8.1% of patients. Staphylococci accounted for 4.1% of cultures and species included Staphylococcus epidermis (2.7%) and other coagulase-negative staphylococci (1.4%). Staphylococci, corynebacteria, and alpha-hemolytic streptococci were the predominant organisms recovered from the lids of control subjects.⁶

In a prospective study in a children’s hospital emergency department published in 2007, conjunctival swabs were obtained for bacterial culture from 111 patients aged 1 month to 18 years (mean age, 33 months) who presented with red or pink eye and/or the diagnosis of conjunctivitis. Bacterial cultures were positive in 78.4% of the patients tested. Nontypeable H influenzae accounted for 82% of positive cultures, S pneumoniae for 16%, and Staphylococcus aureus for 2%.⁷ The decrease in the proportion of isolates positive for S pneumoniae compared to the study published in 1993 may be due to pneumococcal conjugate vaccine immunizations.

A prospective observational cohort study at an urban pediatric emergency department was published in 2010. Conjunctival swabs were taken from children aged 6 months to 17 years who presented with conjunctival erythema, eye discharge, or both. The median age was 3 years. Patients were excluded from the study if they had a history of ocular trauma, were exposed to a noxious chemical, wore contact lenses, or had used antibiotics in the previous 5 days. Bacterial cultures were isolated from 64.7% of the 368 patients enrolled in the study. H influenzae accounted for 67.6% of positive cultures, S pneumoniae for 19.7%, and S aureus for 8.0% (Figure 2).⁸

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This study also investigated how it could be determined that conjunctivitis is not likely to be of bacterial etiology. They determined 4 factors that were likely to be associated with cultures that were negative for bacteria:

• >6 years of age
• Presentation in April through November
• Watery or no discharge
• No glued eye in the morning

In this study, 92.2% of patients with all of these factors had cultures that were negative for bacteria and 76.4% of those with 3 factors had negative cultures. These data can aid a physician in deciding whether or how to treat a patient in some cases.

While the data in these 3 studies are consistent and compelling, physicians must also remember that atypical outbreaks of bacterial conjunctivitis can occur. Two notable outbreaks of bacterial conjunctivitis have been caused by an atypical strain of S pneumoniae.

The outbreak at Dartmouth College in New Hampshire in 2002 is especially significant because outbreaks of conjunctivitis in college-aged students are usually viral in etiology. From January 1 through February 15, 197 students were diagnosed with conjunctivitis. A viral cause was initially suspected, but conjunctival swabs from 12 students grew S pneumoniae. Because of the high number of cases and the unusual bacterial etiology in college-aged students, an investigation was initiated. Specimens were sent to the Dartmouth-Hitchcock Medical Center for culture and identification. Subcultures of presumed S pneumoniae isolates were then sent to the CDC for further analysis.⁹

Results of the investigation demonstrated that between January 1, 2002 and April 12, 2002, 698 of the 5,060 students enrolled at Dartmouth College were diagnosed with conjunctivitis. During similar periods in 2000 and 2001, only 66 and 92 students, respectively, were diagnosed with conjunctivitis. During the 2002 outbreak, 34 students suffered repeated infections as defined by visits to the health center for conjunctivitis by the same student that occurred more than 14 days apart. The attack ratio among the 3,682 undergraduates and 1,378 graduate students was 18.7% and 2.5%, respectively. Of the positive cultures, 43.3% grew nonencapsulated pneumococci.⁹ This outbreak exemplifies that bacterial conjunctivitis can occur in young adults and conjunctivitis should not be assumed to be due to adenovirus in this age group.

Nontypeable pneumococcus also caused an outbreak of bacterial conjunctivitis in Westbrook, Maine later in 2002. From September 20 to December 6, at the index elementary school, a total of 101 students (out of 361) had at least 1 episode of conjunctivitis. Eleven of 20 students tested (55%) had an episode of culture-confirmed pneumococcal conjunctivitis. Additionally, school nurses and child care staff in the community reported an additional 4% of students attending kindergarten through grade 12 at 4 schools, and 9% of children attending 3 community child care centers, having conjunctivitis during this time period.

Among the 53 students with conjunctivitis at other schools, 10 (19%) had a family member at the index school, and seven (29%) of 24 ill child care attendees had a sibling at the index school. Of 15 conjunctival specimens collected from students at other schools, 5 (33%) grew S pneumoniae. The CDC advises, “health care providers and public health officials should be aware that nontypeable S pneumoniae can cause outbreaks of conjunctivitis in school-aged children and college students; outbreaks should be reported to state health departments and the CDC.”¹⁰

Antibiotic Resistance and Bacterial Conjunctivitis

In a retrospective cross-sectional study, the microbiology records of all patients (adults and children) with bacterial conjunctivitis seeking treatment at Bascom Palmer Eye Institute in Miami from January 1, 1994 through December 31, 2003 were reviewed. For an eye to have been included in the study, conjunctival swabs must have resulted in a positive culture. Over this 10-year period in South Florida, the most common isolate from the 2,408 consecutive swabs was S aureus (37.6%). Children < 7 years of age were most likely to have gram-negative infections, most frequently H influenzae, but S aureus was the second most common isolate in children younger than 6 years of age. Of the S aureus isolates, 19.1% were resistant to methicillin. The incidence of methicillin-resistant S aureus (MRSA) increased over the decade. There were also 2-fold and 3-fold increases in resistance of gram-positive organisms to erythromycin and ciprofloxacin.¹¹

Nosocomial and community-acquired MRSA infections have also been reported in children. Many neonatal intensive care units (NICUs) take weekly pharyngeal swabs of every neonate to test for MRSA colonization. Neonates who are colonized with MRSA may show no signs of infection but MRSA infections in neonates are possible. In 1 report, a 7-day-old neonate was referred to the ophthalmology team with a 1-day history of purulent conjunctivitis in the right eye. The conjunctival swab taken before any antibiotics were administered grew MRSA. Both parents were also found to be colonized by MRSA and likely transmitted it to their child.¹² In addition, community-acquired MRSA has caused at least 1 case of orbital cellulitis in a non-immunocompromised child and at least 1 case of chronic dacryocystitis secondary to congenital NLD obstruction.^13,14 Thus, healthy infants can harbor MRSA and pediatric community-acquired MRSA can occur.

H influenzae and S pneumoniae still account for between 85% and 98% of all cases of bacterial conjunctivitis.^6-8 Nontypeable S pneumoniae is also the most common cause of atypical outbreaks of bacterial conjunctivitis. Therefore, when treating a patient empirically, fluoroquinolones are a reasonable choice. They are the only class of drugs effective against both H influenzae and S pneumoniae and against which neither organism has developed significant resistance.¹⁵ S pneumoniae is generally resistant to gentamicin, tobramycin, polymyxin B/trimethoprim, and azithromycin, and H influenzae has developed resistance against erythromycin. The fluoroquinolones are also effective against S aureus, a less common but still significant cause of bacterial conjunctivitis. However, methicillin resistance in S aureus isolates is a marker for multidrug resistance, including resistance to the fluoroquinolones. Of the antibiotics tested by Ocular TRUST, only trimethoprim retained high efficacy against MRSA in vitro; 95% of MRSA isolates were susceptible to trimethoprim.¹⁵

The idea that treating infections with the most potent antibiotic available can lead to drug resistance is inaccurate. A potent, highly effective antibiotic eradicates pathogens quickly, reducing the length of time for bacteria to mutate and therefore develop resistance. Rather, the use of inadequate doses or tapering of antibiotics in ophthalmic use contributes to the development of antibiotic resistance. Another factor in clinical practice is the inappropriate use of systemic antibiotics by physicians and nonadherence by patients. Other causes of the increase in antibiotic resistance are broad-spectrum therapies,¹⁶ widespread use of antibiotics in animal feed,^17,18 and the spread of resistant organisms by increased international travel.^19,20

The US Public Health Service, the CDC, and in-hospital antibiotic monitoring teams disseminate policies to help reduce the spread of antibiotic resistance. However, they can only monitor antibiotic use in humans. The use of antibiotics in agriculture has not been regulated. Food animals receive between 40% and 80% of antimicrobials in the United States each year. Many of these antibiotics are the same or similar to antibiotics that are used in humans. Most of these antibiotics, however, are not used to treat disease. Healthy animals receive low doses of antimicrobial agents in their feed over prolonged periods of time to promote growth, to increase feed efficiency, and to prevent disease. Because resistance genes are bred and transferred within environmental reservoirs that contain bacteria and antibacterial agents in less than bactericidal concentrations, this nontherapeutic use of antibiotics is likely to select for organisms with genes conferring resistance to those antibiotics. Exposure to low dosages of antibiotics over long periods of time creates selective pressure for organisms to mutate, develop resistance genes, and transfer these genes horizontally to other organisms.^17,18

While bacteria spread genes for antibiotic resistance to other bacteria, humans disseminate antibiotic resistant strains of bacteria internationally. Global travel increases the biodiversity of organisms. When bacteria are introduced to a region where they were previously absent, reduced natural selection leads to increased genetic drift and increases the number and variety of strains that develop from that species of bacteria. Certain strains of Saureus were already resistant to methicillin before methicillin was ever used as an antibiotic. These strains have increased in number and diversity. New strains can initially be unique to a geographic region until person-to-person contact spreads these strains across from country to country and across oceans.^19,20

Bacterial Resistance to Fluoroquinolones

Because fluoroquinolones are usually the initial therapy for bacterial conjunctivitis before the results of cultures are obtained (if conjunctival swabs for cultures are, in fact, obtained), preventing the development of fluoroquinolone resistance and increasing fluoroquinolone activity are important goals. The mechanism of action for all newer fluoroquinolones is 2-fold: they target DNA gyrase and topoisomerase IV. The probability of an organism developing 2 simultaneous resistant mutations is extremely low.²¹ Furthermore, topical fluoroquinolones can eradicate bacteria from the eye quickly in the concentration and dosages in which they are prescribed, greatly reducing the opportunity for mutations to occur.²² Studies have shown that newer fluoroquinolones did not contribute to resistance of isolates from the conjunctiva, nose, throat, or cheeks.^22,23 However, because of the high level of in vitro MRSA resistance, the Ocular TRUST study suggests considering alternatives to fluoroquinolones when MRSA is a likely pathogen (Table 2).¹⁵

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In summary, conjunctivitis can have a bacterial, viral, or allergic etiology. Bacteria are the most common cause of conjunctivitis in children, but the possibility of conjunctivitis in adolescents and older children should not be ruled out. Clinicians should be mindful of the likely source of conjunctivitis when deciding how to treat their patients.

References

1. Rose PW, Harnden A, Brueggemann AB, et al. Chloramphenicol treatment for acute infective conjunctivitis in children in primary care: a randomised double-blind placebo-controlled trial. Lancet. 2005;366(9479):37-43.
2. Kowalski RP, Dhaliwal DK. Ocular bacterial infections: current and future treatment options. Expert Rev Anti Infect Ther. 2005;3(1):131-139.
3. Høvding G. Acute bacterial conjunctivitis. Acta Ophthalmol. 2008;86(1):5-17.
4. Bodor FF, Marchant CD, Shurin PA, Barenkamp SJ. Bacterial etiology of conjunctivitis-otitis media syndrome. Pediatrics. 1985;76(1):26-28.
5. Block SL, Hedrick J, Tyler R, et al. Increasing bacterial resistance in pediatric acute conjunctivitis (1997-1998). Antimicrob Agents Chemother. 2000;44(6):1650-1654.
6. Weiss A, Brinser JH, Nazar-Stewart V. Acute conjunctivitis in childhood. J Pediatr. 1993;122(1):10-14.
7. Patel PB, Diaz MC, Bennett JE, Attia MW. Clinical features of bacterial conjunctivitis in children. Acad Emerg Med. 2007;14(1):1-5.
8. Meltzer JA, Kunkov S, Crain EF. Identifying children at low risk for bacterial conjunctivitis. Arch Pediatr Adolesc Med. 2010;164(3):263-267.
9. Martin M, Turco JH, Zegans ME, et al. An outbreak of conjunctivitis due to atypical Streptococcus pneumoniae. N Engl J Med. 2003;348(12):1112-1121.
10. Centers for Disease Control and Prevention (CDC). Pneumococcal conjunctivitis at an elementary school — Maine, September 20 - December 6, 2002. MMWR Morb Mortal Wkly Rep. 2003;52(4):64-66.
11. Cavuoto K, Zutshi D, Karp CL, Miller D, Feuer W. Update on bacterial conjunctivitis in South Florida. Ophthalmology. 2008;115(1):51-56.
12. Sahu DN, Thomson S, Salam A, Morton G, Hodgkins P. Neonatal methicillin-resistant Staphylococcus aureus conjunctivitis. Br J Ophthalmol. 2006;90(6):794-795.
13. Vazan DF, Kodsi SR. Community-acquired methicillin-resistant Staphylococcus aureus orbital cellulitis in a non-immunocompromised child. J AAPOS. 2008;12(2):205-206.
14. Kodsi S. Community-acquired methicillin-resistant Staphylococcus aureus in association with chronic dacryocystitis secondary to congenital nasolacrimal duct obstruction. J AAPOS. 2006;10(6):583-584.
15. Asbell P, et al. Presented at: Annual Meeting of the American Society of Cataract and Refractive Surgery; April 3-8, 2009; San Francisco, CA.
16. Schlech BA, Blondeau J. Future of ophthalmic anti-infective therapy and the role of moxifloxacin ophthalmic solution 0.5% (VIGAMOX). Surv Ophthalmol. 2005;50(suppl 1):S64-S67.
17. Shea KM. Antibiotic resistance: what is the impact of agricultural uses of antibiotics on children's health? Pediatrics. 2003;112(1 Pt 2):253-258.
18. Shea KM; American Academy of Pediatrics Committee on Environmental Health; American Academy of Pediatrics Committee on Infectious Diseases. Nontherapeutic use of antimicrobial agents in animal agriculture: implications for pediatrics. Pediatrics. 2004;114(3):862-868.
19. Hershberg R, Lipatov M, Small PM, et al. High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol. 2008;6(12):e311.
20. Ayliffe GA. The progressive intercontinental spread of methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 1997;24(suppl 1):S74-S79.
21. Comstock TL, Karpecki PM, Morris TW, Zhang JZ. Besifloxacin: a novel anti-infective for the treatment of bacterial conjunctivitis. Clin Ophthalmol. 2010;4:215-225.
22. Nafziger AN, Bertino JS Jr. Besifloxacin ophthalmic suspension for bacterial conjunctivitis. Drugs Today (Barc). 2009;45(8):577-588.
23. Lichtenstein SJ, et al. Paper presented at: American Association for Pediatric Ophthalmology and Strabismus (AAPOS) 36th Annual Meeting; April 14-18, 2010; Orlando, FL.

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.

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 Steven’s-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

References

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2. Smith AF, Waycaster C. Estimate of the direct and indirect annual cost of bacterial conjunctivitis in the United States. BMC Ophthalmol. 2009;9:13.
3. Granet DB, Dorfman M, Stroman D, Cockrum P. A multicenter comparison of polymyxin B sulfate/trimethoprim ophthalmic solution and moxifloxacin in the speed of clinical efficacy for the treatment of bacterial conjunctivitis. J Pediatr Ophthalmol Strabismus. 2008;45(6):352-351.
4. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med. 2003;349(17):1628-1635.
5. Johnson KK, Green DL, Rife JP, Limon L. Sulfonamide cross-reactivity: fact or fiction? Ann Pharmacother. 2005;39(2):290-301.
6. Langlois MR, Derk F, Belczyk R, Zgonis T. Trimethoprim-sulfamethoxazole-induced Stevens-Johnson syndrome: a case report. J Am Pediatr Med Assoc. 2010;100(4):299-303.
7. Mistry RD, Schwab SH, Treat JR. Stevens-Johnson syndrome and toxic epidermal necrolysis: consequence of treatment of an emerging pathogen. Pediatr Emerg Care. 2009;25(8):519-522.
8. Wanat KA, Anadkat MJ, Klekotka PA. Seasonal variation of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with trimethoprim-sulfamethoxazole. J Am Acad Dermatol. 2009;60(4):589-594.
9. Asbell PA, Sahm DF, Shaw M, Draghi DC, Brown NP. Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000 to 2005. J Cataract Refract Surg. 2008;34(5):814-818.
10. Weiss A, Brinser JH, Nazar-Stewart V. Acute conjunctivitis in childhood. J Pediatr. 1993;122(1):10-14.
11. Patel PB, Diaz MC, Bennett JE, Attia MW. Clinical features of bacterial conjunctivitis in children. Acad Emerg Med. 2007;14(1):1-5.
12. Meltzer JA, Kunkov S, Crain EF. Identifying children at low risk for bacterial conjunctivitis. Arch Pediatr Adolesc Med. 2010;164(3):263-267.
13. Yoo JY, Al Naami M, Markowitz O, Hadi SM. Allergic contact dermatitis: patch testing results at Mount Sinai Medical Center. Skinmed. 2010;8(5):257-260.
14. de Groot AC, Maibach HI. Frequency of sensitization to common allergens: comparison between Europe and the USA. Contact Dermatitis. 2010;62(6):325-329.
15. Asbell P, et al. Presented at: Annual Meeting of the American Society of Cataract and Refractive Surgery; April 3-8, 2009; San Francisco, CA.
16. Abelson MB, Heller W, Shapiro AM, Si E, Hsu P, Bowman LM; AzaSite Clinical Study Group. Am J Ophthalmol. 2008;145(6):959-965.
17. Abelson M, Protzko E, Shapiro A, Garces-Soldana A, Bowman L. A randomized trial assessing the clinical efficacy and microbial eradication of 1% azithromycin ophthalmic solution vs. tobramycin in adult and pediatric subjects with bacterial conjunctivitis. Clin Ophthalmol. 2007;1(2):177-182.
18. Dunbar M. Update on Fourth-Generation Fluoroquinolones: A Clinical Perspective. Optometric Management. January 2006. http://www.optometric.com/article.aspx?article=71506. Accessed April 1, 2011.
19. Neu CH. Microbiologic aspects of fluoroquinolones. Am J Ophthalmol. 1991;112(4 suppl):15S-24S.
20. Blondeau JM. Fluoroquinolones: mechanism of action, classification, and development of resistance. Surv Ophthalmol. 2004;49 (suppl 2):S73-S78.
21. Andersson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemother. 2003;51 (suppl 1):1-11.
22. Appelbaum PC, Hunter PA. The fluoroquinolone antibacterials: past, present, and future perspectives. Int J Antimicrob Agents. 2000;16(1):5-15.
23. Domagala JM. Structure-activity and structure-side effect relationships for the quinolone antibacterials. J Antimicrob Chemother. 1994;33(4):685-709.
24. Iquix (levofloxacin ophthalmic solution) 1.5% prescribing information. Jacksonville, FL: Vistakon Inc; 2007.
25. Stein G. The methoxyfluoroquinolones: gatifloxacin and moxifloxacin: structure and mechanisms of action. Medscape Today. http://www.medscape.com/viewarticle/410081_2. Accessed April 1, 2011.
26. Lu T, Zhao X, Drlica K. Gatifloxacin activity against quinolone-resistant gyrase: allele-specific enhancement of bacteriostatic and bactericidal activities by the C-8-methoxy group. Antimicrob Agents Chemother. 1999;43(12):2969-2974.
27. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003;136(3):500-505.
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32. Karpecki P, Depaolis M, Hunter JA, et al. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial conjunctivitis: A multicenter, prospective, randomized, double-masked, vehicle-controlled, 5-day efficacy and safety study. Clin Ther. 2009;31(3):514-526.
33. McDonald MB, Protzko EE, Brunner LS, et al. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis. Ophthalmology. 2009;116(9):1615-1623.
34. Comstock TL, Paterno MR, Usner DW, Pichichero ME. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% in children and adolescents with bacterial conjunctivitis: a post hoc, subgroup analysis of three randomized, double-masked, parallel-group, multicenter clinical trials. Paediatr Drugs. 2010;12(2):105-112.
35. Haas W, Pillar CM, Hesje CK, Sanfilippo CM, Morris TW. Bactericidal activity of besifloxacin against staphylococci, Streptococcus pneumoniae, and Haemophilus influenzae. J Antimicrob Chemother. 2010;65(7):1441-1447.
36. Moxeza (moxifloxacin hydrochloride ophthalmic solution) prescribing information. Fort Worth, TX: Alcon, Inc; 2010.
37. Levy SB. The challenge of antibiotic resistance. Sci American. 1998;278(3):46-53.
38. Hwang D. Antimicrobial resistance in ophthalmology: clinical implications. During: Evolving concepts in ocular infectious disease. Presented at: American Academy of Ophthalmology Annual Meeting; October 16-20, 2005; Chicago, IL.
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41. Sanford J. The Sanford Guide to Antimicrobial Therapy 2010. 40th ed. Sperryville, VA: Antimicrobial Therapy Inc; 2010.

Case 1

A 6-month-old male was treated for bilateral purulent conjunctivitis with polymyxin B/ trimethoprim ophthalmic solution with no relief of symptoms. The health care provider suspected a methicillin-resistant

Staphylococcus aureus (MRSA) infection, ordered that a conjunctival swab be taken for bacterial culture, and prescribed oral cephalexin and trimethoprim/sulfamethoxazole to treat the infection while awaiting results of the culture. Two days later, the culture was positive for penicillin-nonsusceptible Streptococcus pneumoniae (PNSP). The provider stopped oral antibiotics and switched the ocular eye drops to a newer fluoroquinolone, which was effective.

Commentary

Had this provider known that the Sanford Guide¹ recommends newer fluoroquinolones as first-line treatment for bacterial conjunctivitis, the patient would most likely have been cured in 2 days. The expense of the second clinic visit, the laboratory testing, and the cost of the polymyxin B/trimethoprim eye drops, oral cephalexin, and oral trimethoprim/sulfamethoxazole treatments would have been spared.

The recommendations to treat with newer fluoroquinolones are supported by research evidence. For example, in 1 small study, moxifloxacin led to a higher proportion of patients experiencing complete resolution of ocular signs and symptoms at 48 hours compared to polymyxin B/trimethoprim eye drops (81% vs. 44%; P = .001).² Optimal treatment improves quality of life, reduces the spread of disease, and has a significant socioeconomic benefit.

References

1. Sanford J. The Sanford Guide to Antimicrobial Therapy 2010. 40th ed. Sperryville, VA: Antimicrobial Therapy Inc; 2010.
2. Granet DB, Dorfman M, Stroman D, Cockrum P. A multicenter comparison of polymyxin B sulfate/trimethoprim ophthalmic solution and moxifloxacin in the speed of clinical efficacy for the treatment of bacterial conjunctivitis. J Pediatr Ophthalmol Strabismus. 2008;45(6):352-351.

Case 2

The worried mother of a 7-month-old male calls the pediatric clinic after her son woke up with a red left eye. The child had been swimming in a pool almost daily for more than a week. On examination, the child’s eye had purulent discharge but the examination was difficult, with a poor view of the eye. The health care provider prescribed erythromycin ophthalmic ointment twice daily.

The next day, there was no improvement in the child’s conjunctival injection or discharge. The mother called the provider and was advised to continue the erythromycin ointment for 1 more day. By day 3, there was no improvement and possible worsening of the child’s symptoms. The primary care provider then referred the child to an ophthalmologist. The ophthalmologist also had difficulty examining the boy’s eye but discontinued the erythromycin ointment and initiated treatment with a newer fluoroquinolone eye drop 3 times per day.

However, by day 4 the child had still not improved so the mother returned to the ophthalmologist, who was able to get a better examination and diagnosed the boy with a corneal ulcer, likely caused by Pseudomonas aeruginosa. Treatment was escalated to a newer fluoroquinolone drop every 30 minutes for 36 hours followed by one drop every hour for 48 hours. The infection resolved and the ulcer eventually healed.

Commentary

Exposure to contaminated water in heated swimming pools can lead to conjunctivitis caused by P aeruginosa, and a failure in clinical response to any therapy selected should prompt re-examination and reconsideration of treatment.¹

References

1. Zichichi L, Asta G, Noto G. Pseudomonas aeruginosa folliculitis after shower/bath exposure. Int J Dermatol. 2000;39(4):270-273.