Commentaries

Clinical Pediatrics50(1) 7 13 The Author(s) 2011Reprints and permission: http://www. sagepub.com/journalsPermissions.navDOI: 10.1177/0009922810379045http://clp.sagepub.com

Bacterial Conjunctivitis in Children: Antibacterial Treatment Options in an Era of Increasing Drug Resistance

Michael E. Pichichero, MD1

Introduction

Conjunctivitis is one of the most frequently seen eye disorders in the primary care and pediatric setting,1-3 accounting for an estimated 1% to 4% of visits.4 The etiology can be bacterial, viral, allergic, or chemical, but bacterial infections are the most common. Bacterial con-junctivitis occurs more often in preschool children than in older children and adults.2 The most common caus-ative organisms in children are Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis (Table 1).5 Approximately one third of children with bacterial conjunctivitis have con-current otitis media.6

Bacterial conjunctivitis is highly contagious and rapidly transmitted in day-care centers and classrooms.2,3,7 The condition is typically self-limited, with clinical resolu-tion usually apparent by 7 days without treatment.7 How-ever, clearance of the infection can take up to 3 weeks.3 Treatment of acute bacterial conjunctivitis with an anti-infective agent lessens contagion and duration of dis-ease, alleviates patient discomfort, and facilitates earlier resumption of normal activities.3 A meta-analysis of 5 double-blind, placebo-controlled clinical studies with a total of 1034 children and adults concluded that anti-bacterial agents have their greatest impact on clinical and microbiological remission if begun within 2 to 5 days of symptom onset.8

As bacterial resistance to anti-infectives continues to evolve, the selection of an ocular antibacterial has become a challenge. Bacterial resistance to antibiotic therapy can result from a number of factors.9 Nationwide surveillance studies such as the Ocular Tracking Resistance in US Today (TRUST) survey and The Surveillance Network (TSN) have documented emerging resistance among ocu-lar pathogens to ocular anti-infectives.10,11

In this review, the differential diagnosis of bacterial conjunctivitis in children and the efficacy of currently used and newer topical antibacterial treatments for acute bacterial conjunctivitis in the preschool and school-aged

child will be presented in the context of increasing bac-terial resistance.

Diagnosis of Acute Bacterial ConjunctivitisThe history for conjunctivitis should include time of onset of symptoms, precipitating events, progression, and duration and severity of symptoms (i.e., acute, hyperacute, or chronic).5 Exposure to other children/adults at home, school, or day care with similar symp-toms should be noted, as should a history of allergies and whether the conjunctivitis is unilateral or bilateral. The physical exam should include an assessment of the external structural parts of the eye (eyelids, lashes) as well as the cornea and bulbar palpebral conjunctiva. The surrounding skin should be examined and enlarged regional lymph nodes should be noted. In addi-tion, patients should be checked for comorbid otitis media.

Signs and symptoms specific to allergic conjunctivi-tis include itching, stringy or ropy discharge, lid edema, chemosis, red, hyperemic conjunctiva, and comorbid allergic rhinitis. Viral conjunctivitis is characterized by watery discharge and conjunctival injection. The pres-ence of preauricular and/or submandibular lymphade-nopathy can confirm viral conjunctivitis. Children with viral conjunctivitis may be febrile and/or have associ-ated pharyngitis.

Acute bacterial conjunctivitis begins abruptly with early symptoms of irritation or foreign body sensation and tearing. Mucopurulent or purulent discharge,

1Rochester General Hospital, Research Institute Rochester, NY, USA

Corresponding Author:Michael E. Pichichero, Center for Infectious Disease and Immunology, Rochester General Hospital, Research Institute 1425 Portland Avenue, Rochester, NY 14621, USAEmail: michael.pichichero@rochestergeneral.org

8 Clinical Pediatrics 50(1)

frequently occurring with morning crusting, swelling, and comorbid otitis media are the most common indica-tors of acute bacterial conjuctivitis.2,6

Cultures may be used to confirm or deny the etiology; however, these are rarely obtained, unless the conjunc-tivitis is recurrent or severe. In children, nontypeable H influenzae is the predominant organism in acute bacterial conjunctivitis followed by S pneumoniae.3,12 Figure 1 depicts an algorithm for evaluating conjunctivitis based on the age of the child.5

Treatment of acute bacterial conjunctivitis with a broad-spectrum, preferably bactericidal, antibacterial is often initiated empirically because the rapid kill of bacteria shortens the time to recovery1,2,13; limits the spread of disease2; relieves a financial burden by speeding up a childs return to day care or school and, consequently, the parents return to work; and reduces the risk of sight-threatening complications. For acute bacterial conjunctivitis with otitis media, treatment with an oral antibiotic is recommended.14 For uncomplicated acute bacterial conjunctivitis, topical ophthalmic agents are preferred over systemic agents because the concentra-tion of antibiotic achieved on the eye following topical administration is higher than that achieved in the blood following oral administration and systemic side effects of orally administered antibiotics are avoided. Also, the concentration of antibiotic achieved on the surface of the eye following topical administration is expected to exceed both the minimum inhibitory concentration (MIC) required to inhibit 90% of tested isolates (MIC90) and the minimum bactericidal concentration at the target

tissue site.15 To date there has only been one study com-paring the efficacy of oral treatment with that of topical treatment. Wald et al16 showed that oral cefixime and topical polymyxin B/bacitracin were equally effective in achieving clinical cure in children aged 2 months to 6 years with acute bacterial conjunctivitis. From this study one might infer that an effective oral antibiotic with activ-ity against ocular pathogens should be sufficient therapy and the addition of an ocular antibiotic unnecessary. when both conjunctivitis and otitis media are present.

Considerations in choosing the appropriate topi-cal antibiotic for bacterial conjunctivitis include broad coverage of ocular Gram-positive and Gram-negative bacteria,17 rapid kill rate, low bacterial resistance, mini-mal toxicity to the eye, patient comfort, and a convenient dosing schedule to encourage patient adherence. Cur-rently, the most commonly used topical ophthalmic anti-infective options are from one of the following classes: aminoglycosides, polymyxin B combination therapies, macrolides, or fluoroquinolones.9 Sulfonamides and chloramphenicol are no longer favored in the United States because of tolerability/safety concerns of severe stinging on instillation with sulfonamides and aplastic anemia with chloramphenicol and are not addressed in this review. Table 2 presents a brief summary of the currently used topical anti-infectives for bacterial con-junctivitis with their dosage regimens. Most of these antibiotics are approved for children 1 year and older.

AminoglycosidesAminoglycosides (gentamicin, tobramycin, neomycin) are most active against Gram-negative bacteria, particularly Pseudomonas aeruginosa (with the exception of neo-mycin), and are active against methicillin-sensitive S aureus (MSSA) but offer little coverage of streptococci and methicillin-resistant S aureus (MRSA).18 Studies of tobramycin 0.3% and gentamicin 0.3% in patients of all ages found clinical cure rates ranging from 46% to 77% and 39% to 70%, respectively.7 One study demonstrated significantly improved clinical cure rates with tobramy-cin compared with gentamicin (P = .038).19 Results of a study in children (

Pichichero 9

survey of Ocular TRUST, describing data collected from October 2005 through June 2006 showed 65.3% resis-tance among S pneumoniae isolates to tobramycin.10 Tobramycin was active against MSSA, but 63.6% of MRSA were resistant to tobramycin. Additional analysis of archived isolates of S pneumoniae and H influenzae obtained between 1999 and 2006 further showed 59.9% of penicillin-sensitive S pneumoniae (PSSP) isolates were resistant to tobramycin compared with 73.1% of peni-cillin-nonsusceptible S pneumoniae (PNSP) isolates. Of note, little to no aminoglycoside resistance was seen in H influenzae.10

Polymyxin B Combination TherapyPolymyxin B exerts activity against Gram-negative organ-isms only and is, therefore, administered in combination with other antibiotics with complementary modes of action to provide a broader spectrum of coverage. Com-monly used polymyxin B combination products include polymyxin B/trimethoprim, polymyxin B/bacitracin, and polymyxin B/neomycin/bacitracin. Trimethoprim has activity against most staphylococci, streptococci, and some Gram-negatives such as Haemophilus. Most staphylococci and streptococci are susceptible to bacitra-cin. Double-masked, randomized comparisons did not identify any significant differences between the poly-myxin B combination regimens in clinical resolution or bacterial eradication rates when tested in patients of all ages.12

Resistance to Polymyxin B Combination Therapy

In 2000, a pediatric surveillance study by Block et al12 showed that polymyxin B was ineffective against both PSSP and PNSP isolates. Although both polymyxin B/neomycin and polymyxin B/trimethoprim combinations were more active against S pneumoniae isolates than polymyxin B, only the combination of polymyxin B/trimethoprim achieved MIC90 values considered predic-tive of clinical efficacy and then only against penicillin-susceptible S pneumoniae.12 In contrast, most strains of H influenzae remained susceptible to polymyxin B alone or in combination with neomycin or trimethoprim regardless of -lactamase status. Ocular TRUST 1 data reported 100% resistance among S pneumoniae and MSSA to polymyxin B, but no resistance by H influenzae.10 Trimethoprim was effective against PSSP, but 74% of PNSP were resistant to trimethoprim.10

MacrolidesMacrolides are active primarily against Gram-positive cocci with the exception of enterococci and are generally bacteriostatic. Erythromycin has been used as an ocular antibiotic for more than 25 years as a 0.5% ointment. However, resistance among Staphylococcus species and poor activity against H influenzae have relegated eryth-romycin to a marginal role in the treatment of bacterial conjunctivitis.17

Systemicantibiotics,

Eye irritation

Neonate Older infantToddlerSchool-aged child

Adolescent

Gram stainand culture

Child with conjunctivitis

10 Clinical Pediatrics 50(1)

Azithromycin is a newer macrolide topical ophthal-mic antibiotic. Abelson et al21 reported rates of clinical resolution and bacterial eradication of 63.1% and 88.5%, respectively, at day 6 or 7 following treatment initiation with azithromycin 1% in children and adults with bacte-rial conjunctivitis.

Resistance to Macrolides

The Ocular TRUST 1 survey (2005-2006) showed a 22.4% resistance rate to azithromycin among S pneu-moniae isolates, 45.7% resistance among MSSA isolates, and 90.9% resistance among MRSA isolates.10 A study

Table 2. Summary of Commonly Used Topical Antimicrobial Agents for Bacterial Conjunctivitis

Antimicrobial Agent Dosage Comments

AminoglycosidesGentamicin 0.3% solution and

ointmentTobramycin 0.5% solution and

ointment

Solution: instill 1-2 drops every 2-4 hours up to 2 drops every hour for severe infections

Ointment: instill 0.5-inch ribbon 2-3 times/day to every 3-4 hours

Resistance among Gram-positive organisms, particularly Streptococci. May cause hyperemia or keratopathy

MacrolidesErythromycin 0.5% ointment Instill 0.5-inch ribbon 2-6 times/day Generally bacteriostatic. Staphylococcus species

have become resistant to erythromycin; resistance to both erythromycin and azithromycin among Haemophilus influenzae. Azithromycins long half-life is a risk factor for resistance

Azithromycin 1% suspension Instill 1 drop twice a day for 2 days then daily for 5 days

Polymyxin B combinationsPolymyxin B/trimethoprim

sulfate solution 10 000 U/mL, 1 mg/mL

Instill 1-2 drops every 4-6 hours Effective against H influenzae and penicillin-susceptible Staphylococcus pneumoniae. Not reliably bactericidal. Clinical cure may take as long as a week

Polymyxin B/bacitracin ointment10 000 U/g, 500 U/g

Instill 0.5-inch ribbon every 3-4 hours for acute infections or 2-3 per day for mild to moderate infections for 7-10 days

Reports of contact dermatitis of the periocular area with bacitracin

Polymyxin B/neomycin/bacitracin ointment

10 000 U/g, 0.35%, 400 U/g

Instill 0.5-inch ribbon every 3-4 hours for acute infections or 2-3 per day for mild to moderate infections for 7-10 days

Ocular allergic reactions seen with neomycin and contact dermatitis with bacitracin

FluoroquinolonesCiprofloxacin 0.3% solution or

ointmentSolution: instill 1-2 drops every 2 hours

for 2 days, up to 8 times/day, then 4 times/day for 5 days (class labeling)

Ointment: instill 0.5-inch ribbon 3 times/day for 2 days followed by twice daily for 5 days

Effective against a broad spectrum of Gram-negative and Gram-positive organisms. However, resistance has emerged among S pneumoniae

Drug precipitates with frequent dosing reported with ciprofloxacin

Ofloxacin 0.3% solution Same as above (class labeling)Levofloxacin 0.5% solution Same as above (class labeling) Highly effective against a broad spectrum of

Gram-negative and Gram-positive organismsGatifloxacin 0.3% solution Same as above (class labeling) Highly effective against a broad spectrum of

Gram-negative and Gram-positive organismsMoxifloxacin 0.5% solution Instill 3 times/day for 7 days Of the fluoroquinolones, the only one that

does not contain benzalkonium chloride as a preservative

Besifloxacin 0.6% suspension Instill 3 times/day for 7 days Developed only for topical ophthalmic use; potent in vitro efficacy against bacterial strains resistant to other fluoroquinolones, but clinical relevance not known

Source: Merck Manual 2009-2010 Merck Sharp & Dohme Corp. http://www.merck.com/mmpe/sec09/ch101/ch101c.html. Accessed February 15, 2010. Tasman W, Jaeger AE. In: Duanes Ophthalmology. Philadelphia, PA: Lippincott Williams & Wilkins; 2009. Online edition.

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from 32 centers in the United States evaluating conjunc-tival isolates collected in 2006 and 2007 identified 20% resistance to azithromycin among S pneumoniae isolates and 30% resistance among S aureus isolates from 625 patients with bacterial conjunctivitis.22 Resis-tance to azithromycin among 76% of H influenzae iso-lates was reported.

FluoroquinolonesFluoroquinolones offer broad-spectrum coverage against both Gram-positive and Gram-negative organisms.23 The initial topical ophthalmic fluoroquinolones ofloxacin and ciprofloxacin were introduced in the 1990s but have been largely replaced by the newer fluoroquinolones levo-floxacin, moxifloxacin, and besifloxacin because of their improved activity against Gram-positive organisms.

Several randomized, double-masked, controlled clin-ical trials in children and adults with bacterial conjunc-tivitis demonstrated rates of clinical cure ranging from approximately 66% to 96% and microbial eradication ranging from approximately 84% to 96% for the newer fluoroquinolones.24

Besifloxacin, the latest topical ophthalmic fluoro-quinolone, received US Food and Drug Administration approval in May 2009 for the treatment of bacterial con-junctivitis. Treatment of children and adults with bacte-rial conjunctivitis with besifloxacin 0.6% resulted in clinical resolution rates of 45% to 73% and bacterial eradication rates of 88% to 91%.25,26 The efficacy and safety of besifloxacin in children and adolescents aged 1 to 17 years (N = 447 with culture confirmed conjunc-tivitis) were recently reported in a post hoc analysis and were found to be consistent with the overall study population.27

Resistance to FluoroquinolonesDevelopment of resistance to a fluoroquinolone is often achieved through one or more mutations in the genes encoding these enzymes. The newer fluoroquinolones (eg, moxifloxacin and besifloxacin) exhibit balanced dual binding of these enzymes and require multistep mutations, whereas resistance to the older fluoroquino-lones (eg, ciprofloxacin, ofloxacin), which typically target one enzyme in preference to the other, may require only a single such mutation.10,28

Surveillance data thus far has failed to show resis-tance of S pneumoniae or H influenzae isolates to either the older or newer fluoroquinolones.10,12,22 In contrast, there is documented resistance to both older and newer ophthalmic fluoroquinolones among S aureus. From

2004 to 2006 it was reported that 90% to 92% of MSSA isolates, but only 27% to 32% of MRSA isolates, were susceptible to the fluoroquinolones tested (cipro-floxacin, levofloxacin, and moxifloxacin) and a con-sistent annual 2.5% increase in MRSA as a cause of ocular infections was identified.16 Another study reported an increase in resistance to ciprofloxacin by S aureus isolates from 13.3% to 36.0% and the preva-lence of methicillin resistance among these isolates increased concurrently from 4.4% to 42.9%.17 More recently, a study of bacterial conjunctivitis isolates found that 65% of MRSA isolates were resistant to ciprofloxacin.29

Safety of Topical Ophthalmic Antibiotics for Bacterial ConjunctivitisThe topical ophthalmic antibiotics for the treatment of bacterial conjunctivitis are generally safe and well toler-ated with few exceptions. Because systemic exposure fol-lowing topical administration is minimal, adverse events are mostly mild and transient and limited to ocular adverse events. Topical aminoglycosides have been associated with corneal and conjunctival toxicity, especially when used frequently. Superficial punctate lesions have been reported with tobramycin, and ocular allergic reactions have been reported with tobramycin, gentamicin, and neomycin.30 Bacitracin has been associated with cases of contact dermatitis in the periocular area.31 Local irritation may occur in patients treated with polymyxin B/trimethoprim sulfate combination regimens, whereas allergic sensitization reactions may occur with polymyxin B/bacitracin/neomycin combination regimens. Macrolides are associated with minor ocular irritations, redness, and hypersensitivity reactions. Fluoroquinolone oph-thalmic solutions have been well tolerated and are asso-ciated with less toxicity (eg, burning/stinging, chemosis, photophobia, negative effects on corneal epithelium) than other ophthalmic antibacterial classes.18,32,33

Choosing an Appropriate Ophthalmic Antibiotic for Bacterial ConjunctivitisThe ideal topical anti-infective for the treatment of acute bacterial conjunctivitis should be a well-tolerated, broad-spectrum, highly potent, and a bactericidal agent with a high concentration on the ocular surface and rapid kill time. Although there are many classes of topical antibiotic treatment options available to primary care physicians, dif-ferences among them as well as emerging bacterial resis-tance should be considered in selecting the appropriate antibiotic. In addition, agents with convenient dosing

12 Clinical Pediatrics 50(1)

regimens are likely to promote treatment compliance. When local antibiotic resistance to ocular pathogens warrants the increased cost, use of newer fluoroquino-lones might be considered.

Declaration of Conflicting InterestsThe author declared no conflicts of interest with respect to the authorship and/or publication of this article.

FundingThe author received no financial support for the research and/or authorship of this article.

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