Monograph to the January 2006 issue

Bacterial Conjunctivitis in Children: Containing the Infection

Symposium

Differential Diagnosis

Philip A. Brunell, MD: Bacterial conjunctivitis is a contagious disease that may spread easily and quickly. If left untreated, the infection can last up to 10 days. Implementing treatment quickly may prevent spreading of the infection and may reduce the number of days missed from school and work. Choosing a therapy that is comfortable and effective is important in treating ocular infection in children.

This panel discussion will focus on the differential diagnosis of pink eye, bacterial conjunctivitis in children and treatment options, as well as pharmacology.

Rudolph S. Wagner, MD: Most children with pink eye are first seen by pediatricians and, if problems with treatment exist, they will often be referred to a pediatric ophthalmologist. What cases of red eye do pediatricians refer to pediatric ophthalmologists?

G. Scott Cuming, MD: Most children with pink eye present with simple conjunctivitis without many other symptoms. Some children, however, present with symptoms such as fever, cough, pharyngitis or ear pain. The differential diagnosis becomes slightly more complex. For a child that presents with only a red eye, the cause is usually due to a virus or bacterium. The one or two patients a year whom I refer to ophthalmologists have herpetic conjunctivitis (Figure 1), which presents with vesicular lesions around the eye, or persistent conjunctivitis that does not respond to topical antibiotics.

Other known reasons for referral include continued or increasing blurred vision, persistent photophobia, increasing pain, lack of a response to topical therapy or when the cornea is not clear.

The number of patients with conjunctivitis that I see come in small waves, but over the course of one year, I see hundreds of patients. I refer less than 1% of my patients with conjunctivitis to an ophthalmologist for herpetic conjunctivitis, trauma, iritis, or non-response to treatment.

Figure 2 Algorithm for the Differential Diagnosis of Red Eye Red eye can be a symptom of conjunctivitis caused by an allergen, a virus or a bacterium. Other symptoms associated with red eye may indicate an ophthalmic referral. Appropriate diagnosis of red eye is necessary so that proper treatment can be implemented. Reproduced with permission from “Conjunctivitis,” February 15, 1998, American Family Physician. Copyright © 1998 American Academy of Family Physicians. All Rights Reserved.

Wagner: What clinical signs are useful for differentiating suspected bacterial conjunctivitis from viral conjunctivitis?

Cuming: Good indicators of bacterial conjunctivitis are crusting and eyes matted shut with a mucopurulent discharge in the morning. Given the multitude of presenting symptoms that cross over from viral to bacterial, however, it is not always clear which one is being presented. If a child has a significant amount of discharge and the eyes are glued shut and are red, the child will not feel well enough to go to school or day care.

Donald K. Murphey, MD: Differential diagnosis can be divided into three groups (Figure 2).¹ A red, itchy eye is most likely caused by allergies. A red, watery eye may be viral. If a child has mucopurulent drainage and the eyes are matted shut, the cause is most likely a bacterial infection.

Overlap between viral and bacterial conjunctivitis can occur with adenovirus, which causes a significant amount of inflammation. Some of the worst cases of conjunctivitis are adenovirus.

Wagner:Another aspect affecting differential diagnosis is the age of the patient. In a study conducted by Francis Gigliotti, MD, bacterial conjunctivitis was more common in younger children than in older children.² Additionally, in a study conducted by Avery Weiss, MD, 80% of children with acute conjunctivitis had bacterial conjunctivitis (Figure 3). ³

Figure 3 In a randomly selected sample of 95 outpatients with acute conjunctivitis (age range, 4 months to 12 years), 80% of patients (n = 76) had bacterial infections.3 These findings confirm an earlier study in which 82% of patients (age range 1 month to 18 years) had bacterial conjunctivitis.2

Brunell: Stan Block, MD, and colleagues published a study on a general pediatric practice where the average age of children with acute conjunctivitis was 24.3 months, ranging from 2 weeks to 16 years.⁴

Wagner: A study published in The New England Journal of Medicine described an epidemic of Streptococcus pneumoniae that occurred in college-aged students, however.⁵ Another outbreak of S. pneumoniae was documented in college students in New Hampshire (Figure 4).⁶

Murphey: Young children may also present with a persistent high fever and bilateral conjunctivitis associated with Kawasaki syndrome. Prompt and appropriate treatment is critical. Indications of Kawasaki syndrome include a fever persisting for more than five days, as well as at least four of the following: bilateral bulbar conjunctival injection without exudates; erythematous mouth and pharynx, strawberry tongue and red, cracked lips; a polymorphous, generalized, erythematous rash that can be morbilliform, maculopapular or scarlatiniform, or may resemble erythema multiforme; changes in the peripheral extremities consisting of induration of the hands and feet with erythematous palms and soles or periungual desquamation; and acute, nonsuppurative cervical lymphadenopathy with at least one node > 1.5 cm in diameter.^7(p392)

Cuming: If a pediatrician suspects a child has Kawasaki syndrome, the child should also be evaluated by a cardiologist for coronary artery aneurysms and carditis.

Figure 4 During the 2002 winter term at a New Hampshire college, 493 students had probable pneumococcal conjunctivitis and 81 students had confirmed pneumococcal conjunctivitis.5 (Figure courtesy of Morbidity and Mortality Weekly Report.)

Wagner: What is the most common condition diagnosed as conjunctivitis by pediatricians and then referred to ophthalmologists?

Mark S. Dorfman, MD: Ophthalmologists commonly see children with allergic or viral conjunctivitis who were treated with antibiotics and did not feel better three to five days after treatment. Pediatric patients with a red eye but no discharge may have a reaction to medication because agents such as trimethoprim sulfate-polymyxin B, gentamicin sulfate or other sulfas can create hypersensitivity reactions. Ophthalmologists then question how the patient’s condition appeared prior to the onset of topical medication.

Other conditions of red eye that resemble conjunctivitis may be the result of a foreign body that could not be seen. A child may also have uveitis or iritis, but, because the eye was red, an antibiotic was prescribed.

If a child complains of a significant amount of pain, light sensitivity or reduced vision or does not respond within three days to proper medication, the child should be referred to a pediatric ophthalmologist.

Cuming: Conjunctivitis occurs primarily in young children, such as toddlers and preschoolers, so symptoms of decreased vision or pain are usually not conveyed to the pediatrician by the afflicted child. A child may be fussy or irritable, but the pediatrician cannot be sure of the cause.

A foreign body or a corneal abrasion is likely to present unilaterally, and a young child will complain, keep the eye closed and demonstrate photophobia. For all children with suspected conjunctivitis, pediatricians should carefully examine the eye and make sure the cornea is clear, the conjunctiva is not injured or damaged and a foreign body is not apparent. Adequate treatment, such as a topical antibiotic, for a mild corneal abrasion, should be instituted early. If the symptoms do not resolve within 24 hours, however, pediatricians should refer the child to an ophthalmologist.

Is it viral or bacterial? Wagner: Ophthalmologists can use slit lamp examinations to determine whether a patient has viral or bacterial conjunctivitis. Bacterial infection results in a pupillary response to the examination. What can pediatricians without a slit lamp look for to differentiate between viral and bacterial conjunctivitis? Dorfman: Differentiating between viral and bacterial conjunctivitis can be difficult. Clinicians usually can differentiate using the following pearls: Viral conjunctivitis Bacterial conjunctivitis Molluscom viral conjunctivitis (Image courtesy of Rudolph S. Wagner, MD.) Bacterial conjunctivitis (Image courtesy of Rudolph S. Wagner, MD.) Frequently presents unilaterally. Is more often associated with pharyngitis than otitis. Presents with a mucoid discharge or a mucopurulent discharge. Can result in preauricular lymphadenopathy. If clinicians feel a node anterior to a child’s ear, then a virus is most likely the source of the conjunctivitis. Can present as persistent unilateral conjunctivitis, which can be caused by a foreign body, a corneal ulcer, a dendrite or uveitis, and is normally associated with pain and decreased vision. Presents bilaterally. May be associated with otitis. Presents with green, purulent, bilateral discharge.

Wagner: Pediatric ophthalmologists often see patients younger than 1 year old with a nasolacrimal duct obstruction. Although most pediatricians can recognize a nasolacrimal duct obstruction, many parents take their children to an ophthalmologist thinking that, with ophthalmic care, the ailment will be resolved quickly. Do you find parents are looking for fast therapy?

Dorfman: Parents often take their children to ophthalmologists because they find it disturbing to see a significant amount of discharge coming from their children’s eyes. Parents want fast and effective treatment for their children and often request antibiotics. If an eye has a significant amount of discharge and the conjunctiva is extremely white, the child does not have conjunctivitis but a nasolacrimal duct obstruction. Ophthalmologists must educate parents and inform them that, although antibiotics treat the discharge, they will not open the blocked tear duct.

Brunell: What can parents do to assist in unblocking a tear duct?

Dorfman: Parents can massage over the area of the lacrimal sac. Massaging may open a child’s blocked tear duct sooner. Massaging also helps decompress the nasolacrimal sac, so the fluid may not drain, but instead expels through the superior/inferior canaliculus, which decreases infections.

Wagner: Massaging can also help diagnostically. If a pediatrician massages a child’s eye and gets reflux from the puncta, then the diagnosis is nasolacrimal duct obstruction, not bacterial conjunctivitis.

Bacterial conjunctivitis outbreaks

Brunell: What are the most common bacterial organisms that cause conjunctivitis in children?

Dorfman: Bacterial conjunctivitis is most commonly caused by gram-positive organisms such as S. pneumoniae (Figure 5). Many clinicians assume that Haemophilus influenzae, a gram-negative organism, is more prevalent, however.

Brunell: Dr. Block’s studies were surprising because many of the patients he studied had cases caused by pneumococcus.⁴ Pediatricians were always taught that conjunctivitis was most likely caused by H. influenzae, but substantial evidence of a S. pneumoniae is illustrated in several recent studies.^5,6,8,9

Dorfman: An outbreak that was reported in an elementary school in Maine was the same type of bacteria, a non-encapsulated pneumococcal species, that was reported in an outbreak at Dartmouth College in New Hampshire. In New England and the Boston area specifically, erythromycin ointment is often prescribed to treat infections. The bacteria found to be the cause of conjunctivitis in the college and elementary school outbreaks were resistant to erythromycin,^4,8 which was thought to have good coverage for gram-positive organisms.

Wagner: The outbreak at the elementary school primarily affected kindergarten and first- and second-grade students, not students in the higher grades. The outbreak at Dartmouth College, however, infected an older population, but was caused by a similar, non-encapsulated strain of S. pneumoniae. Therefore, outbreaks affecting older populations are not always viral and may respond to antibacterial therapy.

Brunell: The pneumococcal outbreak at Dartmouth College was unique, and it took a long time to type it as it was an unencapsulated pneumococcus; that is why the outbreak was reported.

Dorfman: For many years, ophthalmologists believed that viral infections were more contagious than bacterial infections. However, the above-mentioned studies show that bacterial infections can also be contagious, and it is important to treat them with antibiotics that work quickly. Although bacterial conjunctivitis is a self-limited condition, it can also be contagious and lead to increased school absenteeism, which can be problematic.

Brunell: Have other epidemics been reported?

Wagner: An epidemic of acute conjunctivitis caused by H. influenzae in grade-school children was reported in Georgia in 1981.¹⁰ Thirty-eight percent of patients had unilateral conjunctivitis, and 62% had bilateral.

Cuming: Epidemics of conjunctivitis are not a new problem. Accounts of seasonal conjunctivitis outbreaks in southern states and southern California have existed since 1929.¹¹ Young children were primarily affected, and the outbreaks occurred during summer or early fall.

Preventing transmission

Murphey: School nurses, while protecting the health of all school children, usually try to keep children in school as much as possible. The policies that regulate school absenteeism are sometimes set by school districts, which may be more conservative than what is recommended by the CDC. Weighing the health of the classroom versus the education of a child is a difficult issue.

Brunell: What measures can school nurses or teachers take to prevent the spread of bacterial conjunctivitis?

Cuming: Educating nurses and teachers about the importance of hand washing may have a significant impact on the incidence of conjunctivitis in schools. In a study published in the American Journal of Infectious Control, 290 students from five independent elementary schools were studied to test the effects of a hand washing program.¹² Test classrooms were educated on hand washing and received hand sanitizer. At three months, the number of absences was 50.6% percent lower in the test group than in the control group. The results suggest that a hand hygiene program including education and sanitizers can lower absenteeism.

Brunell: Ensuring that children commit to routine hand washing in school or day care may be difficult. Are there any other options?

Murphey:Alcohol gels are less intrusive and may address some of the nurses’ or teachers’ concerns about getting children to wash and dry hands in the sink. Schools should have hand sanitizer available in the classrooms and encourage students to use it frequently during the day when sinks are not available.

Brunell: Preventing the spread in young children may still prove to be difficult because contact among children and toys, paper or other school supplies that they may touch is difficult to avoid.

Wagner: That is an important point. One of the reasons these epidemics are more likely to occur in younger children may be because contact is hard to control. In day care centers, children are in close contact with each other, whereas, older children, such as those in secondary grade levels, sit at desks and do not usually have the same level of contact.

Dorfman: A teacher is not going to be able to isolate a toy that a young child has played with and clean it with alcohol before putting it back for the next child. Children with conjunctivitis may rub their eyes, then touch a toy before another child picks it up.

Wagner: The outbreak of bacterial conjunctivitis at Dartmouth College may have been unique in that the age group was older than expected of conjunctivitis epidemics but may have been due to similar close contact issues.

A medical student at Dartmouth informed me that students routinely use computer kiosks set up throughout the campuses to communicate with one another in between classes, many times each day and at many locations. Students touching the keyboards then their eyes or hands could have easily contributed to the spread of conjunctivitis.

Treatment

Wagner: The 26th edition of the Red Book states: “Except when viral or bacterial conjunctivitis is accompanied by systemic signs of illness, infected children should be allowed to remain in school once any indicated therapy is implemented…”^7(p142)

Parents, teachers and school nurses want conjunctivitis to be resolved quickly to get children back into school sooner rather than later.

Bacterial conjunctivitis differs from a cold in that the condition may be more uncomfortable to have while in school. Children may find it difficult to read or do schoolwork (Figure 6). Clinicians should treat conjunctivitis with a therapy that influences the course of the disease and shortens it.

Cuming:Although the Red Book recommends excluding a child with a mucopurulent discharge from the eye from school or day care, it does not recommend excluding a child with only a red, watery eye and no systemic symptoms.^7(126-127) I believe that most school nurses and day care personnel continue to send all children with conjunctivitis home, however. Parents are likely told the children may not return until they are treated. Initiating treatment enables parents to return to work and the children to return to day care. The need for parents to return to work seems to be a greater problem now than it was years ago.

Dorfman: Clinicians know that bacterial conjunctivitis is self-limited and, in some children, may take as long as 10 days to resolve if left untreated. Keeping a child with an uncomfortable conjunctivitis out of school for more than is necessary, however, may also keep parents out of work. Health care dollars and education loss add up. I believe that eradication will take a longer time if ineffective therapy is used, and the chance of spread will increase.

Fourth-generation fluoroquinolones, such as moxifloxacin (Vigamox Solution, Alcon Laboratories), eliminate the organism immediately, and I feel that they decrease contagiousness.

Murphey: Children should return to school once they have started on effective therapy, unless they have a systemic illness.

Brunell: Do you prefer to treat bacterial conjunctivitis with fluoroquinolones or nonfluoroquinolones?

Dorfman: I prefer to treat bacterial conjunctivitis with fluoroquinolones. In my experience, nonfluoroquinolones, such as tobramycin and other aminoglycosides, do not work as quickly as fluoroquinolones and have higher rates of sensitivity and allergy in children.

Nonfluoroquinolones may leave eyes red, which can create confusion over whether the bacteria are eradicated (Figure 7).

Fourth-generation fluoroquinolones

Brunell: What therapies provide effective treatment for bacterial conjunctivitis?

Cuming: Because common organisms are resistant to most older antibiotics I prescribe fourth-generation fluoroquinolones. Fourth-generation fluoroquinolones have good gram-positive coverage,^14-17 and moxifloxacin has been shown to rapidly clear conjunctivitis (Figure 8).^13,18

I find moxifloxacin to be the most effective because it is well tolerated. Also, the three-times-a-day dosing is convenient for parents and children and relieves conjunctivitis symptoms quickly.

Wagner: What do pediatricians in hospital-based practices prescribe to treat patients with bacterial conjunctivitis?

Murphey: Pediatricians in hospital-based practices usually see children with complicated diagnoses rather than just routine bacterial conjunctivitis. The children may have preseptal cellulitis, trauma or keratitis.

Hospital-based pediatricians often treat bacterial infection as well as some other problem. It is sensible to prescribe the best agent as soon as possible to eliminate the risk of the bacterial infection exacerbating another process, especially with keratitis.

Pediatricians often prescribe fourth-generation fluoroquinolones so the likelihood of resistance is low, because the risk of serious disease increases if the conjunctivitis worsens despite treatment.

Dorfman: My first-line treatment for bacterial conjunctivitis is a fourth-generation fluoroquinolone, and I predominantly prescribe moxifloxacin for several reasons. Both in vivo and in vitro studies show that moxifloxacin is the most potent of the fourth-generation fluoroquinolones.^{14, 15,19-21} Clinicians want to prescribe an antibiotic with the lowest likelihood of being resistant.

Moxifloxacin covers bacterial organisms, particularly the gram-positives, many of which are resistant to second- and third-generation fluoroquinolones such as ciprofloxacin, ofloxacin and levofloxacin.

I believe that these older drops, as well as nonfluoroquinolones such as gentamicin sulfate and trimethoprim sulfate-polymyxin B, are not as effective as newer fluoroquinolones, such as moxifloxacin, and do not eradicate organisms quickly.

Moxifloxacin’s dosing differs from other fluoroquinolone dosing recommendations. With other fluoroquinolones, drops are instilled every two hours for the first two days, and then four times a day for seven days, taking up to 70 drops to treat bacterial conjunctivitis. The dosing regimen of other fluoroquinolones leads to compliance difficulties with the pediatric population.

Figure 8 In a study that included 544 children and adults with bacterial conjunctivitis, moxifloxacin 0.5% demonstrated rapid improvement in signs of bacterial conjunctivitis after three times daily dosing.13 (Figure courtesy of Mark S. Dorfman, MD.)

Moxifloxacin’s three-times-a-day dosing is convenient, easy and well tolerated and eliminates the need for a second bottle of medication to be kept at school and administered by the school nurse.

Resistance is one factor in deciding which topical therapy to prescribe pediatric patients. Another factor is hypersensitivity in children reacting to the older types of drops that leave eyes red. Gentamicin sulfate, trimethoprim sulfate-polymyxin B and other sulfas burn and sting and can cause red eyes.

Wagner: Neomycin sulfate, which may produce hypersensitivity,²² is present in many compounds that clinicians prescribe, and it should be avoided.

Dorfman: The FDA approved moxifloxacin for administration three times a day. Moxifloxacin is the first fluoroquinolone to achieve a different labeling from other generations of fluoroquinolones.

Brunell: Efficacy of a treatment is based on levels in tears and, most importantly, clinical response and bacterial clearance.⁴

Wagner: My colleagues and I conducted a study on conjunctival concentrations of topical antibiotics.²³ We sampled the conjunctiva of patients who received moxifloxacin, gatifloxacin (Zymar, Allergan), ofloxacin or ciprofloxacin. We found moxifloxacin had the highest concentration at 20 minutes after instillation.

It is notable that moxifloxacin and levofloxacin are 0.5%, but conjunctival concentrations found with moxifloxacin were eight times higher than that with levofloxacin.²³ Something about moxifloxacin’s molecule made the antibiotic more likely to enter the conjunctival cell of the tissue and remain there.

Moxifloxacin, a fourth-generation fluoroquinolone, is advantageous for clinicians treating bacterial conjunctivitis because it remains in the tissue for a significant amount of time.

Murphey: Clinicians cannot assume that using drops such as gentamicin will kill gram-positive organisms. Tears may clear out the antibiotic so that six to eight hours after instillation, little drug may be left, even if a significant amount was instilled. Organisms with high levels of resistance to sulfas and aminoglycosides will most likely not kill bacteria six to eight hours after instillation.

Brunell: In his study, Dr. Block points out that although clearance data on how long the antibiotic levels will persist in tears exist, the data may be irrelevant when considering the antibiotic level in a crying child.⁴ Crying may affect the efficacy of a treatment because a crying child may wash the drops out. The question is are patients better faster with fourth-generation fluoroquinolones than with other topical antibiotics?

Cuming: In my experience, compared with older antibiotics and earlier generation fluoroquinolones, fourth-generation fluoroquinolones are better tolerated and improve symptoms of bacterial conjunctivitis significantly earlier.

Murphey: Fourth-generation fluoroquinolones may clear bacterial conjunctivitis more quickly than treatments such as sulfacetamide or erythromycin

Antibiotics are important for the acute onset, bilateral, mucoid and purulent conjunctivitis cases. Milder cases of redness and irritation or unilateral red, watery eyes are more likely to be allergic or viral in origin.

Cuming: Bacterial conjunctivitis is a self-limited disease. The children who present in the pediatric office are symptomatic enough that their situation is called to the attention of not only the parents but also the day care or the school. As in most diseases, there are mild, moderate and severe forms, and the children with mild cases do not present to the office. Children coming to a pediatrician’s office are likely to have redder eyes, more discharge or more discomfort than children with mild conjunctivitis.

Brunell: Clinicians are concerned about the potential hazards of fluoroquinolones. The amount that gets into the blood from topically administered fluoroquinolones is minuscule, which is why the FDA is not reluctant to recommend it for children, unlike systemically administered fluoroquinolones.

Wagner:There were concerns when ciprofloxacin was introduced systemically. The systemic effects of fluoroquinolones, however, are not as much of a problem as was originally thought to be.

Systemic vs. topical fluoroquinolones

Murphey: Historically, clinicians were concerned about use of systemic fluoroquinolones in children because of potential cartilage and joint toxicity. When systemic fluoroquinolones were first being developed and administered to juvenile animals, signs of cartilage damage in the hips were observed and blebs were sometimes seen in the cartilage.

For years, fluoroquinolones were not prescribed to children. When no agents were available to treat resistant gram-negative infections in children, fluoroquinolones were prescribed and no signs of toxicity were observed. As time went on, anecdotal experience suggested that fluoroquinolones may be safe for use in children, and trials are being conducted to study its safety.

The question now is should fluoroquinolones be used often for children? Most experts would agree that fluoroquinolones are an effective family of antibiotics, but resistance to systemic fluoroquinolones can develop if used for a long time or if the organisms are not quickly killed. Clinicians are interested in reserving systemic fluoroquinolones for use in children only if no other adequate treatment option is available.

Topical therapy used to treat bacterial conjunctivitis is not likely to contribute to resistance in the United States. Resistance to fluoroquinolones with systemic therapy may arise from treating adults with pneumonia or urinary tract infections. In these patients, fluoroquinolones are administered by mouth, and resistance develops in the gastrointestinal tract or in the nasopharynx. Topical therapy is different from systemic therapy. With topical therapy in the eye, the potential for creating resistance is not likely. There is limited distribution of the drug to other sites.

Inhibiting resistance

Wagner: Some resistance to topical medications in ophthalmic cases is developing. These cases are usually induced by prolonged use of low levels of fluoroquinolones, more likely with systemic administration than with topical administration, however. In some patients, fluoroquinolones are administered once every day for three to four weeks and then tapered off. Resistance can develop when antibiotics are not properly used.

Why is it less likely for fourth-generation fluoroquinolones to produce resistance? What about the structure of the molecule may inhibit resistance?

Dorfman: A study performed at the Bascom Palmer Eye Institute showed that resistance to ciprofloxacin and levofloxacin has increased.²⁵ More than 50% of the gram-positive organisms in patients with endophthalmitis were resistant to ciprofloxacin, which is alarming because fluoroquinolones were first introduced to ophthalmologists to treat corneal ulcers and severe eye infections.

Now, gram-positive bacteria are insensitive to those antibiotics and an evolution of the antibiotic was necessary. Fluoroquinolones evolved from nalidixic acid and side chains were added, forming second-generation fluoroquinolones, which were effective against gram-negative organisms and somewhat effective against gram-positive organisms for a time. The second-generation fluoroquinolones worked by inhibiting DNA gyrase and were the best drops ophthalmologists had to treat corneal ulcers, endophthalmitis and bacterial conjunctivitis.

Figure 9 The C-7 chain added onto the fluoroquinolone molecule makes moxifloxacin bulkier than other fluoroquinolones.

With increasing resistance to gram-positive organisms over the past five years, fluoroquinolones have continually evolved. The molecular structure of fourth-generation fluoroquinolones plays a significant role in reducing the resistance from the gram-positive organisms.

A C-7 chain was added onto the fluoroquinolone molecule, making moxifloxacin, a fourth-generation fluoroquinolone, bulkier than other fluoroquinolones (Figure 9).

The molecule with the C-7 chain inhibits two key bacterial enzymes, DNA gyrase and topoisomerase-IV. The organisms that were resistant to other fluoroquinolones are susceptible to fourth-generation fluoroquinolones because the larger molecule now requires bacteria to mutate at two sites.

The moxifloxacin molecule is significantly large and may be the reason the efflux pump that normally pushes the antibiotic out is ineffective. The bulky side chain of the moxifloxacin molecule prevents the efflux pump from pushing it out, and the fluoroquinolone remains in the bacterial cell longer, destroying the bacteria quickly.

Murphey:Clinicians should prescribe enough antibiotic to kill bacteria reliably, for as short a time as possible, because any antibiotic has the potential to cause the development of resistance.

Mutations must occur at two locations for bacteria to develop a resistance to fourth-generation fluoroquinolones. Even if mutations occur at the DNA gyrase site, which is usually the first target for gram-negative organisms, the drug can inhibit topoisomerase-IV and kill bacteria by inhibiting DNA replication and causing cell death, not as quickly but still reliably.

The large side chain on a moxifloxacin molecule is effective at binding both DNA gyrase and topoisomerase fairly well so that a small amount of resistance at one site does not give the organism much advantage.

The bacteria are not able to start replicating quickly with resistance due to changes in the DNA gyrase alone. Resistance must occur at both sites concurrently and is possible if low levels of fluoroquinolones are administered for an extended period. If patients are treated with high enough levels to kill reliably over a short time, resistance should be infrequent, however.

Wagner: In his study, David G. Hwang, MD, states that the use of the newer fluoroquinolones may help to prevent the selection and subsequent proliferation of resistant mutants.²⁶

The more conventional strategy of reserving the use of a newer antimicrobial only when initial treatment with the oldest antimicrobial fails may not be a wise strategy applied to fluoroquinolones used topically. He believes that the primary use of the older fluoroquinolones is more likely to lead to acquisition of the first mutation.

Properly instructing parents on use

Dorfman: Resistance can be prevented if clinicians do not automatically prescribe a topical antibiotic for every patient who presents with red eye. It is essential that clinicians understand what is truly bacterial conjunctivitis and what is not. Topical antibiotics should not be used inappropriately for viral, allergic and other causes of conjunctivitis (Figure 2).

Duration of treatment should also be considered. Many parents may treat their children with an antibiotic and, after two days, if their child looks better, they stop administering the drop and do not follow through with the whole treatment course.

With some of the older agents, organisms are not eradicated quickly, and stopping the treatment protocol in the middle of the course will lead to resistance.

Physicians are responsible for prescribing the medication correctly and also properly educating parents on the importance of how long to use the antibiotic. Clinicians must effectively explain to parents why they should not stop administering it to their children too early and why they should not administer it for longer than the prescribed length of time. Occasionally, parents will keep the antibiotics and every time their child has a red eye, they will administer the same medication. Clinicians should instruct parents to discard the bottle. Properly educating parents is essential to lowering the risk for resistance.

Brunell: The recommended duration of therapy is three times a day for seven days. Has the effectiveness of moxifloxacin administered in shorter durations been studied?

Murphey: A few studies have been conducted assessing the results of administering moxifloxacin for only four days, and results illustrated that the fourth-generation fluoroquinolone was effective.^13,18

Clinicians and parents would be happier hitting the organisms hard and quickly and then stopping drop instillation sooner.

Phone triage

Wagner: Occasionally, pediatricians will receive morning phone calls from parents concerned because their child woke up with some discharge in the eye. Parents will express their need to go to work and to get their child to school. Parents will usually request that the pediatrician call in a prescription without bringing the child in to be seen or ask what they should do to remedy their child. How common is phone triage in a pediatric practice? Is phone triage suitable for diagnosing bacterial conjunctivitis?

Cuming: Phone triage for conjunctivitis has limits. Parents or adolescents may discuss the situation on the phone with a triage nurse or with the pediatrician. If the child is younger than 2 to 3 years old (Figure 10), then an appointment should be scheduled because of the possibility of acute otitis media/conjunctivitis syndrome, herpetic conjunctivitis, foreign body or corneal abrasion. Parents usually understand and accept that their child must be seen by the pediatrician when these risks to the child are explained.

If older children are capable of conversing with the parent or a triage nurse about how he or she feels, however, and there is only a mucopurulent discharge with crusting in the morning and there are multiple cases of conjunctivitis in the classroom or school, then I may feel comfortable to treat over the phone.

Pediatricians should explain, however, that should the symptoms increase or persist after 48 hours of treatment, the child will need to be seen. Bacterial conjunctivitis has such a rapid response to fourth-generation fluoroquinolones that I do not have to tell parents to wait seven to nine days to see an improvement, by which time the infection may have subsided.

If the child is not improving, then the cause of the infection is most likely viral. If a child’s symptoms are worsening, then I would most likely refer the child to an ophthalmologist after first examining the eye.

Brunell: Is it reasonable to assume that if you do not get an improvement with moxifloxacin in three days, then you are most likely not dealing with a bacterial conjunctivitis in these cases?

Dorfman: Yes. I believe that moxifloxacin will completely treat bacterial conjunctivitis within 36 to 48 hours, although it is approved for seven days of use. If after three days the child is not better and the eye is still red, the child should be seen by an ophthalmologist.

Comfort leads to compliance

Wagner: The effectiveness of a drug can be contingent on compliance. For pediatric patients, compliance can therefore be contingent on comfort. Studies have shown that moxifloxacin can be particularly comfortable with use in children.^18,27 My colleagues and I performed a study that compared artificial tears to instilling moxifloxacin. Regarding patient complaints, moxifloxacin and tears were found to be similar. Tolerability is not an issue with moxifloxacin.

With generic medications, the only requirement is that the concentration of the antibiotic is the same as the brand name. The vehicle does not have to have the same pH level as natural tears, however. Using a different vehicle for five varieties of generic trimethoprim-polymyxin B can change the comfort of the drops. In other words, you can have a trimethoprim-polymyxin B eye drop that stings and one that does not sting. Clinicians should keep this in mind if patients complain about discomfort stemming from a particular eye drop.

Dorfman: Because comfort equals compliance, it is sometimes difficult to instill drops into a child’s eye. Two people may be necessary to hold a child down, open the eyelids and instill the drop. Parents will most likely not get a drop in their child’s eye if the drop burns or stings. A drop with a pH that is comparable to natural tears, as well as a dosing regimen that is easy to follow, is essential to increase compliance.

Physicians are obligated to pick the best topical antibiotic that will eradicate the organisms and eliminate the clinical symptoms as fast as possible, keeping in mind that compliance can directly relate to comfort. For bacterial conjunctivitis, fourth-generation fluoroquinolones, such as moxifloxacin, are the best choices for treatment.

Cuming: Moxifloxacin’s three times daily dosing is more convenient than four or more daily doses. For patients and parents, moxifloxacin’s dosing will affect a quicker clinical response because the antibiotic is more tolerable and more comfortable than other topical antibiotics. For a pediatrician, that means fewer return visits of patients with no response to medication and fewer return phone calls for non-response to treatment.

Looking ahead

Brunell: Treating ocular infection in children has greatly improved over the last 10 years. How can ocular infection treatment in pediatric patients be further improved? What would the perfect drug do?

Dorfman: The ideal agent would be efficacious and kill organisms immediately, eradicating the conjunctivitis in one to two days. The drug would have low incidences of resistance and would be comfortable in the eye. At this point, moxifloxacin meets these criteria.

Brunell: Advances in topical antibiotic therapy, such as faster eradication of organisms, shorter duration of therapy and tolerability, may improve treatment of bacterial conjunctivitis in children. The disease may be resolved more quickly, spread of the infection may be prevented and absenteeism from school or work may be reduced.

I would like to thank the panel for their comments, Infectious Diseases in Children for organizing this symposium and Alcon, Inc., for sponsoring this symposium and monograph project.

Infectious Diseases in Children, with the support of Alcon, Inc., gathered a panel of leading pediatricians and ophthalmologists in Irving, Texas, on June 4, 2005, to discuss differential diagnosis of pink eye, bacterial conjunctivitis in children, recent outbreaks of bacterial conjunctivitis and treatment options for pediatric patients. (From left to right: Philip A. Brunell, MD, Rudolph S. Wagner, MD, Donald K. Murphey, MD, Mark S.Dorfman, MD, and G. Scott Cuming, MD)

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