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Antibiotics: What To Do When Empiric Treatment Fails?

by: Sean P. Donahue, MD, PhD

Evaluation of a pediatric patient with conjunctivitis who has failed to respond to empiric antibiotic therapy should begin by reviewing and confirming the diagnosis. The patient’s history and physical examination should be carefully assessed for clues that may help to confirm or exclude the diagnosis of conjunctivitis. Many patients will benefit from changing to another antibiotic, although in some cases, it is reasonable to allow conjunctivitis to resolve spontaneously.

Reviewing the Diagnosis

Reviewing the patient history can be helpful in determining why the treatment has failed (Table 1). The duration of ocular symptoms provides important information about the diagnosis. Bacterial conjunctivitis usually resolves spontaneously within a few days,¹ and symptoms persisting for several weeks suggest another diagnosis. The child should be evaluated for possible exposure to infectious conditions, especially methicillin-resistant Staphylococcus aureus (MRSA), which has increasingly been linked to difficult-to-treat conjunctivitis.² A previous or concurrent upper respiratory infection or acute otitis media requires more intensive treatment with oral antibiotics. A history of photophobia suggests a pathologic process other than bacterial conjunctivitis, including inflammation within the eye or injury to the corneal epithelium or iris.

Similarly, the physical examination may provide clues to the diagnosis, including characterization of any eye discharge, unilateral or bilateral involvement, and the presence of an upper respiratory tract infection (Table 1). Symptoms such as eye crusting, the absence of drainage, and bilateral involvement suggest allergic symptoms rather than bacterial conjunctivitis.² Evaluating the degree of corneal involvement is especially important, which may require slit lamp examination. Assessing whether the child’s visual acuity is impaired, worsening, or improving is also critical. A highly purulent conjunctivitis with gonococcus may result in rapid corneal damage, which is suggested by clinical signs such as epithelial defect, extreme redness of the eye, or photophobia.

Re-evaluating the differential diagnosis for conjunctivitis is also important. A corneal ulcer may occur if the causative pathogen is virulent enough to invade the cornea. Signs of possible corneal ulceration include a corneal white spot, increased light sensitivity, a tendency to close the eye, and secondary discharge. Hypopyon endophthalmitis is an infection of the interior of the eye that results in a layer of pus between the cornea and the iris, which may be visualized with a direct ophthalmoscope set to +5 or +6 D. Other conditions to consider include viral, chlamydial, or toxic conjunctivitis.² All of these conditions are associated with discharge and may be difficult to distinguish from one another. Chlamydial conjunctivitis often persists despite treatment with several topical antibiotics due to resistance, is unusual in patients between 3 and 4 years of age, and is more typically encountered in adolescents. Purulent discharge is usually not present.

Reviewing and Modifying the Treatment Plan

After the diagnosis has been evaluated and confirmed, the treatment plan should be re-evaluated (Table 2). This includes an assessment of whether the treatment is appropriate for the micro-organisms that would be expected for a patient of this age. For example, in young children, most cases of bacterial conjunctivitis are caused by Haemophilus influenzae, followed by Streptococcus pneumoniae, and staphylococcus species or other micro-organisms are less common causes of conjunctivitis.³ Determining when the treatment was initiated is also important in the review of the treatment plan. Treatment with a bacteriostatic drug may result in more gradual improvement of symptoms than a bactericidal agent, but is a reasonable approach.⁴ Treatments also vary in terms of their spectrum of coverage. Evaluating how well the patient’s family is following the treatment regimen is also important. Administering eye drops to pediatric patients is often difficult, and parents may not be successful in getting the drops into the eye or the child may be crying them out. Finally, medication toxicity is relatively common, especially with gentamicin, neomycin, and agents that contain preservatives. Signs of medication toxicity include increasing redness and light sensitivity, possibly accompanied by decreased discharge.

Before deciding to change the treatment plan, it is important to recognize that most cases of pediatric conjunctivitis resolve spontaneously without treatment, with approximately 65% of cases resolving after 1 week. The value of initiating treatment after the fifth day of symptoms is questionable; some studies have found that treatment only improves clinical outcomes when initiated during the first 5 days after symptom onset, whereas other research suggests that patients may benefit when treatment is initiated for up to 10 to 12 days.⁵ However, the absence of any improvement in symptoms after several days suggests that either the patient has not been correctly diagnosed or that a different treatment plan is needed.

Deciding on a new treatment plan for a patient who is not responding adequately to topical antibiotic therapy requires first assessing the severity of the patient’s symptoms. If the symptoms are not severe, it may be preferable to allow the infection to resolve spontaneously. More aggressive treatment is required if the patient is immunocompromised or if there is significant corneal involvement, photosensitivity, vision loss, or severe purulence threatening vision or ocular structures. Referral to a pediatric ophthalmologist should also be considered for patients with severe symptoms, vision changes, or coexisting ocular inflammation, as these conditions may progress rapidly. Culture should be considered for severe cases, or for patients who may have more serious infections such as herpes or chlamydia. Empiric treatment should be re-evaluated and matched to the micro-organisms that are most often associated with conjunctivitis, including H influenzae, methicillin-sensitive S aureus (MSSA), and MRSA. A number of antibiotics may be used for a patient with acute conjunctivitis who has not responded to first-line therapy. Gentamicin is 99% sensitive to H influenzae, and 90% sensitive to staphylococcus species.⁶ Patients who have already been treated with gentamicin may be switched to polymyxin B/trimethoprim. Topical sulfonamides may produce a significant stinging sensation and do not provide optimal broad-spectrum coverage, but may be an acceptable option for older children who are less likely to have conjunctivitis associated with H influenzae. Topical sulfonamides are also an option when there is concern that the patient has MRSA. Vancomycin should be reserved for when there is concern for corneal ulceration or presence of MRSA. A culture should always be performed if MRSA is suspected. Older fluoroquinolones are associated with high rates of treatment resistance, whereas newer fluoroquinolones are appropriate for patients with severe infection, when first-line treatment has failed and they still have significant conjunctival discharge

When treating with antibiotics, the prevention of further resistance must be considered. Maintaining an adequate antibiotic concentration is important to reduce the risk of further antibiotic resistance. Long-acting antibiotics should be considered when selecting empiric therapy. A common mistake is to taper the antibiotic dose at the end of therapy (eg, tapering from 4 times daily to twice and then to once per day). Tapering may contribute to antibiotic resistance by decreasing the concentration of antibiotic to a subtherapeutic level. Newer agents should be reserved for severe or nonresponsive cases.

Topical Antibiotics for Conjunctivitis: Clinical Studies

Several studies have examined the treatment of conjunctivitis using a variety of topical antibiotics. Scoper and colleagues reviewed the in vitro potency and in vivo antimicrobial activity in animal model studies of levofloxacin 1.5% vs. moxifloxacin 0.3% and gatifloxacin 0.5% in 9 studies that were published between 2002 and 2008.⁷ In vitro studies demonstrated greater potency against gram-positive organisms with moxifloxacin and gatifloxacin compared with levofloxacin. For gram-negative organisms, the in vitro potencies of the 3 medications were similar. Limitations of this study include a relatively small number of isolates obtained from young children (adults were also included in this study), and the fact that many of the subjects had micro-organisms other than H influenzae, which is the most common pathogen typically encountered in pediatric conjunctivitis.

Fluoroquinolone resistance is a significant problem that has developed over the last several decades. In 1991, Liebowitz and colleagues reported the results of 2 randomized clinical trials that compared ciprofloxacin with placebo or tobramycin in 288 patients with culture-confirmed bacterial conjunctivitis.⁸ Ciprofloxacin eradicated or reduced bacterial pathogens in approximately 94% of patients. In a study published in 1997, 257 children under the age of 12 with conjunctivitis were randomized to treatment with ciprofloxacin or tobramycin, and microbiological eradication was observed in 90% of ciprofloxacin-treated cultures.⁹ These authors concluded that ciprofloxacin is safe and effective for the treatment of pediatric patients with acute conjunctivitis.

Over time, however, response rates to ciprofloxacin have decreased. In a 2004 study of patients with conjunctivitis or keratitis who were referred to the Bascom Palmer Eye Institute, the investigators used current and historical data to examine resistance of MSSA to ciprofloxacin between 1991 and 2001.¹⁰ The incidence of ciprofloxacin resistance increased from 8% for patients studied between 1990 and 1995 to 20.7% for patients studied between 1996 and 2001. Resistance of MRSA to ciprofloxacin was noted for 56% of isolates. Levofloxacin resistance was noted for 25.5% of isolates. Gentamicin susceptibility was 99% for MSSA and 86% for MRSA. Although these observations are derived from a broad population of patients with conjunctivitis or keratitis and not specifically from pediatric patients, they show that ciprofloxacin resistance has become an increasingly important problem over the last 2 decades. Resistance of MRSA to fluoroquinolones is a significant issue; a recent study demonstrated that 85% of MRSA isolates were resistant to fluoroquinolones, including the newer 8-methoxy fluoroquinolones, gatifloxacin and moxifloxacin.¹¹

Recently, Cavuoto and colleagues examined resistance to ciprofloxacin and oxacillin using isolates from more than 2,408 eyes of patients who were treated between 1994 and 2003 at the Bascom Palmer Eye Institute.¹² H influenzae was the most commonly identified pathogen among patients younger than 7 years of age. Over the 10-year study period, the proportion of MRSA increased from 4% to 43% of all S aureus isolates, and the resistance of gram-positive organisms to ciprofloxacin and oxacillin increased 3-fold. More than 90% of gram-positive organisms and 93% of gram-negative organisms were sensitive to gentamicin.

Many pediatricians believe that antibiotic resistance only develops in patients who are receiving systemic antibiotic therapy, and that topical eye drops do not cause antibiotic resistance. Kim and colleagues examined patterns of antibiotic resistance using isolates from 48 eyes of adult patients undergoing intravitreal antibiotic injections for choroidal neovascularization. None of the patients received systemic antibiotic therapy.¹³ Coagulase-negative staphylococci were identified in 65% of isolates. These investigators found a surprisingly high rate of antibiotic resistance with topical therapy. Resistance to ofloxacin and levofloxacin was noted for 75% of isolates, 33% were resistant to gatifloxacin, and 37% were resistant to moxifloxacin. These observations suggest that resistance to older and newer fluoroquinolones is common even among patients who are receiving only topical antibiotic therapy. Most coagulase-negative staphylococci isolates were resistant to 3 or more antibiotics (Figure). As with ciprofloxacin and other earlier fluoroquinolones, it now appears that newer fluoroquinolones are susceptible to the same rapid development of resistance. In order to reduce the risk of antibiotic resistance, it is prudent to reserve newer fluoroquinolones for patients who truly need them, including those with ocular infections that have not responded adequately to an earlier course of empiric topical antibiotic therapy.

Summary and Conclusions

Evaluation of a patient with conjunctivitis who has not responded to an initial course of empiric topical therapy should begin with a reconsideration of the diagnosis and a thorough review of the patient’s history and findings upon physical examination. Clinical signs and symptoms such as the type of discharge, unilateral or bilateral eye involvement, vision changes, and corneal involvement all provide important clues to the patient’s diagnosis. A review of the initial treatment selection is important to confirm that the antibiotic is appropriate for the pathogens that are likely to be causing the conjunctivitis based on the patient’s age and clinical findings. In some cases, it may be reasonable to wait for the conjunctivitis to resolve spontaneously, whereas other patients require a modified treatment plan. Drug resistance has become an increasingly common problem over the last 2 decades, and may occur with topical antibiotic treatment of conjunctivitis.

Discussion

Is it logical to conclude that there are 3 primary reasons for which a pediatrician should consider referring a patient with pediatric conjunctivitis: persistence of symptoms for more than 10 to 14 days, photophobia, or a vision problem?

Sean P. Donahue, MD, PhD: Yes, any of those features should be a cause for trepidation. A patient with 2 weeks of crusty discharge does not have acute bacterial conjunctivitis, and the potential for vision loss is always a concern.

Do you have any recommendations for improving treatment compliance when administering eye drops to young children?

Donahue: For small children who are still nursing or taking a bottle, the most effective way to administer eye drops is while they are feeding. When we are taking care of children who underwent pediatric cataract surgery or who have glaucoma, we try to keep them on the bottle or nursing as long as possible. They are usually distracted enough during feeding that it makes it easier to instill drops or patches. Administering eye drops becomes more challenging in the older population. Children do not like the eye drops, the drops may sting, and the experience can be very frightening. Administering the eye drops in a nonthreatening manner is important. Administration from the side may be helpful. You can try to position the child against your chest, or with their head on your shoulder, and bring the drops around from the side so that the experience is less threatening. Administering treatment after the child falls asleep at night or during a daytime nap may also be effective.

Which agents are most likely to cause toxic conjunctivitis?

Donahue: Drug-induced conjunctivitis can occur with any of the eye drops. The one that is most widely recognized is neomycin. Toxic conjunctivitis also occurs with gentamicin in possibly 3% to 5% of cases, and is more common in patients who have been on treatment for longer periods of time. Irritation can occur with any eye drops that have preservatives; thimerosal in particular causes irritation in many patients. The onset of toxicity-associated conjunctivitis is related to a number of changes in clinical presentation. The eyes and eyelids generally become more red, and the discharge changes from a copious green, crusty discharge to thinner and more clear. The patient may also become more sensitive to light. In general, when we see a patient who has been treated with 2 or 3 different eye drops over a period of 14 days and they continue to exhibit significant redness of the eyes, these symptoms usually do not reflect bacterial conjunctivitis.

At what age do you typically begin to see chlamydia as a cause of conjunctivitis?
Is this something you would expect to see in sexually active teenagers?

Donahue: Chlamydia infection is most common among sexually active adolescents, but we do occasionally see it in neonates. Usually, our protocols for neonatal conjunctivitis are to eliminate gonococcal organisms from vaginal flora. Chlamydia is less common, but we see it occasionally. In young children, chlamydia infection is one of the few times I will use erythromycin. Also, although it can be difficult to confront, when we see chlamydial conjunctivitis in a child who is not in the sexually active age group, we do need to be concerned about the potential for abuse.

How would you treat patients with chlamydial infections?

Michael E. Pichichero, MD: Fluoroquinolones are effective in the treatment of chlamydial conjunctivitis.

Are there any important potential concerns about the use of fluoroquinolones in a child who is 2 to 6 months of age?

Donahue: The topical antibiotics we have are not FDA-approved for young children, but many of the medications that we use in ophthalmology are not approved for patients younger than 18 years of age. Although these topical antibiotics are not specifically approved for children younger than 1 year of age, I believe that they are for the most part safe and efficacious.

In your treatment paradigm recommendation, you start with empiric antibiotic therapy, and if that does not work, you rotate between gentamicin and polymyxin B/trimethoprim or you switch to a fluoroquinolone, but you would avoid older fluoroquinolones. Is that correct?

Donahue: Yes. The principal limitation is insurance coverage. An insurance company may only allow 1 fluoroquinolone on formulary, and this may be an obstacle with a newer fluoroquinolone.

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