Special Report

Refining Treatment for Bacterial Conjunctivitis

By Terrence P. O'Brien, MD and Onsiri Thanathanee, MD

Bacterial conjunctivitis is an inflammatory condition of the conjunctiva that results from infection due to one or more bacterial species. It is commonly seen in primary care clinics, estimated at approximately 1% of all consultation cases. In addition, acute bacterial conjunctivitis can present to either ophthalmologists or general practitioners. One recent study in the United States estimates a crude incidence rate of 135 cases per 10,000 annually.¹

Staphylococcus aureus and Haemophilus influenzae have been proposed as the most common etiology in adult bacterial conjunctivitis, while Haemophilus influenzae and Streptococcus pneumoniae have been noted as most frequent causes in children.^2,3 The most frequently recovered anaerobes from infectious conjunctivitis patients are Peptostreptococcus spp. and Propionibacterum acnes.^4,5

Due to the benign and self-limited nature in most cases of bacterial conjunctivitis, microbiological workup may not be necessary in nonsevere conjunctivitis involving healthy individuals. However, it should be considered in some instances such as neonatal conjunctivitis, suspected infectious conjunctivitis in immunocompromised patients, refractory cases and severe acute conjunctivitis. Laboratory testing for pathogen identification may be required to aid antimicrobial agent(s) selection in some cases. In general practice, empirical treatment with topical ophthalmic broad-spectrum antibiotic formulations has become a prevailing practice among ophthalmologists and general practitioners.

Treatment of Bacterial Conjunctivitis Remains Controversial

Treatment with empirical topical antibiotics for bacterial conjunctivitis is controversial. Though some authors recommend not using antibiotics, delaying the use of antibiotics together with supportive management are presumed to be the reasonable treatment in primary care clinics. The problems related to burden of illness—such as transmission rate to susceptible individuals and indirect costs associated with lost productivity—should be considered.^1,6 The empiric treatment with broad-spectrum topical antibacterial agent has been proven for shortening the course of disease, diminishing serious complications and reducing the risk of contagion. However, the potential for development of drug resistance has been a cause for alarm and the economic burden as demonstrated by base-case analysis estimated the total direct and indirect cost of treating patients with bacterial conjunctivitis in the United States to be $589 million annually.^1,7,8

Therapeutic options can be divided into two categories, namely, broad-spectrum topical antibiotic treatment for non-severe cases involving healthy individuals, or culture-directed with specific topical antibacterial agent treatment, based on recovered organism for complicated cases.⁹

Figure 1. Haemophilus influenzae conjunctivitis with purulent discharge.

Selection of Topical Agents

To clarify the diagnosis, history-taking and physical examination are occasionally insufficient thus laboratory testing may play a vital role in identification of specific pathogen(s). Conjunctival sampling is performed to obtain material for cultures and/or smears with vital staining. Special handling and transport media are required for detection of anaerobic pathogens which are usually recovered in combination with aerobic bacteria.⁴ In addition, PCR and serodiagnostic testing of tears and serum by microimmunofluorescence has been described for the diagnosis of chlamydial conjunctivitis.

Specific antibiotics were recommended historically, such as gentamicin or tobramycin for gram-negative rod infections and erythromycin, bacitracin, polymyxin B/trimethoprim or neomycin/polymyxin for gram-positive infections.¹⁰ In addition, bacitracin ointment provides activity against anaerobes such as Porphyromonas and Peptostreptococcus spp and erythromycin ointment covers Prevotella, Porphyromonas and Clostridium spp. Chloramphenicol has reasonable activity against anaerobes, including pathogens causing conjunctivitis. However, due to the safety concern about rare but potentially serious side effects of chloramphenicol, it is no longer widely used as a first-line agent in therapy for conjunctivitis. Anaerobic bacteria may be resistant to sulfonamides, polymyxin B and aminoglycosides.⁴

Figure 2. Severe hyperpurulent conjunctivitis with consecutive keratolysis and perforation due to Neisseria gonorrhea.

Empiric Topical Antibacterial Agents

In clinical practice, the precise causative organism may not be identified promptly in most cases. Therefore, treatment with broad-spectrum antibiotics is recommended. Since anaerobic infection is generally discovered with aerobic organisms, the spectrum of antimicrobial agents should cover both. Chloramphenicol eye drops are the drug of choice for treatment of infectious conjunctivitis in many countries. Though chloramphenicol is inexpensive and effective in uncomplicated cases, it is bacteriostatic in mechanism and nondose-related adverse effects, including bone marrow hyoplasia and aplastic anemia, have been reported.¹¹ With the aminoglycoside class, data on in vitro susceptibility of gram-positive and gram-negative bacterial isolates to tobramycin and gentamicin demonstrated that the resistance rate is relatively low, though there is a steady increase in resistance of gram-negative pathogens to aminoglycosides. Therefore, tobramycin and gentamicin are still both reasonably good therapeutic options for bacterial conjunctivitis treatment.¹² However, aminoglycosides have a relatively low therapeutic to toxicity ratio for conjunctival and corneal epithelium.

Despite the advantage of less frequent application, which may improve compliance, clinical trials of treatment of conjunctivitis have demonstrated that the cure rates as measured by median duration of symptoms were similar with fusidic acid therapy as compared to a placebo group.¹³ An ophthalmic formulation of azithromycin 1% is approved based on its effectiveness for the treatment of acute bacterial conjunctivitis. Clinical trials demonstrated superior bacteriological cure with azithromycin treatment compared with treatment with tobramycin.^14,15 The fluoroquinolone class has a high broad-spectrum, bactericidal activity against many aerobic gram-negative or gram-positive pathogens, including anaerobic isolates. Due to its widespread availability and usage, drug resistance has significantly increased to second-generation agents, including ciprofloxacin and ofloxacin with ocular isolates. Levofloxacin has a similar profile and is also approved for treatment of bacterial conjunctivitis treatment, yet resistance patterns are increasing similar to that observed for ciprofloxacin and ofloxacin.¹⁶ Ophthalmic formulations of advanced generation 8-methoxy-fluoroquinolones, including gatifloxacin and moxifloxacin, have been developed and approved for the indication of treatment for acute bacterial conjunctivitis. Recent in vitro studies of bacterial isolates from patients with acute conjunctivitis demonstrated better efficacy than earlier generations of fluoroquinolones against gram-positive bacteria. From meta-analysis, moxifloxacin had more efficacy and less drop-out rates compared to ofloxacin or polymyxin/trimethoprim.^17,18 Furthermore, moxifloxacin also covers anaerobic bacteria superior to activity observed with gatifloxacin.¹⁹ Besifloxacin ophthalmic suspension is the latest chlorofluoroquinolone approved for treating bacterial conjunctivitis has demonstrated clinical efficacy and safety in treatment of adult patients with culture-confirmed acute bacterial conjunctivitis from both aerobic and anaerobic infection.^20,21 From in vitro susceptibility testing, besifloxacin is proven to be effective in methicillin- and ciprofroxacin-resistant strains, especially Staphylococcus aureus. Furthermore, from randomized multicenter clinical trials, besi-floxacin was also shown to be safe and effective in the treatment of bacterial conjunctivitis in pediatric patients aged 1-17 years.²²

With ocular penetration of fluoroquinolones, drug concentrations in tear fluid and conjunctiva following topical ocular administration in the rabbit model were evaluated for besifloxacin, moxifloxacin and gatifloxacin. Besifloxacin achieved the highest concentration in either tear or conjunctival tissue compared with moxifloxacin and gatifloxacin after topical dosing. Even if the AUC0-24/MIC90 ratio of all three fluoroquinolones is sufficiently high to provide anti-bacterial activity against common gram-positive and gram-negative isolates, only besifloxacin achieved the target ratio needed for bactericidal activity against ciprofloxacin-resistant strains of MRSE (methicillin-resistant Staphylococcus epidermidis) and MRSA (methicillin-resistant Staphylococcus aureus) in tear fluid.^23,24 In contrast, in a study of fluoroquinolone penetration in human conjunctival tissue, moxifloxacin demonstrated the highest conjunctival concentration among the three drugs including besifloxacin and gatifloxacin.²⁵

MRSA

A significant increase in the percentage of antibiotic resistance among conjunctival bacterial isolates was observed in the past decade particularly MRSA. From a 10-year review of New York Eye and Ear Infirmary, high levels of resistance to tetracycline, erythromycin and trimethoprim/sulfa-methoxazole (TMP/SMZ) were demonstrated in conjunctival bacterial isolates including Staphylococcus aureus.¹² Fluoroquinolones have been widely used based on previously observed low level resistance to gatifloxacin and moxifloxacin in all bacterial isolates. However, recent trends suggest increasing resistance to 8-methoxyfluoro-quinolones among ocular isolates, indicating that caution should be exercised with empirically chosen agents for initial therapy of suspected MRSA.⁸

Interestingly, there was no resistance of any gram-positive pathogens to vancomycin, which makes it an ideal antibiotic for MRSA. However, it is advisable to limit vancomycin use to MRSA to minimize the risk of resistance.¹²

Conclusions

Identification of pathogens prior to initiation of therapy is rarely established in general clinical practice to specifically guide treatment of bacterial conjunctivitis. As a result, empirical therapy with topical antibacterial agents is considered in uncomplicated bacterial conjunctivitis. For cases of acute suspected infectious conjunctivitis judged to be clinically severe, obtaining material for microbial culture and susceptibility testing is required for organism identification and optimal antibacterial selection.

Though significant benefits from treatment with topical antibiotics have been reported, undesired consequences—particularly drug resistance and high costs—may occur with inappropriate use. Patient education for compliance to medication use and physician instruction together with proper antibacterial agent(s) adjustment may have a beneficial role in the treatment of bacterial conjunctivitis.

References

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	Onsiri Thanathanee, MD, is an ophthalmologist in the Department of Ophthalmology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. She can be reached at onsirit@yahoo.com.
	Terrence P. O'Brien, MD, is professor of Ophthalmology, Charlotte Breyer Rodgers Distinguished Chair in Ophthalmology, Co-Director Ocular Microbiology Laboratory, Bascom Palmer Eye Institute of the Palm Beaches, University of Miami, Miller School of Medicine. He can be reached at tobrien@med.miami.edu