Increasing bacterial resistance to ophthalmic antibiotics

Antibiotics were considered “miracle” drugs when they were introduced in the middle of the 20th century. However, bacterial resistance soon emerged, and today resistance continues to increase at an alarming rate. Organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis and vancomycin-resistant S aureus and Enterococci, as well as the emergence of multidrug-resistant bacteria, have created a serious challenge to the treatment of infectious diseases. Surveillance studies by research groups such as Tracking Resistance in the U.S. Today (TRUST), Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT), the international SENTRY Antimicrobial Surveillance Program, and Active Bacterial Core have documented the increase in bacterial resistance. Some of these studies, such as PROTEKT, have also attempted to track the mechanisms underlying resistance, the understanding of which may help meet this health care challenge.1-4
Bacteria have multiple mechanisms for antibiotic resistance. One common mechanism is acquisition of -lactamases, enzymes that hydrolyze β-lactam antibiotics (e.g., penicillin), and which have evolved rapidly and spread among bacteria. Fortunately, many of the adaptive changes in β-lactamases are exclusive to one type of target, allowing one antibiotic to be effective if another is destroyed by these enzymes. Bacteria are also capable of altering the target site of an antibiotic. For example, mutations in bacterial ribosomes, the targets of aminoglycoside (e.g., streptomycin) and macrolide (e.g., erythromycin) antibiotics can reduce the ability of the antibiotic to bind the ribosomal subunit and inhibit protein synthesis. For fluoroquinolone antibiotics, the major targets are DNA gyrase and topoisomerase IV, enzymes that primarily affect DNA replication.5 Mutation of one or both enzymes confers resistance by preventing the binding of a fluoroquinolone to the enzyme.
Bacterial resistance is increasing in parallel to both systemic and topical antibiotics, including antibiotics for ocular infections such as bacterial conjunctivitis. Table 1 lists the bacteria most commonly found in three types of ocular infections.

Increasing resistance to ophthalmic antibiotics

Bacterial resistance to ophthalmic antibiotics has been well documented worldwide for more than a decade. Studies conducted in the 1990s in North and South America, India, Italy, and Japan found resistance among isolates from ocular infections among staphylococci (resistant to oxacillin, gentamicin, tobramycin, and erythromycin),
S pneumoniae (penicillin resistant), coagulase-negative staphylococci (CoNS) (methicillin resistant), and H influenzae (-lactamase positive).11-15
More recent studies support the continued trend of rising rates of bacterial resistance to ocular infections from resistant bacteria. Cavuoto and colleagues reported an increase in MRSA isolates from pediatric patients with bacterial conjunctivitis from 4.4% in 1994 to 42.9% in 2003. In addition, there was an increase in resistance among S aureus isolates to ciprofloxacin, erythromycin, and oxacillin.6Miller et al likewise reported an increase in MRSA in ocular infections and demonstrated that the MRSA was often community acquired (CA-MRSA).16 Specifically, she reported an increase in the proportion of CA-MRSA among ocular isolates from 18.3% in 2000 to 29.1% in 2005. A study of pediatric cases of bacterial conjunctivitis found that 29% of H influenzae isolates were -lactamase positive, and 60% of S pneumoniae isolates were penicillin resistant.17
An increase in multidrug resistance among ocular pathogens has also been reported. For instance, a survey of ocular bacterial pathogens in 10 European countries found high rates of resistance to ciprofloxacin, ofloxacin, and gatifloxacin among MRSA isolates.18 In this study, 31.3% of CoNS isolates were resistant to the older fluoroquinolones ciprofloxacin and ofloxacin, compared with only 2.1% to the newer fluoroquinolone gatifloxacin. Multidrug resistance was also observed by the Ocular TRUST program, which evaluates the annual change of in vitro antimicrobial susceptibilities in national samples of ocular isolates. The most recently published report from the Ocular TRUST program indicates that 75% to 85% of MRSA isolates studied during the study were resistant to ciprofloxacin, levofloxacin, and moxifloxacin (Table 2).19 More recently, ciprofloxacin resistance was found in 65.4% of MRSA isolates and in 45.9% of methicillin-resistant S epidermidis isolates among recent clinical isolates from three bacterial conjunctivitis studies.20The observation of an increase in multidrug resistance among ocular isolates underscores the need for the development of new ophthalmic anti-infectives. More importantly, the resistance to fluoroquinolones, a commonly prescribed treatment for ocular surface infections, among ocular pathogens resistant to other drugs is of great concern


S aureus, Staphylococcus aureus; S epidermidis, Staphylococcus epidermidis; S pneumoniae, Streptococcus pneumoniae; H Influenzae, Haemophilus influenzae; CoNS, Coagulase-negative staphylococci; S viridans, Streptococcus viridans; P aeruginosa, Pseudomonas aeruginosa; S marcescens, Serratia marcescens; P mirabilis, Proteus mirabilis; P acnes, Propionibacterium acnes; N meningitidis, Neisseria meningitidis


Understanding resistance to fluoroquinolones

The mechanism of action of antibiotics for killing bacteria provides a key for combating bacterial resistance.21 Older fluoroquinolones such as ofloxacin and ciprofloxacin, while targeting both topoisomerase IV and DNA gyrase, preferentially target topoisomerase IV of gram-positive bacteria, while the newer fluoroquinolones moxifloxacin and gatifloxacin target both of those enzymes. Therefore, for high-level resistance to develop to newer fluoroquinolones, bacteria will have to generate resistant mutations in both enzymes. The newer fluoroquinolones also achieve high tissue concentrations relative to their minimum inhibitory concentration (MIC) values, which are generally two- to three-fold lower than the MICs of older fluoroquinolones.21 Nevertheless, as indicated above, there have been reports of ocular pathogen resistance to the new fluoroquinolones gatifloxacin and moxifloxacin.
Conclusion
It remains important to understand the causes of bacterial resistance to topical antibiotics for ocular infections in order to devise strategies to minimize the development of further resistance. With regard to the topical fluoroquinolones—often the clinician’s preferred treatment choice for ocular surface infections—strategies need to be considered to improve the activity of currently available fluoroquinolones, and new fluoroquinolones need to be considered.



MSSA, methicillin-sensitive S aureus; MRSA, methicillin-resistant S aureus

References

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ABOUT THE AUTHOR

Marguerite B. McDonald, M.D., is clinical professor of ophthalmology, New York University School of Medicine, New York; adjunct clinical professor of ophthalmology, Tulane University Health Sciences Center, New Orleans; and in practice at Ophthalmic Consultants of Long Island, Lynbrook, N.Y. She can be contacted at 516-593-7709 or margueritemcdonaldmd@aol.com.