|Year : 2011 | Volume
| Issue : 3 | Page : 218-222
Antibiotic resistance in ocular bacterial pathogens
Laboratory Services, LVPEI-Network, L V Prasad Eye Institute, Patia, Bhubaneswar, Orissa - 751 024, India
|Date of Submission||18-Jun-2011|
|Date of Acceptance||20-Jun-2011|
|Date of Web Publication||17-Aug-2011|
Laboratory Services, LVPEI-Network, L V Prasad Eye Institute, Patia, Bhubaneswar, Orissa - 751 024
Source of Support: None, Conflict of Interest: None
Bacterial infections of the eye are common and ophthalmologists are spoilt for choice with a variety of antibiotics available in the market. Antibiotics can be administered in the eye by a number of routes; topical, subconjunctival, subtenon and intraocular. Apart from a gamut of eye drops available, ophthalmologists also have the option of preparing fortified eye drops from parenteral formulations, thereby, achieving high concentrations; often much above the minimum inhibitory concentration (MIC), of antibiotics in ocular tissues during therapy. Antibiotic resistance among ocular pathogens is increasing in parallel with the increase seen over the years in bacteria associated with systemic infections. Although it is believed that the rise in resistant ocular bacterial isolates is linked to the rise in resistant systemic pathogens, recent evidence has correlated the emergence of resistant bacteria in the eye to prior topical antibiotic therapy. One would like to believe that either of these contributes to the emergence of resistance to antibiotics among ocular pathogens. Until recently, ocular pathogens resistant to fluoroquinolones have been minimal but the pattern is currently alarming. The new 8-fluoroquinolone on the scene-besifloxacin, is developed exclusively for ophthalmic use and it is hoped that it will escape the selective pressure for resistance because of lack of systemic use. In addition to development of new antibacterial agents, the strategies to halt or control further development of resistant ocular pathogens should always include judicious use of antibiotics in the treatment of human, animal or plant diseases.
Keywords: Antibiotic resistance, bacteria, fluoroquinolones, ocular infections
|How to cite this article:|
Sharma S. Antibiotic resistance in ocular bacterial pathogens. Indian J Med Microbiol 2011;29:218-22
| ~ Introduction|| |
Bacteria are closely associated with the eye forming the microbial flora of the external ocular surface at birth while the inner parts of the eye remain sterile. Several protective mechanisms operate on the eye surface and prevent eye infections; however, a breach in surface epithelium due to trauma or lowering of local or systemic immunity may predispose the eye to bacterial infections. The number and virulence of the invading organisms of course play an important role in launching an infection. Similar to bacterial infections in other parts of the body, a combination of host and agent factors determine the ultimate development of disease. The normal conjunctiva contains several immunological components including immune cells, immunoglobulins, complement system, fibronectin, C-reactive protein, lysozyme, transferring, etc., that play an important defense against bacteria.
Despite the protective shield, the resident bacteria of the conjunctival sac or the environmental bacteria can establish infection and need to be treated with antibiotics. A large repertoire of antibiotics is available in the form of eye drops, ointments and injectable formulations. These are in use since the beginning of the antibiotic era and similar to other infections antibiotic resistance in eye infections is a matter of concern to ophthalmologists, ocular microbiologists and vision scientists. Until recently it was thought that the source of resistant bacteria in eye infections is an outcome of bacteria acquiring resistance during treatment of systemic diseases. However, evidence is accumulating that suggests emergence of resistant bacteria in the eye owing to prior antibiotic therapy of the eye.  In this brief review the current status of antibiotic resistance among bacteria causing eye infections is presented.
Antimicrobial pharmacokinetics in the eye
The surface epithelia of the bulbar conjunctiva and the cornea are relatively impermeable, especially to water soluble agents. A breach in surface epithelium allows the entry of these drugs more effectively in the anterior segment of the eye. However, because of the diffusion barrier across the lens zonule compartment and anterior vitreous, entry of drugs through cornea and conjunctiva does not reach the posterior segment of the eye. Inability of the drugs to reach the posterior segment from the anterior segment is also due to movement of the aqueous from the posterior chamber through the pupil and its drainage into the venous circulation. Barriers of the surface epithelium may be overcome by subconjunctival and subtenon injections.
In a normal eye, there are blood-aqueous and blood-retinal barriers that hinder entry of drugs into the retina and across it into the vitreous. In an inflamed eye on the other hand, the concentrations achieved in the ocular compartments during systemic antibiotic therapy are increased owing to partial breakdown of these barriers. However, parenteral therapy always reaches a lower concentration compared to direct intraocular injection, a favored route of administration of antibiotics in serious intraocular eye infection such as endophthalmitis.
Bacteria associated with eye infections
Bacteria are known to cause ocular surface infections such as conjunctivitis, scleritis, keratitis, blepharitis, canaliculitis, dacryocystitis; deeper infections such as orbital cellulitis, preseptal cellulitis, necrotizing fascitis and intraocular infections such as uveitis, endophthalmitis, etc. [Table 1] lists the types of bacteria that are reportedly associated with eye infections.
Antibacterial drugs used in the eye and their mode of action
Treatment of eye infections involves topical instillation, subconjunctival injection, subtenon injection or intraocular injection of antibiotics. Parenteral antibiotics in a minute dose can often be used for injections based on their toxicity to ocular tissues. While eye drops are available in appropriate concentration, fortified drops at higher concentrations are often used to achieve higher concentration in ocular tissues. Fortified topical drops are generally prepared aseptically from parenteral drugs diluted in artificial tear preparations to avoid contamination. Antibacterial drugs that are currently in use, and their mode of action, are listed in [Table 2].
|Table 2: Common antibacterial drugs used to treat eye infections and their mode of action|
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Antibiotic resistance among ocular pathogens is increasing in parallel with the increase of resistance in other systemic pathogens. The factors contributing to development of drug resistance among ocular isolates include overuse of antibiotics for systemic infection as well as overuse of topical antibiotics in the eye.  Other contributory factors may be improper dosing regimen, misuse of antibiotics for viral and other nonbacterial infections, extended duration of therapy and not in the least globalization and migration.
With no certain way to determine antibiotic concentration in ocular tissues during topical therapy, eye tissue-specific breakpoints are not yet available to use for determining the susceptibility of ocular isolates to antibiotics. Susceptibility of bacterial isolates from the eye is evaluated using Clinical and Laboratory Standards Institute (CLSI) procedures based on breakpoints derived from serum/plasma/cerebrospinal fluid levels of antibiotics. These systemic breakpoints may have limited predictive value for ocular isolates. On one hand, the concentration of antibiotic reached in external ocular tissue on topical therapy may exceed the minimum inhibitory concentration for common ocular isolates. , On the other hand, the high concentration of the topical antibiotic in ocular tissue may be rapidly diluted through tearing. Therefore, studies are needed to resolve the dynamics of breakpoint versus antibiotic resistance of ocular isolates and its relationship to clinical response. Many researchers agree that in the current format the use of systemic breakpoints to determine susceptibility of ocular isolates remains useful to track trends of susceptibility and compare data.  The study by Parmar et al provides justification to using CLSI methods for testing ocular isolates.  They found comparable results between keratitis cure rates and in vitro susceptibility results in patients treated with topical gatifloxacin and ciprofloxacin. 
Various classes of topical antibiotics that have been used for the treatment of bacterial conjunctivitis include aminoglycosides, polymyxin B combinations, macrolides and more recently fluoroquinolones. Chloramphenicol, though used in India, is banned in the USA for its rare but serious side effect of bone marrow depression. Resistance to gentamicin, tobramycin and polymyxin B was reported in large number of Streptococcus pneumoniae isolates from acute conjunctivitis in children.  While no resistance was seen in S. pneumoniae between 1989 and 1992 to gentamicin and tobramycin, it rose to 42.3 and 56% for the former in the year 1997 and 2000 and 43.6 and 46% for the latter in the respective years.  In contrast, virtually no resistance has been reported in Haemophilus influenzae, a common cause of bacterial conjunctivitis, against aminoglycosides and polymyxin B. In a 10-year (1994-2003) study of bacaterial conjunctivitis conducted in South Florida, USA, 5.4% isolates of Staphylococcus aureus were found resistant to gentamicin. Moderate to very high resistance to azithromycin has been reported for H. influenzae, S. pneumoniae, S. aureus and S. epidermidis isolates from bacterial conjunctivitis.
The prevalence of methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE) in conjunctivitis varies in different studies. One study has shown an increase in MRSA in bacterial conjunctivitis from 4.4% (1994-5) to 42.9% (2002-3).  High resistance rates in MRSA to a large number of antibiotics has been reported including fluoroquinolones.  Sight-threatening conditions such as keratitis and endophthalmitis are commonly caused by cogulase-negative Staphylococcus (CoNS). Until 2003 approximately 19% of CoNS were reported to be resistant to gentamicin and 2% were resistant to gatifloxacin. , However, by the year 2006, nearly 11% of CoNS from normal ocular surface and 53% of CoNS from endophthalmitis were reported to be resistant to gatifloxacin.  All ciprofloxacin resistant MRSA and MRSE demonstrate resistance to 4 th generation fluoroquinolones such as gatifloxacin and moxifloxacin but not to besifloxacin, the latest among the fluoroquinolones.  Besifloxacin is the first fluoroquinolone that has been developed only for ophthalmic use and it is expected to escape development of resistance among bacteria owing to absence of prior systemic use. Assessment of potential resistance to besifloxacin can only be done by comparison of MICs as there are no CLSI-established breakpoints to determine susceptibility or resistance. In vitro activity of besifloxacin has been compared with fluoroquinolones and azithromycin for bacterial conjunctivitis isolates and this new drug has shown lower MICs compared to all others. 
The choice of antibiotics to treat Pseudomonas infections of the eye is challenging to the ophthalmologist, considering the increase in prevalence of antibiotic resistant isolates. As early as 1986, it was shown that most strains of P. aeruginosa isolated from contact lens associated corneal ulcers were resistant to ampicillin, cephalothin, neomycin and tetracyclins.  In the last decade topical ciprofloxacin has replaced aminoglycosides and is virtually the drug of choice for the treatment of P. aeruginosa keratitis. Because of its broad spectrum activity ciprofloxacin is used for monotherapy in bacterial keratitis and is often used for preoperative prophylaxis. Probably owing to overuse, the percentage of P. aeruginosa isolates showing resistance to ciprofloxacin have increased from less than 1% in 1991-4 to 4% in 1995-8 and 29 % in 2002-3. ,, It is not uncommon to come across multidrug resistant P. aeruginosa isolates, especially in patients with keratitis and endophthalmitis. , Topical or intraocular piperacilin/tazobactum have been used for the treatment of such cases. ,
Fewer studies have reported the level of antibiotic resistance among Enterobacteriaceae isolated from eye infections. In one study, the resistance to gatifloxacin was 3.4%, to ofloxacin and ciprofloxacin was 5.1% and to gentamicin was 8.5%.  Although resistance of Proteus species is a matter of concern in systemic infections ocular isolates of this species are reported to retain their susceptibility to aminoglycosides and ceftazidime. 
Not much is known about the potential use of linezolid to treat ocular infections. In a patient with vancomycin resistant Enterococcus faecium endophthalmitis, intravenous and oral linezolid led to resolution of infection.  No adverse reaction to linezolid was noticed. Reports of vancomycin resistant Enterococcus (VRE) ocular infections are rare. In a series of 26 cases of E. faecalis endophthalmitis, between 1995 and 2007 from India, there was one VRE.  Rau et al reported one among 15 cases of E. faecalis keratitis that had intermediate susceptibility to vancomycin.  Apart from linezolid, another drug that has been approved by US FDA for the treatment of VRE infections is quinupristin/dalphopristin. This drug is a synthetic, parenteral, streptogramin antibiotic that acts by sequential ribosomal binding to inhibit protein synthesis in susceptible bacteria. It is effective in vitro against E. faecium (not E. faecalis), MRSA, S. pneumoniae and other Gram-positive cocci.  Daptomycin and tigecycline are two other antibiotics that are effective in vitro against enterococcal isolates.
Reduced susceptibility of S. aureus to vancomycin was first noted in Japan in 1997 in systemic infections.  Using disc diffusion susceptibility testing method there are some reports of vancomycin resistant S. aureus (VRSA) ocular infections; ,, however, till date there are no confirmed VRSA ocular isolates.
Non-tuberculous mycobacteria and Nocardia species are rare but important causes of keratitis and scleritis. The drug of choice for treatment of these infections is generally amikacin and all ocular isolates are reported to be susceptible to this drug. , Closely classified with these organisms are non-diphtherial Corynebactrium species which have recently been recognized as ocular pathogens. Species of the genus Corynebacterium other than C. diphtheriae form a part of normal flora of the skin and conjunctiva. A particular species, C. macginleyi, has been reported to be associated with conjunctivitis and keratitis. , In these reports the organism was described to be sensitive to a large number of antibiotics including fluoroquinolones. However, in 2008, 11 out of 16 C. macginleyi isolates, derived from conjunctival swabs of patients with conjunctivitis or patients going for surgery, were found to be resistant to three fluoroquinolones) ciprofloxacin, norfloxacin, levofloxacin) by E test. 
Similar to the well-known phenomenon of rebound susceptibility of Salmonella More Details typhi to chloramphenicol after discontinuation of the drug for the treatment of typhoid, a decline in S. pneumoniae resistance to azithromycin was reported after the oral administration of the drug for the treatment of trachoma was discontinued.  This observation suggests that in the absence of continued antibiotic pressure the resistant organism is at a disadvantage for survival and the phenomenon is encouraging in the context of development and sustenance of antibiotic resistance among bacteria.
In conclusion, antibiotic resistance among ocular pathogens is a challenge to the ophthalmologists. Resistance to most groups of antibiotics is increasing with resultant decline in the effectiveness of many commonly used topical antibiotics. It remains to be seen whether newer antibiotics such as besifloxacin will outlive the others before it, especially because of lack of systemic use. A strategy including judicious use of antibiotics in humans, animals and agriculture fields along with development of new products having low-resistance potential is required to end or at least reign in the current trend.
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[Table 1], [Table 2]
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