Update Ocular Anti-infectives

Today's approaches to diagnosing and treating eye infection.

By Terrence P. O'Brien, MD

Release Date: April, 2012
Expiration Date: April 30, 2013

ESTIMATED TIME TO COMPLETE THE ACTIVITY:

2.0 hour(s)

TARGET AUDIENCE:

This educational activity is intended for general ophthalmologists interested in the management, care and treatment of patients with ocular infection.

ACTIVITY PURPOSE:

Educate physicians on the latest information related to ocular infections, including current and upcoming methods of treatment as well as antibiotic resistance.

STATEMENT OF NEED:

Many factors can lead to ocular infections and managing the infected and/or infl amed eye can present a diagnostic and therapeutic challenge to healthcare professionals. This program will discuss the diagnosis and treatment of several types of eye infection and will include a detailed discussion on advances in ocular antiinfective agents.

The growing phenomenon of bacterial resistance is real, and in addition to the development of new antibacterial agents, antibiotic resistance in ocular infections may be reduced by following similar strategies used to minimize antimicrobial resistance in systemic infections. Keeping up to date on trends in antibiotic treatment, including emerging antibiotic resistance, remains a fundamental need among ophthalmologists, as does education on antiviral treatment, including a particular look at pharmacokinetics/pharmacodynamics. This program will also address knowledge gaps in these areas.

LEARNING OBJECTIVES:

After completing this educational activity, participants should be better able to:

  • Describe the different attributes of acute bacterial conjunctivitis and acute viral keratoconjunctivitis.
  • Explain trends in antibiotic treatment, including recently approved drugs.
  • Engage in discussions related to the emergence and spread of antibiotic resistance.
  • Discuss the evolution of ocular antiviral agents, including those recently approved.

DESIRED RESULT/OUTCOME:

Physicians know and apply current strategies in diagnosing and treating the infected and/or infl amed eye to improve patient care.

FACULTY:

David G. Hwang, MD, is Professor and Co-Director of the Cornea Service and Director of the Refractive Surgery Service at the University of California, San Francisco. He is also Director of the UCSF Laser Vision Center and Associate of the Francis I. Proctor Foundation at UCSF. Marguerite B. McDonald, MD, is a Clinical Professor of Ophthalmology at New York University in Manhattan and an Adjunct Clinical Professor of Ophthalmology at Tulane University Medical School in New Orleans. Terrence P. O'Brien, MD, is Professor of Ophthalmology at the University of Miami and is a member of faculty at the Bascom Palmer Eye Institute Campus in the Palm Beaches. Jay S. Pepose, MD, PhD, is Medical Director of Pepose Vision Institute and President of the Midwest Eye Research Institute.

ACCREDITATION STATEMENT:

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Bert M. Glaser National Retina Institute (NRI) and Review of Ophthalmology®/Jobson. NRI is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENT:

The NRI designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credit(s) . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

SCIENTIFIC INTEGRITY:

NRI requires that all continuing medical education (CME) information is based on the application of research fi ndings and the implementation of evidence-based medicine. NRI promotes balance, objectivity and absence of bias in its content. All persons in position to control the content of this activity must disclose any relevant fi nancial relationships. NRI has mechanisms in place to identify and resolve all confl icts of interest prior to an educational activity being delivered to the learners.

NRI is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality of heal care and not a specifi c proprietary business interest of a commercial interest.

PEER REVIEW:

This activity was peer-reviewed for relevance, accuracy of content and balance of presentation by NRI.

DISCLOSURE:

The following individuals have disclosed relevant fi nancial relationships with commercial interests: David G. Hwang, MD, PACS: (C) Inspire; (L) Bausch + Lomb. Marguerite McDonald, MD: (C)(L) Bausch + Lomb. Terrence P. O'Brien, MD: (C) Abbott, Alcon, Allergan, AMO, Bausch + Lomb, Merck; (L) Bausch + Lomb. Jay S. Pepose, MD, PhD: (C)(S)(L) Bausch + Lomb.

The following individuals have disclosed that there are no relevant fi nancial relationships with any commercial interests: Leticia Hall, Jan Beiting and Karen Rodemich.

(C) Consultant/Advisor/Speakers Bureau: Consultant fee, paid advisory boards or fees for attending a meeting (for the past year); (E) Employee: Employed by a commercial entity; (L) Lecture/ Lecture Fees: Lecture fees (honoraria), travel fees or reimbursements when speaking at the invitation of a commercial entity (for the past one year); (O) Equity Owner: Equity ownership/stock options of publicly or privately traded fi rms (excluding mutual funds) with manufacturers of commercial ophthalmic products or services; (P) Patents/Royalty: Patents and/or royalties that might be viewed as creating a potential confl ict of interest; (S) Grant Support: Grant support for the past one year (all sources).

METHOD OF PARTICIPATION:

There are no fees for participating and receiving CME credit for this activity. During the period of April 2012 and April 30, 2013, participants must:

  1. read the learning objectives and faculty disclosures;
  2. study the educational activity;
  3. complete the post-test by recording the best answer to each question;
  4. complete the evaluation form; and
  5. mail it with the answer key (not necessary for online format).

MEDIA:

Monograph/Print Supplement and Internet

EVALUATION METHOD:

Post-Test

OFF-LABELED USE:

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. NRI and Review of Ophthalmology® do not recommend the use of any agent outside of the labeled indications.

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of the patient's conditions and possible contraindications on dangers in use, review of any applicable manufacturer's product information and comparison with recommendations of other authorities.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of NRI and Review of Ophthalmology® . Please refer to the offi cial prescribing information for each product for discussion of approved indications, contraindications and warnings.

CONTACT INFORMATION:

Any questions/problems with registration, CME certifi cate, etc., can be directed to rcombs@jhihealth.com.


The Battle Against Ocular Infection

A review of the differential diagnosis and treatment options for microbial conjunctivitis.
Terrence P. O'Brien, MD

The principal causes of acute conjunctivitis include microbial (both bacterial and viral), allergic and even toxic etiologies. Differentiating among these diagnoses may seem rather straightforward, but the percentages of correct diagnoses based on clinical examination alone are not as high as we might like to think. Cases having other than an obviously bacterial purulent discharge may involve other subtler signs and symptoms that make accurate diagnosis quite challenging. To complicate matters, most patients with conjunctivitis initially present to a pediatrician, family practitioner, or walk-in urgent care clinic. The ophthalmologist may see only complex non-responsive cases that have been misdiagnosed and mistreated elsewhere.

Before making a diagnosis or, certainly, before prescribing an antibiotic, clinicians should ask the basic question, "Is the conjunctiva infected?" Consider the signs and routes of infection. Most are exogenous, with the organism introduced via hand-to-eye contact or, less commonly, by airborne fomites. Endogenous causes, especially in adults, are less likely. Children may more commonly have an ocular infection that is spread from the contiguous paranasal sinuses.

Even among the microbial causes of conjunctivitis, there is significant overlap of clinical symptoms and signs between the bacterial and viral causes of "pink eye." Any one of many bacterial species may be implicated, as may the highly contagious Adenovirus and less common (but more serious) viruses such as Herpes simplex virus (HSV) and even sexually transmitted organisms, including Chlamydia.

Viral Conjunctivitis

Adenovirus not only affects the conjunctiva but also causes a progressive, consecutive keratitis; it is really keratoconjunctivitis. The ocular reaction to viral particles often results in sub-epithelial infiltrates that affect vision and can persist for some time, even after resolution of the conjunctivitis.



The classic corneal sign of herpes simplex virus type 1 (HSV-1) epithelial keratitis is the dendritic lesion. In the past, HSV keratitis was a challenging condition to treat in the United States, because of lack of access to topical acyclovir, long considered standard of care in other parts of the world. Until recently, our only topical option was trifluorothymidine (TFT, Viroptic, Pfizer), dosed 9 times daily. Because of the toxicity of this drug, however, many clinicians opted instead for treatment with oral antivirals such as acyclovir, valacyclovir or famciclovir.



These oral agents have now been frequently replaced in the treatment of ocular epithelial HSV by a new topical antiviral, ganciclovir 0.15% gel (Zirgan, Bausch + Lomb). Ganciclovir inhibits not only HSV-1 and HSV-2, but EpsteinBarr virus, herpes zoster, cytomegalovirus, and HHV6. There is also some evidence that it has activity against adenovirus.

Bacterial Conjunctivitis

The most common cause of microbial conjunctivitis is bacterial. The Gram-positive pathogens most commonly implicated in acute bacterial conjunctivitis are Staphylococcus aureus and Streptococcus pneumoniae. The most common Gram-negative pathogens are Neisseria gonorrhoeae and Hemophilus influenza.



In non-severe cases, most clinicians will treat empirically with a topical ophthlamic antibacterial agent. Although obtaining material for culture is still advisable, this is rarely performed in practice for non-severe conjunctivitis unless the infection does not respond to the initial treatment.

Severe conjunctivitis is characterized by acute onset in one or both eyes, marked lid edema and conjunctival hyperemia, copious purulent discharge, and other distinctive signs. The principle pathogens one might expect to be implicated include N. gonorrhoeae, H. influenza, Streptococcus pyrogenes, and S. aureus. But treatment must be targeted to the specific pathogen, so one should obtain material for both smears for Gram and other vital stains and conjunctival cultures to be certain. N. gonorrhoeae, for example, is a very serious pathogen that can penetrate intact epithelium and lead to perforation of the cornea in a matter of hours if not treated aggressively. Severe bacterial conjunctivitis is often treated with both topically and systemically administered antibacterial agents.



Antibiotic Selection

A number of topical antibiotic agents are available for the treatment of bacterial conjunctivitis. Bacitracin has a spectrum of activity that is similar to penicillin, with reasonably good activity against Staphylococci and Streptococci. In fact, it is the most effective drug we have for treatment of Staphylococcus blepharitis. It rarely produces hypersensitivity. However, because bacitracin is not very soluble and only comes in an ointment form that may be vision-blurring, it is infrequently used to treat conjunctivitis in adults.

The macrolide erythromycin is well tolerated, with very low incidence of local side effects. It is considered quite effective in the treatment of blepharitis and Chlamydial conjunctivitis. However, it is recently less frequently used because of the high frequency of resistance among other ocular isolates. Other macrolides, such as clarithromycin and azithromycin, may still offer useful activity due to high and sustained achievable tissue concentrations.

Polymyxin B acts on the cell wall of Gramnegative bacteria; trimethoprim blocks dihydrofolic acid reductase to inhibit DNA replication of Gram-positive bacteria. By combining these two drugs in an agent such as Polytrim (Allergan), one has a dual agent that can be effective against both Gram-negative and Gram-positive organisms. However, there is increasing resistance especially rapidly achievable with exposure to trimethoprim.

Chloramphenicol is widely used outside the United States, including in the U.K. It is a bacteriostatic, rather than bactericidal, agent. However, due to rare associations with severe bone marrow toxicity, this agent is rarely used in the United States for medico-legal reasons.

Sulfacetamide is an old antibiotic, first introduced in the 1940s. Interestingly, it is still reasonably effective against the bacteria that commonly cause conjunctivitis. Unfortunately, sulfa allergy is relatively common, and for a small percentage of those with severe allergy to sulfa, it can lead to devastating reactions such as Stevens-Johnson syndrome. For this reason, it is not widely used. The fluoroquinolone family of antibiotics, which includes ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin, has gained wide popularity over the past two decades due to its bactericidal activity against a broad spectrum of Gram-positive and Gram-negative organisms. Each generation of this class of antibiotic agents has offered increased bacterial coverage and better pharmacokinetics.

The latest fluoroquinolone agent to be introduced for ophthalmic (but not systemic) use is the new chemical entity besifloxacin. Its mechanism of action—inhibition of DNA gyrase and topoisomerase IV—is consistent with that of other fluoroquinolones, but besifloxacin has a chlorine substituent at the C8 position rather than the methoxy molecule common to gatifloxacin and moxifloxacin, making it a chlorofluoroquinolone.

Antibiotic Resistance

Although many people think that antibiotic resistance is only pertinent to systemic care, we are seeing a rather frightening increase in resistant ocular isolates, as well.



The latest results from the Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study, which was designed to monitor antibiotic susceptibility trends in ocular isolates, indicate that 39 percent of S. aureus ocular isolates were methicillin resistant (MRSA) and 38 percent were fluoroquinolone resistant. Among the coagulase-negative Staphylococci (CoNS) isolates from ocular infections, 53 percent were MRSA and 43 percent were fluoroquinolone resistant.1

This and other reports from Haas and colleagues indicate that even powerful fluoroquinolones like moxifloxacin and gatifloxacin have largely lost activity against resistant organisms.1,2 So far, besifloxacin appears to have a very different susceptibility profile, with MIC that are comparable to vancomycin.1 We do know there is a tendency for cross-resistance to develop among fluoroquinolones, so only time will tell if besifloxacin is able to maintain its current advantages in terms of activity against resistant organisms.

Certainly, the development of antibiotic resistance to fluoroquinolones is a real phenomenon that ophthalmologists should pay attention to and devise strategies to limit. Such strategies include using topical antibiotics only for appropriate acute indications (i.e., not to treat viral or allergic conjunctivitis) and shortterm surgical prophylaxis; dosing appropriately and never tapering or stopping treatment abruptly; and using the most potent fluoroquinolones that will have high concentration levels in the target tissues and achieve microbial killing without survivorship.

In selecting antibiotics, clinicians should "know the enemy" and all the possible agents for treatment. We must be aware of the prevailing susceptibility data and carefully follow changing patterns of resistance, including regional trends. Finally, we must analyze data carefully and objectively, preferring data from randomized, controlled, clinical trials over invitro studies.

References

  1. Haas W, Pillar CM, Torres M, et al. Am J Ophthalmol. 2011;152(4):567-74. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study.
  2. Haas W, Gearinger LS, Usner DW, et al. Integrated analysis of three bacterial conjunctivitis trials of besifloxacin ophthalmic suspension, 0.6%: etiology of bacterial conjunctivitis and antibacterial susceptibility profile. Clin Ophthalmol. 2011;5:1369-79.

 

Antimicrobial Resistance in Ophthalmology

A review of the research on the mechanisms and clinical implications of methicillin and fluoroquinolone resistance by ocular pathogens. David G. Hwang, MD, FACS

Two major resistance-related trends are occurring with ophthalmic antimicrobials. The first is the development of fluoroquinolone resistance by Gram-positive bacteria, Pseudomonas aeruginosa, and atypical mycobacteria. The second is an increase in community-associated methicillin-resistant Staphylococcus aureus (MRSA). These organisms are also typically highly resistant to fluoroquinolones.

The Surveillance Network (TSN), a nationwide surveillance database with participating centers in nearly all 50 states, showed that the proportion of MRSA phenotypes in serious S. aureus ocular infections increased from 2000 to 2005.1 TSN also reported close concordance between the rates of methicillin resistance and fluoroquinolone resistance in U.S. ocular S. aureus isolates. Between 2004 and 2006, for example, only 32 percent of ocular MRSA isolates were susceptible to ciprofloxacin, 29 percent to gatifloxacin, 27 percent to levofloxacin, and 27 percent to moxifloxacin. Methicillin-susceptible strains were far more likely to be susceptible to fluoroquinolones, with 90 percent to 92 percent being susceptible.1

In Ocular TRUST 2, a surveillance effort focused specifically on ocular isolates, participating centers submitted 155 ocular S. aureus isolates for in vitro susceptibility testing. More than half (54 percent) of the S. aureus isolates were methicillin-resistant (MRSA).2 This was a departure from earlier Ocular TRUST reports in which the predominant phenotype was methicillinsusceptible S. aureus (MSSA). Polymyxin B and penicillin were relatively inactive against MSSA (<20 percent susceptibility), while azithromycin was moderately active (62 percent susceptibility). Tobramycin and trimethoprim showed the greatest in vitro activity against MSSA (>95 percent susceptibility). The fluoroquinolones ciprofloxacin, gatifloxacin, levofloxacin, and moxifloxacin were indistinguishable in terms of MSSA susceptibility, all showing excellent activity against methicillin-susceptible strains (89 percent to 93 percent susceptibility).2

Consistent with other reports, MRSA strains tested in Ocular TRUST 2 were multidrugresistant pathogens, with high-level resistance to fluoroquinolones, azithromycin, penicillin, polymyxin B, and tobramycin.2 Of the antibiotics evaluated, only trimethoprim retained high rates of MRSA susceptibility (95 percent). Susceptibility profiles did not differ significantly among the fluoroquinolones tested, regardless of S. aureus phenotype or fluoroquinolone generation. S. aureus was more susceptible to fluoroquinolones than to the macrolide azithromycin.

Among the coagulase-negative staphylococci (CNS) isolates tested in Ocular TRUST 2, 57 percent were methicillin-susceptible; the most common CNS species was Staphylococcus epidermidis (n=51; 55 percent).3 The methicillin-resistant phenotype (MRSE) was less susceptible to all antimicrobials compared to the methicillin-susceptible phenotype (MSSE). CNS susceptibility profiles were the same for all the tested fluoroquinolones, again regardless of generation. And, as with S. aureus, the CNS isolates were more susceptible to fluoroquinolones than to the macrolide azithromycin.

A parallel effort to conduct a national antibiotic resistance surveillance of ocular isolates was initiated in 2009 with ARMOR (Antibiotic Resistance Monitoring of Ocular Microorganisms).4 In this study, 200 S. aureus and 144 CNS ocular isolates were collected from 34 centers across the United States. Of the S. aureus isolates, 39 percent were fluoroquinolone-resistant, 39 percent methicillin-resistant, and 31 percent resistant to both. Of the CNS isolates, 43 percent were fluoroquinolone resistant, 53 percent methicillin-resistant, and 36 percent resistant to both. From these data, we can conclude that resistance to fluoroquinolones, including that to all of the newest fluoroquinolones, is increasing; this rise appears to be directly correlated with an increase in the proportion of infections due to MRSA.

In the United States, MRSA now accounts for >30 percent of all serious S. aureus ocular infections and the incidence is rising annually. More than 80 percent of MRSA strains are resistant to all fluoroquinolones.

The Role of Antibiotic Exposure

In ophthalmology, we have tended to blame the development of resistance on the overuse of antibiotics in agriculture and systemic care. Indeed, a recent meta-analysis confirms that prior systemic use of fluoroquinolones triples an individual's subsequent risk of a MRSA infection.5 Some have argued that topical ophthalmic antimicrobial use is highly unlikely to contribute to the development of antimicrobial resistance due to the fact that ophthalmic antibiotics are delivered in such high, localized concentrations to the target ocular tissues. Yet a number of lines of evidence point to the direct role that prior topical ophthalmic antimicrobial use may play in contributing to the subsequent development of resistance of bacteria on the ocular surface.

Specifically, a number of recently published studies have indicated that exposure to topical fluoroquinolones increases the risk of development of fluoroquinolone-resistance (FQ-R) in ocular isolates recovered both from asymptomatic patients without infection as well as from patients who subsequently develop ocular infections.6-9 For example, there is a 2.8x increased risk of finding the fluoroquinolone resistance phenotype in S. aureus isolated from patients with ocular infection who had used a topical fluoroquinolone within the previous 90 days.6 Most CNS strains (67 percent to 85 percent) recovered after repeated fluoroquinolone dosing (as prophylaxis during a regimen of intravitreal injections for macular degeneration) were FQ-R.7 Forty percent of CNS strains recovered after 4 weeks of tapered fluoroquinolones were highly FQ-R.8

Other researchers have found no direct correlation between the likelihood of developing resistance and the number of treatment episodes with topical ophthalmic fluoroquinolones, but they did identify a high baseline of FQ-R organisms in the nasal and conjunctival flora of patients studied.9 Thus, while a single prior episode of topical fluoroquinolone exposure may be sufficient to result in the development of fluoroquinolone resistance, it is unclear whether repeated exposure may further increase the rates of resistance development.

Several lines of evidence, therefore, now point to a correlation between topical ophthalmic fluoroquinolone use and the subsequent isolation of fluoroquinolone-resistant ocular isolates. Prolonged topical use of ophthalmic fluoroquinolones, especially when underdosed, can rapidly result in development of high-level fluoroquinolone resistance.8 One possible explanation, therefore, for the development of ocular resistance after the use of topical fluoroquinolones is that with real-world prescribing patterns and/or actual patient compliance, dosing frequency is insufficient to sustain maximal tissue concentrations of fluoroquinolone. Achieved tissue concentrations may actually be at or below the minimum inhibitory concentration (MIC) on a prolonged or repeated basis.

Venezia used population analysis profiling to determine the resistance index of fluoroquinolone-susceptible, mecA-positive heteroresistant S. aureus, defined as the proportion of CFU/mL expressing resistance to oxacillin in the presence of below-the-MIC levels of fluoroquinolones. This was expressed as the ratio of the number of colonies growing on agar with oxacillin to the number of colonies on antibiotic-free agar (control). The increase in resistant CFU/mL was greater than 10-fold for ciprofloxacin, 3400-fold for moxifloxacin, 220-fold for levofloxacin, and 49-fold for gatifloxacin compared to control.10 In other words, it appears that fluoroquinolones promote the development of resistance by selectively killing more susceptible S. aureus subpopulations, enriching the surviving subpopulation for strains that are more resistant to both oxacillin and fluoroquinolones.

The probability of recovering antibioticresistant mutations increases exponentially as the fluoroquinolone concentration decreases, even at antibiotic levels above the MIC. So, for example, at 4xMIC levels, rates of resistance of S. aureus to ofloxacin and ciprofloxacin are <10-9 , but they climb more than one thousandfold to ~10-6 as drug concentrations approach 1xMIC.11

Two key enzymes are involved in bacterial DNA replication: DNA gyrase and topoisomerase IV. They facilitate the unwinding and reformation of DNA supercoils during replication, and sufficient disruption of this process can be lethal. Newer fluoroquinolones have been hailed for their dual action against both these enzymes, which makes it more difficult for resistance to develop. Fluoroquinolones disrupt the fidelity of DNA replication and induce the development of random mutations which, if sufficiently burdensome, can result in death of the bacterium.

However, lesser degrees of exposure can induce more subtle mutations, some of which will confer antimicrobial resistance. These antibiotic-resistant strains will be enriched disproportionately in the population of bacteria that may survive fluoroquinolone exposure, since they confer a survival advantage. Furthermore, subsequent and repeated sublethal fluoroquinolone exposure (such as that resulting from infrequent or intermittent dosing) will favor the accumulation of additional mutations conferring resistance, leading to progressive enrichment of the surviving population with strains with multiple mutations that confer progressively higher levels of fluoroquinolone resistance.11

The clinical implications of this are enormous. Antibiotic prophylaxis and treatment strategies must now take into account the possibility of both fluoroquinolone and methicillin resistance and should also consider the critical importance of maintaining optimal dosing to not only treat infections, but to sustain sufficiently high levels of drug at the target tissue to forestall the development of resistance.

Dealing with Resistance

It is important to keep in mind that in vitro resistance does not necessarily equate to in vivo resistance. Supposedly resistant organisms may actually respond to an antibiotic in clinical use and "susceptible" organisms may not, but higher MICs do tend to predict a poorer treatment response. Furthermore, a lower ratio of achieved fluoroquinolone concentration to bacterial MIC predicts reduced clinical efficacy.12,13

Newer fluoroquinolones do seem to offer better clinical efficacy than their older counterparts, but this differential activity may be dependent on the specific susceptibility characteristics of the strain in question, as well as the inoculum. In an experimental model of bacterial keratitis studied by Dajcs and colleagues, all fluoroquinolones tested (ciprofloxacin, levofloxacin and moxifloxacin) performed equally well against fluoroquinolone-susceptible S. aureus strains. Against moderately quinolone-resistant strains, newer fluoroquinolones such as levofloxacin and moxifloxacin performed better than ciprofloxacin, but only in early infection, when the bacterial burden was relatively low. In more established infection, all fluoroquinolones were equally ineffective. Thus, the differential benefit of newer fluoroquinolones against fluoroquino lone-resistant, methicillin resistant S. aureus may be more evident in prophylaxis situations or in treatment of very mild or early infections, rather than severe S. aureus infections with a high established bacterial load.14



For prophylaxis, one would expect levofloxacin, gatifloxacin, moxifloxacin, and besifloxacin to have higher activity than the older fluoroquinolones, ciprofloxacin and ofloxacin. Prophylaxis is not the same as treatment, however. In the Dajcs prophylaxis model, eradication occurred only very early in the infection, less than 10 hours post inoculation.14 So even these newer fluoroquinolones may not be reliable in the treatment of an established infection. Even for prophylaxis, one should opt for higher concentration formulations and always choose fluoroquinolones with lower MICs against MRSA.

The newest member of the fluoroquinolone family, besifloxacin, has been shown to have enhanced in vitro activity compared to other fluoroquinolones against one strain of FQ-R MRSA and the mec Type II subtype of MRSA.15,16 Additional in vitro and in vivo data are needed to confirm these findings and understand their potential clinical implications.

The big question that most people have is whether the newer fluoroquinolones can be used against MRSA or FQ-R S. aureus. Going by the MICs alone, the efficacy trend for these agents against MRSA and MRSE is as follows: besifloxacin > moxifloxacin > gatifloxacin > levofloxacin > ofloxacin.

But even the newer fluoroquinolones have reduced efficacy against MRSA and FQ-R S. aureus compared to their efficacy against MSSA. In both clinical and experimental models, a higher MIC predicts lower efficacy.13 A good clinical response is not precluded, even with higher MICs, but treatment failure or a suboptimal response is more likely, depending on the specific strain and the severity of the infection.

I would stress that none of the available fluoroquinolones can currently be considered a reliable first-line choice for treatment of established MRSA keratitis. The potential role of the newest fluoroquinolones for prophylaxis of MRSA infection is still an open question and deserves further study. Unfortunately, due to fluoroquinolone cross-resistance, even newer fluoroquinolones have reduced efficacy against strains resistant to older fluoroquinolones.

A number of clinical strategies should be employed to limit the development of antimicrobial resistance. First, these agents should be used for the appropriate indications, including treatment of acute (not chronic) infections and short-term surgical prophylaxis. Older agents should be used for mild or self-limited cases. When using a fluoroquinolone, it is critical to dose appropriately. Treatment should not be extended beyond the appropriate duration, nor should it be tapered or stopped abruptly. Finally, one should optimize the antibiotic selection and pharmacodynamic parameters to each case.

Newer fluoroquinolones offer lower de novo resistance potential with Gram-positive organisms.17,18 In the presence of gatifloxacin, for example, about 1 in 108 MRSA cells will mutate to fluoroquinolone resistance and survive, whereas in the presence of levofloxacin the rate of resistant mutations is 12-fold greater, and almost 400-fold greater for ciprofloxacin. A similar result is seen for Streptococcus pneumoniae: appearance of fluoroquinolone resistance is 1000-fold more frequent in the presence of ciprofloxacin than gatifloxacin.

In discussing antimicrobials, we often talk about MIC, but the mutant prevention concentration (MPC) is another important concept. The MPC is the concentration at which first step in vitro mutational resistance is prevented (<10-10 ). For fluoroquinolones used against Gram-positive organisms, the MPC is about 4xMIC. One can predict that resistant mutants will be selected when drug levels are between the MIC and the MPC. Dosing that sustains fluoroquinolone levels at or above the MPC is ideal because it may significantly reduce the propensity for de novo development of resistance.

References

  1. Asbell PA, Sahm DF, Shaw M, et al. Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000 to 2005. J Cataract Refract Surg. 2008;34(5):814-8.
  2. Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol. 2008 Jun;145(6):951-958.
  3. McDonnell PJ, Sahm DF. Longitudinal nationwide surveillance of antimicrobial susceptibility in ocular isolates (Ocular TRUST 2). Presented at the American Academy of Ophthalmology annual meeting, New Orleans, November 10-13, 2008; Poster PO052.
  4. Haas W et al. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance in Ocular Microorganisms (ARMOR) 2009 Surveillance Study. Am J Ophthalmol. 2011;152(4):567-74.
  5. Tacconelli E. Does antibiotic exposure increase the risk of MRSA isolation? A systematic review and meta-analysis. J Antimicrob Chemother. 2008;61:28.
  6. Fintelmann RE, Hoskins EN, Lietman TM, et al. Topical fluoroquinolone use as a risk factor for in vitro fluoroquinolone resistance in ocular cultures. Arch Ophthalmol. 2011;129:399-402.
  7. Kim SJ, Toma HS. Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections. Ophthalmol. 2011;118:1358-63.
  8. Hwang DG. Fluoroquinolone resistance in ophthalmology and the potential role for newer ophthalmic fluoroquinolones. Surv Ophthalmol. 2004;49:S79-83.
  9. Alabaiad CR, Miller D, Schiffman JC, Davis JL. Antimicrobial resistance profiles of ocular and nasal flora in patients undergoing intravitreal injections. Am J Ophthalmol. 2011;152(6):999-1004.
  10. Venezia RA, Domaracki BE, Evans AM, et al. Selection of high-level oxacillin resistance in heteroresistant Staphylococcus aureus by fluoroquinolone exposure. J Antimicrob Chemother. 2001;48:375-81.
  11. Bui DP, Dang SB, Hwang DG. Effect of ciprofloxacin concentration on mutational resistance rates in S. aureus. Invest Ophthalmol Vis Sci. 1995;36(4):S1058.
  12. Wilhelmus KR, Abshire RL, Schlech BA. Influence of fluoroquinolone susceptibility on the therapeutic response of fluoroquinolone-treated bacterial keratitis. Arch Ophthalmol. 2003;121:1229–33.
  13. Wilhelmus KR. Evaluation and prediction of fluoroquinolone pharmacodynamics in bacterial keratitis. J Ocul Pharmacol Ther. 2003;19(5):493-9.
  14. Dajcs JJ, Thibodeaux BA, Marquart ME, et al. Effectiveness of ciprofloxacin, levofloxacin, or moxifloxacin for treatment of experimental Staphylococcus aureus keratitis. Antimicrob Agents Chemother. 2004;48:1948-52.
  15. Haas W, Pillar CM, Hesje CK, et al. Bactericidal activity of besifloxacin against staphylococci, Streptococcus pneumoniae and Haemophilus influenzae. J Antimicrob Chemother. 2010;65:1441-7.
  16. Hesje CK, Sanfilippo CM, Haas W, Morris TW. Molecular epidemiology of methicillin-resistant and methicillin-susceptible Staphylococcus aureus isolated from the eye. Curr Eye Res. 2011;36:94-102.
  17. Fung-Tomc J, Gradelski E, Huczko E, et al. Activity of gatifloxacin against strains resistant to ofloxacin and ciprofloxacin and its ability to select for less susceptible bacterial variants. Int J Antimicrob Agents. 2001;18:77-80.
  18. Fukuda H, Kishii R, Takei M, Hosaka M. Contribution of the 8-methoxy group of gatifloxacin to resistance selectivity, target preference, and antibacterial activity against Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45:1649-53.

 

Evaluation of Ophthalmic Antibiotic Efficacy

The latest agent in the fluoroquinolone family may provide increased activity against resistant strains of the pathogens that cause bacterial conjunctivitis. Marguerite B. McDonald, MD, FACS

The fluoroquinolone family of antibiotics has served ophthalmology well for a number of years, but as resistance to established antimicrobials develops, the search for newer agents continues. In evaluating new antimicrobial agents, one must consider both tissue concentration and potency. Higher tissue concentrations will produce a better kill rate, as will a reduction in the minimum inhibitory concentration (MIC) required to kill a given pathogen.

Antibiotic Concentration and Potency

Inhibitory concentrations are typically and its MICs against each species may be quite Comparative MIC data for these and other expressed in terms of the MIC (the concentration necessary to fully inhibit growth of ≥50 percent of at least 6 independent isolates) and the MIC, the concentration necessary to fully inhibit growth of ≥90 percent of at least 10 independent isolates. MIC profiles are both species and drug-specific. That is, drug A will have a different MIC for each bacterial species, and its MICs against each species may be quite different from those of drug B or C.



The minimum bactericidal concentration (MBC) is the concentration at which the drug successfully kills ≥99.9 percent of bacterial cells, a 3-log kill. The MBC may be several times the MIC. It is desirable to achieve the MBC to fully eradicate bacteria and prevent mutations. Reports that consider only one part of this equation may be misleading. In a recently published, randomized, parallel-group comparison of conjunctival drug concentrations in healthy volunteers, 108 subjects were randomized to receive one drop each of either besifloxacin 0.6%, gatifloxacin 0.3%, or moxifloxacin 0.5%. The conjunctiva was sampled at 15 and 30 minutes, and 2, 6, 12, and 24 hours after dosing. The group with the highest area under the concentration curve (AUC) and the group receiving moxifloxacin.1

Comparative MIC data for these and other antibiotics, however, tells a slightly different story. When the MICs of 200 ocular Staphylococcus aureus isolates were analyzed in the 2009 Antibiotic Resistance Monitoring of Ocular Microorganisms (ARMOR) Study, the lowest MIC50s were those of vancomycin and besifloxacin, each with a MIC50 of 1, compared to 8 for moxifloxacin, and 256 or higher for ciprofloxacin and the non-fluoroquinolones.2

The most comprehensive predictor of antibiotic efficacy is the inhibitory quotient (IQ), which combines measures of potency with the concentration of the drug in the relevanttissue. The IQ is the Cmax of a given drug, divided by its MIC90. When we compare the inhibitory quotients of the newest fluoroquinolones against the S. aureus ocular isolates in the ARMOR study, besifloxacin has an IQ of 2.3, and moxifloxacin an IQ of 1.3. Although besifloxacin achieves lower tissue concentrations, it also has a lower MIC90, resulting in a higher IQ.

Ideally, one would like to see antibiotics achieve high concentrations not only in the conjunctiva, but in the aqueous humor, as well. Drug developers target a ratio of Cmax to MIC90 (or IQ) of 10 at 60 minutes after instillation when developing fluoroquinolones.



In a recent parallel-group study, 105 patients undergoing routine cataract surgery were randomized to receive one drop of besifloxacin 0.6%, gatifloxacin 0.3% or moxifloxacin 0.5% one hour prior to surgery. Aqueous humor samples were collected just prior to cataract extraction. The concentration of the drugs at 60 minutes was 0.135 for besifloxacin, 0.668 for moxifloxacin, and 0.125 for gatifloxacin.3 Consistent with other reports, the concentration of moxifloxacin was 5-fold higher than the other two drugs. Both besifloxacin and moxifloxacin achieved an aqueous humor concentration at 60 minutes that was above their MIC90. None of the fluoroquinolones reached the IQ of 10 that would be predictive of clinical efficacy against methicillinand fluoroquinolone-susceptible S. aureus and Staphylococcus epidermidis. However, these results were from a single drop; with aggressive repeat dosing it should be possible to increase the aqueous humor concentrations.

Understanding Kill Speed

There is also great confusion about the role of the preservative benzalkonium chloride (BAK) in bacterial eradication. When eradication rates for two fluoroquinolones (gatifloxacin and moxifloxacin) are compared in vitro, some studies indicate that gatifloxacin with BAK is much more effective at eradicating MRSA than moxifloxacin without BAK. However, in vehicle controlled bacterial conjunctivitis trials, BAKcontaining vehicles consistently underperform active drugs. In vitro, BAK tends to enhance speed kills results, but since the preservative is rapidly cleared from human tears, the active drug is the most important determinant of speed-kill curve in vivo.4

For more rigorous and clinically valid results, speed of bacterial killing should be measured using physiologically relevant concentrations of active drug, adjusted for relative MIC differences. This ensures that results are not skewed by potency. With this methodology, Haas reports that besifloxacin kills fluoroquinolone-resistant MRSA faster than gatifloxacin or moxifloxacin.5 A similar kill-rate pattern is seen against S. epidermidis. All 3 fluoroquinolones were tested at a concentration that was 4-fold higher than their MIC90. BAK, of course, kills even more rapidly, as it is designed to do in the bottle to maintain sterility—but remember that it cannot maintain the same concentration in human tears.

The Newest Fluoroquinolone

The data on besifloxacin, a new chemical entity fluoroquinolone, are quite interesting. Like other fluoroquinolones, besifloxacin inhibits both DNA gyrase and topoisomerase IV, but a unique combination of substituents at the C7 and C8 positions of the fluoroquinolone core structure provide a different antimicrobial profile.

Besifloxacin is available commercially as a 0.6% sterileophthalmic suspension, at a concentration of 6 mg/mL, with 5 mL in a 7.5 mL bottle. Indicated for the treatment of bacterial conjunctivitis caused by susceptible organisms, it is prescribed as a 7-day course of therapy, dosed three times daily. It has been shown to be bactericidal, with MBCs generally within one dilution of MICs.

For fluoroquinolone-resistant isolates of the four most prevalent species that cause bacterial conjunctivitis (H. influenzae, S. pneumoniae, S. aureus and S. epidermidis), the concentration of besifloxacin in the tear fi lm of healthy human subjects 8 hours after instillation of a single drop remains above levels that are rapidly bactericidal. Even 24 hours after administration of a single drop, the concentration of besifloxacin in tears is higher than or equivalent to those of previous ophthalmic fluoroquinolones. Most importantly, it is sustained above the MIC values observed for 97.4 percent of all the bacterial pathogens isolated during besifloxacin clinical efficacy trials.6

Several human clinical trials to test the efficacy of besifloxacin for clinical treatment of bacterial conjunctivitis have been conducted. Two compare the drug to placebo,7,8 while the third compares besifloxacin to moxifloxacin.9 In all pooled data, there were 1,192 subjects (ages 1-98) receiving besifloxacin, 616 vehicle, and 579 moxifloxacin.

In subjects with culture-confirmed bacterial conjunctivitis, clinical resolution (based on ocular discharge and bulbar conjunctival injection) was achieved at Day 5 in 45.2 percent of eyes treated with besifloxacin versus 33 percent of eyes treated with vehicle.7 Although microbial eradication does not always coincide with clinical outcomes, 91.5 percent of bacteria were eradicated in the eyes treated with besifloxacin, vs. 59.7 percent of the vehicle-treated eyes.7 There were fewer adverse events with besifloxacin (9.2 percent) compared to vehicle (13.9 percent).7 Besifloxacin and moxifloxacin had a similar cumulative frequency of adverse ocular events (12 percent and 14 percent, respectively).9



Besifloxacin offers promise as a novel, broad-spectrum fluoroquinolone with potent activity against prevalent ocular pathogens, including a subset of multi-drug resistant pathogens. Low rates of spontaneous resistance development have been seen in nonclinical studies, but we must be cognizant of the potential for fluoroquinolone cross-resistance.

Both pathogens and antimicrobials continue to evolve. Because of this dynamic, ophthalmologists should carefully evaluate an antimicrobial's clinical efficacy. Knowledge of antibiotic concentration and potency, speed of bacterial killing, and bactericidal activity against the most common and/or dangerous pathogens is critical for effective antibiotic selection.

References

  1. Torkildsen G, Proksch JW, Shapiro A, et al. Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after topical ocular administration. Clin Ophthalmol. 2010;4:331-41.
  2. Haas W, Pillar CM, Torres M, et al. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance in Ocular Microorganisms (ARMOR) 2009 Surveillance Study. Am J Ophthalmol. 2011;152:567-74.
  3. Donnenfeld ED, Comstock TL, Proksch JW. Human aqueous humor concentrations of besifloxacin, moxifloxacin, and gatifloxacin after topical application. J Cataract Refract Surg. 2011;37:1082-9.
  4. Friedlander MH, Breshears D, Amoozgar B, et al. The dilution of benzalkonium chloride (BAK) in the tear film. Adv Ther. 2006;23:835-41.
  5. Haas W, Pillar CM, Hesje CK, et al. In vitro time-kill experiments with besifloxacin, moxifloxacin, and gatifloxacin in the absence and presence of benzalkonium chloride. J Antimicrob Chemother. 2011;66:840-4.
  6. Proksh JW Granvil CP, Siou-Mermet R, et al. Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans. J Ocul Pharmacol Ther. 2009;25(4):335-44.
  7. Tepedino ME, Heller WH, Usner DW, et al. Phase III efficacy and safety study of besifloxacin ophthalmic suspension 0.6% in the treatment of bacterial conjunctivitis. Curr Med Res Opin. 2009;25(5):1159-69.
  8. Karpecki P, Depaolis M, Hunter JA, et al. Besifloxacin ophthalmic suspension 0.6% in patients with bacterial conjunctivitis: A multicenter, prospective, randomized, double-masked, vehicle-controlled, 5-day efficacy and safety study. Clin Ther. 2009;31(3):514-26.
  9. McDonald MB, Protzko EE, Brunner LS, et al. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5% for treating bacterial conjunctivitis. Ophthalmol. 2009;116(9):1615-23.

Treatment of Viral Keratitis

Advances in selective ocular antiviral agents facilitate treatment of herpes simplex dendritic keratitis and may have potential for treating adenoviral keratoconjunctivitis. Jay S. Pepose, MD, PhD

The herpesviridae family of viruses includes herpes simplex virus type 1 (HSV1) and Type 2 (HSV2), as well as varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes virus type 6, 7 and 8 (HHV6, HHV7, HHV8).

Herpes simplex virus forms a symbiotic relationship with its only natural host, humans. It spreads by establishing an acute primary infection that, while often asymptomatic, leads to a dormant period of viral latency in neurons in the trigeminal and autonomic ganglia from which it can be periodically reactivated, causing recrudescent, productive viral replication.1Herpes simplex virus can present in many different forms in the anterior segment. It may cause blepharoconjunctivitis, dendritic or geographic epithelial keratitis, immune or necrotizing stromal keratitis, and inflammatory diseases such as iritis or keratouveitis and disciform endotheliitis. In addition, damage to the nerves and basement membranes can result in meta-herpetic disease.

Herpes Simplex Keratitis

HSV keratitis is the leading cause of corneal blindness, affecting approximately 10 million people worldwide.2By age 5, about 60 percent of the U.S. population shows evidence of infection with the herpes simplex virus. Only 1 percent of those infected go on to develop ocular outbreaks. Still, the numbers are quite large: In 2001, a report of the annual incidence of ocular HSV estimated that 20,000 new primary cases of HSV keratitis were diagnosed each year in the United States, plus 28,000 annual recurrences.3Since the U.S. population has grown from 285 million in 2001 to 312 million, the current annual incidence of new cases of HSV keratitis has risen to 11.8 new cases per 100,000 people or roughly 36,700 new cases per year.4

Large epidemiological studies of ocular HSV suggest that the most common form is epithelial (63 percent), followed by stromal (6 percent) and HSV iritis (4 percent). Cumulative rates of recurrence are 9.6 percent at 1 year, 22.9 percent at 2 years, and 63.2 percent at 3 years.3 Those with a previous case of herpes stromal keratitis have at least a ten-fold increased risk of recurrent stromal keratitis; the risk increases with more episodes.5 A history of non-ocular herpes is not associated with increased recurrence risk, unless concurrent with an ocular lesion.

Recurrences can be triggered by stress, fever, UV exposure (especially to sunlight reflected off snow or water, excimer laser, and collagen crosslinking), recent ocular surgery, trauma, nerve stimulation, and even menstruation. In non-atopic patients, outbreaks are usually unilateral. Herpetic lesions are particularly common in immunocompromised patients (e.g. HIV-infected and organ transplant).

Infectious HSV epithelial keratitis can have one of four different clinical presentations. The earliest lesions are corneal vesicles, cystic lesions of the epithelium that contain active virus but do not produce an epithelial defect. These are minute, raised, clear vesicles that correspond to the vesicular eruptions seen in the skin or mucous membranes. Typically, they coalesce rapidly to form a dendritic ulcer.



The dendritic ulcer is the most common and easily recognized presentation of HSV keratitis. It is a branching, linear lesion with terminal bulbs and swollen epithelial borders that contain active virus. This lesion represents a true ulcer in that it extends through the basement membrane and stains with fluorescein. Devitalized cells at the borders of the lesion will stain with a vital dye such as rose bengal. As the dendritic ulcer expands, it loses its linear shape and can be referred to as a geographic ulcer. The scalloped epithelial borders of this lesion still contain active virus.

Another manifestation of HSV epithelial keratitis is the marginal ulcer, which is essentially a dendritic ulcer in close proximity to the limbus. The limbal blood vessels allow a rapid infiltration of white blood cells, resulting in a stromal infiltrate underlying the ulcer. One will see adjacent limbal injection and peripheral corneal neovascularization. Patients with HSV marginal ulcers are typically more symptomatic than those with central dendritic ulcers due to the intense inflammation associated with the marginal lesion.

Differential Diagnosis of HSV

Even when a lesion appears to be the classic HSV dendritic ulcer, one must consider some other possibilities in the differential diagnosis. These could include recently healed epithelial defects or pseudodendrites (often in a Y-shaped pattern), varicella-zoster, tyrosinemia (Richner-Hanhart syndrome), medicamentosa, Acanthamoeba, Thygeson's superficial punctate keratitis, severe meibomian gland disease, vaccinia, and adenovirus.

In herpes zoster keratitis, the lesions have a coarse, blunted appearance and are more plaque-like than dendritic herpetic ulcers. They also don't have the terminal bulbs that typify herpes simplex. The zoster pseudodendrites are elevated above the corneal surface, so the epithelium may be intact, with no central ulceration. The lesions may stain sparsely with fluorescein or if raised may show negative staining but, unlike herpes simplex, they do not typically stain across their entire length as do true ulcers.



The granular epithelial keratitis caused by Acanthamoeba can mimic herpes simplex dendritic keratitis. Acanthamoeba keratitis is often associated with contact lens wear or the introduction of water to the eye through hot tub use, swimming in lake water, or minor trauma. Patients may develop associated signs and symptoms, such as perineuritis, photophobia, and pain. Here, the differential diagnosis may be aided by confocal microscopy, scraping and staining with Giemsa, periodic acid-Schiff (PAS), calcofluor white or acridine orange stains; and culturing onto non-nutrient agar overlaid with E. coli.

With herpes simplex, one may see significant damage to the nerve and basement membrane that can mimic medicamentosa, or damage to the surface of the cells caused by prolonged use of toxic drugs. Thygeson's superficial punctate keratitis (SPK) can also mimic certain aspects of herpetic disease.

Thygeson's lesions are coarse, round or oval intraepithelial lesions that are scattered across the entire cornea. There may be some edema and stromal haze. The lesions may break through the epithelial surface, with a ragged edge or stellate appearance, but there is no associated conjunctivitis.

Vaccinia was once considered quite rare, but with U.S. Armed Forces now being vaccinated against smallpox due to concerns about biological warfare, it is worth considering this condition in the diagnosis. A vaccinated soldier who rubs the inoculation site and then touches his or her eye could autoinoculate the eye and ocular adnexa and end up with epithelial disease, geographic ulcers, stromal keratitis, or disciform keratitis caused by vaccinia pox virus.

Tyrosinemia Type II is a rare metabolic disorder associated with chromosome 16 defects. Most patients with this condition have mental retardation and hyperkeratotic lesions on their palms and soles. They typically have pseudodendrites in both eyes, ranging from geographic ulcers to actual corneal clouding. These pseudodendrites don't stain fully with fluorescein and do not respond to antiviral therapy. Elevated serum tyrosine levels confirm the diagnosis. Tyrosinemia responds to dietary modifications (i.e., restricting tyrosine and phenylanaline).

Antiviral Therapy for HSV

The first principle of antiviral therapy is to reduce the infectious load through manual debridement and administration of topical antivirals. Topical corticosteroids plus antiviral cover are useful for immunological forms of HSV (marginal keratitis, immune stromal keratitis, endotheliitis, iridocyclitis, trabeculitis). Oral antivirals are indicated for treatment of primary infection, immunocompromised patients, infants, select patients with iridocyclitis who are not responsive to corticosteroids alone, and for prophylaxis in patients with frequent recurrent HSV keratitis (particularly stromal HSV) or post-keratoplasty with a history of HSV.

Several oral antiviral medications are available to the clinician for treatment and prophylaxis of herpetic disease (see Table 1). Dosing may need to be individualized based on a number of factors, such as renal function.



Once an ocular outbreak is under control, prophylaxis is an important component of long-term management. Patients are 9.4 times more likely to have a recurrence of epithelial keratitis, 8.4 times more likely to have a recurrence of stromal keratitis, and 34.5 times more likely to have a recurrence of herpetic blepharitis or conjunctivitis if not being treated prophylactically at the time of the recurrence.4

Six topical ophthalmic antivirals have been or are currently used in the United States and Europe. Firstand second-generation antiviral agents include idoxuridine, iododesoxycytidine, vidarabine and trifluridine (TFT). Most of these have been abandoned by clinicians due to high toxicity. TFT, which was approved in the United States in 1980, is still in use, although toxicity remains a problem. The third-generation antivirals acyclovir and ganciclovir are more selective and less toxic. Of these, only ganciclovir is available in the United States.



Ganciclovir is a synthetic nucleoside analog of 2-deoxyguanosine 9(1,3-dihydroxy-2-propoxymethyl) guanine that inhibits viral replication of HSV1, HSV2, HZV, EBV, CMV, adenovirus and HHV6. The mean effective dose for HSV1 and HSV2 in clinical isolates is 0.23 µg/mL.6,7

Activated ganciclovir inhibits the synthesis of viral DNA in two ways: Competitive inhibition, in which activated ganciclovir directly inhibits viral DNA polymerase, preventing viral replication; and chain termination, in which activated ganciclovir incorporates into viral DNA, preventing further DNA synthesis.8 Ganciclovir penetrates cells infected with the virus, where it is phosphorylated within the cell to ganciclovir monophosphate by a viral encoded thymidine-kinase. The affinity for viral thymidine-kinase allows for specificity in its action. Activation continues due to several cell kinases leading to formulation of ganciclovir triphosphate, which inhibits viral DNA polymerase and incorporates into viral DNA, preventing replication.

Results from three randomized, single-masked, controlled, multicenter clinical trials evaluating ganciclovir ophthalmic gel
0.15% compared to acyclovir ophthalmic ointment 3% in patients with dendritic ulcers demonstrated that ganciclovir treatment results in clinical resolution by Day 7 in 72 percent of cases, compared to 69 percent of cases for acyclovir.9,10 Clinical efficacy is similar, but there are significant differences in adverse effects (see Table 2).9,10 In addition, in contrast to topical thimerosal, ganciclovir offers less frequent dosing, does not require refrigeration, and is preserved with benzalkonium chloride (BAK) rather than thimerosal, which is one of the most allergenic organomercury preservatives.

Adenoviral Keratoconjunctivitis

Adenovirus is the most common ocular viral infection worldwide. There are three major presentations: Follicular conjunctivitis (serotypes 3, 4, 7a); epidemic keratoconjunctivitis (EKC, serotypes 8, 19, 37, 54); and pharyngealconjunctival fever (PCF, serotypes 3, 4, 7a, 11). It is seasonal, occurring most frequently in the summer and winter, and spreads rapidly in crowded environments such as day care, schools and military barracks.

The differential diagnosis for adenoviral keratoconjunctivitis includes HSV, Chlamydia and enterovirus. The common follicular presentation is easily misdiagnosed. Clues in the presentation of herpetic follicular conjunctivitis are accompanying orofacial or lid lesions, especially in atopic individuals. About 20 percent of acute follicular conjunctivitis is herpetic, so one cannot assume that it is always adenovirus. HSV follicular conjunctivitis is less likely than adenovirus to have lymphadenopathy, conjunctival scarring, or pseudomembrane formation. The associated corneal lesions present earlier than with the later-onset adenovirus.



Adenoviral conjunctivitis and keratoconjunctivitis are common and highly contagious. These conditions usually affect both eyes. Patients may have painful conjunctival membranes and palpable preauricular adenotherapy. Adenovirus is non-enveloped, resilient to disinfection and long lasting on fomites.

Diagnosis of adenovirus is greatly facilitated by the Rapid Pathogens Screening (RPS) Adeno Detector Plus immunoassay. This is a simple point-of-care test that takes just 10 minutes to return results, with 93 percent sensitivity and 96 percent specificity. The monoclonal antibodies in the assay detects all 53 adenoviral sero-types, helping the clinician accurately diagnose a specific adenoviral etiology and refrain from ineffective antibiotic treatment.

Treatment options for adenovirus have in the past been limited to supportive therapy (cool compresses, artificial tears) and, in more severe cases, topical corticosteroids. Anecdotal experience suggests 5% povidone-iodine can be effective in eradicating the
virus and preventing sub-epithelial infiltrates, although this has not been tested in formal clinical trials.



Laboratory research has long suggested that ganciclovir is active in vitro against adenovirus.11 In addition, a controlled, randomized double-masked clinical study found that ganciclovir significantly reduced both the duration of disease and the incidence of subepithelial infiltrates in patients with adenovirus kerato-conjunctivitis.12

We are now enrolling patients in a prospective, double-masked, placebo-controlled trial to determine whether topical 0.15% ganciclovir gel can reduce the number of days of adenovirus shedding and limit second eye involvement and spread to family members. In all, 78 adenoviral antigen positive patients within 72 hours of onset of symptoms will be enrolled at 10 to 12 clinical sites. If effective, this treatment would be beneficial in limiting the spread of the adenoviral infection and reducing societal cost due to lost days of work and school.

References

  1. Al-Dujaili LJ, Clerkin PP, Clement C, et al. Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated? Future Microbiology. 2011; 6(8):877-907.
  2. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea. 2001; 20(1):1-13.
  3. Liesegang TJ, Melton LJ, Daly PJ, et al. Epidemiology of ocular herpes simplex. Incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol. 1989;107(8):1155–9.
  4. Young RC, Hodge DO, Liesegang TJ, Baratz KH. Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: the effect of oral antiviral prophylaxis. Arch Ophthalmol. 2010;128(9):1178-83.
  5. Herpetic Eye Disease Study Group. Predictors of recurrent herpes simplex virus keratitis. Cornea. 2001;20(2):123-8.
  6. Inoue Y, Ohashi Y, Shimomura Y, et al. Comparative efficacy of three antiviral drugs in mice herpetic keratitis. Jpn J Ophthalmol. 1989;33:125-31.
  7. Locarnini S, Guo K, Lucas R, Gust I. Inhibition of HBV DNA replication by ganciclovir in patients with AIDS. Lancet. 1989;8673:1225-6.
  8. Castela N, Vermerie N, Chast F, et al. Ganciclovir ophthalmic gel in herpes simplex virus rabbit keratitis: Intraocular penetration and efficacy. J Ocul Pharmacol. 1994;10(2):439-51.
  9. Wilhelmus KR. The treatment of herpes simplex virus epithelial keratitis. Trans Am Ophthalmol Soc. 2000;98:505-32.
  10. Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel (Zirgan 0.15%) in the treatment of herpes simplex keratitis. Cornea. 1997;16:393-9.
  11. Crumpacker CS. Ganciclovir. N Engl J Med. 1996;335(10),721-9.
  12. Tabbara K, Jarade E. Ganciclovir effects in adenoviral keratoconjunctivitis. Abstract 3111, 2001 Association for Research and Vision in Ophthalmology (ARVO).