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At Issue: bacterial resistance
At Issue posed the following question to a panel of experts: "Are doctors seeing a rise in antibiotic resistance?"
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Worldwide Concern
Eduardo C. Alfonso, MD: Antimicrobial resistance is a growing concern worldwide, and ophthalmologists need to be aware of it, although it may rarely involve direct patient care. Since the introduction of antibiotics such as penicillin, micro-organisms have continued to develop methods to protect themselves from these drugs. The answer to this has been to continually develop new strategies and compounds to effectively help the body combat micro-organisms. The fear of reaching a state when micro-organisms have outsmarted us keeps us on our toes and feeds the desire to do the research necessary to win the battle.
We are aware of global resistance patterns such as vancomycin-resistant Staphylococcus aureus and enterococci. These have primarily affected patients in hospital settings. In ophthalmology, we have not seen any significant incidence of clinical resistance. Yet we may contribute to it if we use vancomycin indiscriminately, exposing common organisms such as S. aureus to this potent antibiotic. In our hospital, we have followed Centers for Disease Control guidelines for the use of vancomycin as a strategy to prevent the development of resistant organisms.
We have seen a rise in antimicrobial resistance in the laboratory to the frequently-used fluoroquinolones since their introduction in ophthalmology. This resistance is marked in methicillin-resistant S. aureus. In the past, this resistance has been as high as 65% for ciprofloxacin and ofloxacin and 45% for levofloxacin. One can appreciate the emergence of resistant organisms since the introduction of the fluoroquinolones in ophthalmology. This pattern has also been seen in gram-negative organisms (Figure 1, Figure 2).
Ophthalmologists can select antibiotics that will provide the best coverage for the infection being treated and avoid inappropriate use that may contribute to the emergence of resistant organisms.
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Address the issue now
Noel A. Alpins, MD: The worldwide trend seems to suggest that the incidence of bacterial resistance is currently on the rise. In a specialist refractive surgery setting, I have been fortunate not to have experienced this firsthand. However, as prescribers of antimicrobial agents, all ophthalmologists are in an ideal position to assist in avoiding the development of further resistant strains.
Primarily, bacterial resistance develops secondary to genetic mutation of bacterial genomes, from the misuse or excessive use of antibiotics or a combination of these factors. It is important to ensure an accurate diagnosis of the condition prior to beginning pharmacological therapy. Ideally, when doubt exists and if possible, cultures should be obtained to determine the primary causative pathogen and treatment should be modified accordingly. Armed with the appropriate first-line defense, the offending pathogen, may be selectively destroyed, thus minimizing the duration of treatment.
Of course, not all circumstances allow for such monotherapy, and in a daily practice setting, we will often favor the use of a broad-spectrum antibiotic, commonly a fluoroquinolone. The use of such agents should not be discouraged, but caution should still be exercised by addressing the necessity of the therapy and the dosage regime and duration. For instance, using antibiotics in low doses over a long time frame can promote the emergence of resistant bacterial strains. The opportunity for this to occur seems to be more prevalent within a hospital environment where risk of cross-infection is greater. It is for this reason, too, that patients should be properly instructed to ensure compliance with the therapy initiated.
Undeniably, bacterial resistance is an important issue and will develop more importance as time progresses. By addressing the issue now, the future impact and consequences of bacterial resistance may be delayed or reduced, enabling the development of new antibiotics to keep pace with the emergence of resistant strains.
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Vancomycin in cataract surgery
Steve Arshinoff, MD: It would be very difficult for doctors to personally observe a rise in bacterial resistance to antibiotics, because of the relatively small role infectious disease plays in most ophthalmic practices, except for those who specialize in that field. Nevertheless, epidemiologic reports suggest that bacterial resistance to antibiotics is on the rise, as it has been ever since the invention of penicillin, the first antibiotic.
Is that a cause for panic? I do not believe so. Calm concern for the problem and judicious use of antibiotics is, of course, indicated, but who decides what is judicious? There are always new agents in development by the pharmaceutical companies, and the contest between the rate of new drug development and the rate of bacterial mutagenic response will go on forever.
As a consequence, we should not use our most potent drugs to treat routine cases of conjunctivitis, which are usually viral in origin anyway. But we should also not be reluctant to use our most potent agents when we believe that our patient(s) can really benefit.
In this regard, I have been, and remain, a strong advocate for the use of injections of 1 mg of vancomycin into the capsular bag at the end of cataract surgical procedures. This method is not analagous to placing vancomycin in irrigating solutions or to giving it intravenously to seriously ill patients. In those cases, a considerable volume of the antibiotic gets spread into the environment in low enough concentrations to permit the development of bacterial resistance. When injected into the capsular bag, a tiny dose of the drug is used in high concentration in a confined space, where it remains to be eventually metabolized by the liver prior to environmental dissemination.
Environmental exposure is minimal, and the only way it could induce bacterial resistance in the eye would be if that patient were to develop endophthalmitis, an event I have not observed with intracapsular vancomycin injections in my experience of about 3,000 eyes so far. But I have also observed no cases of postoperative fibrinous iritis and glaucoma, which I occasionally observed before and believe to be due to undetermined infection.
The elimination of observed infection compared to my previous experience has convinced me to give my cataract patients the benefit of this agent, knowing full well the controversy surrounding it and believing that controversy to be based on flawed reasoning that was an extrapolation of experience with systemic administration of antibiotics, with the attendant exposure of the gut flora to the antibiotics, something that does not happen with intracapsular administration.
I believe these issues deserve serious thought by ophthalmologists and that we should do for each patient what we would do for our mothers, if they were the patients.
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No increase
Richard Duffy, MD: No. In my anterior segment practice, I reserve fluoroquinolones for bacterial keratitis and as prophylaxis for intraocular surgery. I do not treat presumed viral or bacterial conjunctivitis with fluoroquinolones as a first-line antibiotic. As such, I have not seen an increase in bacterial resistance to my antibiotic of choice for more serious infections.
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No difference
I. Howard Fine, MD: In our practice, we have not noted any difference with respect to response of infectious clinical syndromes to antibiotics. However, we have made full use of the most recent developments in antibiotic therapy, most notably the fluoroquinolone series. We continue to use in-the- bottle antibiotics, Xalatan 10 mg (latanoprost, Pharmacia) and gentamicin 4 mg per 500 cc at the time of cataract surgery, and we have not had a postoperative endophthalmitis in several years. In addition, use of our own ambulatory surgery center, limited exclusively to eye surgery, is a great advantage because septic cases involving other parts of the body are never brought into the operating room. We are aware of concern regarding increasing resistance of staphylococcal organisms to methicillin but thus far in our practice we have not experienced a change in response to topical or systemic antibiotics.
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MRSA in corneal ulcers
James C. Hays, MD: In the past month, I have seen two apparently unconnected cases of methicillin-resistant S. aureus (MRSA) corneal ulcers. Both occurred in young people tending for relatives with MRSA sepsis. Both of the relatives died, and both of the ulcers were significant. I treated the ulcers with topical vancomycin eye drops 50 mg/cc, given hourly. Both ulcers cleared within about 10 days.
These ulcers were both cultured, and the organisms were resistant to most antibiotics. I do not know if this is just happenstance or whether it represents a real trend. However, I am concerned that it could be a trend.
Prior to these two cases, I had not appreciated any tendency toward increased resistance to antibiotics. I do not routinely culture conjunctivitis, so my impression is based on corneal ulcer treatment.
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Clinically relevant resistance emerging
Kenneth R. Kenyon, MD: The real question at issue is not bacterial resistance to antibiotics as defined by laboratory sensitivity testing but rather as defined by clinical response to therapy. Indeed, regarding the management of ocular surface infections as we considered many years ago, the ability to deliver massive concentrations of antibiotic directly to the site of a corneal ulceration, for example, renders most bacteria clinically “sensitive” despite in vitro evidence of resistance by standard microbiological testing.
The ability to deliver, for example, ofloxacin at concentrations of 3,000 µg/mL by topical application is nonetheless adequately overwhelming to most organisms despite a standard diffusion of disc indication of “resistance” at more than 32 µg/mL.
In fact, most recent reports suggest that most ocular isolates remain sensitive to fluoroquinolones and aminoglycoside. I can additionally reinforce this impression from our local perspective by having recently discussed this question with Ms. Barbara Paton, director of the microbiology laboratory at the Massachusetts Eye & Ear Infirmary, who confirms that, apart from intermediate in vitro resistance of some strep pneumo to fluoroquinolones, all other ocular isolates remain sensitive to fluoroquinolones and/or aminoglycosides.
The single exception, however, is methicillin-resistant S. aureus (from both ocular and ear, nose and throat sources) which requires vancomycin for adequate therapy. This later problem is also suggested in the recent ophthalmic literature.
Regarding the issue of clinical resistance, I have reviewed the cases of bacterial keratitis encountered during the past 5 years in our practice at Cornea Consultants and have identified one case of therapeutic failure with ofloxacin and subsequently with tobramycin, which required fortified vancomycin for successful resolution. This organism also proved to be methicillin-resistant staph. All other cases proved clinically susceptible to either commercially available fluoroquinolones or aminoglycoside, thus the concept of “one-drop stopping” continues to remain appropriate to our practice setting.
But what of the few reports in the literature of clinically substantial antibiotic resistance such that substration of antibiotic therapy has been required to attain salutary clinical outcomes? Such cases of fluoroquinolone-resistant organisms have rarely been published, but the only large series of ciprofloxacin-resistant Pseudo monas keratitis (22 cases) emanates from India, where it may be presumed that the indiscriminate availability of over-the-counter topical and oral preparations of fluoroquinolones has rendered the local microbial species truly resistant to this important antibiotic class. Also, the risks of inducing antibiotic-resistant bacterial strains seem far greater from systemic rather than topical ocular use. The questions of resistance induced by prophylactic topical antibiotic use also seem to be of relatively low risk, but must remain at issue for another occasion.
While bacterial resistance to antibiotics is of constant concern and is, in fact, rarely encountered, there seems to be only limited evidence and experience that clinically relevant antibiotic resistance is emerging, at least in American and European ophthalmic practice.
References:
- Ormerod LD, Heseltine PM, et al. Gentamicin-resistant pseudomonal infection: rationale for a redefinition of ophthalmic microbial sensitivities. Cornea. 1989; 8:195-199.
- Jensen H, Felix C, and the In Vitro Antibiotic Testing Group. In vitro antibiotic susceptibility of ocular isolates in North and South America. Cornea. 1998;17:79-87.
- Watanabe K, Numata-Watanabe K, Hayasaka S. Methicillin-resistant staphylococci and floxacin resistant bacteria from clinically healthy conjunctivas. Ophthalmic Res. 2001;33:136-139.
- Snyder ME, Katz HR. Ciprofloxacin-resistant bacterial keratitis. Am J Ophthalmol. 1992;114:336-339.
- Maffett M, O’Day DM. Ciprofloxacin-resistant bacterial keratitis (letter). Am J Ophthalmol. 1993;115:545-546.
- Garg P, Sharma S, Rao GN Ciprofloxacin-resistant pseudomonas keratitis. Ophthalmology. 1999;106: 1319-1323.
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Continued monitoring needed
William J. Lahners, MD, and David R. Hardten, MD: In order to answer this question, we have reviewed several sources of data — the specific sensitivities that we have as a result of ocular cultures, the pooled results of all cultures (from different sites) of certain organisms and the local Minnesota Department of Health.
First, we considered our experience with our ocular cultures. Sources consisted of corneal scrapings in all cases. Considering the limited statistical power of analyzing a hundred or so ocular cultures with a variety of different organisms, we are not seeing an increase in the emergence of resistant organisms in our ocular isolates.
However, when we look at the pooled results of many more cultures taken from different sites on an inpatient basis in our area, plus the recent annual Minnesota Department of Health report, there are some increasing trends in resistance. Streptococcus pneumoniae has shown consistently increasing resistance to penicillin over the past 3 years, from 6% in 1997 to 46% in 2000. S. aureus has also shown increasing resistance to methicillin over this time period, going from 24% in 1997 to 39% in 2000. At a few of our local hospitals, isolates of Pseudomonas aeruginosa have shown some increasing resistance to gentamicin and ciprofloxacin, although this trend has not been seen at other centers. More alarming is the increase in vancomycin resistance we are seeing in enterococcus: from 3% in 1997 to 10% in 2000.
It should be remembered that this sensitivity information comes from a variety of different anatomic sources, and most of these were inpatients. Also, the sensitivity data are calculated using serum levels and MICs that are much lower than the effective ocular levels.
To summarize, we are seeing increasing numbers of resistant organisms in our inpatient facilities in Minnesota from mostly non-ocular sources, but we are not seeing this trend in our outpatient ophthalmic cultures, although our sample number is much smaller and measuring this trend will be difficult. Continued monitoring of this will help us to protect our patients against the ill effects of resistant bacteria.
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Watch issue carefully
William F. Maloney, MD: I have not seen any indication that there has been an increasing incidence of bacterial resistance to antibiotics in my practice. It should be noted, however, that the incidence of endophthalmitis is rare enough (particularly with state-of-the-art surgical techniques) that such a trend would not become evident for some time. Given that there has been an increase in resistance to antibiotics noted in the general medical community — this is an issue that ophthalmologists must watch carefully.
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Of concern to all
Thomas F. Neuhann, MD: I am not aware of any systematic study of this important question. Therefore, all I can give is the subjective impression from daily work. I have no indication of an increase in bacterial resistance to antibiotics: Antibiograms virtually al ways show good sensitivity against one or more antibiotics that are readily commercially available for topical application; also, the annual report from our microbiological laboratory on the sensitivity pattern for all cultures from the entire hospital does not provide any such indication, also not when comparing to 1, 2 or 3 years past. Altogether, bacterial infections necessitating microbiological workup are fortunately quite rare in the patient population we see.
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Rare in ophthalmic patients
Randall J. Olson, MD: The question raised is both a global and personal issue. On a personal basis, I live in an area where corneal infectious disease is relatively uncommon, so our numbers of corneal ulceration do not lend themselves well to any specific analysis. However, neither I nor my colleagues really have noticed any unusual changes in antibiotic resistance. The one exception is that fluoroquinolones have shown increasing resistance to Strep species.
Our fallback position, however, of topical vancomycin and aminoglycocide for broad-spectrum coverage still have done very well without a resistant species to date. The experience in wetter, warmer climates could be dramatically different.
This takes us to the global concern, and clearly our infectious disease colleagues here are very concerned about vancomycin resistance with little in the way of coverage for such species. Theoretically, they would like to reserve vancomycin for only unusual usage.
I don’t think the intraocular use of vancomycin with a minimal exposure to bacteria or the little that we use vancomycin for corneal ulcers is any significant problem in comparison to the more flagrant abuses of antibiotics, especially in the agricultural field. It is an area, however, that should be of concern to all of us and an issue we need to follow very carefully.
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