Cornea 19(5): 659–672, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia

The Evolution of Therapy for Bacterial Conjunctivitis and Keratitis: 1970–2000

Jules Baum, M.D., and Michael Barza, M.D.

Summary. The editors of this Festschrift asked us to review the agents, sometimes formulating them extemporaneously for topical use of for the treatment of bacterial conjunctivitis and application. A second trend in the evolution of antimicrobial keratitis over the past 25 years, a period coinciding with the life of therapy for the eye relates to the extemporaneous formulation of the Castroviejo Corneal Society. We believe it is more appropriate “fortified” drops, to achieve very high concentrations of drug on to begin our review in the late 1960s, about the time that experi- the cornea. These preparations often contain concentrations in the mental and clinical studies and algorithms for the clinical care range of 5–30 mg/mL, levels that are 50–100 times the maximum derived from these studies helped shape a more rigorous approach to therapy. Those years saw the introduction of antibiotics that serum concentrations in the case of well-tolerated drugs such as were adapted for ophthalmic use, many of which are still being penicillins and cephalosporins and that are 500–1,000 times those used today. We will give more weight to our review of keratitis of drugs such as and vancomycin. than conjunctivitis. This review will be limited to publications written in English. Key Words: Antibiotics—Bacterial conjunctivitis—Bacterial cor- Anecdotal reports will be mentioned only if they appear to be a neal ulcer—Treatment—Pharmacology—Antibiotic toxicity— “first” or have other special significance. Those characteristics of Antibiotic resistance—History. antibiotics that can be found in the general infectious disease lit- erature, such as structure, mechanism of action, and spectrum of activity, will not be addressed herein.

Most bacterial infections of the anterior segment of the eye are treated by topically applied anti-infective drugs. Exceptions are EVOLUTION OF ANTIBIOTICS: A gonococcal and chlamydial conjunctivitis, which are considered BRIEF HISTORY systemic infections. Few infections other than external ocular in- fections are treated topically. The purpose of this article is to In this section, we will review briefly the history of the intro- review the evolution of antibiotic therapy for bacterial conjuncti- duction of new antibiotics in its broadest outlines, emphasizing the vitis and keratitis over the past few decades. This period has wit- advantages of important new classes of drugs and individual nessed the introduction of numerous new antibiotics, some modi- agents for systemic treatment. Some of these new agents became fications in the formulation and mode of administration of the popular for topical application to the eye and these will be men- drugs, and an evolution in therapeutic regimens. With respect to tioned. This review will focus on drugs active against the most conjunctivitis, we will focus on ordinary bacterial infections in common bacterial causes of conjunctivitis and keratitis, namely adults and will not discuss hyperacute conjunctivitis (usually due Staphylococcus aureus, various streptococci, and Haemophilus in- to the gonococcus or meningococcus), chronic conjunctivitis, neo- fluenzae; less frequent causes are Moraxella sp and gram-negative natal conjunctivitis, or chlamydial conjunctivitis. Antibiotic treat- enterics. and other nonenteric gram-negatives will ments of bacterial infections of the anterior segment have evolved be considered because, although they are rare causes of conjunc- in two main ways over the past 30 or 40 years. First, there have tivitis or keratitis in the absence of trauma, soft contact lens wear, been changes in the choice of antimicrobial agents used, as new or some other predisposing cause, they may cause serious infec- agents, introduced initially for systemic treatment, attract the at- tions, especially in the form of corneal ulcers. Anaerobes are rarely tention of ophthalmologists for topical treatment. Many of these involved in external ocular infections. agents are only marginally more active than older agents; their Sulfonamides were introduced in the 1930s and 1940s. Two of chief attraction for systemic treatment may lie in better pharma- the congeners, sulfacetamide and trimethoprim are still used today. cokinetic properties or lesser adverse effects, neither of which may In the 1940s and 1950s, the first true “antibiotics” (so-called be- be important for topical application to the eye. Nevertheless, oph- cause they were produced by living organisms), namely penicillin, thalmologists have not been slow to adopt popular new systemic , and , became commercially available, followed by , polymyxin, and bacitracin. Most Submitted January 30, 2000. Accepted March 11, 2000. cocci (gram-positive and gram-negative) were susceptible to the From Boston Eye Associates (J.B.), Chestnut Hill; and the Department penicillins and tetracyclines and most gram-negative facultative of Medicine (M.B.), Carney Hospital and Tufts University School of Medi- bacilli were susceptible to the tetracyclines or streptomycin. Ac- cine, Boston, Massachussetts, U.S.A. Address correspondence and reprint requests to Dr. J. Baum, Boston Eye cordingly, in the 1950s and early 1960s, early-generation penicil- Associates, 1244 Boylston Street, Suite 202, Chestnut Hill, MA 02467, lins and streptomycin were popular choices for topical treatment of U.S.A. bacterial conjunctivitis and keratitis. Antibiotics, including ceph-

659 660 J. BAUM AND M. BARZA alothin, cephaloridine, , , , co- drop formulations, have been found to be as effective for bacterial listin, and vancomycin, soon became available. keratitis as fortified drops of older agents and are freer of the In the 1960s, as penicillin resistance became common among S. problems of corneal toxicity, short shelf-life, and the need for the aureus isolates, semisynthetic penicillins (e.g., oxacillin, nafcillin) extemporaneous formulation associated with fortified drops.1–3 and first-generation cephalosporins, such as cephalothin and cefa- The newest fluoroquinolones (“third-generation”), such as levo- zolin, all of which were resistant to staphylococcal beta- floxacin, have better potency than the older agents against pneu- lactamases, became popular. At the end of the 1960s, , mococci and are active against penicillin-resistant pneumococci. a potent new congener of the old , streptomycin, This advantage is more theoretical than practical because the ex- was introduced and, because of the upsurge in Pseudomonas ae- ceedingly high tear concentrations achieved by drops of the older ruginosa infections (susceptible to gentamicin but resistant to quinolones overcome most antibiotic resistance, at least in con- streptomycin), became popular for systemic treatment. Over the junctivitis. In more consequential infections, such as keratitis, the next decade, other aminoglycosides, tobramycin and , potential advantage of the newest quinolones is more easily justi- were introduced. These aminoglycosides and first-generation fied. cephalosporins, in extemporaneous formulations, began to be used by ophthalmologists for the treatment of bacterial corneal ulcers. ANTIBIOTIC RESISTANCE: GENERAL TRENDS Although tobramycin gained rapid acceptance, amikacin was rel- egated for use in addressing the problem of gentamicin-resistant Antibiotic resistance has been a problem since the introduction corneal pathogens. Commercial drops then became available (gen- of antibiotics.4 For virtually every antibiotic, intrinsic resistance tamicin, tobramycin), fostering the use of aminoglycosides for the has been detectable in some species even before the drug has been treatment of bacterial conjunctivitis and keratitis. Although used clinically. In at least some instances, the resistance mecha- aminoglycosides are only modestly active against streptococci, nism has been found in the antibiotic-producing organism itself. including the pneumococcus, the high concentrations achieved in The particular mechanisms of resistance vary between different the tear film were adequate to treat ordinary conjunctivitis; for drug and organism combinations. Overall, there are three major keratitis, the use of fortified drops and periocular injections to- mechanisms. The first is degradation of the antibiotic by microbial gether with an agent, such as cefazolin, which is active against enzymes: examples are beta-lactamases and aminoglycoside- gram-positive cocci, offered good activity. inactivating enzymes. The second is barriers between the drug and In the 1970s and 1980s, there was extensive development of its target site: an example is the outer membrane of gram-negative new beta-lactams to overcome the problems of resistant gram- . Through various mechanisms, including loss or modifi- negative bacterial infections and of aminoglycoside toxicity. The cation of porins, membrane permeability may be reduced. The cephamycins (cefoxitin and cefotetan), the “third-generation” third example is modification of the target so that it is no longer cephalosporins (ceftriaxone, ceftazidime, cefotaxime, and others), susceptible to the drug: examples are ribosomal mutations to re- the monobactams (), and the carbapenems (imipenem) sistance to streptomycin, methylation of the to produce were all introduced for systemic treatment. Around the same time, resistance to and , alterations in DNA gy- beta-lactams (amoxicillin, ticarcillin, ampicillin, and rase to produce resistance to quinolones, and modifications of alone or in combination with beta-lactam inhibitors) were devel- folate-synthesis enzymes to produce resistance to folate inhibitors. oped in an effort to combat increasingly resistant gram-negatives The resistance of S. aureus to methicillin, of pneumococci to peni- as well as anaerobes. Some of these agents were used as “fortified” cillin, and of enterococci to vancomycin are all examples of modi- drops for the treatment of microbial keratitis (see Routes and Fre- fication of the target, i.e., cell wall enzymes, so that they no longer quency of Administration). bind readily to beta-lactams. A fourth category, which can be In the late 1980s, pharmaceutical manufacturers began to exploit regarded as a subcategory of barriers to penetration, is the presence an old class of antimicrobial drugs, the quinolones, to produce of efflux mechanisms that pump out antibiotics from the cyto- agents with potent gram-negative activity and good oral absorb- plasm, preventing them from reaching critical concentrations. ability. Nalidixic acid had been introduced decades earlier: it had Such mechanisms have been found to contribute to the resistance a narrow spectrum and produced low serum concentrations. A to tetracyclines, quinolones, and macrolides. variety of manipulations, including the introduction of fluorine Some types of antibiotic resistance, such as the cephalospori- atoms on the molecules, led to drugs with much broader spec- nases of Pseudomonas and Enterobacter, are coded for by chro- trums. An early congener, ciprofloxacin, had great potency against mosomal genes. However, the most common types of antibiotic gram-negative bacilli and H. influenzae but only moderate activity resistance are coded for by genes on plasmids or transposons, against S. aureus and modest activity against streptococci and which can be readily passed “horizontally” from colony to colony pneumococci. Despite the relatively poor activity of these quino- and even between species. Thus, resistance mechanisms may lones against gram-positives, pharmaceutical manufacturers have spread quickly. developed drop formulations of several quinolones. These agents have quickly become popular for use in simple conjunctivitis— ANTIBIOTIC RESISTANCE IN EXTERNAL although there was no evident benefit over older treatments for OCULAR INFECTIONS conjunctivitis. It is difficult to justify the use of fluoroquinolones for the treat- Antibiotic resistance has been a well-recognized and well- ment of ordinary conjunctivitis, which is usually a mild, self- publicized concern with respect to systemic infections for many limited infection. In contrast, keratitis, a potentially serious infec- years. In recent times, this concern has extended to organisms tion, seems to be a more justifiable use of the fluoroquinolones. causing external ocular infections. Because most external ocular The fluoroquinolones, ciprofloxacin and ofloxacin, in commercial infections are acquired in the community, where resistance rates

Cornea, Vol. 19, No. 5, 2000 ANTIBIOTIC THERAPY FOR BACTERIAL CONJUNCTIVITIS AND KERATITIS: 1970–2000 661 are lower than in the hospital, antibiotic resistance has not been as TRENDS IN ANTIMICROBIAL USE FOR obvious a problem as in some other infections. Furthermore, an- CONJUNCTIVITIS: RANDOMIZED TRIALS tibiotic resistance is usually defined in terms of achievable serum concentrations. The high concentrations of drug achievable in the Table 1 provides a list of the randomized, controlled studies of tear film and corneal stroma after topical application, and, if nec- topical antibiotic treatments for conjunctivitis from 1975 to the essary, after subconjunctival injection, overcomes all but the high- present. To some extent, these studies can be considered to mirror est levels of antibiotic resistance. Nevertheless, it must be admitted the interest of ophthalmologists in new treatments for conjuncti- that knowledge of the concentrations of antibiotic in the tear film vitis. As can be seen, from about 1970 until about 1990, the trend and the in vitro susceptibility of the infecting species does not was to study various combinations of folate inhibitors (trim- allow for prediction of the clinical outcome with reasonable cer- ethoprim, sulfacetamide), aminoglycosides (gentamicin, neomy- tainty.5 cin), polymyxin B, and old agents with activity against gram- positive cocci (bacitracin, gramicidin). However, in the 1990s, Resistance to gentamicin has been noted in ocular isolates of S. interest was focused on single agents, primarily fluoroquinolones aureus and coagulase-negative staphylococci.6 During the 1990s, (ciprofloxacin, ofloxacin, lomefloxacin, norfloxacin) and many studies reported an increasing degree of resistance of ocular aminoglycosides (tobramycin, ). Almost all of the trials isolates to fluoroquinolones, especially in regard to S. aureus and showed little difference in efficacy between the comparative P. aeruginosa. Resistance rates of S. aureus to ciprofloxacin and agents (Table 1): an exception is one study that showed chloram- ofloxacin increased 5–35% between 1993 and 1997 in one clinic in phenicol to be inferior to combinations of agents.18 In addition, Pittsburgh, Pennsylvania, U.S.A.7 However, there may be marked because of its potential for inducing an idiosyncratic aplastic ane- variability in resistance rates even between clinics in the same city mia,19 the use of topical chloramphenicol is to be avoided if the and little resistance to fluoroquinolones was found in isolates ob- pathogen is susceptible to other antibiotics. In many of the studies tained in 1993 and 1994 from cases of keratitis in another clinic in 8 cited in Table 1, about 90% of patients were clinically cured within Pittsburgh. A clinic in Miami, Florida, U.S.A. reported that the 7 days. Two studies were placebo controlled: in one, involving rate of resistance of P. aeruginosa to ciprofloxacin rose signifi- children, 62% of those treated with polymyxin-bacitracin and only 9 cantly from 0.4% in 1991–1994 to 4% in 1995–1998. Similar 28% of those given placebo were cured after 3–5 days of treat- increases in ciprofloxacin resistance of gram-positive cocci and P. ment; by 8 days these response rates were 91% versus 72%.20 That 10,11 aeruginosa have been reported from India, a country in which study, and one other,21 showed more rapid improvement with ac- fluoroquinolones are widely used in the treatment of diarrheal tive drug than placebo. However, almost all patients recovered disease. In a recent study, ciprofloxacin-resistant isolates from the even without treatment and excellent efficacy was reported even in lid margin increased from 12.5% at baseline to 50% after 4 weeks studies with appreciable rates of antibiotic resistance.22–24 of topically administered ciprofloxacin in postcataract patients.12 In an in vitro study, investigators from the same laboratory found that the frequency of mutational resistance to ciprofloxacin in S. TEXTBOOK RECOMMENDATIONS aureus increases exponentially as the concentration of the antibi- otic was decreased.13 These data support discontinuing rather than Over the past several decades, most authors of standard text- books have offered a variety of possible choices for the treatment tapering multi-dose antibiotic eye drops. of uncomplicated acute conjunctivitis in adults (Table 2). If trends Individual case reports of failures of treatment due to resistance can be discerned, they are probably toward the use of single agents of the infecting organisms are difficult to interpret because often rather than combination treatments and toward increasing accep- the subsequent, apparently successful treatment involves not only tance of the fluoroquinolones (ciprofloxacin, ofloxacin) as first- a change in the drug but also in drug concentrations and frequency line treatments. of application and, of course, the passage of time. Nevertheless, As noted at the beginning of this section, we are considering plausible cases of failures of treatment with fluoroquinolones have only acute bacterial conjunctivitis in adults in this section. We will been reported.10,14 not discuss neonatal conjunctivitis, hyperacute conjunctivitis, con- In summary, resistance rates of ocular isolates to aminoglyco- junctivitis due to the gonococcus or Chlamydia trachomatis,or sides and to quinolones are increasing in many areas of the world, chronic conjunctivitis (typically caused by S. aureus or Moraxella following the general trend to increased resistance in isolates from lacunata and often associated with blepharitis). Chlamydial and systemic disease and normal flora. In general, the rate of resistance gonococcal conjunctivitis, as well as H. influenzae conjunctivitis to antibiotics is probably related to the total use of the drugs and in children (especially when associated with otitis25), are treated of related drugs for all purposes, including treatment in humans systemically; regimens for the first two usually follow guidelines and animals, and growth promotion in animals. If that assumption issued periodically by the Centers for Disease Control and Pre- is correct, ophthalmic uses of these agents probably play a minor vention, Atlanta, Georgia, U.S.A. role in overall resistance rates. Because drug concentrations in the cornea after topical or subconjunctival applications are so much higher than those in serum after systemic administration, the cat- BACTERIAL KERATITIS egorization of an organism as resistant to an antibiotic based on in vitro testing (which is geared to serum levels) is not necessarily Early History applicable.15,16 Therefore, it has been suggested that initial therapy The sulfonamides were introduced for ophthalmic use in 1938, for a corneal ulcer be modified only when the organism has been followed by penicillin in 1940.26 In 1958, it was reported that most determined to be resistant and the ulcer is clinically unrespon- corneal ulcers benefited from a combination of systemic and local sive.17 therapy,27 including some combination of sulfonamides, chloram-

Cornea, Vol. 19, No. 5, 2000 662 J. BAUM AND M. BARZA

TABLE 1. Randomized, comparative studies of antibiotic treatment for conjunctivitis

Drugs compared Type of study Outcome and comments Year

Gentamicin vs. neomycin-polymyxin B Randomized, double-blind Neomycin-polymyxin B appeared better clinically but 1975203 maldistribution of causative agents and susceptibility may have affected results TMP-polymyxin vs. Randomized, double-blind No differences clinically or in eradication of 1982204 neomycin-polymyxin-gramicidin pathogens; well tolerated drops TMP-polymyxin B vs. Multicenter, randomized, Chloramphenicol inferior; other two equivalent in 198318 neomycin-polymyxin B-gramicidin double-blind clinical efficacy; all well tolerated vs. chloramphenicol drops Polymyxin-bacitracin ointment vs. Children with bacterial acute By 3–5 d, 62% vs. 28% clinically cured; by 8 d, 91% 198420 placebo conjunctivitis, randomized, vs. 72% cured; more rapid eradication of pathogen double-blind with active treatment Conjunctivitis or blepharitis TMP and Randomized comparison No difference; sulfacetamide can be omitted 1984205 polymyxin B with or without sulfacetamide TMP-polymyxin B vs. gentamicin vs. Յ21 y; randomized No difference in clinical outcomes 1988206 sulfacetamide drops TMP-polymyxin B vs. chloramphenicol Summary of four randomized, Rx equally effective and well tolerated 1989207 ophthalmic ointments for double-blind studies conjunctivitis Ciprofloxacin vs. placebo or Multicenter, randomized, not Antibacterial efficacy of ciprofloxacin more than 199121 tobramycin drops blinded placebo but similar to tobramycin Ofloxacin vs. tobramycin drops for Multicenter, double-blinded, Clinical summary score somewhat better with 1992208 “external ocular infection” randomized ofloxacin at day 3–5 but no difference by day 11; no difference in microbiological efficacy between agents Ciprofloxacin vs. tobramycin drops Pediatric (Յ12 y), No difference in clinical or microbiological outcome; 1997209 randomized, double-blind, about 90% clinically cured by day 7 multicenter Netilmicin vs. tobramycin drops Randomized, double-blind No difference in clinical outcomes; almost all patients 199924 responded although 16–36% of pathogens were resistant Lomefloxacin vs. tobramycin drops Randomized, double-blind, No difference in clinical outcomes; resistance rate 199922 multicenter lower with lomefloxacin (3.5%) than tobramycin (11.4%) Lomefloxacin vs. chloramphenicol, Meta-analysis of six Somewhat better clinical outcome with lomefloxacin 199923 gentamicin, tobramycin, fusidic randomized, masked than others combined; most organisms resistant in acid, norfloxacin drops studies vitro were eradicated with regimen used; more burning sensation in control groups phenicol, penicillin, polymyxin, and bacitracin. In 1964, topical cin. Hessberg,31 who advocated antibiotic delivery by subpalpe- polymixin B was found to be effective in treating a pseudomonal bral lavage in a continuous drip delivered by tubing, reviewed data ulcer.28,29 By 1966, topical therapy was deemed “usually satisfac- suggesting that pseudomonal isolates were equally sensitive to tory” but chemical or thermal cautery was noted to have been a both polymyxin B and colistin. He preferred topical polymyxin B popular treatment.30 A combination of routes—topical, subcon- to subconjunctival colistin for the treatment of pseudomonal kera- junctival, and systemic—was suggested for the treatment of the titis because it caused less discomfort.28 Burns32 reported similar more severe ulcers. Among the antibiotics listed for use were findings. neomycin, erythromycin, penicillin G, methicillin, oxacillin, am- The use of gentamicin in the eye was first reported in 1965 by picillin, nafcillin, cephalothin, lincomycin, vancomycin, some tet- Furgiuele et al.33 who, in a series of experimental and clinical racyclines, polymixin B, colistin, chloramphenicol, and gentami- studies, demonstrated the antibiotic’s efficacy in treating pseudo-

TABLE 2. Textbook recommendations for empiric antibiotic treatment of acute conjunctivitis in adults

Ointments Drops recommended recommended Comments Year

Gentamicin or Gentamicin or — 197917 neomycin-gramicidin-polymyxin or neomycin-gramicidin-polymyxin chloramphenicol B or chloramphenicol Sulfacetamide or — Fluoroquinolones and fortified drops (cephalosporins, 1986210 polymyxin-trimethoprim or aminoglycosides) should be reserved for severe gentamicin or tobramycin infections and keratitis Choice should be based on cultures, — Fluoroquinolones highly effective but these drugs, 1988211 if available; if empiric, choose and vancomycin, should be reserved for special broad-spectrum (no specific cases because resistance is emerging recommendations) Sulfacetamide or — — 1994212 trimethoprim-polymyxin Gentamicin or tobramycin or Bacitracin or erythromycin or Mentions other possibilities (sulfacetamide or 1997213 ciprofloxacin or ofloxacin or gentamicin or tobramycin or chloramphenicol or polymyxin-neomycin) polymyxin-trimethoprim polymyxin-bacitracin

Cornea, Vol. 19, No. 5, 2000 ANTIBIOTIC THERAPY FOR BACTERIAL CONJUNCTIVITIS AND KERATITIS: 1970–2000 663 monal keratitis. Both the eyedrop and ointment forms were re- authoritative publications for use as a periocular injection, as was leased in Great Britain for clinical use in 1968, 2–3 years earlier the less locally irritating cephaloridine.45,46 Favorable results were than it was available in the United States. The drug’s clinical reported with subconjunctival cephaloridine/gentamicin.47 Be- efficacy as a topical agent against S. epidermidis, S. aureus, S. cause of the growing use of subconjunctival injections and the pneumoniae, Pseudomonas, Proteus, and Klebsiella conjunctivitis tendency of many of the semisynthetic penicillins and cephalothin or keratitis was demonstrated in a short anecdotal report.34 An- to cause conjunctival irritation or necrosis, cephaloridine was a other report showed good corneal penetration via systemic and drug of choice for the treatment of many gram-positive corneal subconjunctival routes for both penicillin G and dihydrostrepto- infections and was used in combination with gentamicin.47 Its use mycin35 but other studies36,37 demonstrated much higher ocular predominated until a new cephalosporin, cefazolin, was first sug- levels of drug after subconjunctival/sub-Tenon administration. By gested for the treatment of bacterial keratitis.48,49 Similar in its 1970–1971, specialists in cornea and external disease, and perhaps spectrum to cephaloridine, it is much less locally irritating when the general ophthalmic practitioner, seemed to accept this fact. administered subconjunctivally. Further rationale for its use may Interestingly, in 1944, Struble and Bellows38 demonstrated, seem- be found elsewhere.49 ingly for the first time, the superiority of periocular delivery of For purposes of classification, cefazolin is considered to be a antibiotic to the cornea as compared to the systemic route. In 1959, member of the first generation of cephalosporins. First-generation Frederick Theodore, M.D., told one of us (J.B.) that he used a members have a narrower spectrum of antibacterial activity but are subconjunctival injection of an antibiotic prepared from either a more active against gram-positive cocci than are second- or third- parenteral or eyedrop formulation to treat a putative bacterial ulcer generation antibiotics. Methicillin-resistant staphylococci are, in a patient he saw in his private office before the patient was sent however, resistant to all available cephalosporins. Second- and to the hospital. This appears to be the first use of commercially especially third-generation drugs have a broader spectrum against available topical antibiotics for subconjunctival injection. Struble gram-negative bacteria, and a few third-generation agents, includ- and Bellows’ results were not confirmed for two decades, an at- ing ceftazidime, are active against P. aeruginosa. From the late testation to the lack of research in this area during the interval. 1970s until the early 1990s, cefazolin, used with either gentamicin Perhaps the main reason for the small research output in the area or tobramycin, was probably the most widely used and most ef- of cornea and external disease before the early to mid-1960s was fective drug combination for the treatment of bacterial corneal the paucity of fellowship programs in this subspecialty. For some ulcers.48–57 Cefazolin, administered as a subconjunctival injection, years before and after, fellows on the West Coast of the United also demonstrated excellent corneal penetration.58,59 Because such States were trained in external disease (including infections) injections were in vogue in the early 1980s, because injections of whereas those on the East Coast focused on noninfectious corneal the semi-synthetic penicillins available at that time caused more disease and surgery. We appreciate that corneal antibiotic research tissue damage and pain at the injection site than cefazolin, because performed in the 1960s formed a solid basis for the era of the Staphylococcus was the prime cause of bacterial keratitis, and present review. because the drug had excellent gram-positive coverage, cefazolin became the single most widely used antibiotic to treat gram- Antibiotics positive induced corneal ulcers in the early and mid-1980s. This section will highlight the antibiotics that have been of The introduction of gentamicin for the treatment of bacterial greatest benefit combatting the major pathogens associated with keratitis in the 1960s greatly enhanced our ability to sterilize an bacterial keratitis over the past 25 years. Information regarding infection, because this agent is active against Staphylococcus antibiotics used to treat bacterial keratitis has been taken, in large and gram-negative organisms, including Pseudomonas. It was part, from studies in the infectious disease literature; data from that recognized as a drug of choice even before 1970. Its activity literature was used to further evaluate the drug’s potential for against Pseudomonas and other pathogens and its ocular phar- eradicating ocular infection. macology were demonstrated experimentally33,60–70 and clini- Staphylococcus has been and still is the leading cause of bac- cally.28–30,32,34,39,57,71–76 In one study, the authors found a high terial keratitis.39–42 S. pneumoniae, remains an important patho- drug concentration in rabbit cornea after sub-Tenon administration gen, especially in some developing countries43 as does Pseudo- and a correspondingly low concentration after intramuscular in- monas, because of its ability to rapidly destroy the corneal stroma jection.66 They suggested a sub-Tenon injection of 20–40 mg, a and because of its increased prevalence since the introduction of dose we commonly use today. Another experimental study found soft contact lens wear in the 1970s.44 It was with these bacteria in that a more concentrated (20 mg/mL) antibiotic eye drop was more mind that research focused on two classes of antibiotics introduced effective in eradicating bacteria than the less concentrated com- just before and within that decade, the cephalosporins and the mercial strength (3 mg/mL).77 aminoglycosides. Before the introduction of the cephalosporins, The aminoglycoside, tobramycin, after it was introduced as an the use of penicillin G for staphylococcal and pneumococcal kera- ophthalmic solution in 1981, became the most commonly used titis had given way to the semisynthetic penicillins. Methicillin, topical antibiotic prescribed by American ophthalmologists in the oxacillin, dicloxacillin, ampicillin, and nafcillin were suggested for 1980s. Although its spectrum is very similar to that of the much oral or parenteral delivery in 1966 but, curiously, not for topical less expensive gentamicin, its rapid acceptance was probably at- use30; their application as a periocular injection was being inves- tributable to statements highlighting the drug’s 2-fold greater ac- tigated at about the same time.36,37 tivity against P. aeruginosa78 and the rapidly increasing incidence The entry of the cephalosporins into the ocular armamentarium of pseudomonal keratitis associated with soft contact lens use in started slowly and anecdotally. The first congener appears to have the same decade.44,79 Tobramycin was first called nebramycin been cephalothin, which was suggested for parenteral use only as factor 6, and its first experimental application in treating microbial early as 1966.30 By 1972, the drug was included among others in keratitis appeared in 1973.80 Numerous experimental studies80–90

Cornea, Vol. 19, No. 5, 2000 664 J. BAUM AND M. BARZA attest to its efficacy against Pseudomonas, Staphylococcus,89,91 to ciprofloxacin and ofloxacin include streptococci and pseudo- and Proteus.91 A clinical report also found it useful in combination monas species other than aeruginosa. More experimental and clini- with ticarcillin for the treatment of pseudomonal keratitis,92 and cal studies relating to these two topical antibiotics were conducted the drug was similarly recommended by others.49,93 More recently, in a shorter time period than any other series of ocular antibiotic the beta-lactam, imipenem, with broad activity against gram- studies since the introduction of gentamicin, some 20 years earlier. positive and gram-negative bacteria, was found to be highly ef- This was, in part, because of the support of the manufacturers. fective in the experimental treatment of pseudomonas keratitis.94 Experimental studies relating to the use of ciprofloxacin as a The aminoglycoside, amikacin, introduced shortly after tobramy- treatment for bacterial keratitis first appeared in 1988.110 Other cin,95 never gained a significant role in treating the most prevalent such studies then followed.2,8,14,15,97,106,108,111–120 Clinical re- organisms as its activity was suggested to be similar to that of ports further corroborated ciprofloxacin’s effectiveness in eradi- tobramycin.96 cating major bacterial pathogens.2,118,121–123 Similar experimen- Vancomycin, because of its supposed toxicity, was used with tal8,15,97,106,117,124–128 and clinical1,3,129 studies authenticated the caution systemically in the 1960s30 and was not to be used to any value of ofloxacin to treat the disease. Overall, ciprofloxacin has large degree for another 10–15 years, when resistance of gram- somewhat greater in vitro activity against gram-negative patho- positive bacteria to other antibiotics forced a reexamination.97,98 gens than ofloxacin. Whether ofloxacin reaches higher corneal Clindamycin superceded its forerunner, lincomycin,99 as another levels after topical administration125 or whether the two agents tool in treating keratitis caused by gram-positive organisms.100 penetrate equally15 is still unresolved. It is doubtful, however, that Carbenicillin, which preceded ticarcillin and piperacillin for con- these minor differences in activity and penetration convey a clini- joint use with an aminoglycoside in the treatment of pseudomonal cal advantage to either for the initial treatment of an undetermined keratitis, was evaluated for corneal penetration101 in the rabbit. corneal pathogen. Both ticarcillin102 and piperacillin, semi-synthetic penicillins, are To best predict the clinical efficacy of an antibiotic, one must more active against P. aeruginosa than carbenicillin. In the early know both the ability of each drug to penetrate the infected tissue 1990s, a recently introduced third-generation cephalosporin, cefta- and their minimum inhibitory concentration. With this in mind, the zidime, gained a prominent role in the treatment of corneal ulcers. concept of an inhibitory quotient was introduced.130 It is defined as Known to be effective against gram-negative bacteria, especially the concentration of a given antibiotic in the given tissue divided Pseudomonas, the antibiotic also possessed activity against gram- by the minimum inhibitory concentration for 90% of isolates of the positive species, including Staphylococcus. Experimental103 and bacterial group to the specific antibiotic. Thus, the higher the in- clinical104 corneal studies documented its potential for further use. hibitory quotient, the more effective the antibiotic. Because ob- Perhaps the most significant variation in the treatment of mi- taining corneal data for the numerator in the normal living human crobial keratitis during the period covered by this review followed breaches ethical standards, data slowly accrues after corneal trans- the introduction of two commercially available topical fluoroqui- plantation (Table 3). nolone eye drops, ciprofloxacin and ofloxacin in 1991 and 1993, respectively. An extended discussion relating to the clinical use of fluoroquinolones can be found in the Treatment of Bacterial Ulcers Routes And Frequency Of Administration section. Before these two agents were introduced, the older qui- Before 1960, bacterial corneal ulcers were treated with drugs nolone, nalidixic acid, had failed to find a place in the treatment of administered, with few exceptions, by systemic and topical routes bacterial ulcers and the fluoroquinolone, norfloxacin,105–109 never of delivery.27 Pioneers such as Theodore were beginning to use secured its own niche because of the more impressive effective- subconjunctival injections prepared from commercially available ness of ciprofloxacin and ofloxacin and its own greater toxicity.97 eyedrops or from vials of antibiotics meant for parenteral delivery The rapid and wide acceptance of ciprofloxacin and ofloxacin was that they formulated for ocular use. In the early and mid-1960s, all justified by their broad spectrum of activity against gram-negative three routes were suggested.30 This approach was reiterated shortly and many gram-positive organisms, including Staphylococcus and thereafter.131 A short-lived subpalpebral route by continuous drip Pseudomonas, the growing resistance of these bacteria to antibi- was described in 1969.31 By the early 1970s, ophthalmic scientists otics previously used to treat infectious keratitis, and the stability had begun a systematic examination of the pharmacology and of these commercially available agents in eyedrop form at room of the more widely used antibiotics, the corneal temperature, allowing for ease of use. Organisms less susceptible components of which are found in Tables 3–6. Experimental mod-

TABLE 3. Concentration of antibiotics in human cornea after topical administration (postkeratoplasty)

Antibiotic Regimen Corneal concentration (µg/g) Reference Gentamicin 0.3% drops every 5 min for 1 h 0.5–4.0 (inflamed) 68 13.6 mg/mL drops or IM preop 16.2 69 Ciprofloxacin (0.3%) 2 drops every4hfor24h 2.32–25.3 114 1 drop every 15 min for 1 h then every1hfor10h 1.7–10.58 113 4 drops 0.60 106 Ofloxacin (0.3%) 2 drops every4hfor24h 0.37–7.08 124 2 drops every 30 min for 4 h 4.51 125 same plus 400 mg PO×3 8.59 4 drops 0.81 106

Modified from Barza.137 IM, intramuscular; PO, by mouth.

Cornea, Vol. 19, No. 5, 2000 ANTIBIOTIC THERAPY FOR BACTERIAL CONJUNCTIVITIS AND KERATITIS: 1970–2000 665

TABLE 4. Concentration of antibiotics in rabbit cornea after topical applicationa

Antibiotic Regimen Corneal concentration (µg/g) Reference Penicillin G 1.2% corneal bath for 3 h 28 214 5,000–20,000 µ/g in cotton pledget 347–1729 u Cefazolin 33.3 mg/mL, 1 drop For 8 h 1.28 (log 10) 144,145 For 16 h 1.70 (log 10) Gentamicin 0.3% drops for 6 h 15 (Lye ulcer) 61 2 (pseudomonas ulcer) 0.3% drops for 8 h 10 (sterile corneal suture) 68 20 (corneal infection) 68 3 mg/mL drops for 8 h 0.96–1.47 (log 10) 144,145 14 mg/mL drops for 8 h 1.64–2.21 (log 10) Tetracyclines 0.5–2.5% drops or corneal bath for 1 h 3–10 — 35 (abraded or ulcerated cornea) 0.5–2% ointment 3–25 157,215 Erythromycin 2.5% drops for 1 h 4–9 — 10 (abraded cornea) Chloramphenicol 0.25% drops or 5% in propylene glycol for 30 min 25 157,216 1% ointment 70 20 mg/mL drops every 27.43 2 h for 24 h 64.71 (abraded cornea) 217

a Modified from Barza137: unless stated otherwise, studies were performed in normal eyes. Data selected from Benson157 unless otherwise stated. els to study drug levels in corneal tissue and to evaluate bacterial able54,69,140,141 except when corneal perforation exists.49 In 1973, load were also developed in this decade.85,132–136 experimental evidence101,142 persuaded many to include subcon- Many studies have confirmed that systemic administration is an junctival injections as part of their therapy, although others re- inefficient route of antibiotic delivery to the cornea.137 Although sisted, believing that frequent administration of eyedrops was as its adjunctive use has been advocated for the treatment of severe good and certainly less painful.62,143 Subsequent studies (Table 5) keratitis,39,138,139 some have considered its use question- confirmed the ability of subconjunctival injections to afford cor- neal concentrations of drug at least 10-fold higher than attained by TABLE 5. Peak concentration of antibiotics in rabbit cornea after topical delivery. The apparent paradox between a similar effec- subconjunctival administrationa tiveness of both topical and subconjunctival delivery despite a much lower peak concentration of drug after topical dosing was Normal eyes Inflamed 144,145 Dose (µg/g) eyes (µg/g) References clarified. Although subconjunctival injections produced a high tissue drug peak followed by a low trough,35,61,101,146,147 Penicillin G 100 mg 3,000 (→1500) — 35 continual eye drop administration resulted in moderate but sus- 50 mg 300 — 146 tained tissue levels. However, the efficiency of each in eradicating Carbenicillin bacteria was similar with a few special exceptions. Despite differ- 100 mg >300 (→42) >300 (→25) 101 50 mg 15–35 — 218 ences between the rabbit model and the human eye, such as fluo- Methicillin rescein’s streaming out the hole in the rabbit’s conjunctiva after a 100 mg — 700 (→40) 59 Oxacillin subconjunctival injection whereas very little escapes in the human 148 100 mg — 2,000 (→500) 59 eye, the rabbit model has served well. Its validity as a model has Cefazolin been corroborated on one occasion by a primate experiment.60 100 mg — 600 (→100) 59 25 mg >1,000 — 58 Subconjunctival injections are, in almost all clinical instances, an- 12.5 mg — 150 (→40) 59 terior sub-Tenon injections. However, there is probably an insig- 100 mg — 2.25 (log 10) 144,145 Cefamandole TABLE 6. Concentrations of antibiotics in rabbit cornea at peak → 12.5 mg — 140 ( 40) 219 after systemic administrationa Streptomycin 50 mg 1,000 35 Corneal concentration (µg/g) Gentamicin 20 mg — 200 (→25) 220 Normal Inflamed 10 mg — 10 221 Antibiotic Regimen eyes eyes References 5mg 30 10 67 40 mg — 2.19–2.47 (log 10) 144,145 Penicillin G 62 mg/kg SC 4 6 147 5 mg 150 — 60 40 mg/kg IV 9 — 35 20 mg — 320 222 Ampicillin 50 mg/kg IV 3 — 224 Chloramphenicol Amoxicillin 100 mg/kg PO 2 — 225 150 mg 50 — 223 Carbenicillin 100 mg/kg IV 11 85 101 50 mg 500 — 146 Streptomycin 15 mg/kg IV 13 — 35 Clindamycin Gentamicin 1.7 mg/kg IM 0.5 3.4 66 34 mg 100 — 100 1.6 mg/kg/h IV — 10 76 Aztreonam Chloramphenicol 50 mg/kg IV 5 — 226 100 mg — 777 (→10) 222 Clindamycin 100 mg/kg Trace — 227

a Modified from Barza.137 a Modified from Barza.137 Parentheses contain concentrations 3–6 hours after administra- SC, subcutaneous; IV, intravenous; PO, by mouth; IM, intramus- tion. cular.

Cornea, Vol. 19, No. 5, 2000 666 J. BAUM AND M. BARZA nificant therapeutic difference between the two routes.149–151 The tolerated over the 2–3-week period of intensive treatment highest concentration of drug in the cornea exists nearest the in- needed.”46 The next year, another comprehensive article appeared jection site.60,67,146 This uneven topographic distribution suggests that set a scholarly standard for the diagnosis and treatment of that drug enters the cornea mainly by direct diffusion rather than clinical corneal infections.39 Similar articles, published over the through the precorneal tear film.145 next 5 years, reiterated and advanced the therapeutic regi- Administration of antibiotic by eyedrops is, at present, the pre- men.40,48,141,160,167 ferred method of delivery for the treatment of bacterial keratitis. In 1979, in a two-part article, two different viewpoints were Some came to this conclusion early,54,62,143,152–155 whereas others expressed by different authors regarding approaches to the treat- were slower to forgo the routine use of subconjunctival injec- ment of corneal ulcers. In one approach, gram stain results formed tions.145 The advantages of eyedrops over subconjunctival injec- the basis of antibiotic selection for initial treatment except when no tions included the ease of pain-free delivery and the ability to alter organisms were identified on laboratory examination, in which their concentration and frequency of administration. As noted case a broad spectrum approach was advocated.139 In the opposing above, a few practitioners had begun using higher concentrations view, it was recommended that initial treatment commence with a (fortified) of antibiotic eyedrops than were available commercially combination of antibiotics known to be effective against the most before 1960 on an empirical basis. Experimental evi- probable pathogens in the community.49 This latter viewpoint is dence48,77,144,145,154,156–159 together with clinical evidence and reiterated elsewhere.17,48 The latter empiric treatment plan was suggestions by a few corneal specialists39,45,49,139,155,160,161 pub- based, in large part, on what appeared to be a poor correlation lished in the 1970s and 1980s, however, established a justification between gram stain and culture results.40,42,160 In a more recent for the routine use of fortified eyedrops in the treatment of bacte- study, cultures were found to be positive in only 63% of patients rial keratitis, even though it was inconvenient to formulate the with a putative diagnosis of infectious keratitis.168 However, the drops on the basis of individual need and there was a possibility of potential for a false diagnosis, in this report, is considered a lim- osmotic dilution from a hypertonic solution.162 Experimental evi- iting factor. A discussion of the details of the two therapeutic dence from the 1970s suggests that increasing the frequency of regimens is beyond the scope of this review, and readers are re- eyedrop administration increases the corneal levels of ferred to the original descriptions. Both approaches supported the drug.49,61,84,142,154,158,163 Data from these studies were applied in use of fortified topical antibiotics and subconjunctival injections as clinical protocols,48,139 although an earlier publication, probably suggested in earlier publications.45,46 These earlier protocols for based on personal and anecdotal experience, gave similar ad- subconjunctival antibiotic injections included either giving the an- vise.131 Most authors suggested that there be no more than a 15– esthetic separately46 or combining it with the two drugs as a single 30-minute interval between eyedrop administration at the onset of injection.45 The anesthetic agent was subsequently shown not to initial therapy. Treatment should continue throughout the night for affect antibiotic activity.169 the first 1–3 days. The average eyedrop is 0.025–0.040 mL and The introduction of commercial artificial tears afforded the op- drops >0.025 mL overflow the lid margin.164,165 In addition, reflex portunity to facilitate the addition of a more concentrated paren- tear stimulation after instillation of an eye drop lasts approximately teral antibiotic to a small artificial tear bottle for topical delivery.39 5 minutes.165 Thus, administration of two successive drops at Eyedrop delivery, every 15–30 minutes, was generally used for 1-minute intervals does not increase drug effect and it induces a initial therapy during the early and mid-1970s.39,49,131,139 How- washout effect if the second drop consists of a second drug. There- ever, as discussed above, an initial loading dose of one drop every fore, one should wait at least 5 minutes before instilling a second minute for five doses166 offers several advantages. Antibiotics eyedrop solution.164 Commencing therapy with eyedrop delivery used to treat the infection, except for penicillin G, were relatively of a single antibiotic every minute for five doses as an initial stable at room temperature after they were diluted with an artificial loading dose166 has a 2-fold benefit. In addition to raising drug tear solution.161 Antibiotic ointments never gained general accep- tissue levels more rapidly than can be achieved with a drop every tance because of the difficulty of increasing the drug concentration 15 minutes, repeating this protocol every hour166 achieves sus- of the ointment and because the ointment base impaired the cor- tained high levels of drug and allows patients and others admin- neal penetration of a second antibiotic administered as an eyedrop. istering the medications to nap, rest, or work during the 45-minute Cefazolin and tobramycin49 and cefazolin or cephaloridine and hiatus between dosing periods. Other methods not usually used in gentamicin139 were combinations of choice. Antibiotic resistance the treatment of bacterial ulcers, such as ointments, slow and fast patterns were used to determine subsequent therapy for ulcers release depots, soft contact lenses, continuous lavage, and ionto- unresponsive to primary therapy. As discussed above, some au- phoresis, are not discussed in this review. thorities during this same time period used fortified antibiotic eye drops without subconjunctival injections for both initial and sub- Treatment of Bacterial Corneal Ulcers sequent therapy.54,143 In the 1970s and early 1980s, most patients Before the early 1970s, there appears to be no single paper or were hospitalized for therapy. Outpatient treatment became the chapter that presents a systematic approach to the treatment of norm thereafter, with some exceptions, in large part because of the bacterial corneal ulcers. In 1971 and 1972, Theodore45 and Allen46 high cost of inpatient care. detailed their approaches to the treatment of bacterial corneal ul- In the early and mid-1980s, the combinations of cefazolin and cers. They included sections on diagnosis, treatment plans, and a either gentamicin50,51,143,155,170 or tobramycin51,143,155 were prob- discussion of antibiotics and their routes of administration. Tables ably the most widely used therapeutic regimen for initial therapy. list antibiotics with their subconjunctival and topical (fortified) These combinations of antibiotics continued to be used through the doses. Allen states it is his “firm conviction that the frequent and late 1980s and early 1990s with no laboratory examination in intensive use of freshly prepared concentrated solutions of those approximately 50% of cases.52,53,171 The role of subconjunctival specific antibiotics indicated in the individual case are always well injections decreased as the efficacy of fortified eye drops became

Cornea, Vol. 19, No. 5, 2000 ANTIBIOTIC THERAPY FOR BACTERIAL CONJUNCTIVITIS AND KERATITIS: 1970–2000 667 to be better appreciated.50,51,143,155,170 In some parts of the world, a clinical challenge since the beginning of the antibiotic era, and little resistance to these drugs was encountered through the early even before. Whether initial treatment is based on laboratory re- 1990s and their use continued to be recommended.57 This standard sults or empiric therapy, each new antibiotic effective against this of care continued into the 1990s,53 as evidenced by the use of corneal destructive pathogen has undergone rapid ocular evalua- fortified drops of cefazolin/gentamicin or tobramycin as the regi- tion. Furthermore, there is an important exception to the use of mens against which the efficacy of fluoroquinolone therapy was “standard” therapy or topical fluoroquinolone therapy if a pseudo- evaluated.2,3,123 monal ulcer is suspected (e.g., associated with the use of extended- The commercial introduction of two topical antibiotic eyedrops, wear soft contact lenses). It is generally thought that therapy ciprofloxacin and ofloxacin in 1991 and 1993, respectively, should commence with a combination of antibiotics known to be brought about a fundamental change in the initial treatment of effective against the pathogen, such as tobramycin and ceftazi- bacterial corneal ulcers. The ease of administering and prescribing dime. Systemic therapy is important in the infant to prevent sys- a single commercially available antibiotic eye drop, without the temic spread179 and in the treatment of scleral extension, the need to prepare fortified drugs and in concert with the wide gram- spread of which may or may not be enhanced by use of a topical positive and gram-negative spectrum and clinical effectiveness of corticosteroid. Although there is evidence to suggest that if appro- these two fluoroquinolones, served as a strong impetus for reevalu- priate antibiotic therapy is in place, the addition of a corticosteroid ation of the “standard” fortified eye drop approach. Three factors does not encourage pseudomonal activity,180–183 other evidence that minimized treatment delay also contributed to the reevalua- suggests the opposite.29,32,159 We refer the reader to standard oph- tion. Treatment could be started immediately by the local ophthal- thalmic textbooks for a discussion of the complex subject of modi- mologist. Delay was often avoided by obviating travel to a tertiary fication of initial therapy after unresponsive infections. center. Additionally, delay resulting from examination, laboratory work-up, and preparation of fortified eye drops at the tertiary Toxicity Of Topical and Subconjunctivally center could also be avoided.172 Historically, suggestions for Administered Antibiotics change in medical therapy generally follow a series of experimen- Except for the systemic adverse reactions that may occur after tal and clinical studies by the academic community. In this in- topical chloramphenicol (aplastic anemia) and subconjunctival stance, it was the general ophthalmologist who, in large part, fash- beta-lactams (allergic reactions), the usual adverse effect that may ioned the conversion from the “standard” approach.173 Although a follow administration of an antibiotic to the ocular surface is not a majority of ophthalmologists used a fluoroquinolone for initial toxic reaction but rather a local irritation. We will, however, use treatment, the use of fortified antibiotics was considered for treat- the word “toxic” herein because the vernacular is commonly used ment of more severe ulcers.173 Recently, in part because of the by ophthalmologists. A comprehensive review of conjunctival and practitioner’s appreciation for the effectiveness of empiric topical corneal toxicity of the topically applied antibiotics used over the antibiotic therapy, the importance of culturing for less severe in- past 25 years is beyond the scope of this review. Except for reports fection52 has been questioned.174 of toxicity seen clinically, both in vitro and in vivo animal models Although some authors report that 94–96% of cases respond are often difficult to extrapolate to the clinical condition because of well to initial therapy,52,174,175 other authors have reported that species differences and experimental conditions. However, some initial therapy had to be modified because of a worsening clinical generalizations can be made and several specific toxic effects can condition in 14–33% of eyes.53,176,177 The variation in recurrence be identified. rates is partially dependent on whether “culture-positive” or “total Many topical antibiotics can induce conjunctival hyperemia, number” is used for the denominator. In a study in which initial inflammation, and punctate corneal staining. Gentamicin and neo- treatment using two antibiotics to cover both gram-positive and mycin are more likely than other antibiotics to induce drug reac- gram-negative organisms had to be modified 24% of the time, such tions.184 Neomycin, especially, is noted to cause punctate corneal treatment was found to be appropriate in 94% of eyes, based on staining. Conjunctival necrosis and scarring can rarely ensue, es- subsequent culture and sensitivity findings.53 The apparent discor- pecially at concentrations higher than those in commercially pre- dance between in vitro and in vivo findings is discussed in the pared eyedrops.185 Routes and Frequency of Administration section. A 1998 survey of Experimental corneal epithelial studies, both in vivo186,187 and the membership of the Castroviejo Cornea Society, to which 64% in vitro,188–190 attest to aminoglycoside186,188 and vancomycin191 of members responded, revealed that a majority would perform toxicity at “fortified” drug concentration levels. In one study, to- diagnostic laboratory procedures for severe or central ulcers or if bramycin was less toxic than gentamicin.188 The differences be- the infection failed to respond. Of those who responded, 70% said tween the experimental and control study results in vivo, however, they would start therapy with fortified antibiotic eye drops, suggest little to no significant clinical risk. Nonanaphylactic idio- whereas only 10% indicated that they would use a fluoroquinolone syncratic reactions to the penicillins and cephalosporins are remote only as initial therapy178; and, 58% did not use subconjunctival when these antibiotics are administered topically. However, such a injections as a route of delivering antibiotics. Because the survey response may occur after a subconjunctival injection if there is a recipients were cornea specialists, they were more likely than gen- recent anaphylactic or pulmonary reactive history to these drugs. eral ophthalmologists to have laboratory services easily available. Vancomycin was shown to exhibit toxic effects at higher (50 mg/ They were also more likely, we suspect, to have been associated mL) but not lower (25 mg/mL) concentrations.98 Topical cipro- with teaching programs, and they may also have been referred floxacin and ofloxacin showed no greater epithelial toxicity in an more severe infections then those seen by community practitio- experimental in vitro model than a cephalosporin/aminoglycoside ners. Such factors may have affected their diagnostic and thera- combination.97 Topical ofloxacin was associated with a low inci- peutic choices. dence (2/30 patients) of ocular irritation192 in one study and with The treatment of a putative P. aeruginosa keratitis has presented fewer side effects than occurred with fortified combinations in

Cornea, Vol. 19, No. 5, 2000 668 J. BAUM AND M. BARZA another study.1 Crystalline corneal epithelial deposits have been in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis found to be associated with topical fluoroquinolone eye drop in- Study Group. Ophthalmology 1996;103:1854–63. stillation, with a possibly greater incidence associated with cipro- 3. O’Brien TP, Maguire MG, Fink NE, et al. Efficacy of ofloxacin vs. 193,194 cefazolin and tobramycin in the therapy for bacterial keratitis. Report floxacin than with ofloxacin. These deposits may also delay from the Bacterial Keratitis Study Research Group. Arch Ophthalmol reepithelialization.193 1995;113:1257–65. Studies of the toxic effects of antibiotics on the corneal endo- 4. Gold HS, Moellering RC Jr. Antimicrobial-drug resistance. New Engl thelium have usually used intracameral injections or have exposed JMed1996;335:1445–53. 5. Jones DB. Emerging antibiotic resistance: real and relative. Editorial. the endothelium to eye bank storage media containing antibiot- Arch Ophthalmol 1996;114:91–2. 195–202 ic. However, such models may not be the most appropriate 6. Mader TH, Maher KL, Stulting RD. Gentamicin resistance in staph- to evaluate the toxic risk of antibiotics to the endothelium during ylococcal corneal ulcers. Cornea 1991;10:408–10. treatment of microbial keratitis because the concentration of drug 7. Goldstein MH, Kowalski RK, Gordon YJ. Emerging fluoroquinolone reaching this layer will be low. Topically applied antibiotics, ad- resistance in bacterial keratitis. Ophthalmology 1999;106:1313–8. 8. Bower KS, Kowalski RP, Gordon YJ. Fluoroquinolones in the treat- ministered at suggested concentrations, appear to have no signifi- ment of bacterial keratitis. Am J Ophthalmol 1996;121:712–5. cant clinical effect on the corneal endothelium. 9. Chaudhry NA, Flynn HW, Murray TG, et al. Emerging ciprofloxacin- At present, chloramphenicol is not a drug of choice in the initial resistant P. aeruginosa. Am J Ophthalmol 1999;128:509–10. treatment of bacterial corneal ulcers for two main reasons. First, 10. Garg P, Sharma S, Rao GN. Ciprofloxacin-resistant pseudomonas keratitis. Ophthalmology 1999;106:1319–23. there are more effective antibiotics. Second, there is a risk, albeit 11. Kunimoto DY, Sharma S, Garg P, et al. In vitro susceptibility of minimal, of a fatal idiosyncratic aplastic anemia associated with bacterial keratitis pathogens to ciprofloxacin. Ophthalmology 1999; topical administration. Thus, its use is not indicated, unless the 106:80–5. pathogen is resistant to all other antibiotics that can be adminis- 12. Hodge WG, Bui DP, Cevallos V, et al. Frequency of recovery of tered topically.19 ciprofloxacin-resistant ocular isolates following topical ciprofloxacin therapy [abstract]. Invest Ophthalmol Vis Sci 1995;36:S155. 13. Bui DP, Dang SP, Hwang DG. 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