JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 24, Number 2, 2008© Mary Ann Liebert, Inc.DOI: 10.1089/jop.2007.0085

Trends in Resistance to Ciprofloxacin, Cefazolin, andGentamicin in the Treatment of Bacterial Keratitis

NATALIE A. AFSHARI,1 JOSEPH J. K. MA,2 SCOTT M. DUNCAN,1 ROBERTO PINEDA,2CHRISTOPHER E. STARR,2 FRANCIS CHAR DECROOS,1 CARL S. JOHNSON,1

and RON A. ADELMAN3

ABSTRACT

Purpose: The aim of this study was to evaluate the microbial profile, resistance patterns,and antibiotic sensitivity of bacterial keratitis to three commonly used ocular antibiotics.

Methods: All cases of bacterial keratitis referred to the Massachusetts Eye and Ear Infir-mary Microbiology Laboratory from two consecutive annual 10-month periods were reviewed.The bacterial profile and resistance to ciprofloxacin, cefazolin, and gentamicin was evaluatedwithin the two intervals.

Results: Of the 485 cultures analyzed, 66.4% (322) were positive for bacterial isolates. Ofthese, 19.2% were polymicrobial, 87.5% were gram-positive, and 12.5% were gram-negative.The most prevalent isolate was coagulase-negative Staphylococcus (45.5%), followed by S. au-reus (15.2%). The resistance patterns for gram-positive bacteria for ciprofloxacin for the firstversus second time interval were 12% and 22% (P � 0.04) respectively, for cefazolin 13% and23% (P � 0.04), and for gentamicin 4% and 7% (P � 0.36). The resistance patterns for gram-negative bacteria for ciprofloxacin, cefazolin, and gentamicin were not significantly differentin the two tested time periods (all P � 0.05).

Conclusions: There was increased resistance of gram-positive organisms to ciprofloxacinand cefazolin, but not gentamicin, in the two examined time periods. Increased resistance tothese commonly used antibiotics emphasizes the need for close follow-up after initial em-piric treatment, and maintaining a low threshold for selecting alternative therapy.

1Duke University Eye Center, Duke University Medical Center, Durham, NC.2Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA.3Yale University Eye Center, Yale Medical Center, New Haven, CT.

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INTRODUCTION

BACTERIAL KERATITIS CAN THREATEN vision andis considered an ophthalmic emergency. Each

year, 30,000 new cases are reported in the UnitedStates.1–4 To avoid loss of vision, topical antibi-otic treatment should be started immediately, be-fore final bacterial culture results are available.Since the introduction of the second-generation

fluoroquinolones in the 1990s, and the subse-quent studies demonstrating their equivalent ef-ficacy compared to the standard combination ofa fortified aminoglycoside and first-generationcephalosporin, there has been great debate abouthow best to treat bacterial keratitis. Further com-plicating this debate is the recent release of anewer generation of fluoroquinolones. Combina-tion antimicrobial therapy with fortified antibi-

otics remains effective, but this treatment has itsdrawbacks, including a short shelf-life, need forrefrigeration, no commercial availability, in-creased epithelial toxicity, contamination withother microorganisms, and cost.5–9 The principleadvantages of the fluoroquinolones are their lowocular toxicity, good corneal penetration, safetyprofile, commercial availability, and stability atroom temperature.7–18

Ciprofloxacin is a second-generation fluoro-quinalone with broad-spectrum coverage. Multi-ple studies have compared the effectiveness ofciprofloxacin monotherapy with the combinedtherapy of a fortified aminoglycoside andcephalosporin for the treatment of bacterial ker-atitis. These studies have shown that cipro-floxacin monotherapy is a safe, effective alterna-tive to the multidrug therapy.7,9,11,18,19 Otheralternative monotherapies include gatifloxacinand moxifloxacin, two fourth-generation broad-spectrum fluoroquinolones released in 2003.While these newer antibiotics have increased inusage domestically, ciprofloxacin is still heavilyused worldwide. In 2004, ciprofloxacin was avail-able in more than 100 countries, while moxi-floxacin was accessible in less than 10. That sameyear, ciprofloxacin continued to increase in inter-national use, while moxifloxacin was sold pri-marily in the United States.*,† The limited avail-ability, shorter track record, and greater expenseof the fourth-generation fluoroquinolones mayaccount for the disparity in increased utilizationdomestically versus internationally.

Shortly after the release of the antibiotics, therehave been multiple reports of resistant organ-isms. Ciprofloxacin was released in 1991, and in1992, Snyder and Katz reported 3 cases of bacte-rial keratitis that failed treatment with cipro-floxacin and which were culture-positive forciprofloxacin-resistant organisms.16 In 1996,Bower and colleagues looked at resistance pat-terns in 153 isolates from bacterial keratitis andfound an overall resistance to ciprofloxacin of17.7%.6 In a study from Pittsburgh, Goldstein andcoworkers reported resistance to ciprofloxacinwas 16.2% in 1993 versus 23.9% in 1997 (with41.1% resistance to gram-positives in 1997 vs.19.1% in 1993).8 A study by Alexandrakis andcoauthors conducted in South Florida reported anincreasing resistance of Staphylococcus aureus ker-

atitis isolates to ciprofloxacin or ofloxacin (11% in1990 to 28% in 199817). A 7-year report from In-dia looking at 1558 bacterial keratitis isolates re-vealed a 25% resistance to ciprofloxacin in 1991versus a 32% resistance in 1997.14 Marangon andcolleagues compared ciprofloxacin resistanceamong corneal and conjunctival S. aureus isolatesin South Florida for the years 1990–1995, com-pared with the years 1996–2001.20 Resistance inthe first 6 years was 8% (2% for methicillin-sen-sitive S. aureus [MSSA] and 55.8% for methicillin-resistant S. aureus [MRSA]). Resistance in thenext 6 years was 20.7% (5% for MSSA and 83.7%for MRSA).

Introduced in 2003, the fourth-generation flu-oroquinolones, moxifloxacin and gatifloxacin, arebecoming a popular alternative for the mono-therapy of bacterial keratitis. One study reportsimproved gram-positive activity and similar ac-tivity against gram-negatives in vitro, when com-pared to second-generation fluoroquinolones.21

Another study reports increased frequency of ul-cer healing when using gatifloxacin instead ofciprofloxacin.22 Despite the promise of these re-cently introduced antibiotics, resistance remainsa concern. In 2006, Moshirfar and coauthors re-ported the first 2 cases of resistance to the fourth-generation fluoroquinolones,23 and soon after,another series reported 5 more cases of resis-tance.24 Since these antibiotics have been so re-cently introduced, it is unclear whether, overtime, bacterial resistance will gradually emergein similar fashion to ciprofloxacin resistance.

These reports are discouraging for practition-ers worldwide considering ciprofloxacin mono-therapy for the treatment of bacterial keratitis.However, other studies support the continuedutility of ciprofloxacin in bacterial keratitis. Astudy from Brazil examining resistance patternsin bacterial keratitis isolates from 1985 to 2000showed only 7% of Pseudomonas isolates resistantto ciprofloxacin in the years 1997–2000 and only7% of S. aureus isolates resistant.25 Moreover theresistance to ciprofloxacin actually declined, com-pared with the previous 3-year period. Similarly,other studies both abroad and domestically donot demonstrate increased resistance to cipro-floxacin. Data from Australia between 2002 and2003 showed almost all bacterial isolates (51 of 53isolates) remained susceptible to ciprofloxacin,26

while a study in the Southeastern United Statesfrom 1997 to 2004 showed a similar result (63 of65 isolates susceptible).27

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*Alcon Annual Report 2004. 44, 2005.†Alcon Annual Report 2005. 53, 2006.

It is the aim of this paper to provide evidencefrom a retrospective study in Northeast UnitedStates that will help individual practitioners bet-ter understand the role ciprofloxacin monother-apy for certain corneal ulcers. We have comparedthe susceptibility statistics of gentamicin, cefa-zolin, and ciprofloxacin (Ciloxan; Alcon, Ft.Worth, TX) for both gram-positive and -negativebacteria and analyzed bacterial susceptibilityover time.

METHODS

A retrospective study of all cases of bacterialkeratitis that presented to the Massachusetts Eyeand Ear Infirmary Microbiology Laboratory(Boston, MA) from January 1, 1999 to October 31,1999 was compared to data from January 1, 2000to October 31, 2000. Institutional review boardapproval was obtained from the Human StudiesCommittee at the Massachusetts Eye and Ear In-firmary. All culture specimens taken from eyeswith presumed bacterial keratitis were processedaccording to laboratory protocol and followingthe standards of the National Committee for Clin-ical Laboratory Standards. Scrapings were ob-tained by using a Calgi swab and placed on achocolate agar, soy agar, and cooked meatmedium incubated at 37°C. Gram stains were alsoroutinely performed on the scrapings. Resistancepatterns were determined by using the Kirby-

Bauer disc-diffusion method, an automated min-imum inhibitory concentration (MIC) technique,or MicroScan Autoscan 4 (Dade-Behring, Sacra-mento CA) that tests in vitro MIC. Susceptibilitytests were performed for ciprofloxacin, gentam-icin, and cefazolin. The results were comparedacross the two time periods. Chi-square testswere used for statistical analysis.

RESULTS

A total of 485 cultures of bacterial keratitis wereobtained during the 2-year period. From January1, 1999 to October 31, 1999, 224 cultures were ob-tained and 261 were obtained during that sameinterval in 2000. Of the 485 cultures, 322 (66.4%)were culture-positive, and 62 (19.2%) were poly-microbial. In 1999, 70.1% of the cultures were pos-itive, compared with 63.2% in 2000. Polymicro-bial cultures were seen 30% of the time in 1999and in 9.1% in 2000. Among all isolates, 87.5%were gram-positive and 12.5% were gram-nega-tive.

The most prevalent isolate was coagulase-neg-ative Staphylococcus (45.5%), followed by S. au-reus. (15.2%), diphtheroids (5.7%), viridians Strep-tococcus (5.7%), Serratia marcescens (2.7%), S.pneumonia (2.7%), and Pseudomonas aeruginosa(2.7%; Fig. 1).

As shown in Table 1, significant differenceswere noted in cumulative resistance patterns for

ANTIBIOTIC RESISTANCE IN BACTERIAL KERATITIS 219

FIG. 1. Microbial profile of all culture-positive bacterial keratitis.

all isolates for ciprofloxacin in the years 1999 and2000 (11% and 19% respectively; P � 0.06) and forcefazolin (15% and 30%; P � 0.003) (Fig. 2). Theresistance patterns for gram-positive bacteria forciprofloxacin in 1999 and 2000 were 12% and 22%(P � 0.04) respectively, for cefazolin 13% and 23%(P � 0.04) and for gentamicin 4% and 7% (P �0.36). The resistance patterns for gram-negativebacteria for ciprofloxacin in 1999 and 2000 were,respectively, 0% and 4%, for cefazolin 50% and70%, and for gentamicin 6% and 8% (all P � 0.05;Fig. 3).

DISCUSSION

Immediate initiation of effective antibiotics isparamount for the treatment of bacterial keratitisin order to minimize corneal scarring and preventa permanent loss of vision. The necessity of initi-ating treatment with an antibiotic that is highlylikely to be effective is magnified by the fact that

many practitioners do not routinely culturecorneal ulcers.28 Therefore, it is essential that re-sistance patterns be evaluated periodically. An-tibiotic resistance is not a static phenomenon. Asis evidenced by the last decade and a half of re-ports on ciprofloxacin, resistance varies geo-graphically and changes over time.8,12,14–17,29 Aspractitioners, we would like to have a standardtreatment algorithm. However, as this study un-derscores, resistance patterns must be continuallyevaluated, and data from one place and time isnot easily extrapolated to other treatment centersin different years.

In our study, a significant rise in gram-positiveresistance to cefazolin was noted. Our findings ofhigh resistance to cefazolin in gram-positive bac-teria is in contrast to the findings of Schaefer andcolleagues and Bower and coauthors5,6 Theyshowed susceptibility to cefazolin in greater than90% of the isolates. The difference of findings,compared to findings by Schaefer and coworkers,may be due to the difference in the location where

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TABLE 1. PERCENTAGE OF ANTIBIOTIC RESISTANCE FOR THE YEARS 1999 AND 2000

Cumulative Gram-positive Gram-negativeAntibiotic Year resistance resistance resistance

Ciprofloxacin 1999 11 12 02000 19 22 4

Cefazolin 1999 15 13 502000 30 23 70

Gentamicin 1999 5 4 62000 7 7 8

FIG. 2. Percentages of all bacteria resistant to ciprofloxacin, cefazolin, and gentamicin. *Difference between the yearsis statistically significant, P � 0.05.

each study was conducted; New England versusSwitzerland. Gentamicin resistance remained lowfor both gram-positive and gram negative bacte-ria. Gentamicin is not typically utilized in oph-thalmology, perhaps owing to a lack of familiarityof ophthalmologists with the drug. For example,ophthalmologists do not commonly use topicalaminoglycosides in other aspects of their practice,while fluoroquinolones, in contrast, are frequentlyused in cataract surgery chemoprophylaxis. Less-frequent usage of gentamicin relative to cipro-floxacin may be responsible for the low, relativelystable resistance rates we observed.

The microbial profile showed a high rate ofgram-positive infections (87.5%), compared togram-negative infections (12.5%). Comparing ourresults to a similar study at the same institutionfrom 1977 to 1981 demonstrates an increasingproportion of gram-positive bacteria (64% of bac-terial isolates were gram-positive, compared to87.5% in our study).30 Schlegel and others inFrance found a significant increase in the gram-positive bacteria S. aureus and S. pneumoniae be-tween 1998 and 1993.31 However, Goldstein andinvestigators and Alexandrakis and researchersdid not find the same trend.8,16 The trend towardmore gram-positive bacteria may reflect thewidespread use of ciprofloxacin as the drug ofchoice for the treatment of bacterial keratitis. Sev-eral studies have shown ciprofloxacin to be lesseffective against gram-positive isolates, espe-cially S. aureus.8,10,16,29 Since ciprofloxacin is less

effective against gram-positive bacteria, its wide-spread use may have helped select for the in-creased proportion of gram-positive bacteria seenin our review.

Figures 2 and 3 shows increasing resistance tociprofloxacin in all bacteria, but especially ingram-positive bacteria. This is consistent with theresults found by Goldstein and investigators,who found an increased resistance to cipro-floxacin by S. aureus and a trend toward increasedresistance by Streptococcus sp. and coagulase-neg-ative Staphylococcus from 1993 to 1997.8 Alexan-drakis and researchers also found an increasedresistance of S. aureus to ciprofloxacin in SouthFlorida.16 The statistically significant resistance(P � 0.04) found in this study was probably ow-ing to the increased resistance of more than justS. aureus because of the large change in resistanceseen only over the period of 1 year. Knauf andcoworkers also showed a generalized increase inresistance to ciprofloxacin, especially in S. aureusand coagulase-negative Staphylococcus.15 Unlikethe other studies that examined trends over sev-eral years, this study found significant changes inresistance across a 2-year time period. It seemsthat ciprofloxacin resistance has developed muchquicker than originally hypothesized, based onthe location of the DNA gyrase gene.12 The in-creasing resistance in gram-positive, and the sug-gested rising resistance in gram-negative, bacte-ria, combined with the increasing prevalence ofgram-positive bacterial keratitis reported in this

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FIG. 3. Percentages of gram-positive and -negative bacteria resistant to ciprofloxacin, cefazolin, and gentamicin.

study, suggests that ciprofloxacin may not be ap-propriate as a monotherapy for all cases of bac-terial keratitis.

Since newer fourth-generation fluoroquino-lones have become available, the practitionermust weigh the possible benefits, including de-creased resistance and increased effectiveness,with cost and shorter track record. Large studiesexamining resistance patterns of antibiotics thatretain widespread use will be critical in the ever-evolving treatment battle. Moreover, these stud-ies caution against complacency as the transitionto newer generation antibiotics progresses. Expe-rience with the second-generation fluoroquino-lones has taught that knowing regional variation,with respect to both bacterial spectrum and re-sistance, is essential.

It should be noted that our study used in vitrotests, and there are some limitations to thesetests. In the clinical setting, patients that are us-ing ciprofloxacin monotherapy will probablyhave much higher levels of the drug on thecornea than the mean inhibitory concentrationused in the in vitro studies.8,16 Further, there areother aspects of the in vitro procedure that donot correlate to the clinical setting, such ascorneal penetration.16 However, currently, invitro studies are the standard methods for de-termining resistance to antibiotics. Ideally, ameasure is necessary to compare in vitro studiesand clinical outcomes for antibiotics. Futurestudies with larger patient populations shouldalso examine the increased resistance of gram-positive bacteria to cefazolin.

CONCLUSIONS

In summary, our study found a high incidenceof gram-positive bacterial ulcers, which is con-sistent with other reports of increased incidenceof gram-positive bacteria. We noted a slight in-crease in ciprofloxacin resistance for gram-nega-tive bacteria, but more concerning, we observeda significant increase in the resistance of gram-positive bacteria to ciprofloxacin. In addition, in-creased resistance to cefazolin was shown ingram-positive bacteria. Gentamicin resistance re-mained relatively low in all bacteria. Based onthese results, we recommend that caution be usedwhen prescribing ciprofloxacin as monotherapyfor bacterial keratitis. Moreover, we must con-tinue to examine resistance patterns to stay a step

ahead in the continuing effort to close the resis-tance gap.

ACKNOWLEDGMENT

Natalie Afshari MD has research award fromResearch to Prevent Blindness.

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Received: July 22, 2007Accepted: November 19, 2007

Reprint Requests: Natalie A. AfshariDuke University Eye Center

Duke University Medical CenterBox 3802

Durham, NC 27710

E-mail: afsha003@mc.duke.edu

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