|Year : 1999 | Volume
| Issue : 2 | Page : 95-100
Trends in antibiotic resistance of corneal pathogens: Part I. An analysis of commonly used ocular antibiotics
Savitri Sharma1, Derek Y Kunimoto2, Prashant Garg1, Gullapalli N Rao1
1 Jhaveri Microbiology Centre and Cornea Service, L.V. Prasad Eye Institute, Hyderabad, India
2 Harvard Medical School, Boston, USA
L.V. Prasad Eye Institute, L.V. Prasad Marg, Banjara Hills, Hyderabad -500 034
Source of Support: None, Conflict of Interest: None
Purpose: To analyse commonly used ocular antibiotics and determine their in-vitro efficacies against bacterial keratitis pathogens.
Methods: A retrospective review of microbiology records at the LV Prasad Eye Institute in Hyderabad, India identified 1,633 bacterial keratitis isolates. Antibiotic susceptibility of corneal isolates was determined for various ocular antibiotics using the Kirby-Bauer disc-diffusion method. Results: Cefazolin had coverage against 1,296 (83.0%) of 1,562 isolates tested; chloramphenicol against 1,136 (71.7%) of 1,585 isolates; ciprofloxacin against 1,080 (69.3%) of 1,558 isolates; gentamicin against 1,106 (70.6%) of 1,567 isolates; norfloxacin against 1,057 (67.7%) of 1,561 isolates; vancomycin against 463 (84.3%) of 549 isolates; and framycetin against 105 (36.2%) of 290 isolates. Also included is a breakdown by species, and sensitivity profiles for resistant isolates.Conclusion: This study provides information on the efficacies of ocular antibiotics commonly used against bacterial keratitis pathogens. It also examines the antibiotic susceptibility profiles for corneal pathogens that are resistant to an ocular antibiotic but sensitive to other selected antibiotics. It is hoped that this information will aid in the decision-making of empiric initial treatment of bacterial keratitis.
Keywords: Bacterial keratitis, culture, antibiotic sensitivity, antibiotic resistance, treatment
|How to cite this article:|
Sharma S, Kunimoto DY, Garg P, Rao GN. Trends in antibiotic resistance of corneal pathogens: Part I. An analysis of commonly used ocular antibiotics. Indian J Ophthalmol 1999;47:95-100
|How to cite this URL:|
Sharma S, Kunimoto DY, Garg P, Rao GN. Trends in antibiotic resistance of corneal pathogens: Part I. An analysis of commonly used ocular antibiotics. Indian J Ophthalmol [serial online] 1999 [cited 2018 Nov 17];47:95-100. Available from: http://www.ijo.in/text.asp?1999/47/2/95/22799
Bacterial keratitis is a potentially devastating infection that can rob a patient of sight. Many series have attempted to identify predisposing factors, discuss treatment modalities with outcomes, and examine pediatric or elderly populations to highlight unique age-related features, with the aim of improving the diagnosis and management of bacterial keratitis. Equally important is the proper identification of the corneal pathogens which cause the bacterial keratitis.
While certain associations such as Pseudomonas keratitis and the use of contact lens are well described in the literature,, ,  the occurrence rates of corneal pathogens are largely dictated by the local microbial flora, which account for the disparate rates of various pathogens reported in series from different localities.,,
In this communication, the authors present bacterial keratitis culture and in-vitro sensitivity results from the LV Prasad Eye Institute (LVPEI), Hyderabad, India. Part I of this series is addressed mainly to community-based ophthalmologists who do not have access to extensive microbiology facilities, and discusses the in-vitro effectiveness of commonly used ocular antibiotics describing their coverage of bacterial species, in the hope that this information will aid in the decision-making of empiric initial treatment. Part II of this series is addressed to ophthalmologists who have access to microbiology facilities, and describes the trends in antibiotic resistance developed by common ocular pathogens so that when a corneal pathogen is identified, a rational approach for initial therapy may be adopted taking into account changing trends in antibiotic susceptibility.
| Materials and Methods|| |
A retrospective review of microbiology records at LVPEI identified 1,633 bacterial isolates from 1,353 patients of culture-proven bacterial keratitis seen between 1 March, 1991 and 30 June, 1997.
Corneal scrapings were obtained using standard techniques, with a sterile Bard Parker blade (#15). The scrapings were inoculated directly onto sheep blood agar, chocolate agar, thioglycolate, and brain heart infusion broth. These media were incubated at 37°C. The blood agar plates were each incubated under aerobic and anaerobic conditions, and chocolate agar was incubated in 5% carbon dioxide. Media and nutrients to enable growth of fungi and parasites (Acanthamoeba) were also included as part of the standard corneal scraping culture protocol, as was microscopic evaluation of corneal smears by Gram stain, Giemsa stain, KOH preparation, and KOH with calcofluor white under fluorescence. Acid-fast stains (Ziehl-Neelsen and Kinyoun) and immuno-cytochemistry stains were performed when indicated. A culture was considered positive when there was growth of the same organism on two or more media, confluent growth at site of inoculation on one solid medium, growth in one medium with consistent direct microscopy findings, or growth of the same organism on repeated corneal scraping.
Antibiotic susceptibility was determined for all positive cultures using the Kirby-Bauer disc-diffusion method and antibiotic treatment was modified accordingly in the absence of clinical response to initial antibiotic therapy. Susceptibility was graded as either resistant (R), intermediate sensitivity (I), or sensitive (S). Antibiotic discs were obtained from Hi-Media, Mumbai and were always tested for efficacy using standard ATCC (American Type Culture Collection) bacteria (S. aureus, P. aeruginosa and E. coli) as a general quality-control laboratory procedure.
Susceptibility of isolated corneal pathogens to commonly used ocular antibiotics was examined, with sensitive being defined as not R or I by the Kirby-Bauer disc-diffusion method [Table - 1]. All bacterial pathogens not sensitive to a certain antibiotic were examined for susceptibility to other antibiotics [Table - 2].
| Results|| |
A total of 1,633 bacterial isolates from 1,353 patients were examined in this series. Gram-positive cocci accounted for 1,129 (69.1%) of all bacterial isolates, gram-positive bacilli for 309 (18.9%), gram-negative cocci for 22 (1.3%), gram-negative bacilli for 151 (9.2%), and acid-fast or partially acid-fast organisms for 22 (1.3%) (see [Table - 1]).
Cefazolin had coverage against 1,296 (83.0%) of 1,562 tested isolates. Among these organisms, 1000 (91.4%) of 1,094 gram-positive cocci, 250 (89.0%) of 281 gram-positive bacilli, 13 (59.1%) of 22 gram-negative cocci, 25 (17.5%) of 143 gram-negative bacilli, and 8 (36.4%) of 22 acid-fast or partially acid-fast organisms were covered by cefazolin.
Chloramphenicol had coverage against 1,136 (71.7%) of 1,585 tested isolates. Among these organisms, 856 (77.4%) of 1,106 gram-positive cocci, 182 (62.5%) of 291 gram-positive bacilli, 21 (95.5%) of 22 gram-negative cocci, 65 (45.1%) of 144 gram-negative bacilli, and 12 (54.5%) of 22 acid-fast or partially acid-fast organisms were covered by chloramphenicol.
Ciprofloxacin had coverage against 1,080 (69.3%) of 1,558 tested isolates. Among these organisms, 736 (67.5%) of 1,091 gram-positive cocci, 187 (66.8%) of 280 gram-positive bacilli, 20 (90.9%) of 22 gram-negative cocci, 123 (86.0%) of 143 gram-negative bacilli, and 14 (63.6%) of 22 acid-fast or partially acid-fast organisms were covered by ciprofloxacin.
Gentamicin had coverage against 1,106 (70.6%) of 1,567 tested isolates. Among these organisms, 735 (67.1%) of 1,095 gram-positive cocci, 202 (71.9%) of 281 gram-positive bacilli, 21 (95.5%) of 22 gram-negative cocci, 126 (85.7%) of 147 gram-negative bacilli, and 22 (100%) of 22 acid-fast or partially acid-fast organisms were covered by gentamicin.
Norfloxacin had coverage against 1,057 (67.7%) of 1,561 tested isolates. Among these organisms, 732 (67.1%) of 1,091 gram-positive cocci, 175 (62.9%) of 282 gram-positive bacilli, 20 (90.9%) of 22 gram-negative cocci, 124 (86.1%) of 144 gram-negative bacilli, and 6 (27.3%) of 22 acid-fast or partially acid-fast organisms were covered by norfloxacin.
Vancomycin had coverage against 463 (84.3%) of 549 tested isolates. Among these organisms, 343 (94.5%) of 363 gram-positive cocci, 98 (89.9%) of 109 gram-positive bacilli, 9 (100%) of 9 gram-negative cocci, 7 (12.3%) of 57 gram-negative bacilli, and 6 (54.5%) of 11 acid-fast or partially acid-fast organisms were covered by vancomycin.
Framycetin had coverage against 105 (36.2%) of 290 tested isolates. Among these organisms, 68 (34.3%) of 198 gram-positive cocci, 30 (50.8%) of 59 gram-positive bacilli, 1 (25.0%) of 4 gram-negative cocci, 5 (19.2%) of 26 gram-negative bacilli, and 1 (33.3) of 3 acid-fast or partially acid-fast organisms were covered by framycetin.
For those isolates not sensitive to cefazolin, sensitivity to other commonly used ocular antibiotics was examined [Table - 2], with gentamicin found to cover the largest percentage of cefazolin-resistant bacteria (65.3%), and framycetin the lowest percentage of cefazolin-resistant bacteria (26.2%). Of those isolates not sensitive to chloramphenicol, cefazolin covered the largest percentage of chloramphenicol-resistant bacteria (68.1%) and framycetin covered the lowest (40.5%). Of those isolates not sensitive to ciprofloxacin, vancomycin covered the largest percentage of ciprofloxacin-resistant bacteria (80.5%) and framycetin covered the lowest (14.1%). Of those isolates not sensitive to gentamicin, vancomycin covered the largest percentage of gentamicin-resistant bacteria (81.1%) and framycetin covered the lowest (8.7%). Of those isolates not sensitive to norfloxacin, vancomycin covered the largest percentage of norfloxacin-resistant bacteria (79.7%) and framycetin covered the lowest (19.6%). Of those isolates not sensitive to vancomycin, gentamicin covered the largest percentage of vancomycin-resistant bacteria (57.0%) and framycetin covered the lowest (0%). Of those isolates not sensitive to framycetin, cefazolin covered the largest percentage of framycetin-resistant bacteria (75.8%) and vancomycin covered the lowest (26.7%).
| Discussion|| |
An in-vitro susceptibility analysis of all corneal pathogens isolated between 1991 and 1997 reveals that the antibiotics with greatest coverage are vancomycin (84.3% of 549 isolates) and cefazolin (83.0% of 1,562 isolates) [Table - 1]. While both have excellent coverage against gram-positive cocci, which constitute the majority (69.1%) of corneal isolates, a gap of coverage exists in the gram-negative organisms. For this reason, monotherapy with these antibiotics is not advised. However, if combined with another ocular antibiotics such as an aminoglycoside or fluoroquinolone, broader coverage can be achieved [Table - 2]. Fifty-seven percent of vancomycin-insensitive isolates were sensitive to gentamicin, followed by 56.5% sensitive to ciprofloxacin, whereas 65.3% of cefazolin-insensitive isolates were sensitive to gentamicin, followed by 62.6% sensitive to ciprofloxacin. Because second-line coverage by gentamicin is better in combination with cefazolin than with vancomycin, a broader coverage can be obtained with a cefazolin-gentamicin combination than with a vancomycin-gentamicin combination. Of note, this cephalosporin-aminoglycoside combination is an established approach for the initial empiric therapy of bacterial keratitis.,
Fluoroquinolones and their effectiveness as initial monotherapy in the treatment of bacterial keratitis have been the topic of much recent discussion., This series also indicates that fluoroquinolones have a broad spectrum of action, but reveals a rate of insensitivity that is too high to justify its use as monotherapy for initial treatment of bacterial ulcers.
The goal of initial antibiotic therapy for bacterial keratitis is the proper selection of a drug which has coverage for the aetiopathogen. Microscopic evaluation of corneal smears can provide insight into the identity of the pathogen, but when smear examination is uninformative the principle of managing bacterial keratitis has been to use antibiotics which have coverage that is sufficiently broad and effective to treat the leading corneal pathogens.,, In a recent in-vitro study of corneal pathogens, a fluoroquinolone-cefazolin combination was reported as a reasonable alternative to an aminoglycoside-cefazolin combination in the initial treatment of bacterial keratitis. The results of this present study also support the broad coverage and in-vitro effectiveness of a fluoroquinolone-cefazolin combination against corneal pathogens [Table - 1] and [Table - 2]. However, it must be noted that these conclusions are based on theoretical susceptibility and do not consider synergistic or antagonistic effects of antibiotics used in combination. Likewise, based on in-vitro susceptibility, a fluoroquinolone-vancomycin combination is a reasonable alternative to an aminoglycoside-cefazolin combination in the initial treatment of bacterial keratitis [Table - 1] and [Table - 2], although a clinical trial of such a combination has never been reported.
For ophthalmologists without access to microbiology facilities and treating patients on an empirical basis, [Table - 2] provides information which may guide the clinician in making a decision when a change in antibiotic is necessary due to an unsatisfactory clinical response to initial antibiotic therapy. Although results suggest that no single antibiotic tested in this series would be appropriate as initial empiric monotherapy for bacterial keratitis, either due to a gap in coverage or unacceptably low coverage, the information in [Table - 2] allows the clinician to formulate a considered approach in deciding second-line antibiotic use. For instance, if a pathogen does not respond to treatment with ciprofloxacin, vancomycin or cefazolin would be an appropriate second-line antibiotic, since the ciprofloxacin-insensitive isolates in this series were 80.5% susceptible to vancomycin and 79.1% susceptible to cefazolin.
It must be noted that these are in-vitro results, and one of the limitations of using in-vitro antibiotic sensitivity as a surrogate for in-vivo effectiveness is that antibiotic sensitivities do not always mirror the clinical response to an antibiotic for a variety of reasons, including direct topical delivery, corneal penetration of an antibiotic and host factors.,,, However, these results do provide information that allow a clinician to make rationale-based decisions in choosing an initial treatment regimen which provides broad-based coverage for common corneal pathogens. Further, these results provide susceptibility information for corneal pathogens resistant to commonly used ocular antibiotics. As per the Medline search this is the largest such series in the recent literature.
It must also be noted that the data presented here has been accumulated in Hyderabad, India, and varying localities in turn have varying microbial flora. Furthermore, LV Prasad Eye Institute is a tertiary referral care center, and hence the pathogens reported in this series may not be truly representative of the pathogens encountered in a community-based practice.
The information provided in this paper is not intended to encourage the treatment of bacterial keratitis without an attempt to identify the corneal pathogen. Although access to microbiology facilities may be limited in the community-setting, which makes it difficult to follow the proper protocol of taking corneal scrapings in all suspected cases and to modify treatment based on microbiology reports, it is nonetheless essential. It is not advisable to begin treatment with broad-spectrum antibiotics without taking steps to identify the aetiologic microbe. If the proper protocol cannot be followed, the patient should be referred to an institution which has the proper facilities. It is hoped that the information provided in this paper will aid the clinician in formulating rationale-based decisions in the antibiotic treatment of bacterial keratitis.
| Acknowledgement|| |
This study was supported by a grant from Hyderabad Eye Research Foundation.
| References|| |
Burd EM, Ogawa GSH, Hyndiuk RA. Bacterial keratitis and conjunctivitis. In:Smolin G, Thoft RA, editors. The Cornea. Scientific Foundations and Clinical Practice
. 3rd ed. Boston:Little, Brown, & Co, 1994. p 115-67.
Liesegang TJ, Forster RK. Spectrum of microbial keratitis in South Florida. Am J Ophthalmol
Ormerod LD, Hertzmark E, Gomez DS, Stabiner RG, Schanzlin DJ, Smith RE. Epidemiology of microbial keratitis in Southern California. A multivariate mnalysis. Ophthalmology
McClellan KA, Bernard BJ, Billson FA. Microbial investigations in keratitis at the Sydney Eye Hospital. Aust NZ J Ophthalmol
Ormerod LD. Causation and management of microbial keratitis in subtropical Africa. Ophthalmology
Ormerod LD, Murphree AL, Gomez DS, Schanzlin DJ, Smith RE. Microbial keratitis in children. Ophthalmology
Cruz OA, Sabir AM, Capo H, Alfonso EC. Microbial keratitis in childhood. Ophthalmology
Clinch TE, Palmon FE, Robinson MJ, Cohen EJ, Barron BA, Laibson PR. Microbial keratitis in children. Am J Ophthalmol
Ormerod LD. Causes and management of bacterial keratitis in the elderly. Can J Ophthalmol
Neumann M, Sjostrand J. Central microbial keratitis in a Swedish city population. A three-year prospective study in Gothenburg. Acta Ophthalmol Copenh
Leibowitz, HM. Clinical evaluation of ciprofloxacin 0.3% ophthalmic solution for treatment of bacterial keratitis. Am J Ophthalmol
O'Brien TP, Maguire MG, Fink NE, Alfonso E, McDonnell P. Efficacy of Ofloxacin vs Cefazolin and Tobramycin in the therapy for bacterial keratitis. Arch Ophthalmol
Wahl JC, Katz HR, Abrams DA. Infectious keratitis in Baltimore. Ann Ophthalmol
Laibson, PR, Cohen EJ, Rajpal RK. Corneal ulcers related to contact lenses. CLAO J
Fleiszig SM, Efron N, Pier GB. Extended contact lens wear enhances Pseudomonas aeruginosa
adherence to human corneal epithelium. Invest Ophthalmol Vis Sci
Asbell P, Stenson S. Ulcerative keratitis: Survey of 30 years' laboratory experience. Arch Ophthalmol
Gonawardena SA, Ranasinghe KP, Arseculratne SN, Seimon CR, Ajello L. Survey of mycotic and bacterial keratitis in Sri Lanka. Mycopathologia
Williams G, McClellan K, Billson F. Suppurative keratitis in rural Bangladesh:the value of gram stain in planning management. Int Ophthalmol
Jones DB, Liesegang TJ, Robinson NM. Laboratory Diagnosis of Ocular Infections.
Washington DC:Cumitech 13, American Society for Microbiology; 1981.
Hyndiuk RA, Eiferman RA, Caldwell DR, Rosenwasser GO, Santos CI, Katz HR, et al.
Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ophthalmololy
Wilhelmus KR, Hyndiuk RA, Caldwell DR, Abshire RL, Folkens AT Godio LB. 0.3% Ciprofloxacin ophthalmic ointment in the treatment of bacterial keratitis. Arch Ophthalmol
Parks DJ, Abrams DA, Sarfarazi FA, Katz HR. Comparison of topical Ciprofloxacin to conventional antibiotic therapy in the treatment of ulcerative keratitis. Am J Ophthalmol
Jones DB. Decision-making in the management of microbial keratitis. Ophthalmology
Bower KS, Kowalski MS, Gordon YJ. Fluoroquinolones in the treatment of bacterial keratitis. Am J Ophthalmol
Ormerod LD, Heseltine PNR, Alfonso E, Becker MI, Kenyon KR, Baerveldt G, et al.
Gentamicin-resistant Pseudomonal infection:Rationale for a redefinition of ophthalmic antimicrobial sensitivities. Cornea
[Table - 1], [Table - 2]