Microbial Keratitis in Los Angeles The Doheny Eye Institute and the Los Angeles County Hospital Experience Daniel Sand, MD,1 Rosemary She, MD,2 Ira A. Shulman, MD,2,3 David S. Chen, BA,4 Mathew Schur, BA,4 Hugo Y. Hsu, MD5 Objective: To evaluate the spectrum and antibiotic susceptibility panel of infectious keratitis at a major tertiary care referral eye center and a major county hospital in Southern California. Design: Retrospective case series. Participants: All cultured infectious keratitis cases from July 1, 2008, through December 31, 2012, from the Doheny Eye Institute (DEI) and the Los Angeles County þ University of Southern California Medical Center (LACþUSC) were evaluated. Methods: Microbiology records were reviewed retrospectively. Main Outcome Measures: Microbial isolates as well as antibiotic susceptibility patterns were analyzed. Results: One hundred eighty-four (63%) of 290 cases showed positive culture results at DEI and 152 (82%) of 186 cases showed positive culture results at LACþUSC. Gram-positive pathogens were found to be the most common at both DEI (70%) and LACþUSC (68%), with coagulase-negative Staphylococcus being the most common gram-positive organism (58% at DEI and 44% at LACþUSC). Pseudomonas aeruginosa was the most common gram-negative organism (57% at DEI and 43% at LACþUSC). Ciprofloxacin and levofloxacin susceptibility for all tested pathogens was 73% at DEI and 81% at LACþUSC (P ¼ 0.16). Oxacillin-resistant Staphylococcus aureus (ORSA) was found in 42% of cases at DEI and in 45% of cases at LACþUSC (P ¼ 1.00). Conclusions: There is no significant difference in the spectrum of pathogens or antibiotic susceptibility of pathogens at DEI versus LACþUSC, and ORSA was found in approximately half of all S. aureus samples. Ophthalmology 2015;122:918-924 ª 2015 by the American Academy of Ophthalmology.
Microbial keratitis is an ocular emergency and historically has been quoted to affect 11 per 100 000 or 30000 new cases annually in the United States,1,2 and in more recent studies, approximately 30 per 100 000 new cases.3 Certain risk factors, including contact lens wear, can increase the incidence to 180 per 100 000.4 Classically, empiric therapy often is initiated with fortified antibiotics after stain and cultures are sent for microbiologic analysis for further evaluation. More commonly now, many practitioners in the community choose fluoroquinolone monotherapy without culture analysis.5e7 Initial therapy is guided by taking into account the clinical setting and current as well as historical data from the hospital’s antibiogram.8,9 With the evershifting make up of pathogens and resistance patterns, it is important for the clinician to be on the front line and very well aware of the data from local microbiology laboratories and their antibiograms. A recent example of regional differences can be highlighted when comparing publications from the United Kingdom from cities that are fewer than 125 miles apart where a difference in the pathogens was documented.10,11 In the series from Oxford, most of the pathogens were gram positive (54.3%), whereas in the series from East Kent, most of the pathogens were gram negative (61.1%).
918
2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
Los Angeles is a city with the second highest population in the United States. Yet despite this and its unique climate, there is a paucity of infectious keratitis and ocular microbiologic data from Los Angeles and Southern California. Herein we report the isolates and antibiotic resistance pattern of infectious keratitis cases at a major tertiary care referral center in Southern California, the Doheny Eye Institute (DEI), and the major county hospital serving the indigent in the same geographic area, the Los Angeles County þ University of Southern California Medical Center (LACþUSC). These 2 institutions were served by the same department of ophthalmology at the time of the study and are less than 0.5 miles apart from each other, but serve different patient populations. We wished not only to reveal and elucidate the spectrum of pathogens causing microbial keratitis in Southern California, but also to see if the 2 institutions under the same department serving different populations had significantly different antibiotic susceptibility profiles.
Methods An institutional review board-approved retrospective case series review was performed. All infectious keratitis cases that were http://dx.doi.org/10.1016/j.ophtha.2014.11.027 ISSN 0161-6420/15
Sand et al
Microbial Keratitis in Los Angeles
cultured and submitted for microbiologic analysis from July 1, 2008, through December 31, 2012, were reviewed for pathogens and antibiotic susceptibilities. The specimens from DEI were sent to the Keck Medical Center microbiology laboratory, whereas the specimens from LACþUSC were sent to the microbiology department at LACþUSC. Patients at DEI were identified by searching the billing database for the International Classification of Diseases, ninth edition, codes of 370.0x. This was cross-referenced and confirmed with a list of specimens sent to the Keck Medical Center Microbiology Laboratory. The medical record then was used to extract information about growth and susceptibility of pathogens. Patients at LACþUSC were identified by obtaining a list of all ophthalmic specimens submitted to the microbiology department at LACþUSC and by filtering this only for corneal cultures. The medical record then was used to extract information regarding growth and susceptibility of pathogens. Depending on the laboratory and the pathogen as well as its resistance to antibiotics, the following antimicrobial agents were used in susceptibility testing: clindamycin, erythromycin, gentamicin, levofloxacin, oxacillin, trimethoprim plus sulfamethoxazole, vancomycin, tetracycline, rifampin, daptomycin, chloramphenicol, ceftriaxone, ampicillin plus sulbactam, cefoxitin, ampicillin, linezolid, tigecycline, piperacillin plus tazobactam, amikacin, cefepime, meropenem, aztreonam, cefotaxime, cefazolin, imipenem, nitrofurantoin, streptomycin, and quinupristin plus dalfopristin. However, we recorded only medications usually used by ophthalmologists. Routine bacteriologic cultures were performed by the Keck Hospital or the LACþUSC microbiology laboratories. Isolates were identified by the Vitek2 system (bioMérieux, Durham, NC) or by manual biochemical reactions using standard microbiologic protocols. Antimicrobial susceptibility testing was performed by either the Vitek2 system or manually by E-test (bioMérieux) to determine minimal inhibitory concentrations in accordance with Clinical Laboratory Standards Institute performance standards. Statistical analyses were carried out using the chi-square test and Fisher exact test using GraphPad Prism software version 6 (GraphPad, La Jolla, CA). Statistical significance was set at P 0.05.
Results Pathogens Data from Doheny Eye Institute. From the data at DEI, a total of 290 cultured cases were identified. The average age of the patients was 62.5 years (range, 12e102 years). One hundred eighty-four (63%) of 290 cases had positive culture results and 144 (78%) of 184 cases demonstrated a single pathogen in culture. The remaining 40 culture-positive cases were polymicrobial. A total of 236 organisms were isolated from all cultures and 49 unique organisms were identified. One hundred sixty-five (70%) of 236 organisms were gram positive, 49 (21%) of 236 organisms were gram negative, and 22 (9%) of 236 organisms were classified as other. Fungal organisms made up 21 of the 22 other organisms, and there was 1 case of Acanthamoeba. The most common gram-positive pathogen was found to be nonspeciated coagulase-negative Staphylococcus (61 of 165 [37%]), and Staphylococcus epidermidis was found to be the second most common organism (32 of 165 [19%]). The most common gram-negative pathogen was Pseudomonas aeruginosa (28 of 49 [57%]). The most common organism classified as other was Candida tropicalis (3 of 22 [14%]; Table 1). Data from Los Angeles County D University of Southern California Medical Center. A total of 186 cases were identified from the microbiology database. The average age of the patients was 41.7 years (range, 2e97 years). One hundred fifty-two (82%)
of 186 cases had positive culture results, and 98 cases (64%) were monomicrobial. The remaining 54 cases were polymicrobial. A total of 227 organisms were identified, of which 47 were unique. One hundred fifty-four (68%) of 227 organisms were gram positive, 49 (21%) of 227 organisms were gram negative, and 24 (11%) of 227 organisms were classified as other. Fungal organisms made up all organisms in the other category. Nonspeciated coagulasenegative Staphylococcus was the most commonly identified gram-positive bacteria (32 of 154 [21%]) along with S. epidermidis (32 of 154 [21%]). The most common gram-negative pathogen was P. aeruginosa (21 of 49 [43%]). The most common fungal organism was Candida albicans (7 of 24 [29%]).
Antimicrobial Susceptibility Data from Doheny Eye Institute. Ciprofloxacin plus levofloxacin susceptibility of all tested pathogens was 73% (128 of 176), whereas gentamicin plus tobramycin susceptibility was 93% (148 of 160). Forty-two percent of Staphylococcus aureus (8 of 19) cases were classified as oxacillin-resistant S. aureus (ORSA; Table 2). Vancomycin susceptibility of ORSA isolates was 100% (8 of 8). Overall, the susceptibility of S. aureus to ciprofloxacin plus levofloxacin was 37% (7 of 19) with 64% (7 of 11) of oxacillin-susceptible S. aureus being susceptible to ciprofloxacin plus levofloxacin, whereas 0% of ORSA were susceptible to ciprofloxacin plus levofloxacin (0 of 8). All 8 ORSA specimens were susceptible to vancomycin. Forty-two percent of the coagulasenegative Staphylococcus (18 of 43) was oxacillin-resistant coagulase-negative Staphylococcus (ORCNS), and 65% of the S. epidermidis cases (20 of 31) were oxacillin resistant. Vancomycin susceptibility of ORCNS isolates was 100% (18 of 18). The susceptibility of ORCNS and oxacillin-resistant S. epidermidis to ciprofloxacin plus levofloxacin was found to be 18% (3 of 17) and 40% (8 of 20), respectively. The susceptibility of oxacillinsusceptible coagulase-negative Staphylococcus to ciprofloxacin plus levofloxacin was 88% (22 of 25), and the susceptibility of oxacillin-susceptible S. epidermidis was 70% (7 of 10). P. aeruginosa was susceptible to both levofloxacin (n ¼ 22) and ciprofloxacin (n ¼ 11) 100% of the time (Table 2). Data from Los Angeles County D University of Southern California Medical Center. Ciprofloxacin plus levofloxacin susceptibility of all tested pathogens was 81% (64 of 79), whereas overall gentamicin plus tobramycin susceptibility was 93% (82 of 88). Forty-five percent of S. aureus (9 of 20) was classified as ORSA (Table 2). Vancomycin susceptibility of ORSA was 100% (8 of 8). The susceptibility of S. aureus to ciprofloxacin plus levofloxacin was 0% (n ¼ 8). All ORSA specimens were resistant to the fluoroquinolone tested (levofloxacin; 8 of 8). The laboratory protocol did not include testing of oxacillin-susceptible S. aureus against ciprofloxacin plus levofloxacin. The percentage of ORCNS was found to be 30% (3 of 10), and the percentage of oxacillinresistant S. epidermidis was found to be 53% (17 of 32). Vancomycin susceptibility of ORCNS was 100% (3 of 3). Interestingly, of the oxacillin-resistant S. epidermidis cases, there was 1 sample that was found to have intermediate resistance to vancomycin. P. aeruginosa was susceptible to levofloxacin 95% of the time (20 of 21 cases) and ciprofloxacin 100% of the time (17 of 17).
Comparing Doheny Eye Institute and Los Angeles County D University of Southern California Medical Center There is a statistically significant difference between the number of no-yield cultures from DEI when compared with those from LACþUSC (P < 0.0001). There was no statistical difference in the spectrum of pathogens (P ¼ 0.86) between the 2 hospitals or when
919
Ophthalmology Volume 122, Number 5, May 2015 Table 1. Pathogens at Doheny Eye Institute and Los Angeles County þ University of Gram-Positive Organisms
No.
% of Total
Doheny Eye Institute Total CNS 96 40.7 NS CNS 61 25.8 Staphylococcus epidermidis 32 13.6 Staphylococcus warneri 3 1.3 Streptococcus viridans 22 9.3 Staphylococcus aureus OSSA 12 5.1 ORSA 9 3.8 Corynebacterium diphtheroids 11 4.7 Propionibacterium acnes 9 3.8 Streptococcus pneumoniae 4 1.7 Enterococcus faecalis 2 0.8 Escherichia coli 2 0.8 Streptococcus mitis 2 0.8 Bacillus species not anthracis 2 0.8 Other gram-positive 10 4.2 Total 165 69.9 Total organisms 236 Unique organisms 49 Los Angeles County þ University of Southern California Medical Center Total CNS 68 30 NS CNS 32 14.1 S. epidermidis 32 14.1 S. warneri 2 0.9 Staphylococcus capitis 2 0.9 S. aureus OSSA 11 4.8 ORSA 9 4 Propionibacterium species 15 6.6 S. viridans 14 6.2 Diphtheroids 12 5.3 Bacillus species 7 3.1 S. pneumoniae 5 2.2 E. faecalis 2 0.9 Micrococcus species 2 0.9 Cocci (unspecific) 2 0.9 Other gram positive 7 3.1 Total 154 67.8 Total organisms 227 Unique organisms 47
% of Gram Positive 58.2 37 19.4 1.8 13.3
Gram-Negative Organisms Pseudomonas aeruginosa Serratia marcescens Haemophilus influenzae Klebsiella pneumoniae Neisseria species Other gram-negative
7.3 5.5 6.7 5.5 2.4 1.2 1.2 1.2 1.2 6.1 100
44.2 20.8 20.8 1.3 1.3 7.1 5.8 9.7 9.1 7.8 4.5 3.2 1.3 1.3 1.3 4.5 100
P. aeruginosa S. marcescens Moraxella catarrhalis Klebsiella oxytoca Proteus mirabilis Acinetobacter calcoaceticus-baumannii complex Other gram negative
CNS ¼ coagulase-negative Staphylococcus; NS ¼ nonspeciated; ORSA ¼ oxacillin-resistant Staphylococcus aureus; OSSA ¼ oxacillin-susceptible
comparing the susceptibility of pathogens to gentamicin (P ¼ 0.93), tobramycin (P ¼ 0.68), ciprofloxacin (P ¼ 0.15), levofloxacin (P ¼ 0.47), erythromycin (P ¼ 0.60), cefazolin (P ¼ 0.60), or vancomycin (P ¼ 0.20). There was no statistical significance when grouping aminoglycosides (gentamicin plus tobramycin) and comparing the 2 sites (P ¼ 0.84). There was also no statistical significance when grouping fluoroquinolones (ciprofloxacin plus levofloxacin) when comparing the 2 sites (P ¼ 0.16). There was also no statistically significant difference between ORSA or ORCNS cases at DEI compared with those at LACþUSC (P ¼ 1.00 and P ¼ 0.72, respectively).
Discussion Microbial keratitis is a major cause for morbidity and, because of its rapidly progressing nature, needs to be
920
managed by an ophthalmologist as an ocular emergency. This is especially important in the case of infiltrates that involve the central visual axis. Currently, the American Academy of Ophthalmology Preferred Practice Pattern recommends cefazolin 50 mg/ml topically with an aminoglycoside, such as tobramycin plus gentamicin (9e14 mg/ml) or fluoroquinolone monotherapy.8 However, using vancomycin in the setting of resistance of methicillinresistant S. aureus to fluoroquinolones also has been recommended. As a side note, oxacillin has replaced methicillin for testing and is a more specific term. Without having good and recent data on the make up of microbial pathogens in any given area, this information has to be inferred from historical or broader regional data. However, there are clear limits to this approach because it has been
Sand et al
Microbial Keratitis in Los Angeles
Southern California Medical Center from July 1, 2008 through December 31, 2012 No.
% of Total
28 6 5 2 2 6
11.9 2.5 2.1 0.8 0.8 2.5
49
20.8
21 10 3 3 2 2 8
9.3 4.4 1.3 1.3 0.9 0.9 3.5
49
21.6
% of Gram Negative 57.1 12.2 10.2 4.1 4.1 12.2
Other Organisms
No.
% of Total
% of Other
Candida species Aspergillus species Fusarium species Other fungal Acanthamoeba
11 3 2 5 1
4.7 1.3 0.8 2.1 0.4
50 13.6 9.1 22.7 4.5
22
9.3
9 3 2 10
4 1.3 0.9 4.4
24
10.6
100
42.9 20.4 6.1 6.1 4.1 4.1 16.3
Candida species Aspergillus species Fusarium species Other fungal
100
100
37.5 12.5 8.3 41.7
100
Staphylococcus aureus.
shown that there are changes to the trends in microbial keratitis cases and one should not rely on historical data.12 Regional data also can be deceiving, as 2 series from cities in the United Kingdom that are fewer than 125 miles apart have shown us. In these 2 recent publications, the data from Oxford showed a preponderance of gram-positive cultures (54.3%), whereas the data from East Kent showed the opposite (61.1% of cultures were gram negative).10,11 In this study, we report on 2 different populations at hospitals that are located within a few blocks of each other. These 2 hospitals were served by the same department of ophthalmology at the time of the study. The Los Angeles County þ University of Southern California Medical Center serves an indigent population, whereas DEI is a major tertiary care referral center in the region. Our recovery rates were
63% at DEI and 82% at LACþUSC, which were comparable with those reported by other studies (54%e65.6%).10,13e16 Gram-positive pathogens were found to be the most common at 70% for DEI and 68% for LACþUSC. This is in line with other published reports from the last decade, which range from 51% to 78% for gram-positive isolates.10,13e17 Interestingly, we found a rather high percentage of fungal keratitis cases at both of our institutions (9% at DEI and 10% at LACþUSC), which came as a surprise given the dry and desert-like climate of Southern California. Compared with the literature, reports vary from Toronto (6%),16 New Zealand (1.7%),15 Australia (5%),13 Portsmouth, United Kingdom (0.6%),14 and Miami (range, 3%e24%).18e20 A particularly interesting part of this study, however, is the fact that ORSA had such a high prevalence in our study (42%
921
Ophthalmology Volume 122, Number 5, May 2015 Table 2. Pathogens Tested against Antibiotics at Doheny Eye Institute and Gentamicin No. of Susceptible Pathogens Doheny Eye Institute Total OS CNS Total OR CNS OS NS CNS OR NS CNS OS Staphylococcus epidermidis OR S. epidermidis OSSA ORSA Pseudomonas aeruginosa Serratia marcescens Los Angeles County þ University Total OS CNS Total OR CNS OS NS CNS OR NS CNS OS S. epidermidis OR S. epidermidis OSSA ORSA P. aeruginosa S. marcescens
32 23 23 10 9
No. of Pathogens Tested 33 32 23 16 10
Tobramycin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
97 72 100 63 90
0 0 0 0 0
13 16 81 9 9 100 7 7 100 25 25 100 6 6 100 of Southern California Medical Center 2 2 100 1 1 100 2 2 100 1 1 100 0 0 N/A 0 0 N/A 0 0 N/A 1 1 100 21 21 100 10 10 100
Ciprofloxacin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
%
0 0 0 0 0
N/A N/A N/A N/A N/A
10 1 9 1 1
10 1 9 1 1
100 100 100 100 100
0 0 0 22 3
0 0 0 22 3
N/A N/A N/A 100 100
0 3 0 11 1
0 3 0 11 1
N/A 100 N/A 100 100
0 0 0 0 0 0 0 0 21 9
0 0 0 0 0 0 0 0 21 9
N/A N/A N/A N/A N/A N/A N/A N/A 100 100
0 0 0 0 0 0 0 0 17 6
0 0 0 0 0 0 0 0 17 6
N/A N/A N/A N/A N/A N/A N/A N/A 100 100
CNS ¼ coagulase-negative Staphylococcus; N/A ¼ not applicable; NS ¼ nonspeciated; OR ¼ oxacillin resistant; ORSA ¼ oxacillin-resistant Staphylococcus
from the DEI samples and 45% from the LACþUSC samples) compared with other studies in the literature, including those from Portsmouth, United Kingdom (18%),14 Oxford, United Kingdom (13%),10 Australia (5%),13 and Toronto (1.3%).16 Methicillin-resistant S. aureus has been shown to have an increasing incidence in ocular infections from 2000 to 2005 in the United States,21 and a study from Taiwan found that there has been a significantly higher trend in methicillin-resistant S. aureus cases in ocular infections.22 Furthermore, methicillin-resistant S. aureus implicated in microbial keratitis has been shown to be resistant to fluoroquinolones in the literature.23 Hence, given our data and the high prevalence of ORSA, we now exclusively use fortified vancomycin instead of fortified cefazolin in the treatment of infectious keratitis. For the tested aminoglycosides, our study found very good susceptibilities given that 93% of tested specimens at both DEI and LACþUSC were susceptible to tobramycin or gentamicin. There was no statistically significant difference between the 2 hospitals when comparing tobramycin (P ¼ 0.68) or gentamicin (P ¼ 0.93) susceptibilities of pathogens. Our findings are similar to studies in the literature, which have susceptibilities that range from 71% to 100%.10,11,13e17 However, one must still remain cautious in extrapolating these data to specific geographic regions or specific patient populations because the microbial susceptibility profiles may be different.24 Through a survey of ophthalmologists in 4 statesd including Californiada recent publication found that one
922
of the newer fluoroquinolone antibiotics is a common firstline treatment of corneal ulcers for community ophthalmologists.7 Fluoroquinolones have been shown to be equivalent when compared with the standard fortified antibiotic approach in terms of corneal healing.25 Fluoroquinolones also have been shown to be equivalent to standard therapy with fortified antibiotics in several studies.26,27 In terms of antibiotic susceptibility with a special focus on fluoroquinolones, the susceptibilities of other studies in the literature range from 64% to 99%.10,11,13e17 We found that 73% of tested pathogens isolated from DEI were susceptible to ciprofloxacin plus levofloxacin, whereas 81% of tested pathogens isolated from LACþUSC were susceptible to ciprofloxacin plus levofloxacin. Many of the patients sent to our institution at DEI are from local community ophthalmologists who have attempted treatment with a fluoroquinolone that failed, which presumably could create a preponderance of fluoroquinolone-resistant organisms seen at DEI. Although other explanations may exist, this referral and practice pattern is likely an explanation for the statistically significant lower culture-positive rate for the DEI specimens compared with the LACþUSC specimens. In contrast, most patients seeking treatment at LACþUSC do so as the first presentation to an eye care professional or through the emergency room. Given the 2 very different patient populations seen at the 2 institutions, we were surprised to find that there was no statistically significant difference in
Sand et al
Microbial Keratitis in Los Angeles
Los Angeles County þ University of Southern California Medical Center Levofloxacin No. of Susceptible Pathogens
No. of Pathogens Tested
28 11 21 3 7
Erythromycin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
35 37 25 17 10
80 30 84 18 70
5 9 3 4 2
8 7 0 22 6
20 11 8 22 6
40 64 0 100 100
2 0 2 0 0 0 0 0 20 4
2 1 2 1 0 0 0 8 21 4
100 0 100 0 N/A N/A N/A 0 95 100
Cefazolin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
%
16 14 9 5 7
31 64 33 80 29
0 0 0 0 0
0 0 0 0 0
N/A N/A N/A N/A N/A
5 1 0 0 0
9 5 3 0 0
56 20 0 N/A N/A
0 0 0 0 0
0 0 0 0 3
N/A N/A N/A N/A 0
11 5 4 1 7 4 11 0 0 0
22 20 7 3 15 17 11 9 0 0
50 25 57 33 47 24 100 0 N/A N/A
3 1 2 1 1 0 0 0 0 0
3 2 2 2 1 0 0 1 0 10
100 50 100 50 100 N/A N/A 0 N/A 0
aureus; OS ¼ oxacillin susceptible; OSSA ¼ oxacillin-susceptible Staphylococcus aureus.
ciprofloxacin plus levofloxacin susceptibility between the 2 groups of recovered pathogens. A limitation of our study certainly is the fact that only older-generation fluoroquinolones were used in the microbiology laboratories when testing fluoroquinolone susceptibility. Studies have shown that the newer generation fluoroquinolones are deemed to be a better first-line choice for gram-positive cocci in vitro and in vivo,28 which is certainly the community preference.7 Therefore, our ciprofloxacin plus levofloxacin susceptibility profiles may not truly represent the actual agents most commonly used in the community and may underrepresent the susceptibility of pathogens to the newer fluoroquinolones. Another weakness of our study is that these are regional data and this was a retrospective review. The patient populations served by LACþUSC and DEI are relatively unique, and the microbial spectrum anddas stated abovedtheir antibiotic susceptibility profiles should be generalized to other communities and practices with caution. Nonetheless, this study shows that there is further need to study this subject matter and to continue surveillance of regional data to be able to evaluate trends and to adjust practice patterns accordingly. In the literature there have been studies in the United States (Antibiotic Resistance Monitoring in Ocular micRorganisms, Ocular Tracking Resistance in U.S. Today, The Surveillance Network) that report on ocular infections and the antibiotic susceptibility panel of these.21,29,30 We hope to join
the dialog with these data from Southern California and to underscore the need for constant and continued monitoring of regional data in the face of antibiotic resistance evident by the high percentage of ORSA cases as well as the surprising incidence of fungal keratitis at our institution.
References 1. Pepose JS, Wilhelmus KR. Divergent approaches to the management of corneal ulcers. Am J Ophthalmol 1992;114:630–2. 2. Erie JC, Nevitt MP, Hodge DO, Ballard DJ. Incidence of ulcerative keratitis in a defined population from 1950 through 1988. Arch Ophthalmol 1993;111:1665–71. 3. Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of ulcerative keratitis in Northern California. Arch Ophthalmol 2010;128:1022–8. 4. Schein OD, McNally JJ, Katz J, et al. The incidence of microbial keratitis among wearers of a 30-day silicone hydrogel extended-wear contact lens. Ophthalmology 2005;112:2172–9. 5. McDonnell PJ, Nobe J, Gauderman WJ, et al. Community care of corneal ulcers. Am J Ophthalmol 1992;114:531–8. 6. McLeod SD, DeBacker CM, Viana MA. Differential care of corneal ulcers in the community based on apparent severity. Ophthalmology 1996;103:479–84. 7. Hsu HY, Nacke R, Song JC, et al. Community opinions in the management of corneal ulcers and ophthalmic antibiotics: a survey of 4 states. Eye Contact Lens 2010;36:195–200.
923
Ophthalmology Volume 122, Number 5, May 2015 8. American Academy of Ophthalmology. Cornea/External Disease Panel. Preferred Practice Pattern Guidelines. Bacterial Keratitis. San Francisco, CA: American Academy of Ophthalmology; 2013. Available at: www.aao. org/ppp. Accessed April 4, 2014. 9. Critchley IA, Karlowsky JA. Optimal use of antibiotic resistance surveillance systems. Clin Microbiol Infect 2004;10:502–11. 10. Orlans HO, Hornby SJ, Bowler IC. In vitro antibiotic susceptibility patterns of bacterial keratitis isolates in Oxford, UK: a 10-year review. Eye (Lond) 2011;25:489–93. 11. Shalchi Z, Gurbaxani A, Baker M, Nash J. Antibiotic resistance in microbial keratitis: ten-year experience of corneal scrapes in the United Kingdom. Ophthalmology 2011;118:2161–5. 12. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology 2000;107:1497–502. 13. Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea 2008;27:22–7. 14. Ibrahim YW, Boase DL, Cree IA. Epidemiological characteristics, predisposing factors and microbiological profiles of infectious corneal ulcers: the Portsmouth corneal ulcer study. Br J Ophthalmol 2009;93:1319–24. 15. Pandita A, Murphy C. Microbial keratitis in Waikato, New Zealand. Clin Experiment Ophthalmol 2011;39:393–7. 16. Lichtinger A, Yeung SN, Kim P, et al. Shifting trends in bacterial keratitis in Toronto: an 11-year review. Ophthalmology 2012;119:1785–90. 17. Zhang C, Liang Y, Deng S, et al. Distribution of bacterial keratitis and emerging resistance to antibiotics in China from 2001 to 2004. Clin Ophthalmol 2008;2:575–9. 18. Liesegang TJ, Forster RK. Spectrum of microbial keratitis in South Florida. Am J Ophthalmol 1980;90:38–47. 19. Alfonso E, Mandelbaum S, Fox MJ, Forster RK. Ulcerative keratitis associated with contact lens wear. Am J Ophthalmol 1986;101:429–33. 20. Koidou-Tsiligianni A, Alfonso E, Forster RK. Ulcerative keratitis associated with contact lens wear. Am J Ophthalmol 1989;108:64–7.
21. Asbell PA, Sahm DF, Shaw M, et al. Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000 to 2005. J Cataract Refract Surg 2008;34:814–8. 22. Hsiao CH, Chuang CC, Tan HY, et al. Methicillin-resistant Staphylococcus aureus ocular infection: a 10-year hospitalbased study. Ophthalmology 2012;119:522–7. 23. Elsahn AF, Yildiz EH, Jungkind DL, et al. In vitro susceptibility patterns of methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus corneal isolates to antibiotics. Cornea 2010;29:1131–5. 24. Galvis V, Tello A, Guerra AR, et al. Ocular flora and their antibiotic resistance patterns in the midwest: a prospective study of patients undergoing cataract surgery. Am J Ophthalmol 2013;156:623–4. 25. Sharma N, Goel M, Bansal S, et al. Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial. Ophthalmology 2013;120:1173–8. 26. Hyndiuk RA, Eiferman RA, Caldwell DR, et al. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group. Ophthalmology 1996;103:1854–62. discussion 62e3. 27. Ofloxacin monotherapy for the primary treatment of microbial keratitis: a double-masked, randomized, controlled trial with conventional dual therapy. The Ofloxacin Study Group. Ophthalmology 1997;104:1902–9. 28. Parmar P, Salman A, Kalavathy CM, et al. Comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis. Am J Ophthalmol 2006;141:282–6. 29. Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol 2008;145:951–8. 30. Haas W, Pillar CM, Torres M, et al. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study. Am J Ophthalmol 2011;152: 567–574.e3.
Footnotes and Financial Disclosures Originally received: July 15, 2014. Final revision: November 25, 2014. Accepted: November 26, 2014. Available online: January 16, 2015.
Manuscript no. 2014-1104.
1
Department of Ophthalmology, Los Angeles County - University of Southern California Medical Center, Los Angeles, California. 2
Department of Pathology, Keck Medical Center of the University of Southern California, Los Angeles, California. 3 Department of Pathology, Los Angeles County - University of Southern California Medical Center, Los Angeles, California. 4
Keck School of Medicine, University of Southern California, Los Angeles, California. 5 Doheny Eye Centers, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
924
Presented at: American Academy of Ophthalmology Annual Meeting, November 2013, New Orleans, Louisiana. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Abbreviations and Acronyms: DEI ¼ Doheny Eye Institute; LACDUSC ¼ Los Angeles County þ University of Southern California Medical Center; ORCNS ¼ oxacillinresistant coagulase-negative Staphylococcus; ORSA ¼ oxacillin-resistant Staphylococcus aureus. Correspondence: Hugo Y. Hsu, MD, Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California, 1450 San Pablo Street, Suite 3000, Los Angeles, CA 90033. E-mail: [email protected].
Microbial keratitis is an ocular emergency and historically has been quoted to affect 11 per 100 000 or 30000 new cases annually in the United States,1,2 and in more recent studies, approximately 30 per 100 000 new cases.3 Certain risk factors, including contact lens wear, can increase the incidence to 180 per 100 000.4 Classically, empiric therapy often is initiated with fortified antibiotics after stain and cultures are sent for microbiologic analysis for further evaluation. More commonly now, many practitioners in the community choose fluoroquinolone monotherapy without culture analysis.5e7 Initial therapy is guided by taking into account the clinical setting and current as well as historical data from the hospital’s antibiogram.8,9 With the evershifting make up of pathogens and resistance patterns, it is important for the clinician to be on the front line and very well aware of the data from local microbiology laboratories and their antibiograms. A recent example of regional differences can be highlighted when comparing publications from the United Kingdom from cities that are fewer than 125 miles apart where a difference in the pathogens was documented.10,11 In the series from Oxford, most of the pathogens were gram positive (54.3%), whereas in the series from East Kent, most of the pathogens were gram negative (61.1%).
918
2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
Los Angeles is a city with the second highest population in the United States. Yet despite this and its unique climate, there is a paucity of infectious keratitis and ocular microbiologic data from Los Angeles and Southern California. Herein we report the isolates and antibiotic resistance pattern of infectious keratitis cases at a major tertiary care referral center in Southern California, the Doheny Eye Institute (DEI), and the major county hospital serving the indigent in the same geographic area, the Los Angeles County þ University of Southern California Medical Center (LACþUSC). These 2 institutions were served by the same department of ophthalmology at the time of the study and are less than 0.5 miles apart from each other, but serve different patient populations. We wished not only to reveal and elucidate the spectrum of pathogens causing microbial keratitis in Southern California, but also to see if the 2 institutions under the same department serving different populations had significantly different antibiotic susceptibility profiles.
Methods An institutional review board-approved retrospective case series review was performed. All infectious keratitis cases that were http://dx.doi.org/10.1016/j.ophtha.2014.11.027 ISSN 0161-6420/15
Sand et al
Microbial Keratitis in Los Angeles
cultured and submitted for microbiologic analysis from July 1, 2008, through December 31, 2012, were reviewed for pathogens and antibiotic susceptibilities. The specimens from DEI were sent to the Keck Medical Center microbiology laboratory, whereas the specimens from LACþUSC were sent to the microbiology department at LACþUSC. Patients at DEI were identified by searching the billing database for the International Classification of Diseases, ninth edition, codes of 370.0x. This was cross-referenced and confirmed with a list of specimens sent to the Keck Medical Center Microbiology Laboratory. The medical record then was used to extract information about growth and susceptibility of pathogens. Patients at LACþUSC were identified by obtaining a list of all ophthalmic specimens submitted to the microbiology department at LACþUSC and by filtering this only for corneal cultures. The medical record then was used to extract information regarding growth and susceptibility of pathogens. Depending on the laboratory and the pathogen as well as its resistance to antibiotics, the following antimicrobial agents were used in susceptibility testing: clindamycin, erythromycin, gentamicin, levofloxacin, oxacillin, trimethoprim plus sulfamethoxazole, vancomycin, tetracycline, rifampin, daptomycin, chloramphenicol, ceftriaxone, ampicillin plus sulbactam, cefoxitin, ampicillin, linezolid, tigecycline, piperacillin plus tazobactam, amikacin, cefepime, meropenem, aztreonam, cefotaxime, cefazolin, imipenem, nitrofurantoin, streptomycin, and quinupristin plus dalfopristin. However, we recorded only medications usually used by ophthalmologists. Routine bacteriologic cultures were performed by the Keck Hospital or the LACþUSC microbiology laboratories. Isolates were identified by the Vitek2 system (bioMérieux, Durham, NC) or by manual biochemical reactions using standard microbiologic protocols. Antimicrobial susceptibility testing was performed by either the Vitek2 system or manually by E-test (bioMérieux) to determine minimal inhibitory concentrations in accordance with Clinical Laboratory Standards Institute performance standards. Statistical analyses were carried out using the chi-square test and Fisher exact test using GraphPad Prism software version 6 (GraphPad, La Jolla, CA). Statistical significance was set at P 0.05.
Results Pathogens Data from Doheny Eye Institute. From the data at DEI, a total of 290 cultured cases were identified. The average age of the patients was 62.5 years (range, 12e102 years). One hundred eighty-four (63%) of 290 cases had positive culture results and 144 (78%) of 184 cases demonstrated a single pathogen in culture. The remaining 40 culture-positive cases were polymicrobial. A total of 236 organisms were isolated from all cultures and 49 unique organisms were identified. One hundred sixty-five (70%) of 236 organisms were gram positive, 49 (21%) of 236 organisms were gram negative, and 22 (9%) of 236 organisms were classified as other. Fungal organisms made up 21 of the 22 other organisms, and there was 1 case of Acanthamoeba. The most common gram-positive pathogen was found to be nonspeciated coagulase-negative Staphylococcus (61 of 165 [37%]), and Staphylococcus epidermidis was found to be the second most common organism (32 of 165 [19%]). The most common gram-negative pathogen was Pseudomonas aeruginosa (28 of 49 [57%]). The most common organism classified as other was Candida tropicalis (3 of 22 [14%]; Table 1). Data from Los Angeles County D University of Southern California Medical Center. A total of 186 cases were identified from the microbiology database. The average age of the patients was 41.7 years (range, 2e97 years). One hundred fifty-two (82%)
of 186 cases had positive culture results, and 98 cases (64%) were monomicrobial. The remaining 54 cases were polymicrobial. A total of 227 organisms were identified, of which 47 were unique. One hundred fifty-four (68%) of 227 organisms were gram positive, 49 (21%) of 227 organisms were gram negative, and 24 (11%) of 227 organisms were classified as other. Fungal organisms made up all organisms in the other category. Nonspeciated coagulasenegative Staphylococcus was the most commonly identified gram-positive bacteria (32 of 154 [21%]) along with S. epidermidis (32 of 154 [21%]). The most common gram-negative pathogen was P. aeruginosa (21 of 49 [43%]). The most common fungal organism was Candida albicans (7 of 24 [29%]).
Antimicrobial Susceptibility Data from Doheny Eye Institute. Ciprofloxacin plus levofloxacin susceptibility of all tested pathogens was 73% (128 of 176), whereas gentamicin plus tobramycin susceptibility was 93% (148 of 160). Forty-two percent of Staphylococcus aureus (8 of 19) cases were classified as oxacillin-resistant S. aureus (ORSA; Table 2). Vancomycin susceptibility of ORSA isolates was 100% (8 of 8). Overall, the susceptibility of S. aureus to ciprofloxacin plus levofloxacin was 37% (7 of 19) with 64% (7 of 11) of oxacillin-susceptible S. aureus being susceptible to ciprofloxacin plus levofloxacin, whereas 0% of ORSA were susceptible to ciprofloxacin plus levofloxacin (0 of 8). All 8 ORSA specimens were susceptible to vancomycin. Forty-two percent of the coagulasenegative Staphylococcus (18 of 43) was oxacillin-resistant coagulase-negative Staphylococcus (ORCNS), and 65% of the S. epidermidis cases (20 of 31) were oxacillin resistant. Vancomycin susceptibility of ORCNS isolates was 100% (18 of 18). The susceptibility of ORCNS and oxacillin-resistant S. epidermidis to ciprofloxacin plus levofloxacin was found to be 18% (3 of 17) and 40% (8 of 20), respectively. The susceptibility of oxacillinsusceptible coagulase-negative Staphylococcus to ciprofloxacin plus levofloxacin was 88% (22 of 25), and the susceptibility of oxacillin-susceptible S. epidermidis was 70% (7 of 10). P. aeruginosa was susceptible to both levofloxacin (n ¼ 22) and ciprofloxacin (n ¼ 11) 100% of the time (Table 2). Data from Los Angeles County D University of Southern California Medical Center. Ciprofloxacin plus levofloxacin susceptibility of all tested pathogens was 81% (64 of 79), whereas overall gentamicin plus tobramycin susceptibility was 93% (82 of 88). Forty-five percent of S. aureus (9 of 20) was classified as ORSA (Table 2). Vancomycin susceptibility of ORSA was 100% (8 of 8). The susceptibility of S. aureus to ciprofloxacin plus levofloxacin was 0% (n ¼ 8). All ORSA specimens were resistant to the fluoroquinolone tested (levofloxacin; 8 of 8). The laboratory protocol did not include testing of oxacillin-susceptible S. aureus against ciprofloxacin plus levofloxacin. The percentage of ORCNS was found to be 30% (3 of 10), and the percentage of oxacillinresistant S. epidermidis was found to be 53% (17 of 32). Vancomycin susceptibility of ORCNS was 100% (3 of 3). Interestingly, of the oxacillin-resistant S. epidermidis cases, there was 1 sample that was found to have intermediate resistance to vancomycin. P. aeruginosa was susceptible to levofloxacin 95% of the time (20 of 21 cases) and ciprofloxacin 100% of the time (17 of 17).
Comparing Doheny Eye Institute and Los Angeles County D University of Southern California Medical Center There is a statistically significant difference between the number of no-yield cultures from DEI when compared with those from LACþUSC (P < 0.0001). There was no statistical difference in the spectrum of pathogens (P ¼ 0.86) between the 2 hospitals or when
919
Ophthalmology Volume 122, Number 5, May 2015 Table 1. Pathogens at Doheny Eye Institute and Los Angeles County þ University of Gram-Positive Organisms
No.
% of Total
Doheny Eye Institute Total CNS 96 40.7 NS CNS 61 25.8 Staphylococcus epidermidis 32 13.6 Staphylococcus warneri 3 1.3 Streptococcus viridans 22 9.3 Staphylococcus aureus OSSA 12 5.1 ORSA 9 3.8 Corynebacterium diphtheroids 11 4.7 Propionibacterium acnes 9 3.8 Streptococcus pneumoniae 4 1.7 Enterococcus faecalis 2 0.8 Escherichia coli 2 0.8 Streptococcus mitis 2 0.8 Bacillus species not anthracis 2 0.8 Other gram-positive 10 4.2 Total 165 69.9 Total organisms 236 Unique organisms 49 Los Angeles County þ University of Southern California Medical Center Total CNS 68 30 NS CNS 32 14.1 S. epidermidis 32 14.1 S. warneri 2 0.9 Staphylococcus capitis 2 0.9 S. aureus OSSA 11 4.8 ORSA 9 4 Propionibacterium species 15 6.6 S. viridans 14 6.2 Diphtheroids 12 5.3 Bacillus species 7 3.1 S. pneumoniae 5 2.2 E. faecalis 2 0.9 Micrococcus species 2 0.9 Cocci (unspecific) 2 0.9 Other gram positive 7 3.1 Total 154 67.8 Total organisms 227 Unique organisms 47
% of Gram Positive 58.2 37 19.4 1.8 13.3
Gram-Negative Organisms Pseudomonas aeruginosa Serratia marcescens Haemophilus influenzae Klebsiella pneumoniae Neisseria species Other gram-negative
7.3 5.5 6.7 5.5 2.4 1.2 1.2 1.2 1.2 6.1 100
44.2 20.8 20.8 1.3 1.3 7.1 5.8 9.7 9.1 7.8 4.5 3.2 1.3 1.3 1.3 4.5 100
P. aeruginosa S. marcescens Moraxella catarrhalis Klebsiella oxytoca Proteus mirabilis Acinetobacter calcoaceticus-baumannii complex Other gram negative
CNS ¼ coagulase-negative Staphylococcus; NS ¼ nonspeciated; ORSA ¼ oxacillin-resistant Staphylococcus aureus; OSSA ¼ oxacillin-susceptible
comparing the susceptibility of pathogens to gentamicin (P ¼ 0.93), tobramycin (P ¼ 0.68), ciprofloxacin (P ¼ 0.15), levofloxacin (P ¼ 0.47), erythromycin (P ¼ 0.60), cefazolin (P ¼ 0.60), or vancomycin (P ¼ 0.20). There was no statistical significance when grouping aminoglycosides (gentamicin plus tobramycin) and comparing the 2 sites (P ¼ 0.84). There was also no statistical significance when grouping fluoroquinolones (ciprofloxacin plus levofloxacin) when comparing the 2 sites (P ¼ 0.16). There was also no statistically significant difference between ORSA or ORCNS cases at DEI compared with those at LACþUSC (P ¼ 1.00 and P ¼ 0.72, respectively).
Discussion Microbial keratitis is a major cause for morbidity and, because of its rapidly progressing nature, needs to be
920
managed by an ophthalmologist as an ocular emergency. This is especially important in the case of infiltrates that involve the central visual axis. Currently, the American Academy of Ophthalmology Preferred Practice Pattern recommends cefazolin 50 mg/ml topically with an aminoglycoside, such as tobramycin plus gentamicin (9e14 mg/ml) or fluoroquinolone monotherapy.8 However, using vancomycin in the setting of resistance of methicillinresistant S. aureus to fluoroquinolones also has been recommended. As a side note, oxacillin has replaced methicillin for testing and is a more specific term. Without having good and recent data on the make up of microbial pathogens in any given area, this information has to be inferred from historical or broader regional data. However, there are clear limits to this approach because it has been
Sand et al
Microbial Keratitis in Los Angeles
Southern California Medical Center from July 1, 2008 through December 31, 2012 No.
% of Total
28 6 5 2 2 6
11.9 2.5 2.1 0.8 0.8 2.5
49
20.8
21 10 3 3 2 2 8
9.3 4.4 1.3 1.3 0.9 0.9 3.5
49
21.6
% of Gram Negative 57.1 12.2 10.2 4.1 4.1 12.2
Other Organisms
No.
% of Total
% of Other
Candida species Aspergillus species Fusarium species Other fungal Acanthamoeba
11 3 2 5 1
4.7 1.3 0.8 2.1 0.4
50 13.6 9.1 22.7 4.5
22
9.3
9 3 2 10
4 1.3 0.9 4.4
24
10.6
100
42.9 20.4 6.1 6.1 4.1 4.1 16.3
Candida species Aspergillus species Fusarium species Other fungal
100
100
37.5 12.5 8.3 41.7
100
Staphylococcus aureus.
shown that there are changes to the trends in microbial keratitis cases and one should not rely on historical data.12 Regional data also can be deceiving, as 2 series from cities in the United Kingdom that are fewer than 125 miles apart have shown us. In these 2 recent publications, the data from Oxford showed a preponderance of gram-positive cultures (54.3%), whereas the data from East Kent showed the opposite (61.1% of cultures were gram negative).10,11 In this study, we report on 2 different populations at hospitals that are located within a few blocks of each other. These 2 hospitals were served by the same department of ophthalmology at the time of the study. The Los Angeles County þ University of Southern California Medical Center serves an indigent population, whereas DEI is a major tertiary care referral center in the region. Our recovery rates were
63% at DEI and 82% at LACþUSC, which were comparable with those reported by other studies (54%e65.6%).10,13e16 Gram-positive pathogens were found to be the most common at 70% for DEI and 68% for LACþUSC. This is in line with other published reports from the last decade, which range from 51% to 78% for gram-positive isolates.10,13e17 Interestingly, we found a rather high percentage of fungal keratitis cases at both of our institutions (9% at DEI and 10% at LACþUSC), which came as a surprise given the dry and desert-like climate of Southern California. Compared with the literature, reports vary from Toronto (6%),16 New Zealand (1.7%),15 Australia (5%),13 Portsmouth, United Kingdom (0.6%),14 and Miami (range, 3%e24%).18e20 A particularly interesting part of this study, however, is the fact that ORSA had such a high prevalence in our study (42%
921
Ophthalmology Volume 122, Number 5, May 2015 Table 2. Pathogens Tested against Antibiotics at Doheny Eye Institute and Gentamicin No. of Susceptible Pathogens Doheny Eye Institute Total OS CNS Total OR CNS OS NS CNS OR NS CNS OS Staphylococcus epidermidis OR S. epidermidis OSSA ORSA Pseudomonas aeruginosa Serratia marcescens Los Angeles County þ University Total OS CNS Total OR CNS OS NS CNS OR NS CNS OS S. epidermidis OR S. epidermidis OSSA ORSA P. aeruginosa S. marcescens
32 23 23 10 9
No. of Pathogens Tested 33 32 23 16 10
Tobramycin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
97 72 100 63 90
0 0 0 0 0
13 16 81 9 9 100 7 7 100 25 25 100 6 6 100 of Southern California Medical Center 2 2 100 1 1 100 2 2 100 1 1 100 0 0 N/A 0 0 N/A 0 0 N/A 1 1 100 21 21 100 10 10 100
Ciprofloxacin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
%
0 0 0 0 0
N/A N/A N/A N/A N/A
10 1 9 1 1
10 1 9 1 1
100 100 100 100 100
0 0 0 22 3
0 0 0 22 3
N/A N/A N/A 100 100
0 3 0 11 1
0 3 0 11 1
N/A 100 N/A 100 100
0 0 0 0 0 0 0 0 21 9
0 0 0 0 0 0 0 0 21 9
N/A N/A N/A N/A N/A N/A N/A N/A 100 100
0 0 0 0 0 0 0 0 17 6
0 0 0 0 0 0 0 0 17 6
N/A N/A N/A N/A N/A N/A N/A N/A 100 100
CNS ¼ coagulase-negative Staphylococcus; N/A ¼ not applicable; NS ¼ nonspeciated; OR ¼ oxacillin resistant; ORSA ¼ oxacillin-resistant Staphylococcus
from the DEI samples and 45% from the LACþUSC samples) compared with other studies in the literature, including those from Portsmouth, United Kingdom (18%),14 Oxford, United Kingdom (13%),10 Australia (5%),13 and Toronto (1.3%).16 Methicillin-resistant S. aureus has been shown to have an increasing incidence in ocular infections from 2000 to 2005 in the United States,21 and a study from Taiwan found that there has been a significantly higher trend in methicillin-resistant S. aureus cases in ocular infections.22 Furthermore, methicillin-resistant S. aureus implicated in microbial keratitis has been shown to be resistant to fluoroquinolones in the literature.23 Hence, given our data and the high prevalence of ORSA, we now exclusively use fortified vancomycin instead of fortified cefazolin in the treatment of infectious keratitis. For the tested aminoglycosides, our study found very good susceptibilities given that 93% of tested specimens at both DEI and LACþUSC were susceptible to tobramycin or gentamicin. There was no statistically significant difference between the 2 hospitals when comparing tobramycin (P ¼ 0.68) or gentamicin (P ¼ 0.93) susceptibilities of pathogens. Our findings are similar to studies in the literature, which have susceptibilities that range from 71% to 100%.10,11,13e17 However, one must still remain cautious in extrapolating these data to specific geographic regions or specific patient populations because the microbial susceptibility profiles may be different.24 Through a survey of ophthalmologists in 4 statesd including Californiada recent publication found that one
922
of the newer fluoroquinolone antibiotics is a common firstline treatment of corneal ulcers for community ophthalmologists.7 Fluoroquinolones have been shown to be equivalent when compared with the standard fortified antibiotic approach in terms of corneal healing.25 Fluoroquinolones also have been shown to be equivalent to standard therapy with fortified antibiotics in several studies.26,27 In terms of antibiotic susceptibility with a special focus on fluoroquinolones, the susceptibilities of other studies in the literature range from 64% to 99%.10,11,13e17 We found that 73% of tested pathogens isolated from DEI were susceptible to ciprofloxacin plus levofloxacin, whereas 81% of tested pathogens isolated from LACþUSC were susceptible to ciprofloxacin plus levofloxacin. Many of the patients sent to our institution at DEI are from local community ophthalmologists who have attempted treatment with a fluoroquinolone that failed, which presumably could create a preponderance of fluoroquinolone-resistant organisms seen at DEI. Although other explanations may exist, this referral and practice pattern is likely an explanation for the statistically significant lower culture-positive rate for the DEI specimens compared with the LACþUSC specimens. In contrast, most patients seeking treatment at LACþUSC do so as the first presentation to an eye care professional or through the emergency room. Given the 2 very different patient populations seen at the 2 institutions, we were surprised to find that there was no statistically significant difference in
Sand et al
Microbial Keratitis in Los Angeles
Los Angeles County þ University of Southern California Medical Center Levofloxacin No. of Susceptible Pathogens
No. of Pathogens Tested
28 11 21 3 7
Erythromycin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
35 37 25 17 10
80 30 84 18 70
5 9 3 4 2
8 7 0 22 6
20 11 8 22 6
40 64 0 100 100
2 0 2 0 0 0 0 0 20 4
2 1 2 1 0 0 0 8 21 4
100 0 100 0 N/A N/A N/A 0 95 100
Cefazolin
%
No. of Susceptible Pathogens
No. of Pathogens Tested
%
16 14 9 5 7
31 64 33 80 29
0 0 0 0 0
0 0 0 0 0
N/A N/A N/A N/A N/A
5 1 0 0 0
9 5 3 0 0
56 20 0 N/A N/A
0 0 0 0 0
0 0 0 0 3
N/A N/A N/A N/A 0
11 5 4 1 7 4 11 0 0 0
22 20 7 3 15 17 11 9 0 0
50 25 57 33 47 24 100 0 N/A N/A
3 1 2 1 1 0 0 0 0 0
3 2 2 2 1 0 0 1 0 10
100 50 100 50 100 N/A N/A 0 N/A 0
aureus; OS ¼ oxacillin susceptible; OSSA ¼ oxacillin-susceptible Staphylococcus aureus.
ciprofloxacin plus levofloxacin susceptibility between the 2 groups of recovered pathogens. A limitation of our study certainly is the fact that only older-generation fluoroquinolones were used in the microbiology laboratories when testing fluoroquinolone susceptibility. Studies have shown that the newer generation fluoroquinolones are deemed to be a better first-line choice for gram-positive cocci in vitro and in vivo,28 which is certainly the community preference.7 Therefore, our ciprofloxacin plus levofloxacin susceptibility profiles may not truly represent the actual agents most commonly used in the community and may underrepresent the susceptibility of pathogens to the newer fluoroquinolones. Another weakness of our study is that these are regional data and this was a retrospective review. The patient populations served by LACþUSC and DEI are relatively unique, and the microbial spectrum anddas stated abovedtheir antibiotic susceptibility profiles should be generalized to other communities and practices with caution. Nonetheless, this study shows that there is further need to study this subject matter and to continue surveillance of regional data to be able to evaluate trends and to adjust practice patterns accordingly. In the literature there have been studies in the United States (Antibiotic Resistance Monitoring in Ocular micRorganisms, Ocular Tracking Resistance in U.S. Today, The Surveillance Network) that report on ocular infections and the antibiotic susceptibility panel of these.21,29,30 We hope to join
the dialog with these data from Southern California and to underscore the need for constant and continued monitoring of regional data in the face of antibiotic resistance evident by the high percentage of ORSA cases as well as the surprising incidence of fungal keratitis at our institution.
References 1. Pepose JS, Wilhelmus KR. Divergent approaches to the management of corneal ulcers. Am J Ophthalmol 1992;114:630–2. 2. Erie JC, Nevitt MP, Hodge DO, Ballard DJ. Incidence of ulcerative keratitis in a defined population from 1950 through 1988. Arch Ophthalmol 1993;111:1665–71. 3. Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of ulcerative keratitis in Northern California. Arch Ophthalmol 2010;128:1022–8. 4. Schein OD, McNally JJ, Katz J, et al. The incidence of microbial keratitis among wearers of a 30-day silicone hydrogel extended-wear contact lens. Ophthalmology 2005;112:2172–9. 5. McDonnell PJ, Nobe J, Gauderman WJ, et al. Community care of corneal ulcers. Am J Ophthalmol 1992;114:531–8. 6. McLeod SD, DeBacker CM, Viana MA. Differential care of corneal ulcers in the community based on apparent severity. Ophthalmology 1996;103:479–84. 7. Hsu HY, Nacke R, Song JC, et al. Community opinions in the management of corneal ulcers and ophthalmic antibiotics: a survey of 4 states. Eye Contact Lens 2010;36:195–200.
923
Ophthalmology Volume 122, Number 5, May 2015 8. American Academy of Ophthalmology. Cornea/External Disease Panel. Preferred Practice Pattern Guidelines. Bacterial Keratitis. San Francisco, CA: American Academy of Ophthalmology; 2013. Available at: www.aao. org/ppp. Accessed April 4, 2014. 9. Critchley IA, Karlowsky JA. Optimal use of antibiotic resistance surveillance systems. Clin Microbiol Infect 2004;10:502–11. 10. Orlans HO, Hornby SJ, Bowler IC. In vitro antibiotic susceptibility patterns of bacterial keratitis isolates in Oxford, UK: a 10-year review. Eye (Lond) 2011;25:489–93. 11. Shalchi Z, Gurbaxani A, Baker M, Nash J. Antibiotic resistance in microbial keratitis: ten-year experience of corneal scrapes in the United Kingdom. Ophthalmology 2011;118:2161–5. 12. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida and emerging resistance to fluoroquinolones. Ophthalmology 2000;107:1497–502. 13. Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea 2008;27:22–7. 14. Ibrahim YW, Boase DL, Cree IA. Epidemiological characteristics, predisposing factors and microbiological profiles of infectious corneal ulcers: the Portsmouth corneal ulcer study. Br J Ophthalmol 2009;93:1319–24. 15. Pandita A, Murphy C. Microbial keratitis in Waikato, New Zealand. Clin Experiment Ophthalmol 2011;39:393–7. 16. Lichtinger A, Yeung SN, Kim P, et al. Shifting trends in bacterial keratitis in Toronto: an 11-year review. Ophthalmology 2012;119:1785–90. 17. Zhang C, Liang Y, Deng S, et al. Distribution of bacterial keratitis and emerging resistance to antibiotics in China from 2001 to 2004. Clin Ophthalmol 2008;2:575–9. 18. Liesegang TJ, Forster RK. Spectrum of microbial keratitis in South Florida. Am J Ophthalmol 1980;90:38–47. 19. Alfonso E, Mandelbaum S, Fox MJ, Forster RK. Ulcerative keratitis associated with contact lens wear. Am J Ophthalmol 1986;101:429–33. 20. Koidou-Tsiligianni A, Alfonso E, Forster RK. Ulcerative keratitis associated with contact lens wear. Am J Ophthalmol 1989;108:64–7.
21. Asbell PA, Sahm DF, Shaw M, et al. Increasing prevalence of methicillin resistance in serious ocular infections caused by Staphylococcus aureus in the United States: 2000 to 2005. J Cataract Refract Surg 2008;34:814–8. 22. Hsiao CH, Chuang CC, Tan HY, et al. Methicillin-resistant Staphylococcus aureus ocular infection: a 10-year hospitalbased study. Ophthalmology 2012;119:522–7. 23. Elsahn AF, Yildiz EH, Jungkind DL, et al. In vitro susceptibility patterns of methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus corneal isolates to antibiotics. Cornea 2010;29:1131–5. 24. Galvis V, Tello A, Guerra AR, et al. Ocular flora and their antibiotic resistance patterns in the midwest: a prospective study of patients undergoing cataract surgery. Am J Ophthalmol 2013;156:623–4. 25. Sharma N, Goel M, Bansal S, et al. Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial. Ophthalmology 2013;120:1173–8. 26. Hyndiuk RA, Eiferman RA, Caldwell DR, et al. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group. Ophthalmology 1996;103:1854–62. discussion 62e3. 27. Ofloxacin monotherapy for the primary treatment of microbial keratitis: a double-masked, randomized, controlled trial with conventional dual therapy. The Ofloxacin Study Group. Ophthalmology 1997;104:1902–9. 28. Parmar P, Salman A, Kalavathy CM, et al. Comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis. Am J Ophthalmol 2006;141:282–6. 29. Asbell PA, Colby KA, Deng S, et al. Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol 2008;145:951–8. 30. Haas W, Pillar CM, Torres M, et al. Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study. Am J Ophthalmol 2011;152: 567–574.e3.
Footnotes and Financial Disclosures Originally received: July 15, 2014. Final revision: November 25, 2014. Accepted: November 26, 2014. Available online: January 16, 2015.
Manuscript no. 2014-1104.
1
Department of Ophthalmology, Los Angeles County - University of Southern California Medical Center, Los Angeles, California. 2
Department of Pathology, Keck Medical Center of the University of Southern California, Los Angeles, California. 3 Department of Pathology, Los Angeles County - University of Southern California Medical Center, Los Angeles, California. 4
Keck School of Medicine, University of Southern California, Los Angeles, California. 5 Doheny Eye Centers, Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
924
Presented at: American Academy of Ophthalmology Annual Meeting, November 2013, New Orleans, Louisiana. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Abbreviations and Acronyms: DEI ¼ Doheny Eye Institute; LACDUSC ¼ Los Angeles County þ University of Southern California Medical Center; ORCNS ¼ oxacillinresistant coagulase-negative Staphylococcus; ORSA ¼ oxacillin-resistant Staphylococcus aureus. Correspondence: Hugo Y. Hsu, MD, Doheny Eye Institute, Department of Ophthalmology, David Geffen School of Medicine, University of California, 1450 San Pablo Street, Suite 3000, Los Angeles, CA 90033. E-mail: [email protected].
