Gram-Negative Bacterial Keratitis: A 15-Year Review of Clinical Aspects

Eun Young Cho; Sang Bumm Lee

doi:10.3341/jkos.2015.56.10.1479

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Cho and Lee: Gram-Negative Bacterial Keratitis: A 15-Year Review of Clinical Aspects

Original Article

J Korean Ophthalmol Soc 2015;56(10):1479-1488.

Published online: 29 August 2015

DOI: https://doi.org/10.3341/jkos.2015.56.10.1479

Gram-Negative Bacterial Keratitis: A 15-Year Review of Clinical Aspects

Eun Young Cho, M.D, Sang Bumm Lee, M.D, PhD

Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Korea

Address reprint requests to Sang Bumm Lee, MD, PhD Department of Ophthalmology, Yeungnam University Hospital, #170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: 82-53-620-3445, Fax: 82-53-626-5936 E-mail: sbummlee@ynu.ac.kr

‗ This study was presented as an e-poster at the 112th Annual Meeting of the Korean Ophthalmological Society 2014.

Received 24 April 201516 July 2015 Accepted 4 September 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

In this study we investigated pathogenic organisms, antibiotic susceptibility, and clinical characteristics of patients with Gram-negative bacterial keratitis and elucidated risk factors for poor visual outcomes.

Methods

The authors performed a retrospective chart review of 161 eyes (169 isolates) with Gram-negative bacterial keratitis between January 1998 and December 2012 at Yeungnam University Hospital. The study was divided into 5 periods for analysis of the bacteriological profiles and in vitro antibiotic sensitivity. The epidemiological and clinical characteristics were compared according to 3 groups ( Pseudomonas species, Enterobacter species, and Serratia marcescens). Additionally, logistic regression analysis was performed to determine the risk factors.

Results

The prevalence of Gram-negative organisms increased from 34.7 to 73.2% between the 1st and 5th periods ( p < 0.001). Pseudomonas spp. was the most commonly isolated organism (55 eyes, 32.5%) over the total period, followed by Enterobacter spp. (41 eyes, 24.3%) and Serratia marcescens (33 eyes, 19.5%). The effective antibiotics against Gram-negative bacterial pathogens isolated from culture were cefepime (94.5%), levofloxacin (93.4%), ciprofloxacin (93.0%), and amikacin (92.3%). The incidence was higher in the elderly over 60 years of age and in early adulthood patients in their 20s and 30s. The frequent predisposing factors were contact lens wearing and corneal trauma. S. marcescens had the shortest corneal epithelium healing time ( p = 0.012) and the most favorable visual outcome after treatment ( p = 0.004) compared with the other species. Risk factors for poor visual outcomes included a best corrected visual acuity less than 0.1 at initial evaluation ( p < 0.001) and central corneal lesion ( p = 0.027).

Conclusions

Gram-negative bacterial keratitis tended to increase and Pseudomonas spp. was the most common isolate. The clinical prognosis was most favorable in S. marcescens. Early diagnosis of Gram-negative bacterial keratitis and appropriate antibiotic selection including cefepime, quinolone, or amikacin are recommended.

Keywords: Enterobacter species, Gram-negative bacterial keratitis, Pseudomonas species, Serratia marcescens

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Figure 1.

Prevalence of Gram-negative bacterial isolates (n = 169) in total bacterial keratitis at Yeungnam University Hospital during a 15-year period between 1998 and 2012. Number of Gram-positive bacterial isolates (n = 152, published data) dur-ing same study period was included for the counting of total number of isolates.²⁰ The p-value was calculated using Chi-square test to compare the distribution of the Gram-negative bacterial isolates between 2 periods. ^* Gram-negative bacterial isolates significantly increased between 2 periods.

Table 1.

Organisms and shifting trend in Gram-negative bacterial isolates during 1998-2012

Organisms	No. of isolates (%)						p-value^†
	1998-2000	2001-2003	2004-2006	2007-2009	2010-2012	Total^*
	(n = 17)	(n = 18)	(n = 18)	(n = 64)	(n = 52)	(n = 169)
Nonenteric species
Pseudomonas species	8 (47.1)	6 (33.3)	10 (55.6)	14 (21.9)	17 (32.7)	55 (32.5)	0.285
P. aeruginosa	6 (35.3)	5 (27.8)	9 (50.0)	5 (7.8)	9 (17.3)	34 (20.1)	0.285
P. putida	0 (0.0)	0 (0.0)	0 (0.0)	4 (6.3)	4 (7.7)	8 (4.7)	0.041
Other pseudomonas spp.	2 (11.8)	1 (5.6)	1 (5.6)	5 (7.8)	4 (7.7)	13 (2.4)	0.805
Stenotrophomonas maltophilia	0 (0.0)	1 (5.6)	1 (5.6)	7 (10.9)	8 (15.4)	17 (10.1)	0.005
Acinetobacter species	0 (0.0)	2 (11.1)	0 (0.0)	2 (3.2)	1 (1.9)	5 (3.0)	0.741
Other nonenteric species^‡	1 (5.9)	1 (5.6)	0 (0.0)	2 (3.2)	4 (7.7)	8 (4.7)	0.873
Enteric species
Enterobacter species	1 (5.9)	2 (11.1)	0 (0.0)	24 (37.5)	14 (26.9)	41 (24.3)	0.285
E. cloacae	1 (5.9)	0 (0.0)	0 (0.0)	20 (31.3)	10 (19.2)	31 (18.3)	0.322
E. aerogenes	0 (0.0)	1 (5.6)	0 (0.0)	4 (6.3)	4 (7.7)	9 (5.3)	0.089
E. agglomerans	0 (0.0)	1 (5.6)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.6)	0.559
Serratia marcescens	4 (23.5)	4 (22.2)	6 (33.3)	13 (20.3)	6 (11.5)	33 (19.5)	0.188
Klebsiella species	0 (0.0)	2 (11.1)	1 (5.6)	1 (1.6)	1 (1.9)	5 (3.0)	0.873
Other enteric species^§	3 (17.7)	0 (0.0)	0 (0.0)	1 (1.6)	1 (1.9)	5 (3.0)	0.935

^* Eight eyes had mixed infection of 2 Gram-negative bacterial species ( P. aeruginosa & E. aerogenes, Other pseudomonas spp. & S. marces-cens [2 eyes], E. cloacae & S. maltophilia [2 eyes], S. marcescens & S. maltophilia, S. marcescens & K. pneumonia, S. marcescens & A. xylo-soxidans);

^† The p-value was calculated for using Spearman rank correlation coefficient to compare the distribution of the bacterial isolates for 15 years;

^‡ Other nonenteric species included Achromobacter species (4 eyes), Delftia acidovorans (2 eyes), Moraxella species (1 eye), and Ochrobactrum anthropi (1 eye);

^§ Other enteric species included Escherichia coli (2 eyes), Citrobacter diversus (1 eye), Pantoea species (1 eye), and Proteus mirabilis (1 eye).

Table 2.

Trends in antimicrobial susceptibility of Gram-negative bacterial isolates during 1998-2012

Antibiotics	Sensitivity (%, n1/n2^*)						p-value^†
Antibiotics	1998-2000	2001-2003	2004-2006	2007-2009	2010-2012	Total	p-value^†
Beta-lactams
Ampicillin	0.0 (0/9)	0.0 (0/8)	0.0 (0/7)	0.0 (0/37)	9.5 (2/21)	2.4 (2/82)	0.182
Ticarcillin	62.5 (5/8)	63.6 (7/11)	77.8 (14/18)	60.0 (18/30)	70.0 (14/20)	66.7 (58/87)	0.747
Cefoxitin	0.0 (0/2)	25.0 (1/4)	100.0 (7/7)	36.1 (13/36)	14.3 (3/21)	34.3 (24/70)	0.624
Cefotaxime	100.0 (2/2)	41.7 (5/12)	38.9 (7/18)	76.8 (43/56)	66.7 (32/48)	65.4 (89/136)	0.873
Ceftazidime	70.6 (12/17)	83.3 (15/18)	94.4 (17/18)	89.7 (52/58)	100.0 (38/38)	89.9 (134/149)	0.037
Cefepime	90.0 (9/10)	87.5 (14/16)	94.1 (16/17)	94.8 (55/58)	97.8 (44/45)	94.5 (138/146)	0.037
Aminoglycosides
Amikacin	82.4 (14/17)	94.1 (16/17)	88.9 (16/18)	93.1 (54/58)	95.6 (43/45)	92.3 (143/155)	0.188
Gentamicin	70.0 (7/10)	90.9 (10/11)	88.9 (16/18)	89.1 (49/55)	95.3 (41/43)	89.8 (123/137)	0.188
Tobramycin	60.0 (6/10)	92.9 (13/14)	88.9 (16/18)	89.7 (52/58)	92.1 (35/38)	88.4 (122/138)	0.624
Quinolones
Ciprofloxacin	88.9 (8/9)	93.8 (15/16)	100.0 (18/18)	91.2 (52/57)	92.9 (26/28)	93.0 (119/128)	0.747
Levofloxacin	-	-	-	88.9 (16/18)	95.3 (41/43)	93.4 (57/61)	-
TMP/SMX	100.0 (3/3)	75.0 (6/8)	35.3 (6/17)	77.8 (49/63)	72.0 (36/50)	70.9 (100/141)	0.391

TMP/SMX = trimethoprim/sulfamethoxazole.

^* ‘n1’ means number of isolates with susceptibility and ‘n2’ means number of tested isolates;

^† The p-value was calculated using Spearman rank correlation coefficient to compare the distribution of the antimicrobial susceptibility for 15 years.

Table 3.

Demographic characteristics of study subjects with Gram-negative bacterial keratitis during 1998-2012 (n = 161)

Characteristics	No. of cases (%)
Characteristics	1998-2000	2001-2003	2004-2006	2007-2009	2010-2012	Total^*
Gender (male:female)	5:10	13:5	7:11	28:33	31:18	84:77
Age (years)
60≤	4 (26.7)	4 (22.2)	6 (33.3)	24 (39.3)	25 (51.0)	63 (39.1)
40-59	1 (6.7)	2 (11.1)	2 (11.1)	12 (19.7)	11 (22.4)	28 (17.4)
20-39	9 (60.0)	10 (55.6)	9 (50.0)	16 (26.2)	11 (22.4)	55 (34.2)
<20	1 (6.7)	2 (11.1)	1 (5.6)	9 (14.8)	2 (4.1)	15 (9.3)
Length of admission (days)
<7	12 (80.0)	7 (38.9)	2 (11.1)	25 (41.0)	18 (36.7)	64 (39.8)
7-14	2 (13.3)	6 (33.3)	13 (72.2)	23 (37.7)	19 (38.8)	63 (39.1)
>14	1 (6.7)	5 (27.8)	3 (16.7)	13 (21.3)	12 (24.5)	34 (21.1)
Seasonal distribution
Spring (Mar-May)	5 (33.3)	3 (16.7)	2 (11.1)	19 (31.1)	14 (28.6)	43 (26.7)
Summer (Jun-Aug)	2 (13.3)	5 (27.8)	4 (22.2)	20 (32.8)	12 (24.5)	43 (26.7)
Autumn (Sep-Nov)	3 (20.0)	6 (33.3)	8 (44.4)	16 (26.2)	13 (26.5)	46 (28.6)
Winter (Dec-Feb)	5 (33.3)	4 (22.2)	4 (22.2)	6 (9.8)	10 (20.4)	29 (18.0)

^* Patients with culture-positive bacterial corneal ulcers who were treated with at least 1 month from January 1998 through December 2012.

Table 4.

Predisposing factors and demographic characteristics of Gram-negative bacterial keratitis according to the isolated microorganisms

Characteristics	No. of cases (%)
All cases (n = 161)	Pseudomonas spp.(n = 55)	Enterobacter spp. (n = 41)	S. marcescens (n = 33)
Gender (male:female)	84:77	25:30	25:16^*	12:21
Age (years)
60≤	63 (39.1)	20 (36.4)	21 (51.2)^*	4 (12.1)
40-59	28 (17.4)	12 (21.8)	8 (19.5)	1 (3.0)
20-39	55 (34.2)	18 (32.7)	8 (19.5)	23 (69.7)^*
<20	15 (9.3)	5 (9.1)	4 (9.8)	5 (15.2)
Predisposing factors^†
Contact lens wear	59 (36.7)	18 (32.7)	9 (22.0)	27 (81.8)^*
Corneal trauma	56 (34.8)	18 (32.7)	20 (48.8)^*	2 (6.0)^*
Soil/dust	19 (11.8)	6 (10.9)	9 (22.0)^*	1 (3.0)
Vegetable	15 (9.3)	5 (9.1)	5 (12.2)	0 (0.0)
Blunt trauma	14 (8.7)	3 (5.5)	4 (9.8)	1 (3.0)
Metal	8 (5.0)	4 (7.3)	2 (4.9)	0 (0.0)
Ocular surface disease	19 (11.8)	9 (16.4)	5 (12.2)	1 (3.0)
Ocular surgery history	19 (11.8)	5 (9.1)	6 (14.6)	1 (3.0)
Systemic disease	35 (21.7)	12 (21.8)	14 (34.1)^*	2 (6.1)^*
Non-identifiable	46 (28.6)	19 (34.5)	12 (29.3)	4 (12.1)

Pseudomonas spp. = Pseudomonas species; Enterobacter spp.= Enterobacter species; S. marcescens = Serratia marcescens.

^* The p-value was < 0.05, which was calculated for comparison of proportions with all other groups by Chi-square test and Fisher’s exact test;

^† Sum of the number of eyes with each subgroup does not add up to 100% because of overlap of subgroups and no history of identified predispos-ing factors.

Table 5.

Clinical characteristics at initial presentation, epithelial healing time, and visual outcome of Gram-negative bacterial keratitis according to the isolated microorganisms

Characteristics	No. of cases (%)
	All cases	Pseudomonas spp.	Enterobacter spp.	S. marcescens
	(n = 161)	(n = 55)	(n = 41)	(n = 33)
Corneal lesion
Location^†
Central	82 (50.9)	34 (61.8)	21 (51.2)	12 (36.4)
Peripheral	79 (49.1)	21 (38.2)	20 (48.8)	21 (63.6)^*
Size (mm²)
<5	100 (62.1)	30 (54.5)	26 (63.4)	27 (81.8)^*
≥5	61 (37.9)	25 (45.5)^*	15 (36.6)	6 (18.2)
Hypopyon
Yes	29 (18.0)	13 (23.6)	7 (17.1)	2 (6.1)
No	132 (82.0)	42 (76.4)	34 (82.9)	31 (93.9)
Initial BCVA (SA)
<0.1	86 (53.4)	34 (61.8)	21 (51.2)	13 (39.4)
0.1-0.5	44 (27.3)	12 (21.8)	14 (34.1)	11 (33.3)
0.6-1.0	31 (19.3)	9 (16.4)	6 (14.6)	9 (27.3)
Final BCVA (SA)
<0.1	51 (31.7)	23 (41.8)^*	13 (31.7)	3 (9.1)^*
0.1-0.5	39 (24.2)	11 (20.0)	11 (26.8)	7 (21.2)
0.6-1.0	71 (44.1)	21 (38.2)	17 (41.5)	23 (69.7)
Epithelial healing time (days)^‡ (n = 150)
<10	93 (62.0)	27 (52.9)	24 (63.2)	27 (81.8)^*
≥10	57 (38.0)	24 (47.1)^*	14 (36.8)	6 (18.2)
Surgical treatment	11 (6.8)	4 (7.3)	3 (7.3)	0 (0.0)

Pseudomonas spp. = Pseudomonas species; Enterobacter spp.= Enterobacter species; S. marcescens = Serratia marcescens; BCVA = best corrected visual acuity; SA = Snellen acuity.

^* The p-value was < 0.05, which was calculated for comparison of proportions with all other groups by Chi-square test and Fisher’s exact test;

^† ‘Central’ is located within 1/2 radius from the center of the cornea and ‘Peripheral’ is located within 1/2 radius from the limbus;

^‡ The eyes were excluded if surgical treatment was done (11 eyes).

Table 6.

Multivariate logistic regression analysis for risk factors of poor visual outcome in Gram-negative bacterial keratitis

Factor	Poor visual outcome^*
Factor	OR	95% CI	p-value^†
Male	0.83	0.23-2.99	0.775
Age ≥60 (years)	2.32	0.60-8.99	0.224
Previous ocular surgery (+)	4.10	0.78-21.57	0.096
Ocular surface disease (+)	0.66	1.15-2.87	0.578
Systemic disease (+)	1.10	0.29-4.18	0.890
Contact lens wear (+)	0.56	0.09-3.39	0.528
Central corneal lesion	3.69	1.16-11.74	0.027
Epithelial defect size ≥5 (mm²)	2.21	0.64-7.61	0.211
Hypopyon (+)	1.16	0.35-3.79	0.812
Initial BCVA less than 0.1	54.73	6.33-473.06	<0.001
Epithelial healing time ≥10 (days)	0.89	0.28-2.86	0.841
Cultured organism	0.413
Enterobacter species	3.22	0.42-24.81	0.263
Pseudomonas species	4.77	0.76-29.78	0.094
Others	2.90	0.39-21.70	0.299

OR = odds ratio; CI = confidence interval; BCVA = best corrected visual acuity.

^* The visual outcome was classified as poor if they had final BCVA of 0.1 or less;

^† Multivariate logistic regression analysis was performed for the factors which had p-value less than 0.1 in univariate logistic regression analysis.

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