Journal List > J Korean Ophthalmol Soc > v.56(10) > 1010098

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

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.

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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.
jkos-56-1479f1.tif
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
1998-2000 2001-2003 2004-2006 2007-2009 2010-2012 Total
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 (%)
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*
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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