CLINICAL SCIENCE

Clinical Outcomes of Corneal Graft Infections Caused by Multi–Drug Resistant Pseudomonas Aeruginosa Rajat Jain, MS,* Somasheila I. Murthy, MS,* and Swapna Reddy Motukupally, MD†

Purpose: The aim was to assess the clinical outcomes of corneal graft infections caused by multi–drug resistant Pseudomonas aeruginosa (MDR-PA).

Key Words: graft infiltrate, multidrug resistant, Pseudomonas aeruginosa, colistin (Cornea 2014;33:22–26)

Methods: This is a retrospective case series of 38 patients with corneal graft infections caused by MDR-PA managed from June to December 2011. Clinical and demographic details, treatment outcome on primary therapy, cases requiring a repeat graft, their outcome, and recurrence rate on treatment were analyzed. The outcome measure was resolution of infection. Success was “complete” if resolution was seen without subsequent recurrence up to 2 weeks and “partial” if it required intervention such as cyanoacrylate glue application. It was a “failure” if the infection could not be controlled and the patient required a repeat graft or the eye had to be eviscerated.

Results: Thirty-one patients were initially treated with topical cefazolin 5% and ciprofloxacin 0.3%, 6 with topical colistin 0.19%, and 1 was treated with topical imipenem 1%. On this treatment, 9 cases showed complete success and 6 showed partial success. Twenty-two patients required a repeat graft, and 1 eye was eviscerated. The patients with outcome of success had smaller graft infiltrates (median area = 2 mm2; range = 1–24.6 mm2 vs. median infiltrate area = 24.8 mm2; range = 1.5–64 mm2) than those with an outcome of failure (P = 0.02). At the mean follow-up of 50 days, recurrence after the repeat surgery was seen in 4/22 (18.2%) patients. Conclusions: Medical therapy can be tried in sensitive and smaller

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icrobial keratitis occurring after a penetrating keratoplasty (PK) is a major vision-threatening complication that can lead to corneal scarring and graft failure despite providing adequate medical therapy. Uncontrolled infection can lead to endophthalmitis and phthisis.1 It can occur any time after the transplant and is 1 of the major causes of post-PK poor visual outcome.2,3 The reported incidence in the developing world ranges from 1.8% to 7.6%.1 Eroded or broken sutures have been shown to be a major risk factor.4 Both bacteria and fungi have been isolated as etiological agents in post-PK infection. The most common bacteria responsible are gram-positive cocci such as coagulase-negative Staphylococci and Staphylococcus aureus. Gram-negative ulcers are most commonly caused by Pseudomonas aeruginosa, whereas Aspergillus species has been implicated most commonly in fungal graft infiltrates.1 P. aeruginosa is a highly virulent gram-negative organism well known for its resistance to first- and second-line antibiotics in systemic and nosocomial infections.5 Reports of antibiotic resistance to this organism in ocular infections are scarce.6,7 To the best of our knowledge, this study is the first to report multi–drug resistant P. aeruginosa corneal graft infiltrates.

MDR-PA graft infiltrates, but larger infiltrates and those with endophthalmitis require early surgical intervention. Received for publication July 23, 2013; revision received September 2, 2013; accepted September 16, 2013. Published online ahead of print November 14, 2013. From the *Cornea and Anterior Segment Service, L V Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, India; and †Jhaveri Microbiology Services, L V Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, India. The authors have no funding or conflicts of interest to disclose. R. Jain performed the literature review, analyzed the data, and wrote the manuscript. R. Jain, S. Reddy, and S. Murthy were responsible for the study conception and design. S. Murthy and S. Reddy revised the article critically for important intellectual content. All the authors included in this article fulfill the criteria of authorship. On behalf of all the coauthors, Rajat Jain, MS, states that he had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ethics approval: Ethics committee/institutional review board approval was obtained. Reprints: Somasheila I. Murthy, Head, Corneal Diseases, L V Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, Rd No 2, Hyderabad 500034, Andhra Pradesh, India (e-mail: [email protected]). Copyright © 2013 by Lippincott Williams & Wilkins

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MATERIALS AND METHODS Study Design and Subjects This retrospective study was approved by the Institutional Review Board of the L V Prasad Eye Institute, Hyderabad, India. This study included patients who were diagnosed with corneal graft infections caused by multi–drug resistant P. aeruginosa (MDR-PA) from June 2011 to January 2012. All the patients with culture-proven MDR-PA graft infiltrates in which the antibiotic sensitivity patterns had been identified were included. MDR in gram-negative bacteria was defined as bacteria resistant to $3 antimicrobial classes.8–10

Data Collection The clinical and microbiological data were retrieved from the medical records and microbiological archives, respectively. Cornea  Volume 33, Number 1, January 2014

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Clinical Characteristics The clinical data recorded were age, gender, bestcorrected visual acuity (BCVA) at presentation, type, and timing of previous keratoplasty. The clinical characteristics of the infiltrate specifically looked for included its size and depth, presence of satellite lesions, infiltrate doubling time, incidence of progressive thinning or perforation, whether graft–host junction was involved, and the presence or absence of concurrent endophthalmitis. The size of the infiltrate was measured in millimeters using the grid attachment of the Haag-Streit (Haag-Streit, Germany) slit lamp. The measurements were noted at the widest meridian of the infiltrate and at an axis 90 degrees to it.

Multiple Drug Resistant Pseudomonas Aeruginosa Graft Infiltrates

and diluted with 3 mL of distilled water to obtain a final concentration of 0.19% colistin eye drops.

Outcome Measure The primary outcome measure was the resolution of infection. Outcome assessment was done at 2 weeks after the initiation of therapy. Success was termed as “complete” if the resolution of infection occurred with scar formation without subsequent recurrence and “partial” if it required cyanoacrylate glue application (for thinning or perforation) with subsequent scar formation. The outcome was noted as a “failure” if the infection could not be medically controlled and the patient required a repeat graft or the eye had to be eviscerated.

Microbiological Characteristics These included the microbiological data of culture and antibiotic sensitivity. On presentation in the outpatient clinic, the corneal scrapings were collected and processed from all the patients as per the institutional protocol published earlier.11 Using standard techniques, multiple corneal scrapings were obtained by a sterile number 15 blade mounted on a Parker (Asian Surgical Co, Hyderabad, India) handle from each patient and were transferred onto slides for direct microscopic examination and on media for culture. Microscopic examination included Gram stain, 10% potassium hydroxide with 0.1% calcofluor white (KOH + CFW) wet mount, and Giemsa stain. The samples were directly inoculated onto 5% sheep blood agar, chocolate agar, Sabouraud dextrose agar (SDA), potato dextrose agar, Nonnutrient agar with an Escherichia coli overlay, Brain heart infusion broth, and Thioglycollate broth. SDA and potato dextrose agar were incubated at 25 to 27°C, whereas the others were incubated at 37° C and observed for growth. Cultures were considered significant if there was (1) confluent growth in any solid media; (2) growth in .1 medium; (3) growth in 1 medium with consistent findings on direct microscopy; and/or (4) repeated isolation of the organism. For patients undergoing keratoplasty, the corneal tissue excised at keratoplasty was bisected across the ulcer, and half of it was submitted to the microbiology laboratory in a sterile container. The tissue was minced aseptically using a sterile blade, and the fragments were inoculated on blood agar, chocolate agar, SDA, and nonnutrient agar and incubated as mentioned above. The cultures were observed daily for any evidence of growth. All bacterial isolates were subjected to antibiotic susceptibility testing by the Kirby Bauer disc diffusion method according to the Clinical and Laboratory Standards Institute guidelines.

Follow-Up Examinations The primary medical treatment given to the patients was noted. The number of patients who required repeat surgery was recorded. The treatment given to these patients postoperatively and the recurrence rate of infection were noted.

Statistical Analysis All the descriptive parameters were noted in the form of mean and standard deviation if the data were parametric or in the form of median with range if the data were nonparametric. A 2-tailed t test was applied to assess the difference in the outcome based on the size of the infiltrates at presentation. P , 0.05 was considered to be statistically significant.

RESULTS Patient Population During the study period, the total number of culturepositive ocular infections managed in the institute was 1923. Of these, 743 (38.7%) were bacterial including 141 infections caused by P. aeruginosa (7.3%). Among the Pseudomonas infiltrates, 74 (3.8%) were caused by multi–drug resistant P. aeruginosa, and 38 (2%) of these were graft infiltrates (Fig. 1). The mean age of the patients was 46.3 6 16.4 years (range 10–81), and the male: female ratio was 24:14. At presentation, the majority of the patients had a BCVA of counting fingers close to their face or less (27/38 = 71%), whereas 11 patients (29%) had a BCVA of up to finger counting at 3 m. Figure 2 illustrates the distribution of the BCVA at presentation and at the final follow-up.

Medical Therapy After establishing the diagnosis, all the patients were hospitalized and received intensive medical care. Therapy was initiated with broad spectrum antibiotics and later modified according to the culture and sensitivity report. Topical colistin 0.19% was used in a few patients in the management. This was formulated by the hospital pharmacy as follows: Injection colistimethate sodium powder (1 million IU/75 mg; Xylistin, Cipla limited, Mumbai, India) was mixed with 10 mL of distilled water to yield a concentration of 7.5 mg/mL (0.75%). One milliliter of this clear solution was taken Ó 2013 Lippincott Williams & Wilkins

Clinical Characteristics The median time of the presentation of the infiltrate after the previous keratoplasty was 196 days (range 2–960 days). The most common type of previous surgery was therapeutic keratoplasty (20/38, 52.6%) followed by optical keratoplasty (11/38, 28.9%), Descemet stripping automated endothelial keratoplasty (DSAEK) (6/38, 15.7%), and patch graft for a perforated peripheral ulcerative keratitis (1/38, 2.6%). Therapeutic keratoplasty was most commonly done www.corneajrnl.com |

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FIGURE 1. Proportion of MDR graft infiltrates from total culture positive ocular infections managed during the study period.

for mycotic keratitis (17/20). All these cases were infection free before MDR-PA infection. Three patients presented to us with graft perforation (3/38, 8.1%). The mean size of the infiltrate was 21.9 6 19.9 mm2 (median 17 mm2, range 1–64 mm2). Table 1 shows the details of the clinical characteristics of the graft infiltrates in detail. About three-fourths of the infiltrates were full thickness (73.6%) (Fig. 3A). The graft–host junction was involved in 44.7% (17/ 38) patients (Fig. 3B), and 4/38 patients (10.5%) presented with concurrent endophthalmitis, the diagnosis of which was made on B-scan ultrasonography (Fig. 3C). The infiltrate area doubled in less than a day in 52.6% (20/38) patients, and 6/32 patients (18.7%) had satellite lesions at presentation.

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was a combination of Cefazolin 5% and Ciprofloxacin 0.3% eye drops every half hour. Six patients were treated with Colistin 0.19% eye drops, and 1 patient was treated with Imipenem 1% eye drops as primary therapy. The treatment was modified after the culture report was available in 13 patients. The therapy was changed to Imipenem 1% eye drops and Ciprofloxacin 0.3% eye drops every half hour in 3 and 10 patients, respectively. On this treatment, 9 cases showed complete success, and 6 showed partial success, that is, 15/38 patients (39.4%). Of these, 6/15 patients were on topical colistin 0.19%, 1/15 patient was on topical imipenem 1%, and the remaining patients (8/15) were on topical ciprofloxacin 0.3%. No significant differences were noted in the outcome of these 15 cases based on the medical therapy. On comparison with the patients with a failed outcome (23/38, 60.5%), these 15 patients had smaller graft infiltrates (median infiltrate area = 2 mm2; range = 1–24.6 mm2 vs. median infiltrate area = 24.8 mm2; range = 1.5–64 mm2) (P = 0.02). Four patients (4/38, 10.5%) were diagnosed with graft infiltrates with concurrent endophthalmitis at presentation. The outcome in these 4 patients was a failure because they required a repeat graft with vitreoretinal intervention. Pars plana vitrectomy was performed in 2/4 of these patients, and intravitreal injections were given to all (4/4). Recurrence of infection was not seen, and the grafts were clear at 1 month. The final BCVA in these patients was the accurate projection of rays in 3 patients and 20/200 in 1 patient.

Microbiology Cultures from all the corneal scrapings that showed a significant growth of P. aeruginosa were tested for antibiotic sensitivity. Table 2 shows the distribution of the antibiotic sensitivities of the culture isolates from various patients. Infiltrates were resistant to most of the first and second lines of antibiotics and sensitive to Imipenem (44.7%) and Colistin (100%).

Outcome Assessment At presentation, 31 cases were treated with broad spectrum antibiotics, as per the institution protocol, which

Treatment Failures and Adverse Events Twenty-three eyes (60.5%) had a failure of outcome of which 21 required a repeat therapeutic keratoplasty, 1 required a patch graft, and 1 eye was eviscerated. The median duration at which a repeat graft was done was 4 days (range 1–18 days). The indication for surgical intervention was a rapidly progressing infiltrate in most cases. Postoperatively, 4 patients received a combination of cefazolin 5% and ciprofloxacin 0.3% eye drops, 4 patients received imipenem 1%, 2 patients received colistin 0.19%, and 12 patients received ciprofloxacin 0.3%

FIGURE 2. BCVA at presentation and finally.

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TABLE 1. Characteristics of Graft Infiltrates at Presentation No. 1 2

3 4 5 6

Infiltrate Characteristics Size Depth Anterior stromal Midstromal Posterior stromal (Fig. 3A) Graft–host junction involved (Fig. 3B) Endophthalmitis (Fig. 3C) Infiltrate doubling time Satellite lesions

Mean = 21.9 mm2 Range = 1–64 mm2 3/38 7/38 28/38 17/38

7.8% 18.4% 73.6% 44.7%

4/38 10.5% ,24 hrs—52.6% (20/38) 6/32 18.7%

The majority of the infiltrates involved the posterior stroma (73.6%). The graft–host junction was involved in 44.7% cases. The striking features were that the infiltrate doubling time was less than a day in 52.6% patients and 18.7% patients presented with satellite lesions.

eye drops alone. Recurrence was seen in 4 cases (4/22 = 18.2%), 2 each in patients in whom imipenem 1% and ciprofloxacin 0.3% eye drops were used. The final BCVA varied from an accurate projection of rays to 20/25.

DISCUSSION Although the reported rates of incidence of post-PK infection are low, the visual sequelae of graft infection are frequently severe.12 Visual prognosis in these eyes is poor even after optimal therapy, and there is a high rate of graft decompensation.1 Further, the graft clarity rates after successful medical treatment of the ulcer is completed ranges from 23% to 67%.1,13–17 Hence, any corneal graft infection requires prompt and judicious management. Gram-negative bacteria causing graft infections most commonly include P. aeruginosa.1 It is a notoriously difficult organism to control with antibiotics or disinfectants. To compound the problem, there has been an increasing trend of antibiotic resistance to this organism, as reported in systemic infections.18,19 The phenomenon of such antibiotic resistance

is not new. Hwang20 in 2004 suggested that a newer generation of topical ophthalmic fluoroquinolones—levofloxacin, gatifloxacin, and moxifloxacin—offered several advantages over previously available fluoroquinolones. Although antibiotic resistance of P. aeruginosa is well known in systemic and nosocomial inections,21–24 any report of resistance of this organism in corneal graft infections is lacking. This study presents the clinical features and the outcomes of such corneal isolates that are resistant to most of the first- and second-line antibiotics. The authors also attempted to look at the specific clinical features and treatment outcomes to establish baseline treatment guidelines for MDR Pseudomonas infection. This study was prompted by the authors’ observation of an increase in the incidence of graft infiltrates caused by multi–drug resistant P. aeruginosa over the past few years. These infections spread very rapidly in both size and depth with an infiltrate doubling time of less than a day in most cases and with infiltrates extending up to the posterior stroma. A few patients also presented with satellite lesions. In this study, the authors also found a significant difference in the infiltrate size at presentation in patients who responded to medical therapy compared with those patients in whom surgical intervention was necessary. Smaller infiltrates healed without the presence of significant deep vessels even if conventional antibiotics were used at an intensive dosage. The visual acuity postintervention in these cases was low because of the presence of scar. These patients can be later rehabilitated by performing an optical graft. Larger infiltrates frequently required repeat surgery. We believe that infiltrates that are larger at presentation are unlikely to heal with medical therapy, and an early therapeutic keratoplasty is recommended. This is also substantiated by the finding of a low recurrence rate of infection after a repeat graft even without the use of sensitive antibiotics postoperatively. Resolution of infection was seen in all the patients who presented with endophthalmitis in this series but despite clear corneal grafts postsurgery, the visual outcomes in these patients were poor. We believe that this is because of the toxic effects of Pseudomonas endotoxins combined with inflammation of the retina, both of which lead to poor visual recovery.

FIGURE 3. Slit-lamp photograph showing cornea graft infiltrates involving the full thickness of the corneal stroma (A), graft–host junction post endothelial keratoplasty (DSEK) (B), full thickness of the stroma with endophthalmitis on B-scan ultrasonography (C). Ó 2013 Lippincott Williams & Wilkins

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TABLE 2. Antibiotic Sensitivity Patterns of the Graft Infiltrates Antibiotic Amikacin Amoxicillin Amoxyclav Ampicillin Cefazolin Ceftazidime Ceftriaxone Cefotaxim Chloramphenicol Ciprofloxacin Cloxacillin Cotrimoxazole Gatifloxacin Gentamycin Moxifloxacin Ofloxacin Piperacillin Ticarcillin Piperacillin + Tazobactum Tobramycin Imipenem Colistin

Sensitivity Checked Sensitive Resistant Resistant % 38 36 38 26 33 38 36 38 37 37 24 38 37 37 37 36 37 38 38 37 38 38

0 0 0 0 0 3 0 2 0 0 0 0 0 0 0 0 6 1 8 0 21 38

38 36 38 26 33 35 36 36 37 37 24 38 37 37 37 36 31 37 30 37 17 0

100 100 100 100 100 92.1 100 94.73 100 100 100 100 100 100 100 100 83.8 97.3 78.9 100 44.7 0

The majority of the patients were resistant to conventional first- and second-line treatment of antibiotics, and 44.7% patients were sensitive to imipenem and all were sensitive to Colistin.

Although P. aeruginosa cultures isolated from all the patients were resistant to conventional antibiotics, 9/38 (23.7%) patients still responded to treatment with ciprofloxacin 0.3%. The authors hypothesize that intensive dosage (halfhourly and hourly) and direct topical administration in these patients increased the antibiotic concentration in their conjunctival sac and across the cornea much beyond the minimum inhibitory and bactericidal concentration for the organism. Colistin is a reemerging antibiotic option for the treatment of systemic MDR-PA infections.24 There has been only 1 report of the topical use of colistin 0.19% in ocular infections that dates back to 1969.25 The authors used topical colistin 0.19% eye drops in 6/38 (15.7%) patients preoperatively with successful outcomes. Hence, the topical use of colistin 0.19% can be a good option in these cases. This study is the first report of the use of colistin for corneal graft infections. The study has the limitations of being retrospective in nature with multiple antibiotics being used with varying protocols by different treating physicians. The efficacy of colistin 0.19% as a topical agent would be better established by comparing it with other antibiotics in a controlled trial. But considering the frequency of such cases reported, it would be difficult to organize such a study. This study suggests that multi–drug resistant P. aeruginosa graft infections are on the rise and that they tend to progress very rapidly. The use of topical colistin can be tried in patients with sensitive and smaller infiltrates, but the larger

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infiltrates and those with endophthalmitis often required surgical intervention.

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Clinical outcomes of corneal graft infections caused by multi-drug resistant Pseudomonas aeruginosa.

The aim was to assess the clinical outcomes of corneal graft infections caused by multi-drug resistant Pseudomonas aeruginosa (MDR-PA)...
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