ENDOPHTHALMITIS CAUSED BY PSEUDOMONAS AERUGINOSA Clinical Features, Antibiotic Susceptibilities, and Treatment Outcomes JAYANTH SRIDHAR, MD, AJAY E. KURIYAN, MD, HARRY W. FLYNN, JR., MD, DARLENE MILLER, DHSC Purpose: To report the clinical features, antibiotic susceptibilities, and visual outcomes associated with endophthalmitis caused by Pseudomonas aeruginosa. Methods: A consecutive case series. Microbiology database records were retrospectively reviewed for all patients with endophthalmitis caused by P. aeruginosa from January 1, 2002, to December 31, 2012, at a large university referral center. The corresponding clinical records were then reviewed to evaluate the endophthalmitis clinical features and treatment outcomes. Results: In the 12 patients identified, clinical settings included postcataract surgery (n = 4), postpenetrating keratoplasty (n = 3), endogenous source (n = 2), post-pars plana vitrectomy (n = 1), trabeculectomy bleb-associated setting (n = 1), and glaucoma drainage implantassociated setting (n = 1). All patients presented with hypopyon. Presenting visual acuity was hand motions or worse in all cases. All isolates were susceptible to ceftazidime and levofloxacin. When comparing isolates in this study with isolates from a previous study (1987 to 2001), the minimal inhibitory concentration required to inhibit 90% of isolates (MIC 90, in micrograms per milliliter) remained the same for ceftazidime (8), ciprofloxacin (0.5), imipenem (4), tobramycin (0.5), and amikacin (4). Initial treatment strategies were vitreous tap and injection (n = 9) and pars plana vitrectomy with intravitreal antibiotics (n = 3). Final visual acuity was light perception or worse in 11 of the 12 patients (92%). Five patients underwent enucleation (42%). Conclusion: All isolates were susceptible to ceftazidime and levofloxacin, and all MIC 90s for isolates in the current period compared with isolates from 1987 to 2001 remained identical. Despite early and appropriate treatment, outcomes were generally poor with a high rate of enucleation. RETINA 35:1101–1106, 2015
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large series of acute postoperative endophthalmitis ranges from 8% to 34%.3–5 There have also been several reported large outbreaks of postcataract surgery P. aeruginosa endophthalmitis secondary to contamination.6–10 In previous reports, the most common clinical settings for P. aeruginosa endophthalmitis included infectious keratitis, acute-onset postcataract surgery, postpenetrating keratoplasty, and endogenous source.11,12 In other clinical settings, P. aeruginosa has demonstrated increasing levels of resistance to previously effective broad-spectrum antibiotics, including aminoglycosides, cephalosporins, extended-spectrum penicillins, and carbapenems.13,14 In a previous study from 1987 to 2001 from our institution, more than 90% of cases of P. aeruginosa endophthalmitis were
seudomonas aeruginosa is a gram-negative rod often implicated in nosocomial infections. 1 P. aeruginosa only accounted for approximately 1% of culture-positive endophthalmitis cases in the Endophthalmitis Vitrectomy Study.2 However, the incidence of P. aeruginosa as the causative organism in From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. Supported in part by NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Department of Defense (DOD-Grant#W81XWH-09-1-0675). None of the authors have any conflicting interests to disclose. Reprint requests: Jayanth Sridhar, MD, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136; e-mail: [email protected]
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susceptible to initially administered antibiotics.11 Recently, there have been reports of multidrugresistant P. aeruginosa endophthalmitis.15–18 Previous studies have not demonstrated the antibiotic minimal inhibitory concentrations for 90% (MIC 90) of P. aeruginosa isolates in endophthalmitis cases. The purpose of this study was to provide an update on the clinical settings, antibiotic susceptibilities, and visual acuity outcomes in a more recent series of culture-proven P. aeruginosa endophthalmitis. Based on PubMed search, this represents the first study comparing MIC 90 data between periods for cases of endophthalmitis caused by P. aeruginosa.
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a period of up to 2 weeks. Additional culture media, including thioglycollate broth, were performed at the discretion of the ophthalmologist performing the culture. All cultures were read, subcultured on special media as necessary, and classified by Ocular Microbiology Department staff. Shifting trends in in vitro MIC 90 (mg/mL) were analyzed using the E test (Biomerieux, Raleigh, NC). After analyzing microbiology records, the corresponding medical records of these patients were reviewed to ensure clinical course consistent with endophthalmitis. Patient demographics, clinical characteristics, risk factors, treatment strategies, and clinical outcomes were assessed.
Methods Results Institutional Review Board approval was obtained from the University of Miami Miller School of Medicine Sciences Subcommittee for the Protection of Human Subjects. The ocular microbiology department database was searched to identify all patients with positive vitreous chamber cultures for P. aeruginosa between January 1, 2002, and December 31, 2012. Microbiology department records were reviewed to identify the responsible microbial isolates and antibiotic susceptibilities. Vitreous cultures were obtained either at the time of vitreous tap and inject or during vitrectomy. Fluid from vitreous tap was plated directly on to culture media including 5% sheep blood and chocolate agars. For vitrectomy specimens, 30 mL to 50 mL of vitreous washings were filtered using a 0.45-mm filter. The resultant filter paper was divided into sections and was plated on to different culture media, which typically included chocolate and blood agars. Blood and chocolate agars underwent incubation at 35°C for
Over the 11-year study period, 12 eyes from 12 patients were identified to have positive vitreous cultures for P. aeruginosa and clinical course consistent with endophthalmitis (Table 1). The median patient age was 73.5 years (range, 1 month to 88 years). Endophthalmitis occurred in the clinical setting of postcataract surgery (n = 4) (Figure 1), postpenetrating keratoplasty (n = 3), endogenous source (n = 2), post-pars plana vitrectomy (n = 1), trabeculectomy bleb-associated setting (n = 1), and glaucoma drainage implant-associated setting (n = 1). Six patients had a concurrent corneal ulcer in the same eye: one of the postcataract surgery patients, all three of the postpenetrating keratoplasty patients, the trabeculectomy bleb-associated patient, and the glaucoma drainage implant-associated patient. The post-pars plana vitrectomy case was combined with an iris-sutured intraocular lens. One of the endogenous cases occurred in the setting of a premature infant with sepsis and intraventricular hemorrhage,
Table 1. Endophthalmitis Caused by P. aeruginosa: Clinical Settings Patient Number 1 2 3 4 5 6 7 8 9 10 11 12
Age
Clinical Setting
Concurrent Corneal Ulcer
Time After Surgery
74 years 84 years 69 years 75 years 56 years 81 years 53 years 1 month 72 years 79 years 88 years 73 years
Postoperative cataract phacoemulsification Postoperative cataract phacoemulsification Postoperative cataract phacoemulsification Postoperative cataract phacoemulsification Post-PKP Post-PKP Post-PKP Endogenous, premature infant with sepsis, IVH Endogenous, iatrogenic immunosuppression* Trabeculectomy bleb-associated Post-PPV with iris-sutured IOL BGI bleb-associated with tube exposure
No No No Yes Yes Yes Yes No No Yes No No
1 day 2 days 12 days 23 days 7 months 4 months 30 years N/A N/A 5 months 5 days 6 months
*Patient with history of colon cancer and myelofibrosis. BGI, baerveldt glaucoma implant; IVH, intraventricular hemorrhage; IOL, intraocular lens; PKP, penetrating keratoplasty; PPV, pars plana vitrectomy.
ENDOPHTHALMITIS CAUSED BY PSEUDOMONAS SRIDHAR ET AL
Fig. 1. Slit-lamp photograph of a patient with endophthalmitis caused by P. aeruginosa. The patient presented 12 days after cataract surgery because of pain and decreased vision with a suture abscess, hypopyon, and corneal edema.
whereas the other occurred in a patient received immunosuppressive medications for colon cancer and myelofibrosis treatment. With the exception of the premature infant, all patients presented with symptoms of pain and visual loss. Visual acuity on presentation was hand motions or worse in all cases (Table 2). Hypopyon was noted in all 12 patients (100%). The mean intraocular pressure was 29 mmHg (range, 13–40 mmHg). Because of significant anterior segment inflammation and vitreous opacities, no view of the posterior pole was obtainable in any patient. Initial treatment strategies included vitreous tap and injection (n = 9, 75%) and pars plana vitrectomy with injection of intravitreal antibiotics (n = 3, 25%). Intravitreal antibiotics consisted of vancomycin and ceftazidime for all patients. All patients were started on topical antibiotic drops, and a topical steroid drop was started within 48 hours of the initial treatment in
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9 patients (75%). Six patients (50%) received intravitreal corticosteroids. Additional treatment was administered within 2 weeks of initial treatment in 6 patients (50%): 3 patients had an additional vitreous tap and injection of ceftazidime, 2 patients underwent enucleation, and 1 patient underwent glaucoma drainage implant removal. Three other patients underwent enucleation between 1 month and 6 months after initial treatment. One patient underwent additional vitreous tap and injection 55 days after initial treatment because of suspected recurrent endophthalmitis. Initial intraocular cultures were monomicrobial and positive for P. aeruginosa in all patients. All isolates were susceptible to one of the initially administered intraocular antibiotics. All P. aeruginosa isolates tested were susceptible to ceftazidime and levofloxacin. The antibiotic susceptibilities and MIC 90 of P. aeruginosa isolates tested are reported in Table 3 and compared with isolates from 1987 to 2001. The MIC 90 for isolates from 2002 to 2012 and 1987 to 2001 remained the same for ceftazidime (8 mg/mL), ciprofloxacin (0.5 mg/mL), imipenem (4 mg/mL), tobramycin (0.5 mg/mL), and amikacin (4 mg/mL). Final visual acuity was no light perception in 8 patients (67%), light perception in 3 patients (25%), and 20/400 in 1 patient (8%). Median follow-up was 7.5 months (range, 1 week to 4.5 years). Five patients underwent enucleation (42%). Discussion The most common clinical settings for P. aeruginosa endophthalmitis in the current series were postcataract
Table 2. Presentation, Treatment Strategies, and Outcomes of Patients With Endophthalmitis Caused by P. aeruginosa Preinfection No. VA
Initial VA
Initial Tx
Initial Intravitreal Injection(s) VANC + CTZ + DEX VANC + CTZ + TRIAM VANC + CTZ VANC + CTZ VANC + CTZ + DEX VANC + CTZ + AMI + DEX VANC + CTZ + DEX VANC + CTZ VANC + CTZ VANC + CTZ VANC + CTZ + DEX VANC + CTZ
1 2
UK UK
HM LP
T+I T+I
3 4 5 6
UK 20/200 20/70 4/200
LP LP LP HM
PPV PPV T+I PPV
7 8 9 10 11 12
LP UK 20/25 20/40 20/800 20/400
LP UK LP HM LP LP
T T T T T T
+ + + + + +
I I I I I I
Additional Tx (Days After Initial Tx)
Additional Intravitreal Injection(s)
Last VA
None Enucleation (45)
None None
20/400 NLP
T + I (2) T + I (55)* T + I (10) None
CTZ CTZ CTZ None
LP LP NLP LP
6 2 5 2
Enucleation (150) Enucleation (6) Enucleation (11) Enucleation (30) T + I (7) Removal BGI (2)
None None None None CTZ None
NLP NLP NLP NLP NLP NLP
15 months 1 week 9 months 4 years 4.5 years 9 months
Follow-up Time 2.5 years 2 months months months months years
*Additional treatment at the time of suspected recurrent infection. AMI, amikacin; CTZ, ceftazidime; DEX, dexamethasone; HM, hand motions; LP, light perception; NLP, no light perception; No., patient number; PPV, pars plana vitrectomy; T + I, vitreous tap + intravitreal injection; TRIAM, triamcinolone; Tx, treatment; VANC, vancomycin; VA, visual acuity; UK, unknown.
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Table 3. P. aeruginosa Antibiotic Susceptibility and Minimal Inhibitory Concentrations 2002 to 2012 Antibiotic
No. of Isolates Tested
Ceftazidime Ciprofloxacin Levofloxacin Imipenem Tobramycin Amikacin
14 12 14 10 14 12
1987 to 2001
Resistant Isolates (%) 0 1 0 1 1 1
MIC 90 (mg/mL)
No. of Isolates Tested
Resistant Isolates (%)
MIC 90 (mg/mL)
8 0.5 1 4 0.5 4
10 11 0 11 11 10
0 (0) 0 (0) NA 1 (9) 0 (0) 0 (0)
8 0.5 NA 4 0.5 4
(0) (8) (0) (10) (7) (8)
NA, not available; No., number.
extraction and postpenetrating keratoplasty, matching the results from a previous study from our institute published by Eifrig et al11 (Table 4). In contrast, Chen et al12 described in a large series that infectious keratitis and scleritis represented the leading cause of P. aeruginosa endophthalmitis, followed distantly by cataract surgery, penetrating keratoplasty, and endogenous source. A notable difference between this study and those two previous studies was the strict inclusion of only those patients with positive vitreous cultures in this study; this theoretically prevented the inclusion of falsepositive cases with positive anterior chamber cultures secondary to infectious keratitis but no clinical evidence of true endophthalmitis. Visual outcomes in this study were extremely poor with 92% of eyes worse than 20/400 and 67% of eyes with no light perception. Previous large series of P. aeruginosa endophthalmitis have demonstrated a no light perception outcome in 68% to 82% of cases.11,12,18 Anatomical outcomes were also poor; the enucleation rate in this study was 42%, slightly better than the previously reported rate of 50% to 82% observed in those other large
series.11,12,18 P. aeruginosa may cause devastating functional and anatomical outcomes secondary to the nature of its intrinsic enzymes.1 P. aeruginosa produces elastases and exotoxins that once within the cornea, the anterior chamber, or the vitreous cavity may rapidly and permanently degrade the intraocular contents, resulting in uncontrolled inflammation and globe disorganization.19,20 Risk factors for enucleation/evisceration may include the postpenetrating keratoplasty setting, association with infectious keratitis or scleritis, and endogenous etiology.12 This may explain why the rate of globe loss is lower in specific series focusing on only postcataract extraction outbreaks of P. aeruginosa endophthalmitis, ranging from 0% to 50%.7,9,10 Such outbreaks have occurred secondary to contaminated ophthalmic solutions, such as trypan blue, contamination of phacoemulsifier internal fluid, contamination of the intraocular lens solution, and contamination of the phacoprobe.6,9,21–23 This reflects the ability of P. aeruginosa to survive over long periods in aqueous environments.1 Luz et al24 implicated a particular operating room as being
Table 4. Endophthalmitis Caused by P. aeruginosa: Comparison of Studies From Same Institution This Study, January 2002 to December 2012 Eifrig et al,11 January 1987 to December 2001*
Clinical setting Post-cataract surgery Post-PKP surgery Other Initial treatment Vitreous tap + antibiotics PPV + antibiotics Enucleation/evisceration VA outcomes $20/400 ,20/400 NLP Enucleation/evisceration
No. of Patients (%)
No. of Patients (%)
4/12 (33) 3/12 (25) 5/12 (42)
9/28 (32) 5/28 (18) 14/28 (50)
9/12 (75) 3/12 (25) 0/12 (0)
13/28 (46) 8/28 (29) 7/28 (25)
1/12 11/12 8/12 5/12
(8) (92) (67) (42)
*Included patients with positive anterior chamber cultures only. NLP, no light perception; No., number; PPV, pars plana vitrectomy; VA, visual acuity.
1/28 27/28 19/28 18/28
(7) (83) (68) (64)
ENDOPHTHALMITIS CAUSED BY PSEUDOMONAS SRIDHAR ET AL
associated with 7 of 8 cases of postoperative P. aeruginosa endophthalmitis at a single hospital over a 5-year period, likely indicating that P. aeruginosa may contaminate air vents or other environmental sources before migrating to the ocular surface during surgery. In this study, all isolates were susceptible to both ceftazidime and levofloxacin, and the MIC 90 for isolates to the five tested antibiotics remained identical when compared with the previously studied period. Although MIC 90 comparisons have not been previously reported, recent studies have noted high rates of susceptibility of P. aeruginosa endophthalmitis to both fluoroquinolones and ceftazidime.12,17 Maltezou et al,8 however, reported a 12-patient outbreak of P. aeruginosa endophthalmitis with resistance to quinolones, aminoglycosides, and piperacillin–tazobactam. Also, Jindal et al16 found that 21% of P. aeruginosa acute-onset postoperative endophthalmitis cases were resistant to both ceftazidime and amikacin at their hospital. At the same hospital, P. aeruginosa endophthalmitis accounted for more than 70% of multidrug-resistant cases of endophthalmitis.15 These reports raise concern of the increased prevalence of multidrug-resistant P. aeruginosa unresponsive to typical therapy with fluoroquinolones, second-generation and thirdgeneration cephalosporins, or aminoglycosides. P. aeruginosa is able to produce cephalosporinases, resistant to beta-lactamase inhibitors, which confer resistance to many third-generation cephalosporins such as ceftazidime.25 As a result, less frequently selected intravitreal antibiotics may need to be considered in the future. Carbapenems such as imipenem have been shown to limit retinal damage when given early for P. aeruginosa endophthalmitis at doses far less than retinotoxic in animal models.26,27 Because of increased resistance to aminoglycosides and cephalosporins in India, intravitreal imipenem is now often used.16 Intravitreal cefepime, a fourthgeneration cephalosporin, has also been shown to be efficacious histopathologically in rabbit models.28 This study is limited by its retrospective design and relatively a few patients. The use of positive vitreous cultures as the inclusion criteria for the study may have excluded false-negative cultures in the clinical setting of endophthalmitis. Minimal inhibitory concentrations for 90% data were only available for 5 antibiotics in the 1987 to 2001 period and excluded levofloxacin. Despite its limitations, this study provides comparative MIC 90 data for endophthalmitis caused by P. aeruginosa, which had not previously reported, as well as prognostic data regarding the disease progress.
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In conclusion, all isolates of P. aeruginosa remain susceptible to ceftazidime and levofloxacin at our institute. All MIC 90s for isolates in the current period compared with isolates from 1987 to 2001 remained identical. Despite susceptibility to administered antibiotics and early and appropriate treatment, outcomes remain generally poor with a high rate of enucleation. Key words: endophthalmitis, Pseudomonas, bacterial eye infections. References 1. Ramphal R. Chapter 152. Infections due to Pseudomonas species and related organisms. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18e. New York, NY: McGraw Hill; 2012. 2. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol 1995;113:1479–1496. 3. Aaberg TM Jr, Flynn HW Jr, Schiffman J, Newton J. Nosocomial acute-onset postoperative endophthalmitis survey. A 10-year review of incidence and outcomes. Ophthalmology 1998;105:1004–1010. 4. Altan T, Acar N, Kapran Z, et al. Acute-onset endophthalmitis after cataract surgery: success of initial therapy, visual outcomes, and related factors. Retina 2009;29:606–612. 5. Cheng JH, Chang YH, Chen CL, et al. Acute endophthalmitis after cataract surgery at a referral centre in Northern Taiwan: review of the causative organisms, antibiotic susceptibility, and clinical features. Eye (Lond) 2010;24:1359–1365. 6. Zaluski S, Clayman HM, Karsenti G, et al. Pseudomonas aeruginosa endophthalmitis caused by contamination of internal fluid pathways of a phacoemulsifier. J Cataract Refract Surg 1999;25:540–545. 7. Pinna A, Usai D, Sechi LA, et al. An outbreak of post-cataract surgery endophthalmitis caused by Pseudomonas aeruginosa. Ophthalmology 2009;116:2321–2326. 8. Maltezou HC, Pappa O, Nikolopoulos G, et al. Post-cataract surgery endophthalmitis outbreak caused by multidrugresistant Pseudomonas aeruginosa. Am J Infect Control 2012;40:75–77. 9. Ramappa M, Majji AB, Murthy SI, et al. An outbreak of acute post-cataract surgery Pseudomonas sp. endophthalmitis caused by contaminated hydrophilic intraocular lens solution. Ophthalmology 2012;119:564–570. 10. Guerra RL, Freitas Bde P, Parcero CM, et al. An outbreak of forty five cases of Pseudomonas aeruginosa acute endophthalmitis after phacoemulsification. Arq Bras Oftalmol 2012;75: 344–347. 11. Eifrig CW, Scott IU, Flynn HW Jr, Miller D. Endophthalmitis caused by Pseudomonas aeruginosa. Ophthalmology 2003; 110:1714–1717. 12. Chen KJ, Sun MH, Lai CC, et al. Endophthalmitis caused by Pseudomonas aeruginosa in Taiwan. Retina 2011;31:1193–1198. 13. Lister PD. Chromosomally-encoded resistance mechanisms of Pseudomonas aeruginosa: therapeutic implications. Am J Pharmacogenomics 2002;2:235–243. 14. Fatima A, Naqvi SB, Khaliq SA, et al. Antimicrobial susceptibility pattern of clinical isolates of Pseudomonas aeruginosa
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15.
16.
17.
18.
19.
20. 21.
isolated from patients of lower respiratory tract infections. Springerplus 2012;1:70. Pathengay A, Moreker MR, Puthussery R, et al. Clinical and microbiologic review of culture-proven endophthalmitis caused by multidrug-resistant bacteria in patients seen at a tertiary eye care center in southern India. Retina 2011; 31:1806–1811. Jindal A, Pathengay A, Khera M, et al. Combined ceftazidime and amikacin resistance among Gram-negative isolates in acute-onset postoperative endophthalmitis: prevalence, antimicrobial susceptibilities, and visual acuity outcome. J Ophthalmic Inflamm Infect 2013;3:62. Long C, Liu B, Xu C, et al. Causative organisms of posttraumatic endophthalmitis: a 20-year retrospective study. BMC Ophthalmol 2014;14:34. O’Neill EC, Yeoh J, Fabinyi DC, et al. Risk factors, microbial profiles and prognosis of microbial keratitis-associated endophthalmitis in high-risk eyes. Graefes Arch Clin Exp Ophthalmol 2014;252:1457–1462. Kreger AS, Griffin OK. Physicochemical fractionation of extracellular cornea-damaging proteases of Pseudomonas aeruginosa. Can J Microbiol 1985;31:387–392. Pollack M. The virulence of Pseudomonas aeruginosa. Rev Infect Dis 1984;6:617–626. Swaddiwudhipong W, Tangkitchot T, Silarug N. An outbreak of Pseudomonas aeruginosa postoperative endophthalmitis
22.
23.
24.
25. 26.
27.
28.
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caused by contaminated intraocular irrigating solution. Trans R Soc Trop Med Hyg 1995:89;288. Kenchappa P, Sangwan VS, Ahmed N, et al. High-resolution genotyping of Pseudomonas aeruginosa strains linked to acute post cataract surgery endophthalmitis outbreaks in India. Ann Clin Microbiol Antimicrob 2005;4:19. Mateos I, Valencia R, Torres MJ, et al. Nosocomial outbreak of Pseudomonas aeruginosa endophthalmitis. Infect Control Hosp Epidemiol 2006:27;1249–1251. Luz RA, Padoveze MC, Falabella P, et al. Risk factors for postoperative endophthalmitis caused by Pseudomonas aeruginosa: possible role of environment. Am J Infect Control 2013; 41:1287–1289. Strateva T, Yordanov D. Pseudomonas aeruginosa- a phenomenon of bacterial resistance. J Med Microbiol 2009;58:1133–1148. Alfaro DV III, Hudson SJ, Kasowski EJ, et al. Experimental pseudomonal posttraumatic endophthalmitis in a swine model. Treatment with ceftazidime, amikacin, and imipenem. Retina 1997;17:139–145. Loewenstein A, Zemel E, Lazer M, Perlman I. Drug-induced retinal toxicity in albino rabbits: the effects of imipenem and aztreonam. Invest Ophthalmol Vis Sci 1993;34:3466–3476. Deniz N, Aydemir O, Guler M, et al. Comparison of efficiency of intravitreal ceftazidime and intravitreal cefepime in the treatment of experimental Pseudomonas aeruginosa endophthalmitis. Indian J Ophthalmol 2013;61:525–527.
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large series of acute postoperative endophthalmitis ranges from 8% to 34%.3–5 There have also been several reported large outbreaks of postcataract surgery P. aeruginosa endophthalmitis secondary to contamination.6–10 In previous reports, the most common clinical settings for P. aeruginosa endophthalmitis included infectious keratitis, acute-onset postcataract surgery, postpenetrating keratoplasty, and endogenous source.11,12 In other clinical settings, P. aeruginosa has demonstrated increasing levels of resistance to previously effective broad-spectrum antibiotics, including aminoglycosides, cephalosporins, extended-spectrum penicillins, and carbapenems.13,14 In a previous study from 1987 to 2001 from our institution, more than 90% of cases of P. aeruginosa endophthalmitis were
seudomonas aeruginosa is a gram-negative rod often implicated in nosocomial infections. 1 P. aeruginosa only accounted for approximately 1% of culture-positive endophthalmitis cases in the Endophthalmitis Vitrectomy Study.2 However, the incidence of P. aeruginosa as the causative organism in From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. Supported in part by NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Department of Defense (DOD-Grant#W81XWH-09-1-0675). None of the authors have any conflicting interests to disclose. Reprint requests: Jayanth Sridhar, MD, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 900 NW 17th Street, Miami, FL 33136; e-mail: [email protected]
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susceptible to initially administered antibiotics.11 Recently, there have been reports of multidrugresistant P. aeruginosa endophthalmitis.15–18 Previous studies have not demonstrated the antibiotic minimal inhibitory concentrations for 90% (MIC 90) of P. aeruginosa isolates in endophthalmitis cases. The purpose of this study was to provide an update on the clinical settings, antibiotic susceptibilities, and visual acuity outcomes in a more recent series of culture-proven P. aeruginosa endophthalmitis. Based on PubMed search, this represents the first study comparing MIC 90 data between periods for cases of endophthalmitis caused by P. aeruginosa.
2015 VOLUME 35 NUMBER 6
a period of up to 2 weeks. Additional culture media, including thioglycollate broth, were performed at the discretion of the ophthalmologist performing the culture. All cultures were read, subcultured on special media as necessary, and classified by Ocular Microbiology Department staff. Shifting trends in in vitro MIC 90 (mg/mL) were analyzed using the E test (Biomerieux, Raleigh, NC). After analyzing microbiology records, the corresponding medical records of these patients were reviewed to ensure clinical course consistent with endophthalmitis. Patient demographics, clinical characteristics, risk factors, treatment strategies, and clinical outcomes were assessed.
Methods Results Institutional Review Board approval was obtained from the University of Miami Miller School of Medicine Sciences Subcommittee for the Protection of Human Subjects. The ocular microbiology department database was searched to identify all patients with positive vitreous chamber cultures for P. aeruginosa between January 1, 2002, and December 31, 2012. Microbiology department records were reviewed to identify the responsible microbial isolates and antibiotic susceptibilities. Vitreous cultures were obtained either at the time of vitreous tap and inject or during vitrectomy. Fluid from vitreous tap was plated directly on to culture media including 5% sheep blood and chocolate agars. For vitrectomy specimens, 30 mL to 50 mL of vitreous washings were filtered using a 0.45-mm filter. The resultant filter paper was divided into sections and was plated on to different culture media, which typically included chocolate and blood agars. Blood and chocolate agars underwent incubation at 35°C for
Over the 11-year study period, 12 eyes from 12 patients were identified to have positive vitreous cultures for P. aeruginosa and clinical course consistent with endophthalmitis (Table 1). The median patient age was 73.5 years (range, 1 month to 88 years). Endophthalmitis occurred in the clinical setting of postcataract surgery (n = 4) (Figure 1), postpenetrating keratoplasty (n = 3), endogenous source (n = 2), post-pars plana vitrectomy (n = 1), trabeculectomy bleb-associated setting (n = 1), and glaucoma drainage implant-associated setting (n = 1). Six patients had a concurrent corneal ulcer in the same eye: one of the postcataract surgery patients, all three of the postpenetrating keratoplasty patients, the trabeculectomy bleb-associated patient, and the glaucoma drainage implant-associated patient. The post-pars plana vitrectomy case was combined with an iris-sutured intraocular lens. One of the endogenous cases occurred in the setting of a premature infant with sepsis and intraventricular hemorrhage,
Table 1. Endophthalmitis Caused by P. aeruginosa: Clinical Settings Patient Number 1 2 3 4 5 6 7 8 9 10 11 12
Age
Clinical Setting
Concurrent Corneal Ulcer
Time After Surgery
74 years 84 years 69 years 75 years 56 years 81 years 53 years 1 month 72 years 79 years 88 years 73 years
Postoperative cataract phacoemulsification Postoperative cataract phacoemulsification Postoperative cataract phacoemulsification Postoperative cataract phacoemulsification Post-PKP Post-PKP Post-PKP Endogenous, premature infant with sepsis, IVH Endogenous, iatrogenic immunosuppression* Trabeculectomy bleb-associated Post-PPV with iris-sutured IOL BGI bleb-associated with tube exposure
No No No Yes Yes Yes Yes No No Yes No No
1 day 2 days 12 days 23 days 7 months 4 months 30 years N/A N/A 5 months 5 days 6 months
*Patient with history of colon cancer and myelofibrosis. BGI, baerveldt glaucoma implant; IVH, intraventricular hemorrhage; IOL, intraocular lens; PKP, penetrating keratoplasty; PPV, pars plana vitrectomy.
ENDOPHTHALMITIS CAUSED BY PSEUDOMONAS SRIDHAR ET AL
Fig. 1. Slit-lamp photograph of a patient with endophthalmitis caused by P. aeruginosa. The patient presented 12 days after cataract surgery because of pain and decreased vision with a suture abscess, hypopyon, and corneal edema.
whereas the other occurred in a patient received immunosuppressive medications for colon cancer and myelofibrosis treatment. With the exception of the premature infant, all patients presented with symptoms of pain and visual loss. Visual acuity on presentation was hand motions or worse in all cases (Table 2). Hypopyon was noted in all 12 patients (100%). The mean intraocular pressure was 29 mmHg (range, 13–40 mmHg). Because of significant anterior segment inflammation and vitreous opacities, no view of the posterior pole was obtainable in any patient. Initial treatment strategies included vitreous tap and injection (n = 9, 75%) and pars plana vitrectomy with injection of intravitreal antibiotics (n = 3, 25%). Intravitreal antibiotics consisted of vancomycin and ceftazidime for all patients. All patients were started on topical antibiotic drops, and a topical steroid drop was started within 48 hours of the initial treatment in
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9 patients (75%). Six patients (50%) received intravitreal corticosteroids. Additional treatment was administered within 2 weeks of initial treatment in 6 patients (50%): 3 patients had an additional vitreous tap and injection of ceftazidime, 2 patients underwent enucleation, and 1 patient underwent glaucoma drainage implant removal. Three other patients underwent enucleation between 1 month and 6 months after initial treatment. One patient underwent additional vitreous tap and injection 55 days after initial treatment because of suspected recurrent endophthalmitis. Initial intraocular cultures were monomicrobial and positive for P. aeruginosa in all patients. All isolates were susceptible to one of the initially administered intraocular antibiotics. All P. aeruginosa isolates tested were susceptible to ceftazidime and levofloxacin. The antibiotic susceptibilities and MIC 90 of P. aeruginosa isolates tested are reported in Table 3 and compared with isolates from 1987 to 2001. The MIC 90 for isolates from 2002 to 2012 and 1987 to 2001 remained the same for ceftazidime (8 mg/mL), ciprofloxacin (0.5 mg/mL), imipenem (4 mg/mL), tobramycin (0.5 mg/mL), and amikacin (4 mg/mL). Final visual acuity was no light perception in 8 patients (67%), light perception in 3 patients (25%), and 20/400 in 1 patient (8%). Median follow-up was 7.5 months (range, 1 week to 4.5 years). Five patients underwent enucleation (42%). Discussion The most common clinical settings for P. aeruginosa endophthalmitis in the current series were postcataract
Table 2. Presentation, Treatment Strategies, and Outcomes of Patients With Endophthalmitis Caused by P. aeruginosa Preinfection No. VA
Initial VA
Initial Tx
Initial Intravitreal Injection(s) VANC + CTZ + DEX VANC + CTZ + TRIAM VANC + CTZ VANC + CTZ VANC + CTZ + DEX VANC + CTZ + AMI + DEX VANC + CTZ + DEX VANC + CTZ VANC + CTZ VANC + CTZ VANC + CTZ + DEX VANC + CTZ
1 2
UK UK
HM LP
T+I T+I
3 4 5 6
UK 20/200 20/70 4/200
LP LP LP HM
PPV PPV T+I PPV
7 8 9 10 11 12
LP UK 20/25 20/40 20/800 20/400
LP UK LP HM LP LP
T T T T T T
+ + + + + +
I I I I I I
Additional Tx (Days After Initial Tx)
Additional Intravitreal Injection(s)
Last VA
None Enucleation (45)
None None
20/400 NLP
T + I (2) T + I (55)* T + I (10) None
CTZ CTZ CTZ None
LP LP NLP LP
6 2 5 2
Enucleation (150) Enucleation (6) Enucleation (11) Enucleation (30) T + I (7) Removal BGI (2)
None None None None CTZ None
NLP NLP NLP NLP NLP NLP
15 months 1 week 9 months 4 years 4.5 years 9 months
Follow-up Time 2.5 years 2 months months months months years
*Additional treatment at the time of suspected recurrent infection. AMI, amikacin; CTZ, ceftazidime; DEX, dexamethasone; HM, hand motions; LP, light perception; NLP, no light perception; No., patient number; PPV, pars plana vitrectomy; T + I, vitreous tap + intravitreal injection; TRIAM, triamcinolone; Tx, treatment; VANC, vancomycin; VA, visual acuity; UK, unknown.
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2015 VOLUME 35 NUMBER 6
Table 3. P. aeruginosa Antibiotic Susceptibility and Minimal Inhibitory Concentrations 2002 to 2012 Antibiotic
No. of Isolates Tested
Ceftazidime Ciprofloxacin Levofloxacin Imipenem Tobramycin Amikacin
14 12 14 10 14 12
1987 to 2001
Resistant Isolates (%) 0 1 0 1 1 1
MIC 90 (mg/mL)
No. of Isolates Tested
Resistant Isolates (%)
MIC 90 (mg/mL)
8 0.5 1 4 0.5 4
10 11 0 11 11 10
0 (0) 0 (0) NA 1 (9) 0 (0) 0 (0)
8 0.5 NA 4 0.5 4
(0) (8) (0) (10) (7) (8)
NA, not available; No., number.
extraction and postpenetrating keratoplasty, matching the results from a previous study from our institute published by Eifrig et al11 (Table 4). In contrast, Chen et al12 described in a large series that infectious keratitis and scleritis represented the leading cause of P. aeruginosa endophthalmitis, followed distantly by cataract surgery, penetrating keratoplasty, and endogenous source. A notable difference between this study and those two previous studies was the strict inclusion of only those patients with positive vitreous cultures in this study; this theoretically prevented the inclusion of falsepositive cases with positive anterior chamber cultures secondary to infectious keratitis but no clinical evidence of true endophthalmitis. Visual outcomes in this study were extremely poor with 92% of eyes worse than 20/400 and 67% of eyes with no light perception. Previous large series of P. aeruginosa endophthalmitis have demonstrated a no light perception outcome in 68% to 82% of cases.11,12,18 Anatomical outcomes were also poor; the enucleation rate in this study was 42%, slightly better than the previously reported rate of 50% to 82% observed in those other large
series.11,12,18 P. aeruginosa may cause devastating functional and anatomical outcomes secondary to the nature of its intrinsic enzymes.1 P. aeruginosa produces elastases and exotoxins that once within the cornea, the anterior chamber, or the vitreous cavity may rapidly and permanently degrade the intraocular contents, resulting in uncontrolled inflammation and globe disorganization.19,20 Risk factors for enucleation/evisceration may include the postpenetrating keratoplasty setting, association with infectious keratitis or scleritis, and endogenous etiology.12 This may explain why the rate of globe loss is lower in specific series focusing on only postcataract extraction outbreaks of P. aeruginosa endophthalmitis, ranging from 0% to 50%.7,9,10 Such outbreaks have occurred secondary to contaminated ophthalmic solutions, such as trypan blue, contamination of phacoemulsifier internal fluid, contamination of the intraocular lens solution, and contamination of the phacoprobe.6,9,21–23 This reflects the ability of P. aeruginosa to survive over long periods in aqueous environments.1 Luz et al24 implicated a particular operating room as being
Table 4. Endophthalmitis Caused by P. aeruginosa: Comparison of Studies From Same Institution This Study, January 2002 to December 2012 Eifrig et al,11 January 1987 to December 2001*
Clinical setting Post-cataract surgery Post-PKP surgery Other Initial treatment Vitreous tap + antibiotics PPV + antibiotics Enucleation/evisceration VA outcomes $20/400 ,20/400 NLP Enucleation/evisceration
No. of Patients (%)
No. of Patients (%)
4/12 (33) 3/12 (25) 5/12 (42)
9/28 (32) 5/28 (18) 14/28 (50)
9/12 (75) 3/12 (25) 0/12 (0)
13/28 (46) 8/28 (29) 7/28 (25)
1/12 11/12 8/12 5/12
(8) (92) (67) (42)
*Included patients with positive anterior chamber cultures only. NLP, no light perception; No., number; PPV, pars plana vitrectomy; VA, visual acuity.
1/28 27/28 19/28 18/28
(7) (83) (68) (64)
ENDOPHTHALMITIS CAUSED BY PSEUDOMONAS SRIDHAR ET AL
associated with 7 of 8 cases of postoperative P. aeruginosa endophthalmitis at a single hospital over a 5-year period, likely indicating that P. aeruginosa may contaminate air vents or other environmental sources before migrating to the ocular surface during surgery. In this study, all isolates were susceptible to both ceftazidime and levofloxacin, and the MIC 90 for isolates to the five tested antibiotics remained identical when compared with the previously studied period. Although MIC 90 comparisons have not been previously reported, recent studies have noted high rates of susceptibility of P. aeruginosa endophthalmitis to both fluoroquinolones and ceftazidime.12,17 Maltezou et al,8 however, reported a 12-patient outbreak of P. aeruginosa endophthalmitis with resistance to quinolones, aminoglycosides, and piperacillin–tazobactam. Also, Jindal et al16 found that 21% of P. aeruginosa acute-onset postoperative endophthalmitis cases were resistant to both ceftazidime and amikacin at their hospital. At the same hospital, P. aeruginosa endophthalmitis accounted for more than 70% of multidrug-resistant cases of endophthalmitis.15 These reports raise concern of the increased prevalence of multidrug-resistant P. aeruginosa unresponsive to typical therapy with fluoroquinolones, second-generation and thirdgeneration cephalosporins, or aminoglycosides. P. aeruginosa is able to produce cephalosporinases, resistant to beta-lactamase inhibitors, which confer resistance to many third-generation cephalosporins such as ceftazidime.25 As a result, less frequently selected intravitreal antibiotics may need to be considered in the future. Carbapenems such as imipenem have been shown to limit retinal damage when given early for P. aeruginosa endophthalmitis at doses far less than retinotoxic in animal models.26,27 Because of increased resistance to aminoglycosides and cephalosporins in India, intravitreal imipenem is now often used.16 Intravitreal cefepime, a fourthgeneration cephalosporin, has also been shown to be efficacious histopathologically in rabbit models.28 This study is limited by its retrospective design and relatively a few patients. The use of positive vitreous cultures as the inclusion criteria for the study may have excluded false-negative cultures in the clinical setting of endophthalmitis. Minimal inhibitory concentrations for 90% data were only available for 5 antibiotics in the 1987 to 2001 period and excluded levofloxacin. Despite its limitations, this study provides comparative MIC 90 data for endophthalmitis caused by P. aeruginosa, which had not previously reported, as well as prognostic data regarding the disease progress.
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In conclusion, all isolates of P. aeruginosa remain susceptible to ceftazidime and levofloxacin at our institute. All MIC 90s for isolates in the current period compared with isolates from 1987 to 2001 remained identical. Despite susceptibility to administered antibiotics and early and appropriate treatment, outcomes remain generally poor with a high rate of enucleation. Key words: endophthalmitis, Pseudomonas, bacterial eye infections. References 1. Ramphal R. Chapter 152. Infections due to Pseudomonas species and related organisms. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18e. New York, NY: McGraw Hill; 2012. 2. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol 1995;113:1479–1496. 3. Aaberg TM Jr, Flynn HW Jr, Schiffman J, Newton J. Nosocomial acute-onset postoperative endophthalmitis survey. A 10-year review of incidence and outcomes. Ophthalmology 1998;105:1004–1010. 4. Altan T, Acar N, Kapran Z, et al. Acute-onset endophthalmitis after cataract surgery: success of initial therapy, visual outcomes, and related factors. Retina 2009;29:606–612. 5. Cheng JH, Chang YH, Chen CL, et al. Acute endophthalmitis after cataract surgery at a referral centre in Northern Taiwan: review of the causative organisms, antibiotic susceptibility, and clinical features. Eye (Lond) 2010;24:1359–1365. 6. Zaluski S, Clayman HM, Karsenti G, et al. Pseudomonas aeruginosa endophthalmitis caused by contamination of internal fluid pathways of a phacoemulsifier. J Cataract Refract Surg 1999;25:540–545. 7. Pinna A, Usai D, Sechi LA, et al. An outbreak of post-cataract surgery endophthalmitis caused by Pseudomonas aeruginosa. Ophthalmology 2009;116:2321–2326. 8. Maltezou HC, Pappa O, Nikolopoulos G, et al. Post-cataract surgery endophthalmitis outbreak caused by multidrugresistant Pseudomonas aeruginosa. Am J Infect Control 2012;40:75–77. 9. Ramappa M, Majji AB, Murthy SI, et al. An outbreak of acute post-cataract surgery Pseudomonas sp. endophthalmitis caused by contaminated hydrophilic intraocular lens solution. Ophthalmology 2012;119:564–570. 10. Guerra RL, Freitas Bde P, Parcero CM, et al. An outbreak of forty five cases of Pseudomonas aeruginosa acute endophthalmitis after phacoemulsification. Arq Bras Oftalmol 2012;75: 344–347. 11. Eifrig CW, Scott IU, Flynn HW Jr, Miller D. Endophthalmitis caused by Pseudomonas aeruginosa. Ophthalmology 2003; 110:1714–1717. 12. Chen KJ, Sun MH, Lai CC, et al. Endophthalmitis caused by Pseudomonas aeruginosa in Taiwan. Retina 2011;31:1193–1198. 13. Lister PD. Chromosomally-encoded resistance mechanisms of Pseudomonas aeruginosa: therapeutic implications. Am J Pharmacogenomics 2002;2:235–243. 14. Fatima A, Naqvi SB, Khaliq SA, et al. Antimicrobial susceptibility pattern of clinical isolates of Pseudomonas aeruginosa
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