Infectious keratitis for the general ophthalmologist

Infectious keratitis for the general ophthalmologist Presented by Chameen Samarawickrama - Westmead Hospital - Liverpool Hospital - University of Sydney - University of New South Wales The University of Sydney Page 1

Financial disclosures Early Career Research Fellowship (Westmead Charitable Trust) Acknowledgment Inspiration for this lecture is from education provided by: Mr. Steve Tuft Mr. John Dart The University of Sydney Page 2

Microbial keratitis Common cause of visual morbidity Management requires appropriate treatments in an appropriate time frame Regional and temporal changes in pathogens The University of Sydney Page 3

Key questions 1. What organisms occur? 2. What are the risk factors? 3. How do I diagnose it? 4. What treatments should I give? 5. Who should get steroids? 6. What can go wrong? The University of Sydney Page 4

1. Which organisms BACTERIA PROTISTS FUNGI Gram +ve, Gram ve, acid fast Acanthamoeba Yeast, mould, Microsporidia Modified by local risk factors that can vary with time Resulting in geographic and temporal changes SURVEILLANCE FOR EMERGING PATHOGENS The University of Sydney Page 5

Geographic variations (Gram +ve) 49% 83% 41% 62% 36% 68% 54% 71% 71% Shah. BJO. 2011;95:762-67 The University of Sydney Page 6

What about Australia and New Zealand (Gram +ve) 20% (2016) 51% (2008) 76% (2005) 51% (1996) 66% (2005) 72% (2003) 75% (2015) The University of Sydney Page 7

What about Australia and New Zealand (Fungi) 12% (2016) 9% (2008) 4% (2005) 0% (1996) 5% (2005) 9% (2003) 2% (2015) The University of Sydney Page 8

Organisms can even change by season Green. Cornea. 2008;27:33-9 The University of Sydney Page 9

2. Risk factors vary by region Risk factors for MK (2001-3) TRAUMA 36% CONTACT LENS 34% OTHER/UNKNOWN 10% OSD/SYSTEMIC 7% HSV 7% MULTIFACTORIAL 6% 0% 5% 10% 15% 20% 25% 30% 35% 40% Keay. Ophthalmol. 2006;113:109-116 The University of Sydney Page 10

Risk factors vary over time Green. Cornea. 2008;27:33-9 The University of Sydney Page 11

Contact lens wear is an increasing risk factor strong association with Gram ve isolates Causative organisms in culture proven CL related MK * P. aeruginosa Serratia spp. Other Gram -ve spp. Staphlococcus spp. Nocardia spp. Reasonable Streptococcus to spp. assume Other Gram +ve spp keratitis Acanthamoeba in Fungi contact lens wearer is Pseudomonas aeruginosa until proven otherwise Stapleton. AJO. 2007;144:690-98 The University of Sydney Page 12

Contact lens wear new pathogens Microsporidia The University of Sydney Page 13

Contact lens wear new pathogens Fusarium The University of Sydney Page 14

Contact lens wear new pathogens Acanthamoeba The University of Sydney Page 15

3. Features of a microbial keratitis is unreliable Gram +ve Fungi Gram -ve The University of Sydney Page 16 AK

Appearance modified by steroids Crystalline keratopathy The University of Sydney Page 17

Have to rely on clinical suspicion Organism Risks Onset Bacteria CLs, OSD, surgery Acute (1-2 days) Fungi Trauma, CLs, immunosuppression Variable Protozoa CLs, trauma Subacute (1-7 days) HSV Atopy, steroids Subacute (1-7 days) 1:20 cases are non-bacterial Investigation is mandatory for unresponsive cases The University of Sydney Page 18 Stapleton. Ophthalmol. 2008;115:1655-62

Basic investigations 2x glass slides Blood agar Chocolate blood agar Saboraud agar Thioglycolate broth Viral swab (for PCR) Suspicion of acanthamoeba Non-nutrient agar Acanthamoeba PCR HSV serology Negative IgG or rising IgM helpful Samarawickrama. BJO Open Ophthalmol. 2017;1:e00044 The University of Sydney Page 19

Ancillary tests confocal microscopy Operator dependent 50% sensitivity 65-82% specificity High repeatability Do not rely on confocal for diagnosis if the response to treatment is poor The University of Sydney Page 20 Hau et al. BJO. 2010;94:982-987

Debridement acanthamoeba and fungi biopsy and culture Reduces pathogen load Enhances penetration Especially antifungals Can be curative for acanthamoeba if performed within the first 3 weeks Significant only if positive Bacon. Ophthalmol. 1993;100:1238-43 Brooks. Cornea. 1994;13:186-9 The University of Sydney Page 21

Histology corneal biopsy or excisional keratoplasty Confirms the diagnosis Viability uncertain Acanthamoeba cysts (H&E; modified Gomori) Gomori silver stain (fungi) The University of Sydney Page 22

4. Treatment aims 1. Eliminate infection 2. Control inflammation 3. Control pain 4. Avoid toxicity 5. Identify complications 6. Restore vision The University of Sydney Page 23

Sterilization and healing Microbial keratitis Investigation Sterilization Damage limitation Healing The University of Sydney Page 24

Management strategies for keratitis Use algorithms and lists To consider all causes Aid in rational planning of diagnosis and treatments The University of Sydney Page 25

When to treat without investigation The 95% typical bacterial keratitis Small infiltrate (<1mm) Sudden onset Typical risk factors (CL, trauma, OSD) When NOT to treat without investigation (culture and ideally PCR and confocal) The 5% atypical cases (fungi, acanthamoeba & others) CL/trauma/OSD cases with specific risk factors No identifiable risk factors Those which don t fit clinically with bacterial disease The University of Sydney Page 26

Empirical Treatments Based on probability for common organisms in your area (90% bacterial) Highlights importance of ongoing microbial surveillance Initial therapy for BACTERIAL keratitis Unless strong alternative evidence Modulated by risk factors on a case by case basis Treat precipitating causes (eg. exposure, trichiasis etc) Treat ALL cases as PROVISIONAL DIAGNOSIS The University of Sydney Page 27

What empirical antibiotic to use Monotherapy (commercially available, stable for 30days fluoroquinolone) vs Dual Therapy (home made, fortified, 7 day unstable aminoglycoside-cephalosporin) What s the evidence? 16 high quality trials involving 1823 patients 4 RCTs comparing ofloxacin to gentamicin-cefazolin involving 440 patients Constantinou. Ophthalmol. 2007;114:1622-9 Panda. Eye. 1999;13:744-7 Pavesio. Ophthalmol. 1997;104:1902-9 O Brien. Arch Ophthalmol. 1995;113:1257-65 1 meta-analysis McDonald. BJO. 2014;98:1470-7 The University of Sydney Page 28

Ofloxacin vs Gentamicin-Cefazolin No difference in treatment success (RR 0.94: 95% CI 0.68 to 1.30) no difference when fluoroquinolones as a class compared to aminoglycoside-cephalosporins; 10 trials with 1265 patients (RR 1.01: 95% CI 0.94 to 1.08) The University of Sydney Page 29 McDonald. BJO. 2014;98:1470-7

Ofloxacin vs Gentamicin-Cefazolin No difference in treatment success (RR 0.94: 95% CI 0.68 to 1.30) no difference when fluoroquinolones as a class compared to aminoglycoside-cephalosporins; 10 trials with 1265 patients (RR 1.01: 95% CI 0.94 to 1.08) No difference in time to cure (MD 3.57: 95% CI -4.23 to 11.37) no difference when fluoroquinolones as a class compared to aminoglycoside-cephalosporins; 4 trials with 259 patients (MD 2.09: 95% CI -1.26 to 5.44) No difference in serious complications Corneal perforation Therapeutic keratoplasty Enucleation The University of Sydney Page 30 McDonald. BJO. 2014;98:1470-7

Ofloxacin vs Gentamicin-Cefazolin Ofloxacin reduced risk of ocular discomfort by 78% with NNT of 4 292 patients, RR 0.22: 95% CI 0.13 to 0.39 Fluoroquinolones as a class reduced the risk of ocular discomfort by 68% with NNT of 6 3 trials, 693 patients, RR 0.32: 95% CI 0.22 to 0.47 Ofloxacin reduced risk of chemical conjunctivitis by 80% with NNT of 7 410 patients, RR 0.20: 95% CI 0.10 to 0.41 Ciprofloxacin has a 24 fold increased risk of white precipitates, rarely seen in ofloxacin The University of Sydney Page 31 McDonald. BJO. 2014;98:1470-7

Resistance to fluoroquinolones? Green. Cornea. 2008;27:33-9 The University of Sydney Page 32

Clear winner Investigate ALL cases where infection is not improving after 5 days Hourly D/N Hourly by day 2 hourly by day QID 1 2 3 4 5 6 7 8 9 10 11 12 13 14 days The University of Sydney Page 33

Herxheimer effect Acute inflammatory response due to death of microbe with appropriate antimicrobial treatments Reaction to endotoxin-like products Common in Gram negative bacterial keratitis and acanthamoeba keratitis Can look worse, but patient feels better! The University of Sydney Page 34

5. Steroids for bacterial keratitis (3 month results) 500 culture positive BACTERIAL cases Exclusions: fungus, acanthamoeba, HSV, impending perforation, previous PK Moxifloxacin q1h for 48hrs prior to randomization, then tapered Prednisolone 1% QID for 7d, BD for 7d, then daily for 7 days (3 weeks total) BSCVA at 3 months Scar Re-epithelialization Perforation IOP P=0.82 P=0.4 P=0.44 P>0.99 Higher in placebo (p=0.04) Subgroup analysis suggests benefit of steroids for severe central ulcers Baseline BSCVA (CF or worse) Location (central 4mm) P=0.03 P=0.04 The University of Sydney Page 35 SCUT. Arch Ophthalmol. 2012;130:143-50

Steroids for bacterial keratitis (12 month results) BSCVA at 12 months Scar Entire cohort results P=0.39 P=0.69 Subgroup analysis: Nocardia vs Non-nocardia keratitis BSCVA at 12 months Nocardia infections P=0.10 Non-Nocardia infections P=0.02 (mean 1 line improvement) Scar Nocardia infections P=0.02 (larger scar) Non-Nocardia infections P=0.46 1 line benefit of steroids for non-nocardia microbial keratitis SCUT 2. AJO. 2014;157:327-33 The University of Sydney Page 36

6. When things don t work to plan If clinically not improving after 5 days, re-evaluate your treatment paradigm and INVESTIGATE FURTHER Poor compliance Uncommon organism Reassess microbiology Unrepresentative culture Polymicrobial infection (10%) Culture negative Treatment toxicity (aminoglycosides) Persistent inflammation Failure to heal Consult your algorithm for progression Do NOT sit on these patients The University of Sydney Page 37

CULTURE - CULTURE, PCR or CONFOCAL + Treated before or inadequate treatment Consider other possible causes Adequate treatment for likely causes CONFOCAL PCR RECULTURE after 24-48 hours off therapy BIOPSY PERFORATION Inadequate treatment Treatment toxicity Persistent inflammation Intensive treatment Reduce toxicity No preservatives or aminoglycosides Treat host response Trial of steroids Debride RESOLUTION Infection uncontrolled Glue Infection controlled Unrepresentative culture Failure to heal Correct precipitating factors EYE LOST Therapeutic/ tectonic penetrating transplant RESOLUTION The University of Sydney Page 38

The University of Sydney Page 39 Allan. BJO. 1995;79:777-86

Special cases Mycobacteria Acid fast aerobic bacteria Lowenstein-Jensen medium Microsporidia Unicellular, obligate intracellular fungi Stains (Gram, Giemsa, acid fast) Nocardia Gram + rods (bacteria) with acid fast branching filaments Strict aerobes Blood, chocolate blood, Saboraud Propionibacterium acnes Gram + anaerobic rod Capnocytophaga Gram anaerobic rod Chocolate blood agar in increased CO 2 The University of Sydney Page 40

Fungal keratitis Superficial infection 1. Natamycin 5% 2. Debride lesion If no response in 7 days 3. Add Chlorhexidine 0.2% Diagnosis Empirical therapy Deep stromal infection/endophthalmitis 1. Natamycin 5% and Chlorhexidine 0.2% 2. Oral Voriconazole* If no response in 7 days Alternatives: Voriconazole 1% Amphotericin 0.15% Culture results Yeast (min 1 month) 1. Amphotericin 0.15% 2. Voriconazole 1% 3. Chlorhexidine 0.2% Filamentary (3 months) 1. Natamycin 5% 2. Chlorhexidine 0.2% 3. Intralesional Voriconazole 4. Intracameral Voriconazole 5. Excisional/therapeutic keratoplasty MUTT1. JAMA Ophthalmol. 2013;131:422-9 MUTT2. JAMA Ophthalmol. 2016;134:1365-72 FlorCruz. Cochrane Database. 2015;4:CD004241 The University of Sydney Page 41

Excisional keratoplasty Early surgical intervention (2-3 weeks) in deteriorating cases or extension into anterior chamber or sclera 1. 2mm clearance 2. Remove iris and lens as required 3. Peripheral iridectomy 4. Voriconazole 50-100µg in 0.1ml 5. Interupted sutures 6. Intracameral tissue plasminogen activator (tpa) 12.5µg in 0.05ml 7. Use topical antifungals for months 8. Use cyclosporin A (antifungal and anti-inflammatory) 9. IV amphotericin in bad cases 10. No topical steroids for 4-8 weeks or longer Failure rate for first grafts are about 20-30% The University of Sydney Page 42

Steroids for fungal keratitis Steroids exacerbate growth of fungus DO NOT use for filamentary fungus Can use carefully for Candida (after 2-4 weeks) if infiltrate improving but cornea vascularizing The University of Sydney Page 43

Acanthamoeba keratitis Choice based on in vitro cysticidal data MARKED superiority of biguanides 82 respondents from Cornea Society USA Biguanide with diamidines most widely used combination therapy In vitro evidence that Timolol Sandoz 0.5%: Damages acanthamoeba on a mitochodrial level Potentially encourages excystation Drug (cidal conc µg/ml) Biguanides Polyhexanide (PHMB) Troph The University of Sydney Page 44 Cyst 1.56 3.13 Chlorhex 3.13 12.50 Diamidines Propamidine (Brolene) 125 250 Haxamidine 15.63 125 Kilvington. IOVS. 2004;45:165-9 Oldenburg. Cornea. 2011;30:1363-8 Sifaoui. Exp Parasitol. 2017;183:117-23

Acanthamoeba treatment paradigm PHMB + Brolene Q1h day and night for 48 hours Q1h by day for 5-7 days Then reduce to 6x/day Taper to QID as disease is brought under control Drug toxicity is common with diamidines but NOT PHMB Stop brolene first Timolol 0.5% BD for entirety of treatment When have you won: 1 month off ALL treatment (including steroids) without any signs of inflammation The University of Sydney Page 45

Control inflammation Topical Steroids In cases of: Increasing inflammation Vascularization Melt Defer for 2 weeks after initiation of treatment Only use with biguanides (PHMB or chlorhexidine) Continue biguanides for 4 weeks after steroids discontinued Worsening pain or scleritis Oral NSAIDS Oral steroids Immunosuppression (cyclosporin) Persistent inflammation does not always equate to viable organisms The University of Sydney Page 46

Summary Know the common organisms in your area Know the risk factors Know the presenting features Use a management algorithm to aid rational planning of diagnoisis and treatments Fluoroquinolone monotherapy is effective for the majority of bacterial keratitis Remember 1 in 20 are fungal or amoeba High index of suspicion 10% are polymicrobial Investigate ALL cases of presumed bacterial keratitis not improving after 5 days The University of Sydney Page 47

References 1. Shah. BJO. 2011;95:762-67 2. Leck. BJO. 2002;86:1211-15 3. Samarawickrama. Health Infect. 2015;20:128-133 4. Butler. BJO. 2005;89:591-6 5. Green. Cornea. 2008;27:33-9 6. Gebauer. Eye. 1996;10:575-80 7. Richards. CEO. 2016;44:205-7 8. Leibovitch. EJO. 2005;15:23-6 9. Wong. BJO. 2003;87:1103-8 10. Keay. Ophthalmol. 2006;113:109-116 11. Stapleton. AJO. 2007;144:690-98 12. Stapleton. Eye & CL. 2013;39:79-85 13. Tran. CEO. 2014;42:793-4 14. Stapleton. Ophthalmol. 2008;115:1655-62 15. Samarawickrama. BJO Open Ophthalmol. 2017;1:e00044 16. Hau et al. BJO. 2010;94:982-987 17. Bacon. Ophthalmol. 1993;100:1238-43 18. Brooks. Cornea. 1994;13:186-9 19. Constantinou. Ophthalmol. 2007;114:1622-9 20. Panda. Eye. 1999;13:744-7 21. Pavesio. Ophthalmol. 1997;104:1902-9 22. O Brien. Arch Ophthalmol. 1995;113:1257-65 23. McDonald. BJO. 2014;98:1470-7 24. SCUT. Arch Ophthalmol. 2012;130:143-50 25. SCUT 2. AJO. 2014;157:327-33 26. SCUT Nocardia. AJO. 2012;154:934-9 27. Allan. BJO. 1995;79:777-86 28. MUTT1. JAMA Ophthalmol. 2013;131:422-9 29. MUTT2. JAMA Ophthalmol. 2016;134:1365-72 30. FlorCruz. Cochrane Database. 2015;4:CD004241 31. Kilvington. IOVS. 2004;45:165-9 32. Oldenburg. Cornea. 2011;30:1363-8 33. Sifaoui. Exp Parasitol. 2017;183:117-23 The University of Sydney Page 48