Infectious keratitis for the general ophthalmologist€¦ · Steroids for bacterial keratitis (3...

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Infectious keratitis for the

general ophthalmologist

Presented by

Chameen Samarawickrama- Westmead Hospital

- Liverpool Hospital

- University of Sydney

- University of New South Wales


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


Microbial keratitis

– Common cause of visual morbidity

– Management requires appropriate treatments in an appropriate time frame

– Regional and temporal changes in pathogens


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 ?


1. Which organisms

– Modified by local risk factors that can vary with time

– Resulting in geographic and temporal changes

– SURVEILLANCE FOR “EMERGING PATHOGENS”

BACTERIA Gram +ve, Gram –ve, acid fast

PROTISTS Acanthamoeba

FUNGI Yeast, mould, Microsporidia


Geographic variations (Gram +ve)

49%

62%

68%

83%

41%

54% 71% 71%

36%

Shah. BJO. 2011;95:762-67


What about Australia and New Zealand (Gram +ve)

51% (2008)

72% (2003)

76% (2005)

66% (2005)

75% (2015)

51% (1996)

20% (2016)


What about Australia and New Zealand (Fungi)

9% (2008)

9% (2003)

4% (2005)

5% (2005)

2% (2015)

0% (1996)

12% (2016)


Organisms can even change by season

Green. Cornea. 2008;27:33-9


2. Risk factors vary by region

6%

7%

7%

10%

34%

36%

0% 5% 10% 15% 20% 25% 30% 35% 40%

MULTIFACTORIAL

HSV

OSD/SYSTEMIC

OTHER/UNKNOWN

CONTACT LENS

TRAUMA

Risk factors for MK (2001-3)

Keay. Ophthalmol. 2006;113:109-116


Risk factors vary over time



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.

Streptococcus spp. Other Gram +ve spp Acanthamoeba Fungi

Stapleton. AJO. 2007;144:690-98

*

Reasonable to assume keratitis in contact lens wearer is

Pseudomonas aeruginosa until proven otherwise


Contact lens wear – “new pathogens”Microsporidia


Contact lens wear – “new pathogens”Fusarium


Contact lens wear – “new pathogens”Acanthamoeba


3. Features of a “microbial” keratitis is unreliable

Gram

+ve

Gram

-ve

Fungi

AK


Appearance modified by steroidsCrystalline keratopathy


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

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 helpfulSamarawickrama. BJO Open Ophthalmol. 2017;1:e00044


Ancillary tests – confocal microscopy

– Operator dependent

– 50% sensitivity

– 65-82% specificity

– High repeatability

Hau et al. BJO. 2010;94:982-987

Do not rely on confocal for diagnosis if

the response to treatment is poor


Debridement – acanthamoeba and fungi

– 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

biopsy and culture


Histology – corneal biopsy or excisional keratoplasty

– Confirms the diagnosis

– Viability uncertain

Gomori silver stain (fungi)

Acanthamoeba cysts

(H&E; modified Gomori)


4. Treatment aims

1. Eliminate infection

2. Control inflammation

3. Control pain

4. Avoid toxicity

5. Identify complications

6. Restore vision


Sterilization and healing

Microbial

keratitis

Investigation

SterilizationDamage

limitation

Healing


Management strategies for keratitis

– Use algorithms and lists– To consider all causes

– Aid in rational planning of diagnosis and treatments


When to treat without investigation

– The 95% typical bacterial keratitis– Small infiltrate (


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


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


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)

McDonald. BJO. 2014;98:1470-7



– 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

McDonald. BJO. 2014;98:1470-7



– 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

McDonald. BJO. 2014;98:1470-7


Resistance to fluoroquinolones?



Clear winner

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

Investigate ALL cases where infection is not improving

after 5 days


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!


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 P=0.82

Scar P=0.4

Re-epithelialization P=0.44

Perforation P>0.99

IOP Higher in placebo (p=0.04)

SCUT. Arch Ophthalmol. 2012;130:143-50

Baseline BSCVA (CF or

worse)

P=0.03

Location (central 4mm) P=0.04

Subgroup analysis suggests benefit of steroids

for severe central ulcers


Steroids for bacterial keratitis (12 month results)

SCUT 2. AJO. 2014;157:327-33

BSCVA at 12 months P=0.39

Scar 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

Entire cohort results

1 line benefit of steroids for non-Nocardia microbial keratitis


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


Intensive

treatment

Treatment toxicity

Inadequate

treatment

CULTURE, PCR or CONFOCAL +

Unrepresentative

culture

Persistent

inflammation

RESOLUTION

Reduce toxicityNo preservatives or

aminoglycosides

Treat host responseTrial of steroids

Debride

Correct precipitating

factors

CONFOCAL

PCR

RECULTURE

after 24-48

hours off therapy

CULTURE -

Treated before or

inadequate

treatment

Consider other

possible causes

Adequate treatment

for likely causes

BIOPSY

PERFORATION

Glue

Infection

controlled

Infection

uncontrolled

EYE LOST

Failure to heal

RESOLUTION

Therapeutic/ tectonic penetrating

transplant


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

CO2


Fungal keratitisDiagnosis

Empirical

therapy

Superficial infection

1. Natamycin 5%

2. Debride lesion

If no response in 7 days

3. Add Chlorhexidine 0.2%

Alternatives:

Voriconazole 1%

Amphotericin 0.15%

Deep stromal

infection/endophthalmitis

1. Natamycin 5% and

Chlorhexidine 0.2%

2. Oral Voriconazole*

If no response in 7 days

3. Intralesional Voriconazole

4. Intracameral Voriconazole

5. Excisional/therapeutic

keratoplasty

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%

MUTT1. JAMA Ophthalmol.

2013;131:422-9

MUTT2. JAMA Ophthalmol.

2016;134:1365-72

FlorCruz. Cochrane Database.

2015;4:CD004241


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%


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


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)

Troph Cyst

Biguanides

Polyhexanide

(PHMB)

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


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


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


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

Infectious keratitis for the general ophthalmologist€¦ · Steroids for bacterial keratitis (3...

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