Post Injection Endophthalmitis (PIE)

Article initiated by:

Yogita Gupta, MD

All authors and contributors:

Atul Kumar, Hernoor Athwal, Koushik Tripathy, MD (AIIMS), FRCS (Glasgow), Yogita Gupta, MD, Francesc March de Ribot, MD, PhD, Neelakshi Bhagat, MD, FACS, Jennifer I Lim MD

Assigned editor:

Diana V. Do, MD

Review:

Assigned status Update Pending

 by Neelakshi Bhagat, MD, FACS on July 21, 2021.

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Contributing Editors:	add

Disease Entity

Post Injection endophthalmitis (PIE)

Transmission of oral flora through respiratory droplets is particularly concerning during intravitreal injection. PIE is a dreaded complication and refers to specific endophthalmitis developing following the intravitreal administration of drug injections, most commonly being anti-vascular endothelial growth factor (anti VEGF) agents. It is not uncommon in today's era when the use of anti-VEGF drugs is wide-spread and a very commonly performed out-patient procedure in clinical ophthalmic practice. Its incidence is between 0.028- 0.056% and does not appear to vary based on geographic location.

Post Injection Cluster-endophthalmitis (PICE)

Cluster endophthalmitis is defined as an outbreak of five or more cases on a particular day in a single operating room in the same center.

Definition of cluster endophthalmitis
Five or more (≥5) cases on a particular day in a single operating room in the same center

Etiology

The most common causative organisms have been identified as coagulase-negative staphylococci (CONS), most commonly Staphylococcus epidermidis, which is fairly abundant in the conjunctival flora of the normal human eye. Viridans streptococci, the second commonest group of organisms causing PIE, are also an important part of human oral flora. A significantly higher proportion of PIE cases vs postcataract endophthalmitis are related to Streptococci (30% vs 9%). It is important to minimize such cases as Streptococcal endophthalmitis is associated with poorer visual outcomes. The following organisms are common causative pathogens involved in PIE and cluster endophthalmitis:

• Coagulase-negative staphylococci
• Viridans Streptococci
• Staphylococcus aureus
• Pseudomonas species.
• Stenotrophomonas maltophilia
• Burkholderia cepacia

Risk Factors

Table 1. Risk factors for the occurrence of post-injection endophthalmitis

Drug-related	Injection-related	Patient-related intrinsic factors
Counterfeit drugs	Contaminated needles	Microbial flora in Conjunctival and periorbital skin
Improper drug storage	Use of same vial more than once	Nasolacrimal duct obstruction (NLDO) (pre-existing)
Lapse of cold chain	Speaking while performing the procedure (esp risk for Streptococcus viridans)	Diabetes (controversial)
	Unsterile surrounding where the procedure is performed (office or operating room)	Any localized or systemic infection (e.g. adnexal infection)
	Viscous anesthetics: may diminish physical distribution and effectiveness of antiseptics
	Extensive eyelid manipulation and eyelid scrubs may increase contamination from meibomian gland discharge, and eyelid/ conjunctival surface bacteria

Counterfeit drugs: Injection vials procured from unauthenticated sources and fake drug dealers are the commonest cause for PIE post-Avastin© (bevacizumab drug). The authorized drug manufacturer and supplier for Avastin in most countries  is ROCHE. Drugs should always be bought from authorized dealers.

Cold chain breakage/lapse:

Table 2. Various potential sites of lapse of cold chain and the preventive measures

	Manufacturer level	Distributor level	Hospital setting
Site details	At Manufacturer-site	From manufacturer-site to final distributor site; got as a carton	At the point of use
Ideal Storage details	In vials of ~0.2 ml of drug, immediately stored in cold 2-8 degrees Celsius	At 2-8 degrees Celsius in a clean plastic container to prevent wetting of carton	Exclusive refrigerator at 2-8 degrees Celsius with a temperature display and power backup
Other instructions for purchaser	Check the cold chain log	Check the cold chain log. Kezzler code of authentic drug distributor when purchasing the vial	Check the cold chain log. Check for any unusual turbidity in the drug vial.

Breach in asepsis: Any breach in sterilization may lead to loss of aseptic conditions. Several activities or wrong-doing may contribute to this. These may include:

• Speaking while performing the procedure - The organisms from the oral flora may contaminate the environment
• Failure of optimal sterilization of injection site
• Improper scrubbing by the surgeon

Diagnosis

Table 3. Clinical presentation of PIE and PICE

Classification of PIE and PICE	Usual clinical presentation
Fulminant	< 4 days
Acute	5-7 days
Chronic	>4 weeks

Clinical presentation usually ranges from : 24 hours to 26 days (average: 4 days)

The clinical course of PIE is different from post-surgical endophthalmitis as it is usually:

• More severe with aggressive clinical course
• Presents earlier
• Some virulent strains may show antimicrobial resistance to high-end antibiotics like fluoroquinolones.

History and Symptomatology

There would be a history of drug administration via the intravitreal route at an ophthalmic facility.

Patients usually present with severe pain, redness, and watering. There may be purulent discharge associated with the development of endophthalmitis.

Pain may be troublesome and often not relieved with common painkillers (e.g. NSAIDs). Patients may describe it as " severe boring'' pain.

Ocular examination

Signs on ophthalmic examination:

• Conjunctival hyperemia
• Limbal congestion
• Swollen lids
• Discharge from eyes (watery/purulent/mucopurulent)
• Poor fundus red reflex - as assessed with distant direct ophthalmoscopy / retroillumination
• Ocular tenderness
• Hypopyon may be seen in fulminant cases
• Corneal Edema
• Anterior chamber (AC) reaction will be evident: AC cells and flare should be noted carefully with a 1x1 mm slit
• Iris may be swollen with hazy details
• In many cases, the lens or anterior vitreous details may be hazy
• Vitritis (Vitreous reaction) may be visible on slit-lamp or indirect ophthalmoscopy
• Intraocular pressure may be high
• Media haze
• Fungal balls or fluffy exudates or string of pearls may be seen in fungal endophthalmitis
• There may be an associated corneal ulcer

Clinical diagnosis

PIE is a clinical diagnosis and antimicrobial drugs need to be started on an empirical basis and systemic and local therapy should be initiated as early as possible. An ultrasound B-scan will confirm the inflammatory component of the condition. AC tap, vitreous tap, or a vitreous biopsy can be taken to ascertain the microorganism causing endophthalmitis, and treatment given accordingly.

Diagnostic investigations

1. DIRECT OPHTHALMOSCOPY
2. SLIT LAMP EXAMINATION
3. INDIRECT OPHTHALMOSCOPY
4. ULTRASONOGRAPHY : US-B scan (8-10 MHz) will confirm the vitreous reaction in cases with no red reflex. One must assess the following in ultrasound
   • Presence of vitreous exudates
   • Chorioretinal thickness
   • Presence of retinal detachment
   • Presence of vitreous membranes

Laboratory tests

Vitreous tap or biopsy should be sent for bacterial and fungal culture and sensitivity.

Methods for obtaining a vitreous biopsy.

Methods to obtain vitreous biopsy in endophthalmitis
Using 23 G or 25 G vitrectomy cutter, while attaching a syringe to its aspiration tube end, before starting irrigation through pars plana port.
From cassette fluid of vitrectomy machine and from fluid in the tubing
A vitreous tap may be aspirated using a 23 G needle from the pars plana region.

Differential diagnosis

• Uveitis: A flare-up of uveitis may be mistaken for early endophthalmitis. But hypopyon is normally absent and usually less severe signs/symptoms are seen in uveitis.
• Culture-negative sterile endophthalmitis
• Panophthalmitis : Ocular movements will be restricted
• Vitreous hemorrhage : There is usually an absence of anterior segment inflammation and the vitreous is reddish in color in acute vitreous hemorrhage.

Prevention of PIE and PICE

• PREOPERATIVE MEASURES
  • Thorough preoperative screening and control of risk factors like localized adnexal infection or systemic condition
  • Sterility of the surroundings where the injection is being performed, outpatient office facility or the OR.
  • Role of prophylactic topical antibiotics: There is a lack of evidence for their use. However, preprocedural use of topical antibiotics may be done as per the surgeon's personal experience and discretion. Increased bacterial resistance can occur
  • Maintenance of cold chain should be ensured during drug procurement
  • COMPOUNDING PHARMACY - with Class 10 facility with LAMINAR HOOD FLOW facility is ideal for aliquoting of anti-VEGF drugs. In such a facility, a 100 mg/4ml vial is divided into 0.2ml vials which are sent for microbial cultures and used after 48 hours
• INTRAOPERATIVE MEASURES
  • Thorough surgical scrubbing and the use of gloves and masks
  • Cleaning of periocular skin with 10 % topical povidone-iodine solution (for 3 minutes)
  • Cleaning of the conjunctival cul-de-sac with 5% povidone-iodine solution (for 3 minutes)
  • Eyelid Retraction (manually or with an eyelid spectrum) to decrease needle contamination by eyelash and eyelid bacteria

WHO Recommendation for surgical scrubbing (worldwide followed)
Minimum three scrubs with 4% w/v CHLORHEXIDINE GLUCONATE solution for 5-7 minutes

• PROPER OR (OPERATING ROOM) STERILIZATION
  • OR fumigation
  • Cultures of OR: Blood agar culture plates should be placed for 30 minutes in OR and sent for cultures
  • OR floors: Hydrogen peroxide H2O2 solution (diluted)
  • OR walls: Alcohol-based solutions, a combination of glutaraldehyde and formaldehyde (e.g. Bacillol)

Management

Treatment must be tailored depending upon the clinical presentation of individual cases. Nevertheless, the treatment should be aggressive in PIE, maybe more than post-surgical endophthalmitis. Early surgical intervention should be preferred in these cases. Pars plana vitrectomy, if performed in time, can help remove the infection nidus in these cases.

Alternatively, one may choose to administer intravitreal antibiotics first. On the first presentation, giving empirical antibiotics (as per local microbiology department drug sensitivity information), followed later by giving specific drugs (as per the microbial culture and drug sensitivity report) is recommended. Empiric intravitreal antibiotics that are often used include vancomycin 1 mg plus ceftazidime 2.25 mg, each diluted in 0.1 ml of sterile water or saline. While there is variable data on the usefulness of adjunctive systemic antibiotics, they are suggested for severe or fulminant cases. Specifically, moxifloxacin (400 mg orally once daily for 5-7 days) was found to have a beneficial impact on clinical outcomes.

Additional Resources

VRSI guidelines:

Guidelines for intravitreal injections: A book by Vitreo-retinal Society of India. Avastin_Guidlines_Book.pdf [Internet]. [cited 2018 Nov 28]. Available from: http://vrsi.in/wp-content/uploads/2018/02/Avastin_Guidlines_Book.pdf

OT sterilization

Sharma N, Kumar A, et al. Ocular Infections: Prophylaxis and Management. Jaypee Brothers Medical Publishers (P) Ltd., 2017.

See also

• Sterile endophthalmitis with intravitreal injections