Post-intravitreal injection endophthalmitis (PIE)

Key points at a glance

Key Points at a Glance

• Post-injection endophthalmitis (PIE) is an exogenous endophthalmitis that occurs after intravitreal injection. Although the incidence is low (0.028–0.056%), it can lead to severe visual outcomes.
• Severe eye pain, sudden vision loss, and hypopyon are the three major signs, typically developing within a few days after injection.
• Coagulase-negative staphylococci (mainly S. epidermidis) are the most common causative organisms, with a culture positivity rate of approximately 94%.
• First-line treatment is intravitreal antibiotic injection (vancomycin 1 mg + ceftazidime 2 mg). If no improvement within 48 hours, pars plana vitrectomy (PPV) should be considered.
• “Pseudoendophthalmitis,” presenting as white opacities in the anterior chamber without eye pain, is caused by migration of triamcinolone crystals into the anterior chamber and must be differentiated from infectious endophthalmitis.
• Preoperative use of povidone-iodine and avoiding conversation during injection are fundamental preventive measures. Evidence for prophylactic topical antibiotics is insufficient.
• The frequency of anti-VEGF injections often decreases after PIE, making regular follow-up important.

1. What is Post-Injection Endophthalmitis (PIE)?

Post-injection endophthalmitis (PIE) is an intraocular infection that occurs as a complication of intravitreal injection (IVI). After intravitreal administration of anti-VEGF agents, steroids, or other drugs, pathogenic bacteria invade the eye, causing acute endophthalmitis.

Intravitreal injections are widely performed for the management of neovascular age-related macular degeneration (nAMD), diabetic retinopathy, retinal vein occlusion, and other conditions, and the number of procedures is increasing worldwide. The incidence is reported to be 0.028–0.056% (0.28–0.56 per 1000 injections)²⁾, and PIE accounts for up to 8.5% of all endophthalmitis cases¹⁾.

Endophthalmitis is broadly classified into three types based on the mode of onset and the virulence of the causative organism.

Fulminant Type

Onset: Within 1–3 days after injection

Causative organisms: Highly virulent bacteria such as Streptococcus species.

Features: Rapid intraocular inflammation. Severe hypopyon and vitreous opacification, with the worst visual prognosis.

Acute type

Onset: Within 2–7 days after injection

Causative organisms: Mostly coagulase-negative staphylococci (e.g., S. epidermidis).

Features: The most common form. Early intervention improves visual prognosis.

Pseudo-endophthalmitis

Onset: Within 1 day to a few days after injection

Causative organisms: None (non-infectious)

Features: Crystals (e.g., triamcinolone) migrate into the anterior chamber, forming a white opacity. The absence of eye pain is a key distinguishing feature.

Q Does the risk of endophthalmitis increase with repeated intravitreal injections?

A

The incidence per injection is constant, and the cumulative risk increases proportionally with the number of injections. In the MARINA trial, the risk per injection was 0.05%, while in the VIEW trial, the cumulative 1-year risk was less than 1.0%⁶⁾.

2. Main symptoms and clinical findings

Subjective symptoms

PIE often develops rapidly within a few days after injection, with the following characteristic symptoms.

• Rapid vision loss: May decrease to hand motion (HM) or light perception (PL) level¹⁾.
• Eye pain: Often accompanied by severe pain. The absence of eye pain in pseudo-endophthalmitis is important for differentiation ³⁾.
• Redness: Severe ciliary and conjunctival injection is observed.
• Photophobia and tearing: Increase as inflammation spreads.

Clinical Findings

Evaluation combines slit-lamp microscopy and fundus findings.

• Hypopyon: Purulent exudate settling in the lower anterior chamber. An important indicator of infectious endophthalmitis. In the case reported by Kvopka et al., it increased from 1.8 mm to 3.0 mm at initial presentation ¹⁾.
• Vitreous opacity: Floating particles and white opacities in the vitreous reduce fundus visibility.
• Anterior chamber flare and cell reaction: Indicate protein leakage and leukocyte infiltration in the anterior chamber.
• Fundus non-visibility: In severe cases, vitreous opacity is so dense that fundus examination becomes difficult.

The culture positivity rate is high at approximately 94% ²⁾, and identification of the causative organism contributes to treatment decisions.

Q How to differentiate pseudo-endophthalmitis from infectious endophthalmitis?

A

Pseudo-endophthalmitis is a condition where crystals such as triamcinolone migrate into the anterior chamber, often without eye pain and with minimal visual loss ³⁾. Infectious endophthalmitis is accompanied by eye pain, rapid visual loss, and vitreous opacity. When differentiation is difficult, it is safe to manage as infectious.

3. Causes and Risk Factors

Causative Organisms

The distribution of causative organisms in post-intravitreal injection endophthalmitis is shown below.

Causative bacteria	Approximate frequency
S. epidermidis (CoNS)	Approximately 59%
Other gram-positive bacteria	Around 30%
Gram-negative bacteria (e.g., M. morganii)	Rare

Staphylococcus epidermidis (coagulase-negative staphylococcus) is the most common, accounting for approximately 59%²⁾. Co-infection with Enterococcus faecalis and Morganella morganii has been reported as the first case worldwide, suggesting the involvement of multidrug-resistant bacteria¹⁾.

Routes of infection and risk factors

The main sources of PIE infection are considered to be the patient’s own conjunctival resident bacteria and oral droplets.

• Conjunctival bacterial flora: The main route is when conjunctival resident bacteria enter the eye through the needle insertion site during injection.
• Oral droplets: Contamination by droplets from conversation between the operator and patient during the injection procedure has been reported.
• Immunocompromised state: Patients with systemic immunosuppression are at increased risk.
• Incorrect injection site: The recommended site is 3.5 mm posterior in pseudophakic eyes and 4 mm posterior in phakic eyes⁴⁾; deviation increases the risk of infection.

Prevention and Daily Care

Here are key points for preventing infection when receiving intravitreal injections.

• Before the injection, the conjunctival sac is disinfected with povidone-iodine (diluted solution). This is the most important measure to prevent PIE⁴⁾.
• Minimize conversation during the injection. Bacteria from the mouth can enter the eye as droplets.
• If eye pain, vision loss, or redness appears rapidly after the injection, see an ophthalmologist immediately.
• Prophylactic topical antibiotics currently have insufficient evidence for prevention⁴⁾.

4. Diagnosis and Examination Methods

Basic Diagnostic Approach

PIE should be diagnosed promptly based on clinical findings, and treatment should be started immediately. Do not delay treatment while waiting for test results.

The main examination methods used for diagnosis are listed below.

Examination	Purpose	Notes
Slit-lamp microscopy	Check for hypopyon and flare	Essential, first choice
B-scan ultrasonography	Confirms vitreous opacity and retinal detachment	Essential when fundus is not visible
Anterior chamber and vitreous tap	Identifies causative organism	Collect samples before treatment

Sample Collection

Collect the following samples immediately before intravitreal antibiotic injection:

• Anterior chamber aspirate: Collected by puncture at the corneal limbus.
• Vitreous fluid: Collected using a 27- to 30-gauge needle or vitreous biopsy device.

The collected samples are used for culture, Gram staining, and drug susceptibility testing.

Differential Diagnosis

• Pseudo-endophthalmitis: A non-infectious condition where crystals (e.g., triamcinolone acetonide) migrate into the anterior chamber, forming white opacities. It is suggested that disruption of the blood-retinal barrier (BRB) allows drug particles to move into the anterior chamber ³⁾. There is no eye pain, vision is relatively preserved, and it resolves spontaneously with observation.
• TASS (Toxic Anterior Segment Syndrome): Non-infectious inflammation after intraocular surgery. It can be caused by impurities or endotoxins in injectable preparations. Cultures are negative, and observation or anti-inflammatory drugs are effective.

5. Standard Treatment

First-line: Intravitreal antibiotic injection

The first-line treatment for PIE is intravitreal injection of two broad-spectrum antibiotics.

Standard doses and administration of antibiotics are shown below.

Drug	Dose	Target bacteria
Vancomycin	1 mg/0.1 mL	Gram-positive bacteria
Ceftazidime	2–2.25 mg/0.1 mL	Gram-negative bacteria

Intravitreal administration of vancomycin 1 mg plus ceftazidime 2–2.25 mg is considered standard treatment ¹⁾. Administer promptly after specimen collection. After culture results are available, switch to antibiotics targeting the causative organism.

Evaluation of treatment progress and surgical therapy

If clinical improvement is not achieved within 48–72 hours after the initial injection, consider pars plana vitrectomy (PPV).

Kvopka et al. (2023) reported a case in which vitrectomy was performed after two intravitreal injections of vancomycin 1 mg + ceftazidime 2.25 mg failed to resolve hypopyon, and the BCVA at 12 weeks was 6/90 (0.12)¹⁾. The causative organisms were a co-infection of M. morganii and E. faecalis.

A large study using the IRIS Registry (1044 cases) showed no significant difference in final visual acuity between early vitrectomy and injection-only treatment⁵⁾. This result supports the validity of a stepwise approach (first intravitreal injection, then PPV if no improvement).

Resumption of Intraocular Injections After PIE

It has been reported that the frequency of anti-VEGF injections decreases and the injection interval significantly lengthens after the onset of PIE (1.09 times/month before onset → 0.52 times/month after onset, p=.001)²⁾. In 12% of cases, injections were not resumed after PIE²⁾. The average time to resumption was 44±30 days²⁾.

The incidence of endophthalmitis after vitrectomy is low, at less than 0.05%⁷⁾.

Treatment Considerations

• When the causative organism is a multidrug-resistant Gram-negative bacterium such as M. morganii, first-line drugs may be ineffective¹⁾. Monitor culture and sensitivity results closely and change antibiotics promptly.
• Interruption of anti-VEGF therapy after PIE may lead to worsening of the underlying disease (e.g., nAMD). It is important to resume injections at an appropriate time²⁾.
• Vancomycin and ceftazidime should not be mixed in the same syringe. Inject each using separate syringes.

Q If PIE develops, must anti-VEGF therapy be permanently discontinued?

A

In many cases, injections are resumed after PIE. One report found that the average time to resumption was 44±30 days²⁾, and complete discontinuation occurred in 12% of cases. Consider resuming at an appropriate time while assessing the activity of the underlying disease.

6. Pathophysiology and Detailed Mechanism of Onset

Mechanism of Infection Establishment

PIE is an exogenous endophthalmitis caused by the entry of external microorganisms into the eye during intravitreal injection. The two most important routes of infection are as follows:

• Intraocular invasion of conjunctival commensals: When the needle is inserted, commensal bacteria (mainly S. epidermidis) present on the conjunctival epithelium are pushed into the vitreous cavity.
• Oral droplet contamination: Oral bacteria from the surgeon or patient contaminate the injection site as droplets. Therefore, talking during the injection procedure is considered a risk factor.

Morganella morganii is a multidrug-resistant Enterobacteriaceae Gram-negative rod, and its involvement in intraocular infection has been reported as a rare case worldwide¹⁾.

Mechanism of Pseudoendophthalmitis

Pseudoendophthalmitis is not infectious; it occurs when crystalline particles of the injected drug (mainly triamcinolone acetonide) migrate into the anterior chamber³⁾. If there is pre-existing disruption of the blood-retinal barrier (BRB) (e.g., increased vascular permeability associated with neovascularization), drug particles are thought to move more easily from the posterior chamber to the anterior chamber³⁾. The reported rate of endophthalmitis after bevacizumab injection is approximately 0.066%, and after triamcinolone, 0.10–0.87%³⁾.

Changes in nAMD Activity After PIE

A phenomenon in which exudative changes in nAMD temporarily stabilize or decrease after PIE has been observed in some cases²⁾. It is speculated that post-inflammatory fibrosis and proliferation suppression may affect neovascular activity in nAMD, but the mechanism remains unclear²⁾.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please read this

The following content is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Large-scale Analysis Using the IRIS Registry

A retrospective study (2025) of 1044 cases using the US IRIS Registry (Intelligent Research in Sight) showed no significant difference in final visual acuity between the early vitrectomy group and the initial injection-only group⁵⁾. This result supports the current stepwise approach of not performing vitrectomy uniformly for all PIE cases but rather responding to intravitreal injection response.

Observational Study on nAMD Course After PIE

Binczyk et al. (2023) reported that anti-VEGF injection frequency significantly decreased after PIE in 17 eyes (1.09→0.52 IVI/month, p=.001), and nAMD activity stabilized in some cases²⁾. Further prospective studies are needed on the impact of local inflammation after PIE on the pathology of nAMD.

First Case Report of M. morganii Endophthalmitis

Kvopka et al. (2023) reported the world’s first case of PIE caused by co-infection with Morganella morganii and Enterococcus faecalis¹⁾. This case demonstrates the difficulty of treating intraocular infections caused by multidrug-resistant gram-negative bacteria and highlights the importance of culture and antibiotic susceptibility testing.

Tunneled Technique

The “tunneled technique” has been proposed to reduce the risk of reflux and infection by changing the injection needle insertion angle to create a non-linear needle track⁴⁾. Comparative studies with standard techniques are still limited, and further evidence is needed for widespread clinical adoption.

Q Can prophylactic topical antibiotics prevent PIE?

A

Current evidence is insufficient to support that prophylactic topical antibiotics reduce PIE⁴⁾. The mainstay of prevention is conjunctival sac disinfection with povidone-iodine, and routine use of antibiotic eye drops may carry the risk of promoting antibiotic resistance.

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8. References

1. Kvopka M, Lake S, Bhagat K. Simultaneous Morganella morganii and Enterococcus faecalis endophthalmitis following intravitreal injection: a world first case report. BMC Ophthalmol. 2023;23:450.
2. Binczyk NM, Plemel DJA, Seamone M, Rudnisky CJ, Tennant MTS. Decrease in Anti-VEGF Injections After Post-injection Endophthalmitis in Patients With Neovascular Age-Related Macular Degeneration. J VitreoRetin Dis. 2023;7(6):528-532. doi:10.1177/24741264231200470.
3. Singh R, Davoudi S, Ness S. Preventive factors, diagnosis, and management of injection-related endophthalmitis: a literature review. Graefes Arch Clin Exp Ophthalmol. 2022;260(8):2399-2416. doi:10.1007/s00417-022-05607-8.
4. Lam LA, Mehta S, Lad EM, et al. Intravitreal Injection Therapy: Current Techniques and Supplemental Services. J VitreoRetin Dis. 2021;5(5):438-447. doi:10.1177/24741264211028441.
5. Ross CJ, Ghauri S, Gilbert JB, et al.; IRIS Registry Analytic Center Consortium. Intravitreal Antibiotics versus Early Vitrectomy Plus Intravitreal Antibiotics for Postinjection Endophthalmitis: An IRIS Registry Analysis. Ophthalmol Retina. 2025;9(3):224-231. doi:10.1016/j.oret.2024.09.002.
6. American Academy of Ophthalmology. Age-Related Macular Degeneration Preferred Practice Pattern. AAO; 2025.
7. American Academy of Ophthalmology. Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern. AAO; 2024.