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A (VAST)IN Saga

Dr. Bikramjit Pal, Associate Consultant, Department of Vitreoretina, Sankara Nethralaya
Dr. Parthopratim Dutta Majumder, Consultant, Department of Uvea, Sankara Nethralaya

Vascular endothelial growth factor (VEGF)-A is a key mediator of angiogenesis. The discovery of VEGF-A, like many other major discoveries in medicine, happened partly by observations and partly by chance. Napoleone Ferrara and his team were working on a population of non-hormone-secreting cells from the anterior pituitary of cows. (1) One day Ferrara mixed some isolates from cultures of follicular cells with endothelial cells. Ferrara was surprised to see the rapidly proliferating endothelial cells started rapidly. Ferrara understood that the pituitary cells were secreting an angiogenic protein. With this observation, Ferrara worked on the isolation and cloning of this angiogenic protein. In 1989, Napoleone Ferrara and Hazel at Genentech laboratory were the first to isolate and clone vascular endothelial growth factor (VEGF). Ferrara recalls, “I worked on the isolation of VEGF in my spare time during my first six months to a year at Genentech. Once we cloned VEGF in 1989, the company became interested and this became more and more my full time persuit.”  In 1993, Ferrara reported that inhibition of VEGF-induced angiogenesis by specific monoclonal antibodies led to dramatic suppression of the growth of a variety of tumors in vivo. Thus bevacizumab (Avastin), a recombinant humanized anti-VEGF monoclonal antibody was developed in Ferrara’s laboratory and Genentech, the company with which he used to work licensed ranibizumab for ophthalmic use (2).  

 

BEVACIZUMAB:

Bevacizumab consists of a full-length monoclonal antibody. It was approved for the treatment of metastatic colorectal cancer in 2004.

 

STRUCTURE OF BEVACIZUMAB:

Bevacizumab consists of a full-length monoclonal IgG1-antibody that binds to all isoforms of VEGF-A. Bevacizumab is produced in Chinese hamster ovary (CHO) cells, which is the cellular production pathway, which includes glycosylation of the proteins. The resulting bevacizumab anti-body contains 93% of the human amino acid sequence. Bevacizumab contains the Fab and Fc portions of a regular antibody, with a molecular weight of 148 kDa and binds to the identical epitope on VEGF molecules

Bevacizumab at a glance:

Acute Intraocular Inflammation / Sterile Endophthalmitis with intravitreal injection of bevacizumab:

It is characterized by significant anterior chamber and/or vitreous inflammation following intravitreal injection of the drug, in the absence of infection. Such a massive immunological response following intravitreal injection of bevacizumab is a possible event, described in literatures and may occur even after preceding uneventful interventions. It is similar to the toxic anterior segment syndrome (TASS) that can occur after cataract surgery
Inflammation induced by bevacizumab is usually an early onset associated with a painless drop in VA mostly without conjunctival injection. Patients present with a marked anterior chamber reaction, mostly without hypopyon. Vitritis is characterised by large cellular aggregates of pseudogranulomatous aspect.
Inflammation induced by intravitreal bevacizumab differs from infectious endophthalmitis in following features: (4,5)

The cause of inflammation induced by intravitreal bevacizumab remains unclear. However various possible mechanism has been suggested.  It is believed to occur due to an immunogenic mechanism in which foreign epitopes are presented by antigen-presenting cells to B and T cells. (6) Bevacizumab can diffuse into the anterior chamber more readily, and remain in the anterior chamber and vitreous for significantly longer than ranibizumab (7). Also larger protein load and size of bevacizumab molecule with an additional Fc fragment, make it more immunogenic than ranibizumab. Bevacizumab is harvested from cultures of mammalian ovarian cancer cells, that is the cellular production pathway, which includes glycosylation of the proteins with a higher immunogenic potential than the nonglycosylated pure proteins produced by a bacterial pathway (E. coli) in ranibizumab. It has been estimated that bevacizumab preparations contain about 70% of nonhumanised material (5) and  these excess particulate matter, which is still within normal limits for intravenous use, may be one of the cause for such inflammation . Further, bevacizumab solution has a pH of 6.2, well below the normal vitreous pH of 6.5–8.5.(8) Also, commercially bevacizumab is manufactured for intravenous infusion and therefore possibly undergoes relatively less tight purification procedure than drugs formulated for intraocular use.

 

Endophthalmitis with intravitreal injection of bevacizumab:

An exhaustive Medline search of studies citing endophthalmitis (between 2011-15) after usage of Bevacizumab (Avastin, Genentech, South San Francisco, California, USA) revealed a varying incidence. Smaller studies appeared to have a higher (small study effect) incidence compared to studies having a larger number. Similarly, prospective studies had a different incidence as compared to one retrospective in nature. Although there were many studies looking into endophthalmitis after use of anti VEGF, the studies specifically focusing on Avastin were less. Overall endophthalmitis rate post Avastin usage varies between 0% - 0.54% (9,10)
Avastin had received a negative media hype in West a few years back and is again under scrutiny following some untoward incidences in India. As cited “Avastin doesn’t blind people, people blind people” (11). The use of an “off label” drug has been prompted by the severe prohibitory cost of its sibling Ranibizumab (Lucentis, Genentech). In an Indian scenario where the cost is largely borne by the patient, having a cheaper drug which works just as fine as its costly sibling in terms of efficacy and side effects seems like a legitimate option.
Avastin is generally available as a 4ml or a 16 ml single use glass vial. Ophthalmological practices involve either a single puncture and dividing into multiple aliquots (to be used in single or divided days), or involves multiple puncture for individual cases. The procedure of aliquoting involves stringent measures and United States Pharmacopeia (USP) ‘chapter 797’ details the correct way of doing it. A gist of the procedure can be found in the reference titled “Avastin doesn’t blind people” (11). In India where the concept of compounding pharmacy doesn’t exist in all places, the drug is hence divided in house. The patients are either pooled in, whereby a single puncture is made into the rubber stopper and the drug divided into multiple tuberculin syringes to be used in the same day or the glass vial and the rubber stopper is punctured at multiple occasions as and when need arises. The former is more common in bigger institutes and private chains where a continuous flow of patients exists. The latter is commoner in practices involving smaller numbers.
The role of antibiotics in the peri-injection period has been a topic of constant debate. The points in favor of not using any prophylaxis are many, the most important one being induction of drug resistance.  Use of anti VEGF in a patient is generally not a onetime affair, hence increased chances of resistance in subsequent uses. Use of antibiotics as a pre or post injection prophylaxis on a regular basis allows selection of a more virulent strain altering the normal ocular flora (12,13). Repeated use of a particular antibiotic not only induces resistance to the particular agent but also against others. (14). The bactericidal effect if used immediately in the pre injection period is also of questionable value (12). Studies involving large number of subjects have found no difference in endophthalmitis rates when comparing antibiotic and non-use of the same (12,15, 16, 17). A recent study by CATT study group (18) states no particular advantage of antibiotics in reducing the endophthalmitis rate. On the contrary use of antibiotics may increase the endophthalmitis rate (15). Although many surgeons still use antibiotics, the current trend is not using one.
Since the procedure of intravitreal injection involves puncturing of the ocular coats, an ideal scenario would be the standard operating room. Injections in the West and few parts of Europe employ the procedure room or the office setting for giving an intravitreal injection. This consists of clean room in the outpatient area which, although not up to operating room standards serves the purpose. In fact, most of the current studies employ office scenario to inject and studies specifically looking into this aspect have not found any increase in endophthalmitis incidence when given as an office procedure (19)
Although the process of an intravitreal injection involves multiple steps, the only steps which are almost universally agreed upon are the usage of topical povidone iodine and sterile eye speculum (bladed or wired). The use of surgical gloves, sterile caps, surgical masks, sterile drapes, displacement of conjunctiva are not universally agreed upon. Bactericidal effect of iodine varies between 0.005% to 10% with its effect seen within sixty seconds (20). The effect of a drop of 5% povidone iodine is supposed to last for 24 hrs and a single application has a bactericidal effect equivalent to antibiotic use for 3 days (21). A recently cited paper brings up an interesting point of the pathology for which an antiVEGF is being given, playing a part in the etiology of endophthalmitis (22). According to their paper, patient receiving injections for retinal vein occlusions had lowest chances of endophthalmitis. Patients receiving injections for diabetic macular edema and AMD had more chances of infection. A poor immune status along with altered conjunctival flora were cited as causes for increased predisposition in diabetics whereas age was a factor in patients with AMD.
Although bacterial infections are much more common post anti VEGF, fungal infections can also occur (23). The most common organism causing post injection endophthalmitis is the coagulase negative staphylococci (24) followed by viridans streptococci. Compared to a normal intraocular surgery, the chances of post streptocoocal infections are three times higher in an intravitreal setting (25). The role of viridans streptococci in the context of intravitreal scenario is mainly due its commensalism with the human nasopharyngeal tract and its possible role as a contaminant through aerosol route. Study by authors (26,27) have shown the increased chances of infection by act of talking and not wearing a mask. Although many studies don’t mention the use or non-use of face masks, few that report of not using one don’t have a higher incidences of infection (12,28). The absolute diagnosis of the causative organism is to get a positive culture. Half of the cases leading to endophthalmitis are culture negative (29). The usual culture positivity varies between 57% to 66% (30).


The visual outcome of patients with post injection endophthalmitis depends on many factors such as the causative organism, how soon the patient presents, his general overall condition. Before labelling one as endophthalmitis it is important to rule out ‘sterile inflammation’. Although reported mainly with Bevacizumab; sterile reactions can also occur with ranibizumab (30). It is important to remember that Avastin has been meant for intravenous use. We use it intraocularly which has a smaller volume and confined space compared to the overall body when given intravenously, hence effects seen intraocularly may not be seen when administered intravenously. Endotoxins which are normally occurring byproducts of commercially made immunoglobulins are supposed to play a major role in these sterile reactions. The role of immune reaction to the antibody (since seen more commonly on sequential injections) have also been implied. Furthermore the role of silicone oil contaminants and temperature fluctuations which supposedly increases the immunogenicity may also have a role to play ( 31, 32).
The literature provides us many different variations of the clinical presentation of post injection endophthalmitis.  Severe pain, lid edema, signs of severe intraocular inflammation generally denotes an infective etiology although it is not a rule. A sterile reaction can present almost in a similar way. Generally sterile inflammation presents early with less signs of pain, hypopyon, does well with topical steroids and visual recovery is faster. These features cannot be generalized as hypopyon with pain can also be a presenting feature (32). The best thumb rule is to have a high index of suspicion and treat any case presenting with intraocular inflammation after injection as infective until proven otherwise.  The initial management involves as any other case of endophthalmitis which needs immediate principle of tap and inject. Aqueous or a vitreous tap generally yields material for staining and culture. A negative culture does not rule out an infection. Visual recovery is generally poor in culture positive cases specially with streptococci (25, 33). Since results of culture may be delayed, its ideal to start treatment depending on the clinical and microbiological results. Polymerase Chain Reaction (PCR) when available is a useful guiding tool but like any other diagnostic modality it not hundred percent sensitive in ruling out an infective agent. It is ideal to wait for some time to see the clinical progression and the effect of topical medications before shifting to surgery. An early surgical intervention in terms of vitrectomy may not be helpful in all cases. Worsening of visual acuity, pain, and intra ocular inflammation can be used as guiding principles to decide on surgery (34).
Endophthalmitis is a dreaded post injection complication which no surgeon wants to have. In spite of doctors having the best intention for the patient, sometimes such unfortunate accidents do happen. It is best to be vigilant when such a scenario arises and try to find the cause for the accident rather than shying away. Informing the right authorities and also keeping the patient abreast helps regain patient confidence and trust.

Check list before Avastin

Pre Procedure

1) Check systemic status: glycemic index, blood pressure, any drug allergy, cardiac function, h/o anticoagulants
2) Check locally: rule out any ocular infections like blepharitis, external or internal hordeolum, conjunctivitis, dacryocystitis, keratitis, scleritis
3) Perform a detailed retinal examination to rule out any untreated retinal holes, tears. Inform patient about risk of inducing a PVD in high myopes. Presence of lattice is not a contraindication, however if same/other eye has history of retinal detachment, it’s better to do laser to concerned lesion before antiVEGF
4) Examine the optic nerve head to rule out any glaucoma
3) Avoid injecting without an attendent

When preparing Bevazizumab

1) The person withdrawing it should wear sterile gloves, face mask and ideally should be done in a sterile environment.
2) Best to puncture once and divide into multiple doses which should be used up on the same day. Pooling patients offers the most secure method
3) Once a vial is opened the drug should ideally be used up in 1-3 weeks* . Remember to clean the rubber stopper with isopropyl alcohol and betadine before withdrawing again.
4) If the drug has been divided and kept, remember to send few samples for microbiological analysis before you inject.
5) Microbiological analysis can be done before each injection when vial kept for a longer time
6) Always inspect the bottle before withdrawing.
7) Maintaining cold chain is MUST ( 2-8 degrees). DO NOT FREEZE
* Sterility and stability of bevacizumab has been studied and is supposed to be effective and stable upto six months under sterile condition (27)

 

Procedural

1) Place of injection: Office/OT (surgeon preference)
2) Pre injection antibiotics: surgeon preference
3) Use of povidone iodine is MUST
4) Topical anaesthetic in form of drops or jelly
5) Sterile speculum is MUST
6) Use of face mask, sterile gloves, surgical cap, patient drape is surgeon and institution preference. In Indian scenario it’s better to have all of the above.
7) Post injection antibiotic: surgeon preference
8) Eye patch: not must
9) Head bath: withhold for 24 hrs
10) Review within a week

Summary of studies citing post bevacizumab endophthalmitis between 2011- 2015 

Author / Year

Pro/Retro

Total Inj.

Endophthalmitis

Office/OR

Pre AB

Post AB

Shah et al 2011 (38)

Retrospective

10958

12 (0.10%)

Office

no

Yes

Chen et al 2011 (25)

Retrospective

6675

3 ( 0.45%)

NM

Yes

Yes

Moshfeghi et al 2011 (44)

Retrospective

39700

7 ( 0.018%)

NM

No

Yes

Inman et al 2011(41)

Retrospective

1841

0

NM

No

Yes

Cheung et al 2012 (15)

Retrospective

5386

4 (0.074%)

Office

Variation

Variation

Mithal et al 2013(36)

Retrospective

15035

7 (0.04%)

NM

NM

NM

Englander et al 2013 (43)

Retrospective

2315

0

NM

NM

Variation

Falavarjani et al 2013(10)

Retrospective

5901

6 (0.10 %)

NM

No

Variation

Khurram et al 2013 (34)

Retrospective

28705

15 (0.05%)

NM

Yes

Yes

Shimada et al 2013 (20)

Retrospective

846

0

Office

Yes

Yes

Tabandeh et al 2014(28)

Retrospective

6169
2364

2 (0.032%)
0

Office Based
OR

No
Yes

Yes
Yes

Cheema et al 2014 (42)

Retrospective

2769

1 (0.036%)

Office

Yes

Yes

Casparis et al 2014 (9)

Retrospective

3518

0

OR

No

Variation

Falvarjani et al 2014 (39)

Retrospective

8037

1 (0.01%)

OR

no

Yes

Storey et al 2015 (45)

Retropsective

20873

12 (0.05%)

Office

Variation

Variation

Bhavsar et al 2015 (12)

Retrospective

15479

1 (0.006%)

Office

no

No

CATT study 2015 (18)

Prospective

586

7

 

variation

Variation

VanderBeek et al 2015(37)

Retrospective

296565

49 ( 0.017%)

NM

NM

NM

Terzic et al  2015 (40)

Retrospective

986

2 (0.20%)

OR

NM

Yes

NM: Not Mentioned, Variation: varied between surgeons, no fixed protocol AB: Antibiotic
 

Suggested Reading for preferred practice pattern

 Reference

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  20. Shimada H, Hattori T, Mori R, Nakashizuka H, Fujita K et al. Minimizing the endophthalmitis rate following intravitreal injections using 0.25% povidone-iodine irrigation and surgical mask. Graefes Arch Clin Exp Ophthalmol. 2013 Aug;251(8):1885-90
  21. Isenberg SJ, Apt L, Yoshimori R, Khwarg S. Chemical preparationof the eye in ophthalmic surgery. IV. Comparison ofpovidone-iodine on the conjunctiva with a prophylactic antibiotic.Arch Ophthalmol 1985;103:1340–1342
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  23. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. JAMA Ophthalmol. 2013 Jul;131(7):864-9
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  25. Chen E, Lin MY, Cox J, Brown DM. Endophthalmitis after intravitreal injection: the importance of viridans streptococci. Retina. 2011 Sep;31(8):1525-33
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  28. Tabandeh H, Boscia F, Sborgia A, Ciracì L, Dayani P. Endophthalmitis associated with intravitreal injections: office-based setting and operating room setting. Retina. 2014 Jan;34(1):18-23
  29. Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012 Feb;153(2):204-208.e1
  30. Cunningham MA, Tlucek P, Folk JC, Boldt HC, Russell SR. Sequential, acute noninfectious uveitis associated with separate intravitreal injections of bevacizumab and ranibizumab. Retin Cases Brief Rep. 2013 Fall;7(4):355-8
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  32. Orozco-Hernández A, Ortega-Larrocea X, Sánchez-Bermúdez G, García-Aguirre G, Cantón VM, Velez-Montoya R. Acute sterile endophthalmitis following intravitreal bevacizumab: case series. Clin Ophthalmol. 2014 Sep 9;8:1793-9.
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  36. Mithal K, Mathai A, Pathengay A, Jalali S, Relhan N et al. Endophthalmitis following intravitreal anti-VEGF injections in ambulatory surgical centre facility: incidence, management and outcome. Br J Ophthalmol. 2013 Dec;97(12):1609-12
  37. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol. 2015 Oct;133(10):1159-64
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  39. Falavarjani KG, Aghamirsalim M, Modarres M, Hadavandkhani A, Hashemi M et al. Endophthalmitis after resident-performed intravitreal bevacizumab injection. Can J Ophthalmol. 2015 Feb;50(1):33-6
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  45. Storey P, Dollin M, Rayess N, Pitcher J, Reddy S et al. The effect of prophylactic topical antibiotics on bacterial resistance patterns in endophthalmitis following intravitreal injection. Graefes Arch Clin Exp Ophthalmol. 2016 Feb;254(2):235-42

Statutory Warning

Materials / Informations provided here are for educational purpose only ; and not to be used for medical advice, diagnosis or treatment