Global reported endophthalmitis risk following intravitreal injections of anti-VEGF: a literature review and analysis

Figures & data

Table 1 Indications for intravitreal injections

	Bevacizumab	Ranibizumab	Total
exAMD	32,153	82,100	114,253
PED	118	356	474
PCV	1,286	2,885	4,171
RAP	376	620	996
CNVM (PD)	32	0	32
CNVM (myopia)	2,607	1,353	3,960
CNVM (POHS)	1,259	155	1,414
CNVM (inflammatory)	488	0	488
CNVM (AS)	330	329	659
CNVM (PIC)	27	15	42
CNVM (MCP)	82	0	82
CNVM (idiopathic)	170	56	226
CNVM (various)	112	203	315
DME	5,566	13,109	18,675
CME (post ERM peel)	12	0	12
CME (uveitic)	146	26	172
CME (PCIOL)	79	0	79
CME (RP)	0	15	15
CRVO	2,183	1,214	3,397
BRVO	3,622	2,291	5,913
RVO	1,097	544	1,641
RAM	16	0	16
PDR	757	20	777
NVI (PDR)	12	0	12
NVI (various)	57	0	57
CSR	101	72	173
FMVD	0	126	126
IMT	77	180	257
Radiation retinopathy	431	0	431
NAION	17	0	17
NVG	0	71	71
Various	122,911	163,639	286,550

Abbreviations: exAMD, exudative age-related macular degeneration; PED, pigment epithelial detachment; PCV, polypoidal choroidal vasculopathy; RAP, retinal angiomatous proliferation; CNVM, choroidal neovascular membrane; PD, pattern dystrophy; POHS, presumed ocular histoplasmosis syndrome; AS, angioid streaks; PIC, punctate inner choroidopathy; MCP, multifocal choroiditis and panuveitis; DME, diabetic macular edema; CME, cystoid macular edema; ERM, epiretinal membrane; PCIOL, posterior chamber intraocular lens; RP, retinitis pigmentosa; CRVO, central retinal vein occlusion; BRVO, branch RVO; RAM, retinal arterial macroaneurysm; PDR, proliferative diabetic retinopathy; NVI, neovascularization of the iris; CSR, central serous chorioretinopathy; FMVD, foveomacular vitelliform dystrophy; IMT, idiopathic macular telangiectasia; NAION, nonarteritic ischemic optic neuropathy; NVG, neovascular glaucoma.

Table 2 Percentage of papers positively reporting specific perioperative techniques

	Bevacizumab	Ranibizumab	RRa (95% CI)
Povidone iodine	69.00%	52.30%	1.00 (0.99–1.01) P=0.9617
Antibiotics	50.90%	48.00%	0.96 (0.94–0.97) P<0.0001
Lid speculum	33.70%	24.00%	1.00 (0.98–1.02) P=0.9617
Mask	6.80%	6.30%	1.00 (0.96–1.05) P=0.9786
Operating room	7.00%	3.80%	1.00 (0.94–1.08) P=0.9308

Notes:

a Calculated with the random-effect model with Wald P-values comparing the reporting between drugs. Percentages are the proportion of injections for which the technique was positively reported.

Abbreviations: RR, relative risk; CI, confidence interval.

Table 3 Overall occurrence of postinjection endophthalmitis cases by perioperative technique

	Injections	Cases	Riskc (%)	Relative riskd (95% CI)
Povidone iodine
Reporteda	262,361	105	0.040%
Not reportedb	183,142	77	0.042%	1.09 (0.60–1.99) P=0.7594
Antibiotic
Reported	218,975	94	0.043%
Not reported	226,528	88	0.039%	0.67 (0.43–1.05) P=0.0690
Speculum
Reported	124,052	55	0.044%
Not reported	321,451	127	0.040%	0.74 (0.39–1.38) P=0.3137
Mask
Reported	28,799	4	0.014%
Not reported	416,704	178	0.043%	2.39 (0.62–9.31) P=0.1487
Operating room
Reported	22,564	5	0.022%
Not reported	422,939	177	0.042%	2.30 (0.64–8.36) P=0.1358

Notes:

a Perioperative technique was reported to be used;

b perioperative technique was either not used or use was unspecified;

c risk of developing endophthalmitis;

d relative risk calculated with random-effect model with Wald P-values.

Abbreviation: CI, confidence interval.

Table 4 Occurrence of culture-positive postinjection endophthalmitis cases

	Injections	Cases	Riskc (%)	Relative riskd (95% CI)
Drug
Ranibizumab	269,379	24	0.011%
Bevacizumab	176,124	30	0.017%	1.11 (0.55–2.26) P=0.7512
Year of publication
2013	181,630	15	0.008%	1.00 (reference)
2012	67,727	7	0.013%	2.11 (0.23–19.59)
2011	34,684	3	0.011%	1.98 (0.16–24.00)
2010	41,989	4	0.010%	2.87 (0.26–31.54)
2009	47,268	8	0.028%	5.11 (0.63–41.15)
2008	56,636	15	0.030%	7.88 (0.94–66.01)
2007	3,832	2	0.066%	14.60 (1.01–209.52)
2006	11,737	0	0	0 P=0.2556
Study type
Prospective	109,541	7	0.010%
Retrospective	335,962	47	0.014%	2.89 (0.49–16.97) P=0.1060
Povidone iodine
Reporteda	262,361	42	0.016%
Not reportedb	183,142	12	0.007%	0.55 (0.12–2.40) P=0.3153
Antibiotic
Reported	218,975	41	0.019%
Not reported	226,528	13	0.006%	0.37 (0.14–0.94) P=0.0207
Speculum
Reported	124,052	25	0.021%
Not reported	321,451	29	0.009%	0.35 (0.09–1.39) P=0.0778
Mask
Reported	28,799	0	0	–
Not reported	416,704	54	0.013%	–
Operating room
Reported	22,564	0	0	–
Not reported	422,939	54	0.013%	–

Notes:

a Perioperative technique was reported to be used;

b perioperative technique was either not used or use was unspecified;

c risk of endophthalmitis adjusted for the difference in culture rates between groups;

d random-effect model with Wald P-values.

Abbreviation: CI, confidence interval.

Table 5 Occurrence of culture-negative postinjection endophthalmitis cases

	Injections	Cases	Riskc (%)	Relative riskd (95% CI)
Drug
Ranibizumab	269,379	33	0.015%
Bevacizumab	176,124	64	0.036%	2.12 (1.26–3.57) P=0.0026
Year of publication
2013	181,630	36	0.020%	1.00 (reference)
2012	67,727	17	0.032%	1.16 (0.16–8.16)
2011	34,684	4	0.014%	0.38 (0.03–5.45)
2010	41,989	25	0.062%	1.45 (0.15–13.66)
2009	47,268	4	0.014%	0.74 (0.07–7.52)
2008	56,636	6	0.012%	0.81 (0.07–72.63)
2007	3,832	1	0.033%	1.83 (0.05–72.63)
2006	11,737	4	0.040%	2.07 (0.05–87.13) P=0.9266
Study type
Prospective	109,541	14	0.021%
Retrospective	335,962	83	0.025%	1.89 (0.41–8.72) P=0.2787
Povidone iodine
Reporteda	262,361	48	0.018%
Not reportedb	183,142	49	0.029%	1.46 (0.36–5.90) P=0.4948
Antibiotic
Reported	218,975	40	0.018%
Not reported	226,528	57	0.027%	0.64 (0.32–1.29) P=0.1844
Speculum
Reported	124,052	20	0.016%
Not reported	321,451	77	0.024%	0.84 (0.19–3.82) P=0.7806
Mask
Reported	28,799	2	0.012%
Not reported	416,704	95	0.023%	1.36 (0.09–2.06) P=0.0868
Operating room
Reported	22,564	1	0.019%
Not reported	422,939	96	0.023%	4.08 (0.11–156.18) P=0.2415

Notes:

a Perioperative technique was reported to be used;

b perioperative technique was either not used or use was unspecified;

c risk of endophthalmitis adjusted for the difference in culture rates between groups;

d random-effect model with Wald P-values.

Abbreviation: CI, confidence interval.

Table 6 Endophthalmitis risk in the US and Europe

	US	Europe	RR (95% CI)a
Injections	172,991	119,477
Endophthalmitis cases	80	33
Riskb	0.046%	0.028%	1.25 (0.44–3.52) P=0.5402
Cases cultured	96.25%	63.64%
Culture-positive cases	22	8
Culture^+ riskb	0.013%	0.007%	1.94 (0.24–15.74) P=0.3868
Normalized riskc	0.013%	0.010%	–
Culture-negative cases	55	13
Culture^− riskb	0.032%	0.011%	2.05 (0.44–9.49) P=0.2323
Normalized riskc	0.032%	0.016%	–

Notes:

a Random-effect model with Wald P-values comparing the risk of endophthalmitis between geographic areas (it is not possible to use this model with normalized risks);

b occurrence of endophthalmitis;

c risk of endophthalmitis adjusted for the difference in culture rates between groups.

Abbreviations: RR, relative risk; CI, confidence interval.

Table 7 Organisms identified from culture-positive endophthalmitis

	Bevacizumab	Ranibizumab
Total endophthalmitis	103	79
Cultured	94	57
No growth	64	33
Staphylococcus epidermidis	4	6
Coagulase-negative Staphylococcus	8	1
Staphylococcus aureus	2	1
Total Staphylococcus spp.	14	8
Streptococcus viridans	1	2
Streptococcus salivarius	0	1
Streptococcus oralis	1	0
Streptococcus mitis	0	1
Streptococcus (unspecified)	2	1
Total Streptococcus spp.	4	5
Enterococcus faecalis	1	0
Haemophilus influenzae	1	0
Haemophilus (unspecified)	1	0
Unknown organism	5	11
Propionibacterium acnes	2	0

Table 8 Factors influencing the risk of postinjection endophthalmitis (prospective data)

	Injections	Cases	Riskc (%)	Relative riskd (95% CI)
Drug
Ranibizumab	114,135	51	0.045%
Bevacizumab	36,742	13	0.035%	0.62 (0.29–1.32) P=0.1740e
Year of publication
2013	22,932	8	0.035%	1.00 (reference)
2012	53,610	28	0.052%	1.21 (0.43–3.37)
2011	18,454	2	0.011%	0.29 (0.05–1.68)
2010	8,848	3	0.034%	0.70 (0.14–3.52)
2009	29,202	10	0.034%	0.76 (0.21–2.74)
2008	4,175	1	0.024%	0.57 (0.05–6.13)
2007	1,330	1	0.075%	1.97 (0.19–20.17)
2006	12,326	11	0.089%	3.71 (1.02–13.49) P=0.1212e
Povidone iodine
Reporteda	47,001	22	0.047%
Not reportedb	103,876	42	0.040%	0.95 (0.39–2.30) P=0.8996
Antibiotic
Reported	42,550	22	0.052%
Not reported	108,327	42	0.039%	0.70 (0.30–1.64) P=0.4060
Speculum
Reported	32,173	16	0.050%
Not reported	118,704	48	0.040%	0.70 (0.24–2.00) P=0.4753
Mask
Reported	4,689	0	0	–
Not reported	146,188	64	0.044%	–
Operating room
Reported	6,585	0	0	–
Not reported	144,292	64	0.044%	–
Culture-positive cases
Bevacizumab	114,135	0	0	–
Ranibizumab	36,742	12	0.033%	–
Culture-negative cases
Bevacizumab	114,135	4	0.004%
Ranibizumab	36,742	14	0.038%	0.16 (0.00–4.32) P=0.1436

Notes:

a Perioperative technique was reported to be used;

b perioperative technique was either not used or use was unspecified;

c occurrence of endophthalmitis;

d random-effect model with Wald P-values except where indicated;

e log-likelihood comparison.

Abbreviation: CI, confidence interval.

Figure S1 Endophthalmitis risk by year.

Table S1 Number of intravitreal injections by region/country

	Bevacizumab	Ranibizumab	Total
Asia	0	979	979
Australia	3,040	2,624	5,664
Austria	3,514	4,095	7,609
Belgium	120	178	298
Bosnia and Herzegovina	225	0	225
Brazil	444	20	464
Canada	8,756	11,188	19,944
People’s Republic of China	3,678	717	4,395
Croatia	142	36	178
Czech Republic	90	0	90
Denmark	106	7,990	8,096
Egypt	281	225	506
Europe	91	1,701	1,792
France	1,361	4,456	5,817
Germany	5,444	844	6,288
Greece	1,589	1,869	3,458
India	1,603	376	1,979
Iran	6,946	0	6,946
Ireland	188	0	188
Israel	2,828	0	2,828
Italy	2,600	1,348	3,948
Japan	5,507	20,840	26,347
Jordan	60	0	60
Lebanon	1,534	179	1,713
Mexico	0	91	91
Nepal	196	0	196
Netherlands	1,794	0	1,794
North America	12,585	14,320	26,905
Norway	0	65	65
Oman	17	0	17
Poland	232	162	394
Portugal	503	662	1,165
Saudi Arabia	11	0	11
Singapore	29	183	212
Slovenia	760	0	760
South Korea	6,223	2,213	8,436
Spain	2,739	6,586	9,325
Sweden	538	1,665	2,203
Switzerland	3,807	41,873	45,680
Taiwan	746	100	846
Thailand	29	76	105
Tunisia	267	0	267
Turkey	5,808	626	6,434
UK	4,688	8,982	13,670
US	78,819	94,172	172,991
Multiple	6,186	37,938	44,124

Notes: Multicenter trials involving countries from a single continent are grouped by region. Multicenter trials involving countries from multiple continents are grouped under “Multiple”.