Comparison of Safety and Efficacy of Intrastromal Injections of Voriconazole, Amphotericin B and Natamycin in Cases of Recalcitrant Fungal Keratitis: A Randomized Controlled Trial

Figures & data

Figure 1 Participant flow diagram.

Table 1 Baseline Demographic, Microbiological and Clinical Characteristics of All Three Groups

Drug	Age (Years) Mean±SD	Gender Distribution	History of Trauma	Duration of Signs and Symptoms (Mean±SD)	Organism Traced Fu/As/Ca/Al/Cu
ISVCZ (n=20)	43.82±12.3	12M, 8F	12	18.7±6.4days	8/10/0/1/1
ISAMB (n=20)	39.45 ±10.0	14M, 6F	13	20±5.5days	8/10/1/1/0
ISNTM (n=20)	40.42±10.9	14M, 6F	13	20.8±5.1days	8/12/0/0/0
p-value	0.41	0.82	0.8	0.51	0.23

Abbreviations: ISVCZ, intrastromal voriconazole; ISAMB, intrastromal amphotericin; ISNTM, intrastromal natamycin; Fu, Fusarium; AS, Aspergillus; Ca, Candida; Al, Alternaria; Cu, Curvularia.

Table 2 Baseline Features in All Three Groups

Drug	Epithelial Defect	Stromal Infiltrate	Presence of Hypopyon	Height of Hypopyon	Retro Corneal Plaque	Visual Acuity (LogMAR)
	Mean±SD	Mean±SD		Mean±SD		Mean±SD
ISVCZ (n=20)	3.0 ± 1.1	4.0± 1.1	14	1.15±0.49	9/20	2.2±0.3
ISAMB (n=20)	3.5±1.15	4.3±1.05	13	1.13±0.50	8/20	2.3±0.4
ISNTM (n=20)	3.0±1.02	4.1±1.1	13	1.30±0.73	8/20	2.2±0.4
p-value	0.75	0.49	0.8	0.85	0.9	0.70

Abbreviations: ISVCZ, intrastromal voriconazole; ISAMB, intrastromal amphotericin; ISNTM, intrastromal natamycin.

Table 3 Comparison of Post-Treatment Parameters of All Three Groups

Drug	Success Rate		Failure	Overall Repeat Injections	Graft Infection	Duration Till Resolution			Final Scar Size (mm)	Complication
	Overall	With 1st/2nd/3rd Injection				Epithelial Defect	Stromal Infiltrates	Hypopyon		Deep Vessels	Cataract
ISVCZ (n=20)	19 (95%)	12/6/1	1 (5%)	8 (40%)	0/1	36.1±4.8days	35.3±4.3days	18.4±3.1days	2.7±0.5	5 (25%)	14 (70%)
ISAMB (n=20)	18 (90%)	11/5/2	2 (10%)	9 (45%)	1/2	39.2±7.2days	36.8±7.4days	22.3±3.4days	2.8±0.8	10 (50%)	15 (75%)
ISNTM (n=20)	19 (95%)	13/5/1	1 (5%)	7 (35%)	0/1	34±5.2days	35.3±6.4days	15±2.5days	2.6±0.7	6 (30%)	13 (65%)
p-value	0.8	0.8	0.8	0.8	—	0.02	0.41	0.009	0.75	0.02	0.2

Abbreviations: ISVCZ, intrastromal voriconazole; ISAMB, intrastromal amphotericin; ISNTM, intrastromal natamycin.

Figure 2 (A, C and E) Clinical photographs of recalcitrant fungal keratitis at day 0 in voriconazole, natamycin and amphotericin B groups, respectively. (B, D and F) Clinical photographs of cases (depicted in A, C and E) after healing in the voriconazole, natamycin and amphotericin B groups, respectively.

Figure 3 Kaplan–Meier analysis showing the duration of re-epithelialization.

Notes: The Kaplan–Meier curve shown has three intervention groups: ISVCZ, ISAMB and ISNTM. The number of people at risk at time point 0 is 20 in each intervention group. From the p-value (0.02) and hazard ratio (1.44) shown in the graph, it is clear that there is a significant difference between the three intervention groups, with a higher risk of failure in the ISAMB group.

Table 4 Post-Treatment (BCVA) Using ITT and Per-Protocol Analysis Method

Analysis Method	BCVA (logMAR)	ISVCZ^a	ISAMB^b	ISNTM^c	p-value
ITT analysis	Baseline	2.27±0.34	2.24 ±0.40	2.23±0.35	0.9
	Final follow-up	1.2±0.38	1.35±0.47	1.2±0.37	0.54
Per-protocal analysis	Baseline	2.27±0.34	2.24±0.40	2.23±0.35	0.9
	Final follow-up	1.1±0.1	1.1±0.1	1.0±0.1	0.59

Abbreviations: BCVA, Best corrected visual acuity; ITT, intention to treat; ISVCZ^a, intrastromal voriconazole; ISAMB^b, intrastromal amphotericin B; ISNTM^c, intrastromal natamycin.

Table 5 Comparison of BCVA for Central, Paracentral and Peripheral Ulcers (logMAR)

Ulcer Location	ISVCZ	ISAMB	ISNTM	P value
Central	n=2	n=2	n=2
Baseline	2.7±0.22	2.7±0.5	2.5±0.12	0.9
Final follow-up	2.15±0.12	2.7±0.14	2.08±0.13	0.1
Paracentral	n=13	n=14	n=14
Baseline	2.23±0.7	2.3±0.3	2.25±0.34	0.9
Final follow-up	1.28±0.6	1.3±0.5	1.27±0.7	0.7
Peripheral	n=5	n=4	n=4
Baseline	1.74±0.6	1.76± 0.3	1.85±0.4	0.7
Final follow-up	1±0.2	1.12±0.6	0.8±0.3	0.3

Abbreviations: ISVCZ, intrastromal voriconazole; ISAMB, intrastromal amphotericin B; ISNTM, intrastromal natamycin; BCVA, best corrected visual acuity.

Table 6 Clinical Details of Patients with Treatment Failure

Parameters	ISVCZ, n=1	ISAMB, n=2	ISNTM, n=1
Size of epithelial defect (mm)	6*6	5*5.5	5.5*5
		5*4
Hypopyon height (mm)	1	0.5	1
		1.5
BCVA Log MAR	2.7	Case1–2.7	2.3
		Case 2–2.7
Duration of symptoms (days)	30	Case1–15	14
		Case 2–14
Time to failure (days)	3	Case 1–7	3
		Case 2–3
Depth of ulcer	>75%	Case1–75%	3
		Case2 >75%

Abbreviations: ISVCZ, intrastromal voriconazole; ISAMB, intrastromal amphotericin B; ISNTM, intrastromal natamycin.