Bacterial Resistance in Patients Receiving Post-Intravitreal Injection Antibiotics

• ClinicalTrials.gov Identifier: NCT02223338
• Recruitment Status: Completed
• First Posted: August 22, 2014
• Results First Posted: November 7, 2017
• Last Update Posted: November 7, 2017
• Sponsor: Loma Linda University
• Information provided by (Responsible Party): David Sierpina, Loma Linda University

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Screening
• Condition: Bacterial Resistance
• Interventions: Drug: Ciprofloxacin; Drug: Standard Aseptic Technique
• Enrollment: 120

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Ciprofloxacin	Standard Aseptic Technique
Arm/Group Description	Ciprofloxacin: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These patients must have been instructed to use post-injection topical ciprofloxacin 0.3% 4x daily for 3 days. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Ciprofloxacin: Use of topical ciprofloxacin 4x daily for 3 days after intravitreal injection using standard aseptic techniques with Povidone-Iodine is a common practice intervention in the United States, and is thought by some to reduce the risk of post-injection endophthalmitis.	Standard Aseptic Technique: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These injections must have been given with povidone-iodine only applied to the injection site and conjunctival fornix prior to injection, but no post-injection antibiotics were given. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Standard Aseptic Technique: Patients in this group will have received Povidone-Iodine Only following injections of anti-VEGF agents at least 3 times in the last 6 months.
Period Title: Overall Study
Started	60	60
Completed	60	60
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Ciprofloxacin	Standard Aseptic Technique	Total
Arm/Group Description		Ciprofloxacin: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These patients must have been instructed to use post-injection topical ciprofloxacin 0.3% 4x daily for 3 days. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Ciprofloxacin: Use of topical ciprofloxacin 4x daily for 3 days after intravitreal injection using standard aseptic techniques with Povidone-Iodine is a common practice intervention in the United States, and is thought by some to reduce the risk of post-injection endophthalmitis.	Standard Aseptic Technique: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These injections must have been given with povidone-iodine only applied to the injection site and conjunctival fornix prior to injection, but no post-injection antibiotics were given. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Standard Aseptic Technique: Patients in this group will have received Povidone-Iodine Only following injections of anti-VEGF agents at least 3 times in the last 6 months.	Total of all reporting groups
Overall Number of Baseline Participants		60	60	120
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants	60 participants	120 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	19 31.7%	12 20.0%	31 25.8%
	>=65 years	41 68.3%	48 80.0%	89 74.2%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	60 participants	60 participants	120 participants
		69.78 (12.99)	74.68 (13.96)	72.23 (13.65)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants	60 participants	120 participants
	Female	35 58.3%	37 61.7%	72 60.0%
	Male	25 41.7%	23 38.3%	48 40.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	60 participants	60 participants	120 participants
		60	60	120

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Resistance of Ocular Flora to Commonly Used Post-injection Prophylactic Antibiotics
Description	Resistance of all coagulase negative staph and staph aureus species to a panel of commonly used antibiotics will be determined and compared between groups. Resistance will be measured using minimum inhibitory concentrations which will be tested on the Siemens MicroScan instrument by doubling broth dilutions. Antibiotic susceptibility interpretations using the categories "S" for susceptible, "I" for Intermediate and "R" for Resistance based on the Clinical and Laboratory Standards Institute (CLSI) guidelines. Ciprofloxacin will be tested using the Biomerieux "E test" strip. The test directly quantifies antimicrobial susceptibility in terms of discrete MIC values on a continuous gradient strip. The MIC values are also based on the CLSI guidelines giving interpretations of "S", "I" or "R". For information on other antibiotics to be tested, please contact the investigator or provide more characters for input.
Time Frame	Cultured organisms will be subjected to resistance panels once they have grown and been identified. Cultures will be followed for 7 days total, and if no growth is recorded at that time they will be considered sterile.

Outcome Measure Data

Analysis Population Description

All culture positive samples growing Staphylococcus aureus or coagulase negative Staphylococcus species.

Arm/Group Title	Ciprofloxacin	Standard Aseptic Technique
Arm/Group Description:	Ciprofloxacin: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These patients must have been instructed to use post-injection topical ciprofloxacin 0.3% 4x daily for 3 days. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Ciprofloxacin: Use of topical ciprofloxacin 4x daily for 3 days after intravitreal injection using standard aseptic techniques with Povidone-Iodine is a common practice intervention in the United States, and is thought by some to reduce the risk of post-injection endophthalmitis.	Standard Aseptic Technique: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These injections must have been given with povidone-iodine only applied to the injection site and conjunctival fornix prior to injection, but no post-injection antibiotics were given. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Standard Aseptic Technique: Patients in this group will have received Povidone-Iodine Only following injections of anti-VEGF agents at least 3 times in the last 6 months.
Overall Number of Participants Analyzed	18	22
Measure Type: Count of Participants; Unit of Measure: Participants
	10 55.6%	6 27.3%

2. Secondary Outcome

Title	Average Number of Antibiotics to Which Isolated Organisms Were Resistant
Description	Average number of antibiotics to which isolated organisms were resistant, isolated organisms include only coagulase negative Staphylococcus species and Staphylococcus aureus. Antibiotics are those described in the methods section.
Time Frame	Through study completion, average of 4 weeks

Outcome Measure Data

Analysis Population Description

All isolates of coagulase negative Staphylococcus and Staphylococcus aureus

Arm/Group Title	Ciprofloxacin	Standard Aseptic Technique
Arm/Group Description:	Ciprofloxacin: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These patients must have been instructed to use post-injection topical ciprofloxacin 0.3% 4x daily for 3 days. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Ciprofloxacin: Use of topical ciprofloxacin 4x daily for 3 days after intravitreal injection using standard aseptic techniques with Povidone-Iodine is a common practice intervention in the United States, and is thought by some to reduce the risk of post-injection endophthalmitis.	Standard Aseptic Technique: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These injections must have been given with povidone-iodine only applied to the injection site and conjunctival fornix prior to injection, but no post-injection antibiotics were given. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Standard Aseptic Technique: Patients in this group will have received Povidone-Iodine Only following injections of anti-VEGF agents at least 3 times in the last 6 months.
Overall Number of Participants Analyzed	18	22
Mean (Standard Deviation); Unit of Measure: antibiotics
	5.44 (4.29)	3.23 (3.66)

Adverse Events

Time Frame	1 week
Adverse Event Reporting Description	Data was collected on patients returning to clinic with complaints relating to the study procedure of collecting a conjunctival swab.
Arm/Group Title	Ciprofloxacin	Standard Aseptic Technique
Arm/Group Description	Ciprofloxacin: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These patients must have been instructed to use post-injection topical ciprofloxacin 0.3% 4x daily for 3 days. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Ciprofloxacin: Use of topical ciprofloxacin 4x daily for 3 days after intravitreal injection using standard aseptic techniques with Povidone-Iodine is a common practice intervention in the United States, and is thought by some to reduce the risk of post-injection endophthalmitis.	Standard Aseptic Technique: Patients with choroidal neovascularization due to wet age-related macular degeneration or any other cause, clinically significant macular edema or cystoid macular edema over age 18 who have been treated with at least 3 monthly intravitreal injections of an anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These injections must have been given with povidone-iodine only applied to the injection site and conjunctival fornix prior to injection, but no post-injection antibiotics were given. On the visit of their next injection, a conjunctival swab will be taken in the inferior fornix prior to instillation of any ophthalmic drops. Standard Aseptic Technique: Patients in this group will have received Povidone-Iodine Only following injections of anti-VEGF agents at least 3 times in the last 6 months.
All-Cause Mortality
	Ciprofloxacin	Standard Aseptic Technique
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/60 (0.00%)	0/60 (0.00%)
Serious Adverse Events
	Ciprofloxacin	Standard Aseptic Technique
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/60 (0.00%)	0/60 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Ciprofloxacin	Standard Aseptic Technique
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/60 (0.00%)	0/60 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. David Sierpina
• Organization: Loma Linda University
• Phone: 9095582154
• EMail: dsierpina@llu.edu

Publications:

McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011 Apr;31(4):654-61. doi: 10.1097/IAE.0b013e31820a67e4.

Moshfeghi AA, Rosenfeld PJ, Flynn HW Jr, Schwartz SG, Davis JL, Murray TG, Smiddy WE, Berrocal AM, Dubovy SR, Lee WH, Albini TA, Lalwani GA, Kovach JL, Puliafito CA. Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center. Retina. 2011 Apr;31(4):662-8. doi: 10.1097/IAE.0b013e31821067c4. Erratum In: Retina. 2012 Jul;32(7):1441.

Kim SJ, Toma HS. Ophthalmic antibiotics and antimicrobial resistance a randomized, controlled study of patients undergoing intravitreal injections. Ophthalmology. 2011 Jul;118(7):1358-63. doi: 10.1016/j.ophtha.2010.12.014. Epub 2011 Mar 21.

Kim SJ, Toma HS. Antimicrobial resistance and ophthalmic antibiotics: 1-year results of a longitudinal controlled study of patients undergoing intravitreal injections. Arch Ophthalmol. 2011 Sep;129(9):1180-8. doi: 10.1001/archophthalmol.2011.213.

Mino De Kaspar H, Hoepfner AS, Engelbert M, Thiel M, Ta CN, Mette M, Schulze-Schwering M, Grasbon T, Sesma-Vea B, Casas JM, Iturralde-Goni R, Klauss V, Kampik A. Antibiotic resistance pattern and visual outcome in experimentally-induced Staphylococcus epidermidis endophthalmitis in a rabbit model. Ophthalmology. 2001 Mar;108(3):470-8. doi: 10.1016/s0161-6420(00)00545-5.

Miller D, Flynn PM, Scott IU, Alfonso EC, Flynn HW Jr. In vitro fluoroquinolone resistance in staphylococcal endophthalmitis isolates. Arch Ophthalmol. 2006 Apr;124(4):479-83. doi: 10.1001/archopht.124.4.479.

Green-Simms AE, Ekdawi NS, Bakri SJ. Survey of intravitreal injection techniques among retinal specialists in the United States. Am J Ophthalmol. 2011 Feb;151(2):329-32. doi: 10.1016/j.ajo.2010.08.039. Epub 2010 Dec 18.

Bhatt SS, Stepien KE, Joshi K. Prophylactic antibiotic use after intravitreal injection: effect on endophthalmitis rate. Retina. 2011 Nov;31(10):2032-6. doi: 10.1097/IAE.0b013e31820f4b4f.

Cheung CS, Wong AW, Lui A, Kertes PJ, Devenyi RG, Lam WC. Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology. 2012 Aug;119(8):1609-14. doi: 10.1016/j.ophtha.2012.02.014. Epub 2012 Apr 4.

• Responsible Party: David Sierpina, Loma Linda University
• ClinicalTrials.gov Identifier: NCT02223338
• Other Study ID Numbers: 5140215
• First Submitted: July 28, 2014
• First Posted: August 22, 2014
• Results First Submitted: August 6, 2017
• Results First Posted: November 7, 2017
• Last Update Posted: November 7, 2017