<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02223338</url>
  </required_header>
  <id_info>
    <org_study_id>5140215</org_study_id>
    <nct_id>NCT02223338</nct_id>
  </id_info>
  <brief_title>Bacterial Resistance in Patients Receiving Post-Intravitreal Injection Antibiotics</brief_title>
  <official_title>Conjunctival Floral Resistance in a Single Practice Site Comparing Povidone- Iodine Prep With or Without Post-Intravitreal Injection Second Generation Fluoroquinolones.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Loma Linda University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Loma Linda University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      1. Background: Over 1 million intravitreal injections are performed annually in the United&#xD;
           States. The most devastating complication related to these injections is&#xD;
           endophthalmitis, with an incidence of 0.02 - 0.1% per injection. Techniques aimed at&#xD;
           prevention of this complication have been studied, though emergence rates of antibiotic&#xD;
           resistant bacteria in a single clinic population comparing antiseptic technique with&#xD;
           iodine vs. use of post-injection second generation fluoroquinolones has not been&#xD;
           reported in the literature.&#xD;
&#xD;
        2. Objectives: The purpose of the study is to help determine the best way to prevent&#xD;
           infection and limit antibiotic resistance in patients receiving eye injections.&#xD;
&#xD;
        3. Procedures Involved (Research Interventions): After the patient is chosen based on&#xD;
           inclusion criteria and agrees to participate in the study, exclusion criteria will be&#xD;
           reviewed, cognizance will be determined, informed consent and HIPAA compliance forms&#xD;
           will be signed. At this point and prior to the instillation of ophthalmic medications, a&#xD;
           Rayon swab will be passed along the inferior fornix of the study eye while the patient&#xD;
           looks up and the examiner lowers the lower eyelid. The swab will then be used to&#xD;
           inoculate chocolate agar and a blood agar culture plates and a glass slide. These will&#xD;
           be brought to the FMO microbiology department for culture and Gram stain. All&#xD;
           Staphylococcus aureus and coagulase negative Staphylococcus species identified will be&#xD;
           subjected to sensitivity testing using the Gram Positive antibiotic panel available at&#xD;
           Loma Linda, with the addition of ciprofloxacin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Previous studies have demonstrated that bacteria in the eye may become resistant to&#xD;
      antibiotics used after injections when compared to the bacteria found in untreated eyes.&#xD;
      However, no study published to date compares resistance rates in eyes where an iodine-based&#xD;
      preparation is used, which is standard of care, to those in which an antibiotic is also given&#xD;
      after the injection in a single practice setting. This is an important issue, because&#xD;
      resistant bacteria can cause infections that are more damaging and difficult to treat than&#xD;
      non-resistant bacteria. Moreover, previous studies have focused on the emergence of&#xD;
      resistance to fourth generation fluoroquinolones including moxifloxacin and gatifloxacin,&#xD;
      though use of second generation fluoroquinolones is still practiced in the United States by&#xD;
      some retina specialists, including at the investigators institution. Currently in the United&#xD;
      States, 81% of retina specialists give antibiotics after eye injections, although the results&#xD;
      of several large studies suggest that this practice does not reduce rates of endophthalmitis&#xD;
      compared with use of iodine alone.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">May 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Screening</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Resistance of Ocular Flora to Commonly Used Post-injection Prophylactic Antibiotics</measure>
    <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.</time_frame>
    <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 &quot;S&quot; for susceptible, &quot;I&quot; for Intermediate and &quot;R&quot; for Resistance based on the Clinical and Laboratory Standards Institute (CLSI) guidelines.&#xD;
Ciprofloxacin will be tested using the Biomerieux &quot;E test&quot; 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 &quot;S&quot;, &quot;I&quot; or &quot;R&quot;.&#xD;
For information on other antibiotics to be tested, please contact the investigator or provide more characters for input.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Average Number of Antibiotics to Which Isolated Organisms Were Resistant</measure>
    <time_frame>Through study completion, average of 4 weeks</time_frame>
    <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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Bacterial Resistance</condition>
  <arm_group>
    <arm_group_label>Ciprofloxacin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Ciprofloxacin:&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Aseptic Technique</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard Aseptic Technique:&#xD;
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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ciprofloxacin</intervention_name>
    <description>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.</description>
    <arm_group_label>Ciprofloxacin</arm_group_label>
    <other_name>ciloxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard Aseptic Technique</intervention_name>
    <description>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.</description>
    <arm_group_label>Standard Aseptic Technique</arm_group_label>
    <other_name>betadyne</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with choroidal neovascularization due to wet age-related macular degeneration&#xD;
             or any other cause, clinically significant macular edema or cystoid macular edema over&#xD;
             age 18 who have been treated with at least 3 monthly intravitreal injections of an&#xD;
             anti-Vascular Endothelial Growth Factor (anti-VEGF) agent in the last 6 months. These&#xD;
             injections must have been given in either Dr. Fan's clinic using povidone-iodine and&#xD;
             post-injection topical ciprofloxacin 0.3% 4x daily for 3 days, or in Dr. Rauser's&#xD;
             clinic where povidone-iodine only is applied to the injection site and conjunctival&#xD;
             fornix but no post-injection antibiotics are given.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Administration of anti-VEGF agents outside of Dr. Fan's or Dr. Rauser's clinics&#xD;
&#xD;
          -  Intraocular surgery&#xD;
&#xD;
          -  Use of topical antibiotics other than ciprofloxacin 0.3%&#xD;
&#xD;
          -  Infections of the eye or ocular adnexa within the last 3 months&#xD;
&#xD;
          -  Use of oral antibiotics within the last 30 days&#xD;
&#xD;
          -  Contact lens wear.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Rauser, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Loma Linda University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Loma Linda University of Health Sciences Faculty Medical Offices</name>
      <address>
        <city>Loma Linda</city>
        <state>California</state>
        <zip>92354</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>21330939</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21836400</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21420176</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21911665</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>11237900</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>16606872</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21168821</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>21659941</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>22480743</PMID>
  </reference>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>July 28, 2014</study_first_submitted>
  <study_first_submitted_qc>August 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2014</study_first_posted>
  <results_first_submitted>August 6, 2017</results_first_submitted>
  <results_first_submitted_qc>October 29, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">November 7, 2017</results_first_posted>
  <last_update_submitted>October 29, 2017</last_update_submitted>
  <last_update_submitted_qc>October 29, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 7, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Loma Linda University</investigator_affiliation>
    <investigator_full_name>David Sierpina</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ciprofloxacin</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Ciprofloxacin</title>
          <description>Ciprofloxacin:&#xD;
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.&#xD;
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.</description>
        </group>
        <group group_id="P2">
          <title>Standard Aseptic Technique</title>
          <description>Standard Aseptic Technique:&#xD;
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.&#xD;
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.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="60"/>
                <participants group_id="P2" count="60"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="60"/>
                <participants group_id="P2" count="60"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Ciprofloxacin</title>
          <description>Ciprofloxacin:&#xD;
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.&#xD;
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.</description>
        </group>
        <group group_id="B2">
          <title>Standard Aseptic Technique</title>
          <description>Standard Aseptic Technique:&#xD;
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.&#xD;
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.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="60"/>
            <count group_id="B2" value="60"/>
            <count group_id="B3" value="120"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="89"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="69.78" spread="12.99"/>
                    <measurement group_id="B2" value="74.68" spread="13.96"/>
                    <measurement group_id="B3" value="72.23" spread="13.65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="37"/>
                    <measurement group_id="B3" value="72"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60"/>
                    <measurement group_id="B2" value="60"/>
                    <measurement group_id="B3" value="120"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Resistance of Ocular Flora to Commonly Used Post-injection Prophylactic Antibiotics</title>
        <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 &quot;S&quot; for susceptible, &quot;I&quot; for Intermediate and &quot;R&quot; for Resistance based on the Clinical and Laboratory Standards Institute (CLSI) guidelines.&#xD;
Ciprofloxacin will be tested using the Biomerieux &quot;E test&quot; 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 &quot;S&quot;, &quot;I&quot; or &quot;R&quot;.&#xD;
For information on other antibiotics to be tested, please contact the investigator or provide more characters for input.</description>
        <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.</time_frame>
        <population>All culture positive samples growing Staphylococcus aureus or coagulase negative Staphylococcus species.</population>
        <group_list>
          <group group_id="O1">
            <title>Ciprofloxacin</title>
            <description>Ciprofloxacin:&#xD;
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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Standard Aseptic Technique</title>
            <description>Standard Aseptic Technique:&#xD;
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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Resistance of Ocular Flora to Commonly Used Post-injection Prophylactic Antibiotics</title>
          <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 &quot;S&quot; for susceptible, &quot;I&quot; for Intermediate and &quot;R&quot; for Resistance based on the Clinical and Laboratory Standards Institute (CLSI) guidelines.&#xD;
Ciprofloxacin will be tested using the Biomerieux &quot;E test&quot; 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 &quot;S&quot;, &quot;I&quot; or &quot;R&quot;.&#xD;
For information on other antibiotics to be tested, please contact the investigator or provide more characters for input.</description>
          <population>All culture positive samples growing Staphylococcus aureus or coagulase negative Staphylococcus species.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Average Number of Antibiotics to Which Isolated Organisms Were Resistant</title>
        <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.</description>
        <time_frame>Through study completion, average of 4 weeks</time_frame>
        <population>All isolates of coagulase negative Staphylococcus and Staphylococcus aureus</population>
        <group_list>
          <group group_id="O1">
            <title>Ciprofloxacin</title>
            <description>Ciprofloxacin:&#xD;
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.&#xD;
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.</description>
          </group>
          <group group_id="O2">
            <title>Standard Aseptic Technique</title>
            <description>Standard Aseptic Technique:&#xD;
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.&#xD;
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.</description>
          </group>
        </group_list>
        <measure>
          <title>Average Number of Antibiotics to Which Isolated Organisms Were Resistant</title>
          <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.</description>
          <population>All isolates of coagulase negative Staphylococcus and Staphylococcus aureus</population>
          <units>antibiotics</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.44" spread="4.29"/>
                    <measurement group_id="O2" value="3.23" spread="3.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 week</time_frame>
      <desc>Data was collected on patients returning to clinic with complaints relating to the study procedure of collecting a conjunctival swab.</desc>
      <group_list>
        <group group_id="E1">
          <title>Ciprofloxacin</title>
          <description>Ciprofloxacin:&#xD;
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.&#xD;
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.</description>
        </group>
        <group group_id="E2">
          <title>Standard Aseptic Technique</title>
          <description>Standard Aseptic Technique:&#xD;
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.&#xD;
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.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. David Sierpina</name_or_title>
      <organization>Loma Linda University</organization>
      <phone>9095582154</phone>
      <email>dsierpina@llu.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02223338
org study id: 5140215
nct id: NCT02223338
lead sponsor: 
has dmc: No
1. Background: Over 1 million intravitreal injections are performed annually in the United
           States. The most devastating complication related to these injections is
           endophthalmitis, with an incidence of 0.02 - 0.1% per injection. Techniques aimed at
           prevention of this complication have been studied, though emergence rates of antibiotic
           resistant bacteria in a single clinic population comparing antiseptic technique with
           iodine vs. use of post-injection second generation fluoroquinolones has not been
           reported in the literature.

        2. Objectives: The purpose of the study is to help determine the best way to prevent
           infection and limit antibiotic resistance in patients receiving eye injections.

        3. Procedures Involved (Research Interventions): After the patient is chosen based on
           inclusion criteria and agrees to participate in the study, exclusion criteria will be
           reviewed, cognizance will be determined, informed consent and HIPAA compliance forms
           will be signed. At this point and prior to the instillation of ophthalmic medications, a
           Rayon swab will be passed along the inferior fornix of the study eye while the patient
           looks up and the examiner lowers the lower eyelid. The swab will then be used to
           inoculate chocolate agar and a blood agar culture plates and a glass slide. These will
           be brought to the FMO microbiology department for culture and Gram stain. All
           Staphylococcus aureus and coagulase negative Staphylococcus species identified will be
           subjected to sensitivity testing using the Gram Positive antibiotic panel available at
           Loma Linda, with the addition of ciprofloxacin.
Previous studies have demonstrated that bacteria in the eye may become resistant to
      antibiotics used after injections when compared to the bacteria found in untreated eyes.
      However, no study published to date compares resistance rates in eyes where an iodine-based
      preparation is used, which is standard of care, to those in which an antibiotic is also given
      after the injection in a single practice setting. This is an important issue, because
      resistant bacteria can cause infections that are more damaging and difficult to treat than
      non-resistant bacteria. Moreover, previous studies have focused on the emergence of
      resistance to fourth generation fluoroquinolones including moxifloxacin and gatifloxacin,
      though use of second generation fluoroquinolones is still practiced in the United States by
      some retina specialists, including at the investigators institution. Currently in the United
      States, 81% of retina specialists give antibiotics after eye injections, although the results
      of several large studies suggest that this practice does not reduce rates of endophthalmitis
      compared with use of iodine alone.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Screening
masking: None (Open Label)
measure: Number of Participants With Resistance of Ocular Flora to Commonly Used Post-injection Prophylactic Antibiotics
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.
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.
measure: Average Number of Antibiotics to Which Isolated Organisms Were Resistant
time frame: Through study completion, average of 4 weeks
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.
arm group label: Ciprofloxacin
arm group type: Active Comparator
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.
arm group label: Standard Aseptic Technique
arm group type: Active Comparator
description: 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.
intervention type: Drug
intervention name: Ciprofloxacin
description: 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.
arm group label: Ciprofloxacin
other name: ciloxan
intervention type: Drug
intervention name: Standard Aseptic Technique
description: 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.
arm group label: Standard Aseptic Technique
other name: betadyne
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Rauser, MD
role: Principal Investigator
affiliation: Loma Linda University
facility: 
country: United States
citation: 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.
PMID: 21330939
citation: 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.
PMID: 21836400
citation: 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.
PMID: 21420176
citation: 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.
PMID: 21911665
citation: 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.
PMID: 11237900
citation: 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.
PMID: 16606872
citation: 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.
PMID: 21168821
citation: 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.
PMID: 21659941
citation: 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.
PMID: 22480743
responsible party type: Principal Investigator
investigator affiliation: Loma Linda University
investigator full name: David Sierpina
investigator title: MD
mesh term: Ciprofloxacin
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 