Experimental Human Infection With Neisseria Gonorrhoeae

Phase 1

Completed

Conditions: Gonococcal Infection

Interventions: Drug: Cefixime
Drug: Ceftriaxone
Drug: Ciprofloxacin
Biological: Neisseria gonorrhoeae strain FA7537
Biological: Neisseria gonorrhoeae strain FA1090 A26

Registration Number: NCT03840811

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: This is a Phase 1, interventional, non-randomized, experimental infection model study with healthy adult males adults (N=32) between the ages of 18-36 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra. The duration for all participants will be about 3 weeks. Study duration will be approximately about 18 months for implementation and enrollment. The primary objectives of the present study are to: (1) compare infectivity of different isogenic mutants with wild-type (WT) N. gonorrhoeae in noncompetitive infections and to (2) assess relative fitness of the mutant in competitive infections initiated by inocula containing equivalent numbers of both WT and mutant strains for mutants with WT infectivity.

Detailed Description: This is a Phase 1, interventional, non-randomized, experimental infection model study with healthy adult males adults (N=32) between the ages of 18-36 at study enrollment. The study is designed to test the requirements of predicted N. gonorrhoeae virulence determinants for gonococcal infection in the male urethra. For each mutant to be investigated under this protocol, groups of subjects will be enrolled first in noncompetitive infection studies: Group 1 (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain, and Group 2 (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain. If primary and secondary outcomes are not different for the isogenic mutant and WT strains, a group of subjects will be enrolled in competitive infection studies: Group 3 (up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain. All subjects will be examined daily for symptoms of infection and receive antibiotic treatment at the end of the inpatient portion of the trial. Within 7 days of antibiotic treatment, subjects will return for a follow-up examination. A final follow-up phone interview will be conducted within 2 weeks of antibiotic treatment. The duration for all participants will be about 3 weeks. Study duration will be approximately about 18 months for implementation and enrollment. The primary objectives of the present study are to: (1) compare infectivity of different isogenic mutants with wild-type (WT) N. gonorrhoeae in noncompetitive infections and to (2) assess relative fitness of the mutant in competitive infections initiated by inocula containing equivalent numbers of both WT and mutant strains for mutants with WT infectivity. Note, competitive infections will not be performed if non-competitive infections are substantially different. If this is the case, there will be no analysis for this primary objective. The study secondary objective is to compare the clinical course of infection with mutant and WT N. gonorrhoeae in noncompetitive infections.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 27

Inclusion Criteria

Healthy man > / = 18 and < 36 years old
Able and willing to be located easily by providing street address and telephone number (land line and/or cell phone number)
Willingness to provide written informed consent
Able and willing to attend all study visits including 6-day stay in the Clinical Translational Research Center (CTRC) during the trial (with ability to leave the unit during the day) and follow-up visit during the week after treatment
Able and willing to abstain from all sexual activity until completion of the study and the follow-up test for gonorrhea is negative
Acceptable medical history by screening evaluation
No clinically significant abnormalities on physical exam
Urinalysis: leukocyte esterase, and White Blood Cell (WBC) values within normal limits (WNL)
CH50 WNL
Urine negative for chlamydia, gonorrhea, and trichomonas
Negative Human Immunodeficiency Virus (HIV), syphilis, and Hepatitis C (HCV) test results
Negative Hepatitis B (HBV) core and surface antibodies or results consistent with immunization (negative HBV core antibody/positive HBV surface antibody)
Denies history of Sexually Transmitted Infections (STIs) including gonorrhea, chlamydia, syphilis, HIV, HBV, and HCV
Denies history of bleeding diathesis
Denies history of seizures (due to reports of seizures with ciprofloxacin)
Denies history of cancer, except basal cell carcinoma of the skin > 5 years ago
Denies history of drug abuse
Denies history of genitourinary surgery

Exclusion Criteria

Student or employee under the direct supervision of any of the study investigators
Any known immunodeficiencies including complement deficiency, antibody deficiency, chronic granulomatous disease or Human Immunodeficiency Virus (HIV) infection
Psychiatric disorders that, in the opinion of the physician, would interfere with the integrity of the data or volunteer safety
Unstable depression (defined as receiving either < 3 months of the same medication (and dose) or a decompensating event during the previous 3 months) or depression that, in the opinion of the investigator, will compromise the subject's ability to comply with protocol requirements
Heart murmur or heart disease
Anatomic abnormality of the urinary tract
Any antibiotic treatment in the past 30 days, or azithromycin in the past 60 days
Self-reported chemotherapy within the past year
Current steroid use, except for topical application
Allergy to penicillin, cephalosporins or ciprofloxacin or to lidocaine
Treatment with medications in the previous month that are contraindicated with cefixime, ceftriaxone or ciprofloxacin and that cannot be withheld for the single doses given in this study
Serum creatinine level < 0.7 or > 1.75 mg/dL and deemed clinically significant by the study physician
Serum ALT level < LLN or > 105 U/L and deemed clinically significant by the study physician
WBC count < 2.5 or > 15.0 x 10^9/L and deemed clinically significant by the study physician
Absolute neutrophil count (ANC) < 1.5 or > 7.5 x 10^9/L and deemed clinically significant by the study physician Exception: For African Americans, ANC values as low as 1.3 x 10^9/L will be allowed (25)
Hemoglobin level < 12.0 g/dL or above ULN and deemed clinically significant by the study physician
Urinalysis: Qualitative protein level > 1+ or RBC count > 10/hpf

Medications not permitted with cefixime or ceftriaxone:

Warfarin
Probenecid
Aspirin
Diuretics such as furosemide
Aminoglycoside antibiotics
Chloramphenicol

Medications not permitted with ciprofloxacin:

Tizanidine
Theophylline
Warfarin
Glyburide
Cyclosporine
Probenecid
Phenytoin
Methotrexate
Antacids, multivitamins, and other dietary supplements containing magnesium, calcium, aluminum, iron or zinc
Caffeine-containing medications
Sucralfate or didanosine chewable or buffered tablets

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1	Neisseria gonorrhoeae strain FA7537	Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain
Group 2	Ciprofloxacin	Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.
Group 2	Neisseria gonorrhoeae strain FA1090 A26	Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.
Group 3	Ceftriaxone	Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain
Group 3	Ciprofloxacin	Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain
Group 3	Neisseria gonorrhoeae strain FA1090 A26	Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain
Group 3	Neisseria gonorrhoeae strain FA7537	Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain
Group 1	Cefixime	Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain
Group 1	Ceftriaxone	Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain
Group 1	Ciprofloxacin	Subjects (n = up to 8) will receive a bacterial inoculum containing only the isogenic mutant N. gonorrhoeae strain
Group 2	Cefixime	Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.
Group 2	Ceftriaxone	Subjects (n = up to 8) will receive a bacterial inoculum containing only the wild-type (WT) N. gonorrhoeae strain.
Group 3	Cefixime	Subjects (n= up to 16) will receive a bacterial inoculum containing a mixture of equivalent numbers the isogenic mutant and WT strain

Primary Outcome Measures

Name	Time	Method
The Competitive Index of the Mutant Compared to Wild Type Proportion of Organisms With the Predicted Competitive Advantage Recovered From Urine and/or Urethral Swab Specimens From Infected Participants	Baseline and the day of treatment, any day between Day 2 and Day 6	The competitive index (CI) is defined by the ratio of colony forming units (cfu) of the two strains recovered from urine cultures on the day of treatment (output) compared to the ratio of strains in the inoculum (input): CI = mutant cfu(output)/wild-type cfu(output) ÷ mutant cfu(input)/wild-type cfu(input). The CI is used to assess whether the fitness of a given mutant is different than that of wild-type, and CI as a ratio is compared to 1. If it's not significantly different than 1, then no significant difference in the fitness was observed. Mutant or wild-type cfu values of 0 were replaced by 1 in the calculation of competitive index. The assessment was performed in the MtrD trial mixed group.
Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture Among Infections Initiated With Individual N. Gonorrhoeae Strains in Non-competitive Infections	day of infection, any day between Day 2 and Day 6	Infection is defined by a positive urine or urethral swab culture. The proportion of infected participants by Day 6 with N. gonorrhoeae was assessed in each trial by group among participants with non-competitive infections. Participants could become infected and received treatment any day before or on day 6.
Proportion of Participants That Become Infected as Defined by a Positive Urine or Urethral Swab Culture for Infections Initiated With Mixed Inocula	day of infection, any day between Day 2 and Day 6	Infection is defined by a positive urine or urethral swab culture. The proportion of infected participants by Day 6 with N. gonorrhoeae was assessed in each trial among participants with infections initiated with mixed inocula. Participants could become infected and received treatment any day before or on day 6.

Secondary Outcome Measures

Name	Time	Method
Median Time From Inoculation to Treatment Among Infected Participants by Day 6, by Strain, in Non-competitive Infections	Day 2 through the day of treatment, up to Day 6	The median time from inoculation to antibiotic treatment were calculated for each group.
Proportion of Participants With Occurrence of Bacteriuria in Non-competitive Infections, by Strain	Day of occurrence, any day between Day 2 and Day 6	Bacteriuria is defined as Log10 cfu N. gonorrhoeae/mL urine sediment.
Proportion of Participants With Occurrence of Signs and Symptoms of Urethritis Attributable to Gonococcal Infection in Non-competitive Infections, by Strain	Day of occurrence, any day between Day 2 and Day 6	Participants with any subjective symptoms or objective signs (observed urethral discharge) during period 01 (post-inoculation and before treatment which can occur on or before day 6) from the Solicited Events Form were captured.
Proportion of Participants With Occurrence of Urethritis in Non-competitive Infections	Day of occurrence, any day between Day 2 and Day 6	Urethritis is defined as \>= 5.8 Log10 WBC/mL urine sediment.