Nonspecific factors have been implicated in natural resistance to gonococcal infection. In women, changes in the genital pH and hormones may increase resistance to infection at certain times of the menstrual cycle. Urine contains bactericidal and bacteriostatic components against N. gonorrhoeae. Factors in urine that may be important are pH, osmolarity, and the concentration of urea. The variability in the susceptibility of gonococcal strains to the bactericidal and bacteriostatic properties of urine is thought to be one of the reasons some males apparently do not develop a gonorrhea infection when exposed.

Most uninfected individuals have serum antibodies that react with gonococcal antigens. These antibodies probably result from colonization or infection by various Gram-negative bacteria that possess cross-reactive antigens. Such "natural antibodies" may be important in individual natural resistance or susceptibility to infection. demonstrated.

Infection with N. gonorrhoeae stimulates both mucosal and systemic antibodies to a variety of gonococcal antigens. Mucosal antibodies are primarily IgA and IgG. In genital secretions, antibodies have been identified that react with Por, Opa, Rmp and LOS. Vaccine trials have suggested that specific anti-fimbrial antibodies inhibit the fimbrial-mediated attachment of the homologous gonococcal strain. In general, the IgA response is brief and declines rapidly after treatment; IgG levels decline more slowly.  Anti-Por antibodies apparently are bactericidal for the gonococcus. IgG that reacts with Rmp blocks the bactericidal activity of antibodies directed against Por and LOS. Genital infection with N. gonorrhoeae stimulates a serum antibody response against the LOS of the infecting strain. Disseminated gonococcal infection results in much higher levels of anti-LOS antibody than do genital infections.

Strains that cause uncomplicated genital infections usually are killed by normal human serum and are termed serum sensitive. This bactericidal activity is mediated by IgM and IgG antibodies that recognize sites on the LOS. Strains that cause disseminated infections are not killed by most normal human serum and are referred to as serum resistant. Resistance is mediated, in part, by IgA that blocks the IgG-mediated bactericidal activity of the serum. Serum from convalescent patients with disseminating infections contains bactericidal IgG to the LOS of the infecting strain.

Individuals with inherited complement deficiencies have a markedly increased risk of acquiring systemic neisserial infections and are subject to recurring episodes of systemic gonococcal and meningococcal infections, indicating that the complement system is important in host defense. Gonococci activate complement by both the classic and alternative pathways. Complement activation by gonococci leads to the formation of the C5b-9 complex (membrane attack complex) on the outer membrane. In normal human serum, similar numbers of C5b-9 complexes are deposited on serum-sensitive and serum-resistant organisms, but the membrane attack complex is not functional on serum-resistant organisms.

Fluoroquinolone-resistant N. gonorrhoeae (QRNG) were observed sporadically in the United States during the 1990s and 2000s. During this period, fluoroquinolones were widely used for treatment of gonorrhea because they were safe, effective, inexpensive, and available in oral forms. Fluoroquinolone resistance is caused by the acquisition of parC and gyrA mutations that alter binding sites on enzymes DNA gyrase and topoisomerase IV. QRNG strains emerged in East Asia during the 1990s. In the early 2000s. QRNG emerged in the United States, initially in Hawaii and California. By 2007, the prevalence of QRNG was >5% among isolates collected throughout the United States, prompting CDC to no longer recommend the use of fluoroquinolones for gonorrhea treatment. Spectinomycin, an alternative treatment, had not been available in the United States since 2006, so cephalosporins (such as cefixime and ceftriaxone) were the only remaining antimicrobials recommended for treatment of gonococcal infections.

Cephalosporins remained the foundation of gonorrhea treatment in the 2010 CDC STD treatment guidelines. These updated guidelines increased the recommended dosage of ceftriaxone to 250 mg and included broadened recommendations for combination therapy: a cephalosporin, preferably ceftriaxone 250 mg as a single intramuscular dose, should be administered with a second antimicrobial. Combination therapy treats frequently co-occurring pathogens (e.g., Chlamydia trachomatis) and might hinder the spread of cephalosporin antimicrobial resistance.

Gonorrhea is transmitted almost exclusively by sexual contact. Any sexually active person can be infected with gonorrhea. In the United States, the highest reported rates of infection are among sexually active teenagers, young adults, and African Americans. Persons who have multiple sex partners are at highest risk. Rates of gonorrhea are higher in males and in minority and inner-city populations.

Gonorrhea is usually contracted from a sex partner who is either asymptomatic or has only minimal symptoms. It is estimated that the efficiency of transmission after one exposure is about 35 percent from an infected woman to an uninfected man and 50 to 60 percent from an infected man to an uninfected woman. More than 90 percent of men with urethral gonorrhea will develop symptoms within 5 days; fewer than 50 percent of women with genital gonorrhea will do so. Women with asymptomatic infections are at higher risk of developing pelvic inflammatory disease and disseminated gonococcal infection.