Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents

INTRODUCTION — Gonococcal infections, including urethritis, cervicitis, epididymitis, and proctitis, are a significant cause of morbidity among sexually active men and women. The treatment of these sexually transmitted infections (STIs) has evolved over the years, mainly due to the emergence of antibiotic resistance.

This topic will address the treatment of these gonococcal infections, with a focus on urogenital infections. The discussion in this topic is largely consistent with the United States Centers for Disease Control and Prevention (CDC) recommendations on treatment of STIs, which were updated in 2021 [1].

The clinical manifestations and diagnosis of gonorrhea are discussed elsewhere. The treatment of complicated infections, such as disseminated gonococcal infection and pelvic inflammatory disease, is also found elsewhere.

●(See "Epidemiology and pathogenesis of Neisseria gonorrhoeae infection".)

●(See "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents" and "Cutaneous manifestations of gonorrhea".)

●(See "Disseminated gonococcal infection".)

●(See "Pelvic inflammatory disease: Treatment in adults and adolescents".)

Prevention of gonorrhea and other STIs is also discussed elsewhere. (See "Prevention of sexually transmitted infections".)

GENERAL BACKGROUND

Definition of uncomplicated infection — Urogenital, anogenital, pharyngeal, and ocular gonococcal infections that are not associated with bacteremic or ascending spread of the pathogen to other organs are considered uncomplicated.

In contrast, disseminated gonococcal infection and pelvic inflammatory disease are complicated infections. Treatment of these is discussed elsewhere. (See "Disseminated gonococcal infection", section on 'Management' and "Pelvic inflammatory disease: Treatment in adults and adolescents", section on 'Antibiotic selection'.)

Therapeutic principles — Antimicrobial treatment is required for all patients diagnosed with gonorrhea. It is a highly transmissible infection that can result in serious sequelae if untreated, even in asymptomatic individuals. The role of treatment is to resolve symptoms if present, prevent complications of infection, and decrease transmission to others.

It is desirable for a therapeutic gonococcal regimen to:

●Be highly effective at all anatomic sites of infection

●Be well tolerated (particularly in patients with recurrent infections)

●Offer the feasibility of single-dose therapy at the point of care

Therapeutic regimens should have efficacy rates of greater than 95 percent because treatment failure has significant public health implications related to ongoing transmission of infection [2,3]. Single-dose therapy decreases the reliance on patient adherence; nonadherence can negatively affect eradication rates and increase the risk of drug resistance. Because of progressive development of drug resistance to various classes of antibiotics, at present, only one drug, ceftriaxone, meets these strict treatment efficacy goals with single-dose therapy, few adverse effects, and relatively low rates of drug resistance [4]. (See 'Antibiotic resistance' below and 'Initial treatment of urogenital infection' below.)

Copathogens — The selection of antibiotics for the treatment of gonorrhea must also consider the possibility of copathogens, such as Chlamydia trachomatis and Mycoplasma genitalium, which can cause cervicitis in women and urethritis in men [5-7]. Some epidemiologic surveys have shown a coinfection rate for C. trachomatis of up to 46 percent among men and women with gonorrhea [5]. (See "Treatment of Chlamydia trachomatis infection" and "Epidemiology of Chlamydia trachomatis infections" and "Mycoplasma genitalium infection".)

ANTIBIOTIC RESISTANCE — The era of N. gonorrhoeae antibiotic resistance began in the 1940s with the emergence of sulfonamide resistance. Subsequently, gonococcal infections were treated with penicillins, but by 1989, >5 percent of cases of gonorrhea were caused by strains that produced a plasmid-mediated beta-lactamase and >17 percent were associated with chromosomally-mediated resistance [2]. N. gonorrhoeae has uniformly developed increasing minimum inhibitory concentrations (ie, decreasing susceptibility) to antibiotics employed for treatment, followed by frank resistance, thus progressively reducing available therapeutic options [8].

Most of the data on gonococcal drug resistance is inferred through in vitro susceptibility data and epidemiologic surveys, rather than through clinical trials demonstrating increased treatment failure rates. In the United States, trends in drug resistance among males with urethral gonorrhea at sentinel sites throughout the country have been monitored by the Centers for Disease Control and Prevention (CDC)-sponsored Gonococcal Isolate Surveillance Project (GISP), which was created in 1986 [2]. Similar programs have been collecting data on N. gonorrhoeae antimicrobial resistance in other regions of the world [9-11]. Such surveillance programs have demonstrated increased resistance worldwide to multiple classes of antibiotics, including penicillins, tetracyclines, macrolides, and fluoroquinolones, with documented cross-resistance between two or more classes [12,13]. An especially alarming trend in N. gonorrhoeae drug resistance has been the progressive decrease in susceptibility to the cephalosporins and azithromycin [14]. (See 'Cephalosporins' below.)

The emerging threat of antimicrobial-resistant gonorrhea is more evident among men who have sex with men (MSM) than among men who have sex exclusively with women (MSW). Surveillance data from GISP which included more than 34,000 episodes of symptomatic gonorrhea found that isolates from MSM were significantly more likely to demonstrate antimicrobial resistance to all the antibiotic classes noted above, including cephalosporins, than isolates from MSW [15].

In 2023, the first isolates of multidrug-resistant (MDR) N. gonorrhoeae with reduced susceptibility to ceftriaxone, cefixime, and azithromycin and resistance to ciprofloxacin, penicillin, and tetracycline were reported in the United States [16]. The MDR N. gonorrhoeae strain was previously identified in the United Kingdom [17] and the Asia-Pacific region. Although ceftriaxone was effective for treatment, the isolates were confirmed to have the presence of a mosaic penA60 allele conferring reduced ceftriaxone susceptibility [18]. (See 'Ceftriaxone' below.)

In the setting of these trends, there has been renewed interest in drugs from other antibiotic classes, such as the carbapenems (eg, ertapenem), as potentially effective agents for individualized therapy, as dictated by resistance data [14,19-22]. In addition, new drugs are in development. (See 'Monitoring for and managing treatment failure' below and 'Investigational strategies' below.)

Cephalosporins — The rising rates of gonococcal resistance to non-cephalosporin classes of antimicrobial agents led to the use of cephalosporins, particularly intramuscular injections of ceftriaxone and oral cefixime [23]. However, trends in increasing mean minimum inhibitory concentrations (MICs) of N. gonorrhoeae for both agents, indicating decreasing susceptibility, have been reported worldwide and have led to changes in the recommendations for use of these agents. (See 'Preferred regimen' below.)

The Clinical and Laboratory Standards Institute (CLSI) has not defined MIC criteria for resistance of N. gonorrhoeae to cephalosporins but considers MIC ≥0.5 mcg/mL to reflect decreasing susceptibility. However, surveillance uses lower breakpoints (for example, ≥0.125 mcg/mL for ceftriaxone and ≥0.25 mcg/mL for cefixime) to indicate decreasing susceptibility in order to better detect trends in emerging resistance [1].

Cefixime — Surveillance of N. gonorrhoeae samples in the United States demonstrates that the percentage of isolates with elevated cefixime MICs (≥0.25 mcg/mL) increased from 0.1 percent in 2006 to 1.4 percent in 2010, started to decline in 2015, and was 0.3 percent in 2020 [24]. Among 23 European countries reporting on cefixime susceptibility in the World Health Organization Gonococcal Surveillance Programme (GASP), four countries (Belgium, Denmark, Greece, and Norway) reported resistance rates ≥5 percent [25]. Although no confirmed treatment failures with cefixime have been reported in the United States as of 2020, such failures have been reported in Canada, Europe, and Japan [26-29]. Furthermore, in a retrospective study of patients treated for culture-confirmed N. gonorrhoeae infection with a single oral dose of cefixime 400 mg at a Canadian clinic, 13 of 133 patients who returned for a test of cure were again culture positive, and nine (6.8 percent) were considered treatment failures [30]. With regards to location of infection, clinical failure occurred in 4 of 76 urethral, 2 of 7 pharyngeal, and 3 of 39 rectal infections (5.3, 28.6, and 7.7 percent, respectively). Although the possibility that some of these cases represented reinfection instead of treatment failure cannot be definitively excluded, these data highlight the increasing concern of the inadequacy of cefixime for gonococcal infections.

In light of domestic MIC trends and international treatment failures, cefixime is not a preferred agent for the treatment of gonorrhea [1]. (See 'Other cephalosporins' below.)

Ceftriaxone — Decreasing susceptibility and resistance of gonorrhea to ceftriaxone have emerged as a global problem. In 2011, the first N. gonorrhoeae strain with high-level resistance to ceftriaxone (MIC 2 to 4 mcg/mL) was isolated from the pharynx of a sex worker in Japan [31,32]. This was followed by a report from France of a different ceftriaxone-resistant strain isolated from the urethra of an MSM who had earlier failed treatment with cefixime [33]. Ceftriaxone-resistant isolates have subsequently been identified in other countries, including the United States and United Kingdom [18,34], and ceftriaxone treatment failure has been documented in locations such as Australia and Europe [35-37]. (See 'Monitoring for and managing treatment failure' below.)

There has also been a progressive evolution over time toward higher MICs for ceftriaxone globally, as reflected by resistance patterns in isolates reported to surveillance programs in the United States, Canada, Latin America, Europe, Australia, and Asia [9,10,38-43]. Between 2016 and 2020 in the United States, the proportion of reported gonococcal isolates with decreased susceptibility to ceftriaxone (MIC ≥0.125 mcg/mL) has fluctuated between 0.1 and 0.3 percent [24]. Rates of decreased susceptibility to ceftriaxone exceed 5 percent in many countries/regions throughout Asia, including Japan, South Korea, Hong Kong, India, and Indonesia [44].

These developments highlight the pressing need for improving control of the spread of drug resistance in N. gonorrhoeae and clinically investigating other viable therapeutic options [8,45,46]. Nevertheless, ceftriaxone remains a highly reliable treatment, especially at higher doses. (See '"High" dose intramuscular (IM) ceftriaxone' below.)

Azithromycin — Drug resistance to macrolides has been increasing significantly worldwide, according to gonococcal surveillance data. In the United States, data from the GISP demonstrate increasing MICs for azithromycin since surveillance for the drug's activity against N. gonorrhoeae began in 1992, and elevated MICs have been reported in all geographic regions [47,48]. In 2020, 5.8 percent of isolates had an azithromycin MIC ≥2 mcg/mL (indicating reduced susceptibility), an increase from 0.3 percent in 2011 and 3.6 in 2016 [24]. The risk of azithromycin resistance might be particularly high among MSM; in one study from an urban STI clinic, 93 percent of isolates with decreased susceptibility to azithromycin were from MSM, among the prevalence of azithromycin MIC ≥2 mcg/mL was 5 percent [48]. Very high-level resistance to azithromycin (MIC >512 mcg/mL) has also been reported in the United States, first identified in Hawaii, and several such isolates have also demonstrated reduced susceptibility to ceftriaxone [49,50].

In Europe, the prevalence of decreased susceptibility to azithromycin (MIC ≥1 mcg/mL) ranges from none (eg, in France and Iceland) to 23 and 33 percent in Greece and Cyprus, with a mean of 5.4 percent across 21 countries [9]. Azithromycin resistance is also common in Asia [51-53], where rates exceed 5 percent in Japan, Hong Kong, Mongolia, and Indonesia [25]. One laboratory study of gonococcal isolates in Hong Kong from 2005 to 2010 demonstrated that 30 percent of all gonococcal isolates were azithromycin resistant [54].

Decreased susceptibility to azithromycin has been associated with recent use of azithromycin (eg, for other STIs) [55].

These findings emphasize the importance of ongoing drug resistance surveillance for all drugs commonly used in the treatment of gonorrhea and prompted reversal of the recommendations for dual azithromycin and ceftriaxone therapy for gonorrhea in the United States and other countries. (See 'Preferred regimen' below.)

Tetracycline — Tetracycline resistance has been reported in the range of 10 to 20 percent of gonococcal isolates in the United States and Europe [47,56]. Cross-resistance to doxycycline is presumed.

Aminoglycosides

●Spectinomycin – Resistance to spectinomycin has remained low in systematic surveillance reports from the United States, Europe, and Australia [9,10,47]. However, this agent is not available in the United States and is otherwise not widely used in other areas. When it was used more frequently as a single agent, resistance was more common. Among 99 United States military personnel treated for urethral gonorrhea in Korea (where spectinomycin monotherapy was the preferred regimen), 8.2 percent experienced treatment failure and 6.1 percent had laboratory confirmed high-level resistance to spectinomycin [57]. (See 'Spectinomycin' below.)

●Gentamicin – Although susceptibility breakpoints for gentamicin have not been defined for N. gonorrhoeae, the overall MICs are low across Europe [9]. In Malawi, gentamicin has been used with doxycycline as first-line syndromic treatment for urethritis for years [58]. However, in a more recent study of males with gonococcal urethritis in Malawi, 19.9 percent of N. gonorrhoeae isolates had elevated MICs to gentamicin; furthermore, MICs poorly predicted response to gentamicin, with gentamicin treatment failure observed with isolates that had low MICs [59]. Surveillance for gentamicin susceptibility is not being performed in the United States. The potential clinical use of gentamicin (in combination with azithromycin) is discussed elsewhere. (See 'Azithromycin plus gentamicin or gemifloxacin' below.)

Fluoroquinolones — The prevalence of quinolone-resistant N. gonorrhoeae (QRNG) ranges from 10 to nearly 100 percent of isolates reported throughout the world, and these drugs are no longer recommended for the treatment of gonorrhea [2,9,10]. In several regions, such as the United States and Europe, the prevalence of quinolone resistance has decreased somewhat compared with previous years, likely reflecting decreased use of the drug [9,47]. However, resistance levels remain high elsewhere despite the avoidance of these drugs for treatment of gonorrhea and the resultant decrease in selection pressure. In vitro and animal studies suggest that certain quinolone resistance mutations also confer a fitness advantage, which could explain the persistence of resistance in the absence of selection pressure [60,61].

Several molecular tests that identify the gyrase A gene point mutation associated with fluoroquinolone resistance are under development and may allow reintroduction of fluoroquinolone therapy by allowing rapid identification of susceptible isolates. In one study of 106 patients identified as having a fluoroquinolone-susceptible N. gonorrhoeae infection based on one such test, a single-dose of ciprofloxacin resulted in microbiologic cure at all anatomic sites among those who had sufficient follow-up; the molecular testing results correlated with in vitro susceptibility testing [62].

INITIAL TREATMENT OF UROGENITAL INFECTION — The alarming rates of antibiotic resistance to N. gonorrhoeae reported worldwide has rendered the treatment of uncomplicated gonococcal infections more complex, with fewer treatment options, than in the past [12,63,64]. Due to rising rates of gonococcal resistance to other agents (sulfonamides, penicillins, tetracyclines, and fluoroquinolones), third-generation cephalosporins are considered first-line monotherapy [1]. Of these, ceftriaxone is favored because drug resistance and treatment failure have been documented less frequently than with other cephalosporins, such as cefixime.

Preferred regimen

"High" dose intramuscular (IM) ceftriaxone — Single-agent therapy with ceftriaxone is the preferred regimen for treatment of gonococcal infections. We agree with the following dose recommendations from the United States Centers for Disease Control and Prevention (CDC) for treatment of uncomplicated gonococcal infections [1]:

●For individuals who weigh <150 kg – Ceftriaxone 500 mg IM in a single dose

●For individuals who weigh ≥150 kg – Ceftriaxone 1 g IM in a single dose

These doses of ceftriaxone are higher than previously recommended due to concerns regarding rising gonococcal minimum inhibitory concentrations (MICs) worldwide. High doses of ceftriaxone are also recommended by other national guidelines; for example, 1 g as a single dose (IM or intravenously) is recommended by the British Association for Sexual Health and HIV (BASHH) in the United Kingdom [65], in China [66,67], and in Japan [68,69].

Additionally, routine use of a second agent for treatment of gonococcal infections, which was included in previous CDC treatment guidelines, is no longer recommended. However, if chlamydial coinfection has not been excluded (eg, nucleic acid amplification testing [NAAT] at exposed sites has not been performed), presumptive treatment of chlamydia should be administered at the same time. (See 'Presumptive treatment for chlamydia' below.)

Ceftriaxone is highly effective against susceptible N. gonorrhoeae. Earlier studies had suggested that ceftriaxone dosed IM at either 125 mg or 250 mg resulted in microbiologic cure in 99 percent of uncomplicated urogenital and anorectal infections [4,70]. Ceftriaxone is also more effective than oral cephalosporins. In a meta-analysis of trials evaluating treatment of uncomplicated gonorrhea, higher cure rates were reported with ceftriaxone 250 mg than cefixime 400 mg (odds ratio [OR] 1.77, 95% CI 1.11-2.8) with equivalent side effects [70].

However, these doses (125 mg to 250 mg) are unlikely to be effective against isolates with higher MICs, which have increased in prevalence since those trials were performed. Pharmacokinetic and pharmacodynamic modeling and animal studies have demonstrated that a dose of at least 5 mg/kg of ceftriaxone is necessary to achieve levels higher than an MIC ≥0.125 mcg/mL (the threshold for decreased susceptibility to ceftriaxone) for a sufficient duration of time above the MIC [38,71]. Thus, the CDC has increased the recommended dose of ceftriaxone from 250 mg to 500 mg or 1 g in a single dose, depending on the patient's weight. Additionally, pharyngeal infection, which is often asymptomatic and may accompany infection at other sites, is more difficult to eradicate than urogenital or anorectal gonococcal infections and may serve as a reservoir of infection, possibly related to less predictable ceftriaxone levels in the pharynx [72]. This consideration was another reason for the increase in the recommended dose. (See 'Pharyngeal infection' below.)

Evaluation for cephalosporin resistance in patients with persistent or recurrent symptoms is essential to controlling the spread of drug resistance. Thus, all patients need to understand the importance of further evaluation if symptoms persist. (See 'Monitoring for and managing treatment failure' below.)

The current recommendations also reflect a departure from prior recommendations for dual therapy of gonorrhea with ceftriaxone and azithromycin [1]. Dual therapy did not improve gonorrhea clearance rates [73] but had been theorized to reduce the risk of emergent resistance, based on evidence from other pathogens that demonstrated lower rates of resistance with the use of at least two agents that act upon different molecular targets. However, this was never demonstrated for N. gonorrhoeae, and in fact, treatment failure of a pharyngeal infection following dual therapy with subsequent decreased susceptibility to ceftriaxone and azithromycin has been reported [74]. Decreasing susceptibility to azithromycin in N. gonorrhoeae and other organisms is now thought to outweigh any theoretical benefit [1,48]. (See 'Azithromycin' above.)

Agents other than ceftriaxone are not appropriate as preferred regimens because of high rates of resistance. (See 'Antibiotic resistance' above.)

Clinical trials and novel therapeutics are urgently needed to identify the most appropriate treatment strategy for N. gonorrhoeae in the face of rising antimicrobial resistance. (See 'Investigational strategies' below.)

Presumptive treatment for chlamydia — If concurrent C. trachomatis infection has not been excluded with molecular testing, presumptive treatment for chlamydia should be given at the same time as treatment for N. gonorrhoeae. We agree with CDC recommendations to use doxycycline (100 mg orally twice daily for seven days) for presumptive treatment of chlamydia in nonpregnant individuals with gonococcal infection. (See "Treatment of Chlamydia trachomatis infection", section on 'Doxycycline as preferred agent'.)

Azithromycin is an alternative to doxycycline for treatment of chlamydia. Increasing rates of decreased azithromycin susceptibility among N. gonorrhoeae isolates have been reported [75], and azithromycin exposure has been associated with high azithromycin MICs in N. gonorrhoeae [76]. (See 'Azithromycin' above.)

Alternate regimens — Alternate regimens should only be used if the preferred regimen is not available or precluded because of severe allergies or intolerance. If ceftriaxone is not available, certain other cephalosporins can be used in its place. In the case of severe hypersensitivity reactions to cephalosporins, options include high-dose azithromycin with gentamicin or gemifloxacin and spectinomycin. However, both gemifloxacin and spectinomycin have limited or no availability in the United States, and these alternate regimens all have drawbacks that further limit their use, as discussed below.

Other cephalosporins — For treatment of urogenital or anorectal gonococcal infection in situations where ceftriaxone is not available, a different injectable cephalosporin (eg, ceftizoxime [500 mg IM], cefoxitin [2 g IM with probenecid 1 g orally], or cefotaxime [500 mg IM]) can be used; however, there is no advantage of any of these injectable cephalosporins over ceftriaxone, and their efficacy in pharyngeal infection is less certain. Additionally, availability of these agents may be limited (eg, injectable ceftizoxime and cefotaxime are not available in the United States).

If an injectable cephalosporin is not available, cefixime is the only oral cephalosporin that can be used for gonococcal therapy. The recommended dose is 800 mg orally once, which is an increased dose compared with prior recommendations [1]. Cefixime has been shown to result in microbiologic cure in more than 96 percent of patients with uncomplicated urogenital or anorectal gonorrhea [77,78]. However, it is not as effective as ceftriaxone [70], and in particular, cefixime has been associated with high treatment failure rates for pharyngeal gonorrhea infection [30,79]. These studies had evaluated cefixime at a lower dose of 400 mg. An increased dose has been recommended to increase plasma levels of the drug in light of these findings and decreased susceptibility of N. gonorrhoeae to oral cephalosporins in the United States and throughout other parts of the world [54,80,81]. (See 'Cephalosporins' above.)

For any of these regimens, additional therapy for chlamydia is warranted if coinfection has not been ruled out. (See 'Presumptive treatment for chlamydia' above.)

Azithromycin plus gentamicin or gemifloxacin — Some patients with beta-lactam allergies can still use a cephalosporin (see 'Penicillin-allergic patients' below). For patients with urogenital or anorectal gonococcal infection who have severe allergies that preclude cephalosporin use, we favor gentamicin (240 mg IM once for individuals >45 kg; 5 mg/kg IM once for individuals ≤45 kg) plus azithromycin (2 g orally once). Gemifloxacin (320 mg orally once) plus azithromycin (2 g orally once) can also be used as an alternate regimen; however, the limited availability and cost of gemifloxacin can be prohibitive. In the United States, the CDC does not include the gemifloxacin combination as an alternative regimen because of these and antimicrobial stewardship concerns.

There are limited data regarding the efficacy of both alternative regimens for extragenital infections. Furthermore, adverse effects (eg, gastrointestinal [GI] side effects with the higher dose of azithromycin), other toxicities, and availability may limit their use. Azithromycin monotherapy for gonorrhea is not recommended. The primary reason for using a second agent with azithromycin is to prevent the emergence of azithromycin resistance, but this theoretical benefit has not been directly evaluated in studies. If one of these regimens is used, additional therapy for chlamydia is not necessary, even if it has not been ruled out.

Some evidence suggests that these regimens are highly effective for urogenital and anogenital infections. The combinations of azithromycin (2 g orally once) with either gentamicin or gemifloxacin were evaluated in a study of men and women who presented with suspected gonococcal urethritis or cervicitis to sexually transmitted infection (STI) clinics in the United States [82]. Approximately one-third of the participants were men who have sex with men (MSM). Among the patients with documented N. gonorrhoeae infection who completed the regimen without early vomiting and returned for follow-up, the microbiologic cure rates were 100 percent (95% CI 98.5-100) with azithromycin plus gentamicin and 99.5 percent (95% CI 97.6-100) for azithromycin plus gemifloxacin. Both regimens resulted in 100 percent cure of anorectal infections, but the number (n = 6) was small in this trial. In another study evaluating gentamicin (240 mg once) plus azithromycin (2 g orally once), all of the 40 participants identified with anorectal infection who received that regimen had microbiologic and clinical cure at that site [83].

However, in another trial, 720 men and women with uncomplicated gonococcal infection were randomly assigned to receive IM gentamicin (240 mg once) or ceftriaxone (500 mg once), each in combination with azithromycin (1 g orally once) [84]. Gentamicin resulted in a lower rate of N. gonorrhoeae clearance (based on NAAT) at all sites compared with ceftriaxone (91 versus 98 percent, adjusted risk difference -6.4 percent; 95% CI -10.4 to -2.4), with particularly low rates at pharyngeal (80 versus 96 percent) and rectal sites (90 versus 98 percent). It is unknown whether use of the higher dose of azithromycin (2 g orally once) would have resulted in a higher cure rate.

There are several other drawbacks to these regimens. In addition to the GI side effects, the volume of gentamicin used for IM injection (two 3 mL doses) may make the azithromycin plus gentamicin combination unacceptable to some patients. The combination of gemifloxacin and azithromycin may also have potential drug interactions (ie, prolonged QT interval) and increase the risk of Clostridioides difficile colitis with inclusion of a fluoroquinolone. These issues should be considered when selecting an alternate regimen.

While a 2 g single oral dose of azithromycin monotherapy could treat both gonorrhea and chlamydia infections, it is not a recommended regimen due to increasing gonococcal drug resistance to azithromycin [1]. In a large randomized controlled trial, the 2 g dose had a cure rate of 99 percent (95% CI 97.9-100 percent), equivalent to that reported with ceftriaxone, but was associated with GI side effects in 35 percent [85]. A lower dose of azithromycin is not adequately effective against gonococcal infections. In a systematic review of studies in which azithromycin was used for treatment of uncomplicated urogenital infection, the aggregate cure rate for the 1 g dose fell just below the 95 percent cure rate, the efficacy threshold for gonorrhea [86].

Spectinomycin — Spectinomycin (2 g IM) is a safe and effective parenteral alternate for patients with genitourinary infection and a severe beta-lactam allergy that precludes cephalosporin use, but it is not available in the United States and its availability elsewhere is limited [87]. Spectinomycin should not be used for treatment of pharyngeal infection, as it has poor penetration of the Waldeyer tonsillar ring and has been associated with low cure rates at this site [4].

If spectinomycin is used, additional therapy for chlamydia is warranted if coinfection has not been ruled out. (See 'Presumptive treatment for chlamydia' above.)

OTHER GONOCOCCAL INFECTIONS

Pharyngeal infection — Pharyngeal N. gonorrhoeae infection may serve as an important reservoir of infection and contribute to ongoing transmission [88,89]. First-line treatment of pharyngeal infection is the same as for urogenital and anorectal infection, with a single high dose of intramuscular (IM) ceftriaxone and presumptive treatment of chlamydia, as detailed above. (See 'Preferred regimen' above.)

However, the optimal alternative regimens for pharyngeal infection are less clear. The alternative single-agent regimens (cefixime, gentamicin, and spectinomycin) are associated with low rates of gonococcal eradication in the pharynx and should not be used [3,90]. For individuals with pharyngeal infection who have a beta-lactam allergy, options depend on the type of allergy and could still include use of ceftriaxone, possibly with a test-dose procedure or following skin testing. (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Our approach' and "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Use of related antibiotics in cephalosporin-allergic patients'.)

Azithromycin plus gentamicin may be an effective alternative regimen for pharyngeal infection, but it should be reserved for patients with a severe beta-lactam allergy that precludes cephalosporin use. In an open-label randomized trial conducted in the Czech Republic that included 143 patients with pharyngeal and/or rectal gonorrhea, gentamicin 240 mg plus azithromycin 2 g resulted in 100 percent clinical and microbiologic cure rates, the same as with a ceftriaxone 500 mg-based regimen [83]. However, in another randomized controlled trial from the United Kingdom, cure rates with gentamicin 240 mg plus azithromycin were lower than with ceftriaxone 500 mg with azithromycin (80 versus 96 percent, respectively) [84].

A test of cure is recommended for all pharyngeal gonococcal infections, regardless of treatment regimen used, because of the challenges to effective treatment at this site [1]. (See 'Test of cure' below.)

Data regarding the optimal therapy of pharyngeal gonococcal infection are limited [91,92]. Pharyngeal infections appear to be more difficult to cure [72,91]. This issue was well illustrated in a meta-analysis of 144 controlled and uncontrolled trials, which found that standard antimicrobial therapy led to cure rates of 79 percent for pharyngeal infections in men compared with 98 and 95 percent for urethral and rectal infections, respectively [72].

Theories have been proposed to explain the lower cure rate for pharyngeal infections:

●Pharyngeal isolates are "naturally" less susceptible to antimicrobials, possibly due to the exchange of antimicrobial resistance genes with commensal Neisseria spp. Pharyngeal gonorrhea is mostly asymptomatic, and gonococci and commensal Neisseria spp can coexist for long time periods in the pharynx and share genetic material [93].

●Anatomically, Waldeyer tonsillar ring is characterized by a crypt system consisting of a highly complex network of canals with specialized stratified squamous epithelium [94]. Bacterial infection can be associated with bacterial "plugs" within the crypts that make treatment more difficult.

●Antimicrobials may work less effectively for asymptomatic pharyngeal gonorrhea due to absence of inflammation at the mucosal surface of the pharynx. The penetration of antibiotics into the oropharyngeal mucosa is a complex process, in which the presence of inflammation and antimicrobial pharmacokinetic properties are important factors to consider [95].

●Immune defense mechanisms are less effective at the mucosal surface of the pharynx than at other sites, and eradication at that site is therefore more dependent upon the efficacy of the antimicrobial agent.

Gargling with antiseptic mouthwash should not be relied on for treatment or prevention of pharyngeal gonococcal infection. Although one trial suggested that gargling with alcohol-containing mouthwash could reduce gonococcal growth from pharyngeal cultures [96], a subsequent trial found no difference in pharyngeal gonococcal infection rates among men who have sex with men who were randomly assigned to receive either alcohol-containing or non-alcohol-containing mouthwash for 12 weeks [97].

Rectal infection — Treatment for N. gonorrhoeae rectal infection is the same as for urogenital infection, with a single high dose of IM ceftriaxone and presumptive treatment of chlamydia, as detailed elsewhere. (See 'Preferred regimen' above.)

Regimens recommended for urogenital infection are highly effective for rectal infection as well. In a meta-analysis that included 1813 cases of rectal gonorrhea treated with various regimens, pooled microbiologic cure rates with ceftriaxone-based regimens were 100 percent [98]. Untreated rectal N. gonorrhoeae infection can serve as a reservoir for transmission [99,100]. As an example, the medial duration of rectal gonorrhea in a prospective, longitudinal study involving 140 men who have sex with men (MSM) was nine weeks [101].

Patients with acute proctitis associated with N. gonorrhoeae also warrant evaluation and potentially empiric therapy for other sexually transmitted infections (STIs). The approach to evaluation and management of proctitis is discussed in detail elsewhere. (See "Evaluation of anorectal symptoms in men who have sex with men", section on 'Proctitis'.)

Conjunctivitis — All patients with documented or suspected gonococcal conjunctivitis should be evaluated emergently by an ophthalmologist. Gonococcal conjunctivitis is treated with a single 1 g IM dose of ceftriaxone and presumptive treatment for chlamydia infection (see 'Presumptive treatment for chlamydia' above). In a small study of 13 patients with culture-proven, non-neonatal gonococcal conjunctivitis, a single 1 g IM injection of ceftriaxone effectively treated all participants [102].

A topical fluoroquinolone, saline irrigation, and daily monitoring are also recommended because of the risk of corneal involvement and perforation [103]. If corneal involvement is identified or cannot be excluded because of lid and conjunctival swelling, some experts recommend that the patient be hospitalized and treated with ceftriaxone 1 g intravenously every 12 to 24 hours until resolution.

The clinical manifestations and diagnosis of gonococcal conjunctivitis are discussed in detail elsewhere. (See "Conjunctivitis", section on 'Hyperacute bacterial conjunctivitis'.)

Epididymitis — N. gonorrhoeae or C. trachomatis are the most frequent pathogens in epididymitis among sexually active men <35 years of age, and empiric treatment of acute epididymitis covers these organisms [104]. Management of patients with acute epididymitis is discussed elsewhere.

Pelvic inflammatory disease (PID) — N. gonorrhoeae is rarely documented as the causal pathogen in PID, but empiric treatment for this pathogen is an important component of PID management because the organism may be difficult to recover when it has ascended to the upper tract. The treatment of PID is discussed in detail elsewhere. (See "Pelvic inflammatory disease: Treatment in adults and adolescents".)

Disseminated gonococcal infection — The management of septic arthritis due to N. gonorrhoeae and other manifestations of disseminated gonococcal infection is discussed in detail elsewhere. (See "Disseminated gonococcal infection", section on 'Management'.)

SPECIFIC POPULATIONS

Penicillin-allergic patients — The management of the penicillin-allergic patient depends on the clinical suspicion of true allergy and the type of the allergy (eg, morbilliform rash versus IgE-mediated reactions, such as urticaria). Treatment with ceftriaxone is likely safe if the patient only has a history of rash without IgE manifestations. (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Management of mild reactions WITHOUT history of features of immediate allergy (minimal risk of immediate allergy)'.)

Although true IgE-mediated penicillin allergy is rare, for those with a history concerning for an IgE-mediated reaction, options for treatment depend upon how urgently treatment is needed, how severe the past reaction was, and whether consultation with an allergist for skin testing is readily available (algorithm 1). (See "Choice of antibiotics in penicillin-allergic hospitalized patients", section on 'Management of reactions WITH features of immediate allergy (some risk)'.)

Alternate treatment choices among patients who have urogenital or anogenital gonococcal infection and cannot use a beta-lactam include spectinomycin (where available), or azithromycin (2 g as a single oral dose) combined with either gentamicin (240 intramuscularly once) or, if available, gemifloxacin (320 mg orally once). (See 'Alternate regimens' above.)

If molecular tests that can detect fluoroquinolone resistance are available, a single dose of ciprofloxacin 500 mg orally is an effective option when a fluoroquinolone-susceptible N. gonorrhoeae infection is confirmed [62]. However, these tests are not widely available. (See 'Fluoroquinolones' above.)

For non-pregnant individuals with pharyngeal infection who cannot use a beta-lactam, gentamicin plus azithromycin can be considered as an alternative regimen. (See 'Pharyngeal infection' above.)

Pregnant women — Pregnant women with uncomplicated gonorrheal infection should be treated with the same preferred regimen as the general population. (See '"High" dose intramuscular (IM) ceftriaxone' above.)

Presumptive treatment for chlamydia (ie, if coinfection has not been ruled out) should be with azithromycin rather than doxycycline. (See "Treatment of Chlamydia trachomatis infection", section on 'Pregnant individuals'.)

If a pregnant patient has a severe IgE-mediated allergy to cephalosporins, desensitization procedures should be employed prior to administration.

If desensitization cannot be performed or the severe beta-lactam allergy otherwise precludes a cephalosporin, gentamicin plus azithromycin can be used as an alternate regimen for urogenital or anorectal infection during pregnancy. In pregnant women with a severe beta-lactam allergy and pharyngeal gonorrhea, infectious disease consultation is warranted. A test of cure is recommended if a pregnant patient is treated with an alternative regimen. (See 'Test of cure' below.)

All individuals, including pregnant women, should be retested following treatment within three months; pregnant women who are at continued high risk for gonorrhea should be tested again during the third trimester [1]. (See 'Retesting' below.)

All pregnant women with pelvic inflammatory disease should be hospitalized and given parenteral antibiotics, due to the potential complications of infection resulting in adverse pregnancy outcomes. (See "Pelvic inflammatory disease: Treatment in adults and adolescents".)

PATIENT COUNSELING

Sexual activity — Although gonococci are eliminated from the genital tract within one day after successful treatment [105], patients are generally counseled to avoid sexual activity until seven days following treatment initiation [1]. Patients should only resume having sex after symptoms have resolved and sex partners have been treated. (See 'Management of sexual partners' below.)

Screen for HIV and other STIs — As infection with one sexually transmitted infection (STI) increases the risk of infection with others, individuals diagnosed with N. gonorrhoeae infection should be tested for other STIs, including HIV, chlamydia, and syphilis [1]. Screening for viral hepatitides may also be warranted. Screening for STIs is discussed in detail elsewhere. (See "Screening for sexually transmitted infections" and "Screening and diagnostic testing for HIV infection".)

In particular, persons with incident gonorrhea are at high risk for HIV infection [106-108]. One study demonstrated that 27 percent of persons who had recently acquired HIV infection (n = 191) were diagnosed with gonorrhea in the 12 months preceding HIV acquisition [109]. Pre-exposure prophylaxis against HIV should be considered for individuals with recent gonorrhea diagnosis who test negative for HIV. (See "HIV pre-exposure prophylaxis".)

Pregnancy testing — Women with reproductive potential and urogenital gonococcal infection should undergo pregnancy testing.

PATIENT FOLLOW-UP

Test of cure — Patients who have resolution of symptoms following treatment for uncomplicated urogenital or anorectal gonococcal infections do not need to return for a test of cure [1]. However, the United States Centers for Disease Control and Prevention (CDC) recommends that a test of cure be performed in all individuals with oropharyngeal gonococcal infection.

Test of cure can be with either culture or nucleic acid amplification tests (NAATs) conducted 7 to 14 days following therapy [1]. Culture is ideal for test of cure as it also allows for susceptibility testing if there is growth of N. gonorrhoeae; however, it is less readily available than NAAT. If NAAT is performed as test of cure, it should be done with sufficient time after treatment (ie, closer to 14 days after treatment) to avoid false-positive results from detection of nonviable organisms that may not represent persistent infection [110,111]. Individuals with a positive NAAT test of cure should also undergo confirmatory culture, if possible, prior to repeat treatment, and all positive culture tests of cure should be submitted for susceptibility testing. In the absence of risk for reinfection, patients with a positive test of cure should be considered as treatment failures.

The utility of culture as a follow-up to positive NAAT was illustrated in a study in which 190 men who have sex with men (MSM), among whom there were 100 pharyngeal and 100 rectal gonorrhea infections, were retested with NAAT at the infected sites following treatment with ceftriaxone and azithromycin [112]. At days 7 and 14 after therapy, 13 and 8 percent of pharyngeal specimens and 6 and 8 percent of rectal specimens were positive for persistent N. gonorrhoeae deoxyribonucleic acid (DNA), respectively. Persistent NAAT positivity was associated with higher baseline minimum inhibitory concentrations (MICs) to ceftriaxone and azithromycin. However, all specimens except for one rectal sample at 14 days were culture negative, and one case was a documented reinfection. The clinical significance of the persistent NAAT positivity is unclear; it may represent nonviable genetic material, or it could reflect a low level of pathogen persistence that culture is not sensitive enough to detect.

Monitoring for and managing treatment failure — Patients should be instructed to return to care for evaluation for treatment failure and antimicrobial resistance if they experience persistent or recurrent symptoms soon (eg, three to five days) after completing therapy for gonorrhea. Treatment failure is also suspected in individuals who have a positive test of cure. In particular, MSM appear to have a higher prevalence of antimicrobial-resistant gonococcal infections than men who have sex exclusively with women [15].

Many of these cases are due to reinfection or other sexually transmitted infections, which should be assessed for, since rates of coinfection (eg, C. trachomatis, M. genitalium) are high (see 'Postgonococcal urethritis' below). If reinfection seems likely, the patient can be treated with the usual preferred regimen. (See '"High" dose intramuscular (IM) ceftriaxone' above.)

If reinfection is unlikely (eg, if there were no additional sexual exposures following treatment), treatment failure and resistance are a greater concern. Relevant specimens (eg, urethral, oropharyngeal, and/or rectal samples depending on exposure) should be submitted for culture and NAAT for N. gonorrhoeae detection, and culture isolates should be sent for susceptibility testing [1].

Any case of suspected treatment failure (isolation of N. gonorrhoeae following therapy and low suspicion for repeat infection) or gonococcal isolates with reduced susceptibility to cephalosporins (MIC ≥0.5 mcg/mL) should be reported to governmental public health agencies. In the United States, cases should be reported to the CDC at 404-718-5447 and through state and local public health authorities. Isolates should also be submitted to CDC for susceptibility testing if not already performed.

The optimal management of suspected treatment failure to ceftriaxone is uncertain, as there are minimal data evaluating efficacy of different regimens in this situation; consultation with an expert in treating sexually transmitted infections is warranted [1]. Ideally, therapy should be guided by susceptibility testing. Higher antibiotic doses may be able to overcome moderately elevated MICs in some cases of treatment failure (eg, using 1 g of ceftriaxone if 500 mg was initially used) [74]. If an alternative regimen (eg, cefixime) was initially used, ceftriaxone 500 mg once may be adequate. Azithromycin (2 g) plus gentamicin and gemifloxacin in combination are other potential options for isolates with decreased cephalosporin susceptibilities, although side effects or availability may limit their use. (See 'Azithromycin plus gentamicin or gemifloxacin' above.)

Other agents not typically used for gonorrhea may be future options for highly resistant infections, if more data further support their use. Three days of intravenous ertapenem successfully eradicated a N. gonorrhoeae strain with an elevated MIC to ceftriaxone (0.5 mcg/mL) and high-level azithromycin resistance that was isolated from a heterosexual man who failed therapy with ceftriaxone 1 g intramuscular as well as spectinomycin [37]. Although there are no established ertapenem breakpoints for N. gonorrhoeae, ertapenem was chosen because the MIC of this isolate was low. Other studies have documented ertapenem efficacy for non-resistant N. gonorrhoeae. In a randomized trial, microbiologic clearance rates for anorectal or urogenital gonorrhea were similar with a single dose of ertapenem 1 g versus ceftriaxone 500 mg, each given intramuscularly (99 versus 100 percent) [113].

Test of cure with both culture and NAAT is recommended following retreatment [1]. (See 'Test of cure' above.)

Retesting — Patients diagnosed with gonorrhea are at risk for repeat infection as well as infections with other sexually transmitted infections, including HIV. All patients should return at three months after treatment (or, if that is not possible, within 12 months of treatment) for retesting for N. gonorrhoeae infection. (See "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents".)

POSTGONOCOCCAL URETHRITIS — Postgonococcal urethritis refers to symptoms that persist after successful eradication of gonococcal infection. Postgonococcal urethritis may be related to other untreated copathogens, such as chlamydia, trichomonas, or M. genitalium. Herpes simplex virus (HSV) may also be a causative agent, although HSV is often distinguished from these other pathogens on physical examination. Evaluation and management of persistent symptoms after treatment for urethritis are discussed elsewhere. (See "Urethritis in adult males", section on 'Recurrent or persistent symptoms'.)

PUBLIC HEALTH ISSUES

Reporting — In the United States, gonorrhea is reportable to public health authorities in every state and the District of Columbia; case reporting may be performed by the laboratory or provider.

Management of sexual partners — All individuals who have had sexual contact with patients diagnosed with N. gonorrhoeae within the past 60 days of the diagnosis should be evaluated and treated. If the patient had no sexual contact within the 60 days prior to diagnosis, the most recent sexual partner should be evaluated and treated.

Sexual partners, particularly women, may be asymptomatic and, unless treated, will reinfect the index patient or spread infection to other partners. In the United States, the traditional approach has been to utilize members of a public health field team to notify exposed sex partners, but many health departments are no longer tracing these partners due to staffing shortages and lack of resources [114]. In lieu of public health advocacy, patients should be asked to notify their partners of the need for medical evaluation and treatment (partner notification [PN]). Unfortunately, this approach is sometimes inefficient and may result in few treated partners [114]. In some situations, expedited partner therapy may be an alternative strategy for partner management.

●Expedited partner therapy (EPT) – This refers to the clinical practice of treating the sex partners of patients diagnosed with sexually transmitted infections (STIs) without formal evaluation of the partner(s), by providing prescriptions or medications to the patient to deliver to the partner(s). Although clinical evaluation and treatment for gonorrhea are preferred, we suggest EPT for heterosexual contacts of patients with gonorrhea in whom clinical evaluation is unlikely. EPT is not routinely recommended for men who have sex with men (MSM) because of a high risk for coexisting infections, especially undiagnosed HIV infection, in their partners, and EPT does not offer opportunities to counsel or evaluate partners regarding this risk. Additionally, MSM may be at greater risk of pharyngeal infection, for which there is a risk of treatment failure with cefixime as the oral agent used for EPT (see 'Pharyngeal infection' above). If EPT is used for MSM, they should be made aware of these risks.

•For partners of patients with gonorrhea, oral cefixime 800 mg orally once (plus presumptive treatment for chlamydia if not ruled out in the index patient) is used for EPT [1]. Partners should also be given written information about gonorrhea, the importance of therapy, and instructions to present to medical care for symptoms or adverse effects.

In the United States, the legal status of EPT remains an area of uncertainty and currently depends on whether individual state regulations allow health care providers to provide a prescription for a patient's partner without a prior evaluation or relationship with the partner. The practice of EPT is permissible in the majority of states [115]. The legal status of EPT options can be found at the United States Centers for Disease Control and Prevention website.

Advocates for EPT cite its overall positive impact on reducing rates of reinfection and increasing the proportion of patients receiving therapeutic interventions [116]. In randomized trials, EPT was more effective than traditional partner notification programs (ie, the patient notifies the partner of the need for evaluation and treatment) in reducing persistent or recurrent urogenital gonococcal infection among index patients [44,117]. However, limitations of this strategy include lost opportunities for STI/HIV screening and risk of unmonitored adverse events related to antibiotic administration [114,117].

INVESTIGATIONAL STRATEGIES — Several novel agents in development have good in vitro activity against N. gonorrhoeae and drug-resistant strains, but clinical data are limited. In one early clinical trial, a single dose of gepotidacin, a novel bacterial topoisomerase inhibitor, resulted in microbiologic cure in ≥95 percent of 69 patients with uncomplicated urogenital gonorrhea; however, three treatment failures were due to a common gene mutation associated with gepotidacin resistance [118]. A single dose of zoliflodacin, a novel oral spiropyrimidinetrione antibiotic that inhibits DNA synthesis, also resulted in high rates of microbiologic cure with a favorable safety profile in a trial of 141 patients with culture-confirmed uncomplicated urogenital gonococcal infection (96 versus 100 percent cure with a single 500 mg ceftriaxone injection) [119]. It was associated with lower eradication rates for pharyngeal infection, similar to the pattern of lower cure rates at this anatomic site with other agents [72]. Global phase III trials are underway for both investigational agents.

Given the time between new drug development and its approval and licensure, vaccine development for N. gonorrhoeae is also an important initiative. Vaccines to prevent gonorrhea are discussed in detail elsewhere. (See "Prevention of sexually transmitted infections", section on 'Vaccines'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Chlamydia and gonorrhea (The Basics)")

●Beyond the Basics topic (see "Patient education: Gonorrhea (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Importance of therapy – Antimicrobial treatment is required for all patients diagnosed with gonorrhea. It is a highly transmissible infection that can result in serious sequelae if untreated, even in asymptomatic individuals. The role of treatment is to resolve symptoms if present, prevent complications of infection, and decrease transmission to others. (See 'Therapeutic principles' above.)

●Selecting a treatment regimen

•Ceftriaxone as preferred therapy for gonorrhea – Ceftriaxone is standard of care for treatment of gonorrhea. It is highly effective against susceptible N. gonorrhoeae. Although isolates with decreasing susceptibility and resistance to cephalosporins have emerged, ceftriaxone has the lowest rates of gonococcal drug resistance. (See 'Antibiotic resistance' above.)

For suspected or confirmed uncomplicated gonococcal infection, we suggest a single intramuscular dose of ceftriaxone rather than any other regimen (Grade 2C). We suggest a ceftriaxone dose of 500 mg (or 1 g for patients ≥150 kg) rather than lower doses (table 1) (Grade 2C). Higher doses are used because of decreasing susceptibility. (See '"High" dose intramuscular (IM) ceftriaxone' above and 'Rectal infection' above and 'Pharyngeal infection' above.)

Uncomplicated infection is generally limited to the urogenital tract, anorectal tract, and/or oropharynx. Other regimens are used for complicated infections, which are characterized by disseminated infection (eg, bacteremia, gonococcal arthritis) or ascending spread to other organs (eg, pelvic inflammatory disease). (See 'Definition of uncomplicated infection' above and "Disseminated gonococcal infection", section on 'Management' and "Pelvic inflammatory disease: Treatment in adults and adolescents".)

•Plus presumptive treatment of chlamydia – Because of the high rate of coinfection, we also suggest presumptive treatment for C. trachomatis for individuals with gonorrhea unless it has been excluded through microbiologic testing (Grade 2C). Doxycycline 100 mg twice daily for seven days is the preferred regimen for treatment of C. trachomatis in nonpregnant individuals. Alternatives are listed in the table (table 1). (See 'Presumptive treatment for chlamydia' above.)

●Limited role for alternative regimens – These include other cephalosporins (including cefixime) and high-dose azithromycin with gentamicin, but all have drawbacks that limit their utility (table 1). They should be reserved for patients who have urogenital or anorectal infection and cannot take ceftriaxone because of unavailability or severe allergies. There is a high risk of failure with alternative regimens for oropharyngeal infection. (See 'Alternate regimens' above.)

●Test for and prevent other sexually transmitted infections (STIs) – Individuals diagnosed with gonorrhea should be tested for other STIs, including HIV, chlamydia, and syphilis, if not already done at the time of diagnosis (table 2). (See 'Screen for HIV and other STIs' above.)

Individuals newly diagnosed with gonorrhea are at increased risk for HIV infection and should be evaluated for pre-exposure prophylaxis against HIV if they test negative. (See "HIV pre-exposure prophylaxis".)

●Managing sex partners – Treatment of sex partners is essential for preventing reinfection and controlling the spread of infection. The following individuals should be presumptively treated for gonorrhea:

•Any sex partner within 60 days prior to the diagnosis of infection

•The most recent sex partner if sex last occurred >60 days before infection

For sex partners of patients with documented gonococcal infection who are unlikely to present for evaluation and treatment, we suggest expedited partner therapy (EPT) (Grade 2C). This entails providing a single dose of oral cefixime 800 mg (plus presumptive treatment for chlamydia if not ruled out in the index patient (table 1)) to sex partners.

The exception is in men who have sex with men, for whom we prefer direct evaluation and management after notification by the patient or public health department because of the high risk for coexisting infections, including HIV. (See 'Management of sexual partners' above.)

●Follow-up testing – This depends on the site of infection. (See 'Patient follow-up' above.)

•Urogenital or anorectal infection:

-If symptoms resolve with initial treatment, there is no need to test for cure. We retest after three months to evaluate for reinfection.

-If symptoms persist or recur shortly (eg, three to five days) after treatment completion, we retest for gonorrhea and other STIs to evaluate for coinfections, treatment failure, and reinfection.

•Oropharyngeal infection:

-We perform test of cure at the oropharynx, regardless of symptom resolution, at 7 to 14 days post-treatment to ensure eradication.

-We also retest after three months to evaluate for reinfection.

●Treatment failure – When evaluating suspected treatment failure, we submit specimens from all sites of exposure for both culture and nucleic acid amplification testing (NAAT), and culture isolates should be sent for susceptibility testing. These cases should also be reported to governmental public health agencies. The optimal management of suspected treatment failure to ceftriaxone is uncertain. (See 'Monitoring for and managing treatment failure' above.)

●Specific circumstances

•Pregnancy – Uncomplicated gonorrheal infection during pregnancy is treated the same as in the general population. Pregnant individuals should undergo retesting three months following therapy, and those at continued high risk for gonococcal infection should be retested during the third trimester. (See 'Pregnant women' above.)

•Penicillin allergy – The management of the penicillin-allergic patient depends upon the clinical suspicion of true allergy and the type of the allergy (eg, morbilliform rash versus IgE-mediated reactions, such as urticaria). Most patients with a penicillin allergy can still use ceftriaxone. (See 'Penicillin-allergic patients' above.)