National Guidelines on Diagnosis and Treatment of Gonorrhea in China (2020)#

National Center for STD Control, Chinese Centers for Disease Control and Prevention; Committee of STD, Branch of Dermatovenereology, Chinese Medical Association; Committee of STD, Chinese

Dermatologist Association; Qian-Qiu Wang1,∗, Rui-Li Zhang2, Quan-Zhong Liu3, Jin-Hua Xu4,

Xiao-Hong Su1, Yue-Ping Yin1, Shu-Zhen Qi1, Dong-Mei Xu5, Ping-Yu Zhou6, Yu-Ye Li7,

Xiao-Fang Li1, Min-Zhi Wu8, Xian-Biao Zou9, Li-Gang Yang10, Xiang-Sheng Chen1,

Xiang-Dong Gong1, Guo-Jun Liang1, Juan Jiang1, Hao Cheng11, Feng-Qin Ge1

1Hospital for Skin Diseases (Institute of Dermatology), Chinese Academy of Medical Sciences and Peking Union Medical College and National Center for STD Control, Chinese Centers for Disease Control and Prevention, Nanjing, Jiangsu 210042, China;2Department of Dermatology, Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, China;3Department of Dermatology, General Hospital of Tianjing Medical University, Tianjing 300052, China; 4Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040, China; 5Department of Neurology, Ditan Hospital of Capital Medical University, Beijing 100050, China; 6Department of Dermatology, Shanghai Hospital for Skin Disease and STD of Tongji University, Shanghai 200050, China; 7Department of Dermatology, The First Affiliated Hospital of Kunming Medical University,Kunming, Yunnan 650032, China; 8Department of Dermatology, The 5th People’s Hospital of Suzhou, Suzhou, Jiangsu 215007 China; 9Department of Dermatology, The First Affiliated Hospital of General Hospital of PLA, Beijing 100048, China; 10Department of Dermatology, The Skin Disease Hospital of Southern Medical University, Guangzhou, Guangdong 510091 China; 11Department of Dermatology, Sir Run Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310020, China.

Abstract Gonorrhea is one of the main sexually transmitted diseases in China. It mainly affects the genitourinary tract, and its clinical manifestations vary from asymptomatic to complicated types.The diagnosis of gonorrhea should be based on the patient’s epidemiological history,clinical manifestations,and laboratory examination results.Treatment should be prompt and standardized and should involve the recommended treatment regimens.Patients should be appropriately followed up after treatment.The antimicrobial resistance of gonococcal isolates has become a severe problem of clinical concern.In order to provide technical guidance of the diagnosis and treatment of gonorrhea for health care workers,the authors developed the guidelines based on the version of 2014,which will be of important in the standardizing medical care of gonorrhea, and further facilitating control and prevention of the disease.

Keywords: gonorrhea, diagnosis, treatment, guidelines

Introduction

Gonorrhea is a classic sexually transmitted disease caused by infection with the bacterium Neisseria gonorrhoeae(N.gonorrhoeae). It is characterized primarily by suppurative inflammation of the urogenital mucosa, and the most common manifestations are urethritis in men and cervicitis in women. The most frequent local complications of gonorrhea are epididymitis in men and pelvic inflammatory disease in women.Other sites of primary infection include the pharynx, rectum, and conjunctiva. Spread of N.gonorrhoeae through the blood can result in disseminated gonococcal infections,but these are rare in clinical settings.

Diagnosis

Epidemiological history

Factors associated with gonorrhea include high-risk sexual behavior,a history of multiple sexual partners or partners with gonococcal infections,and a history of close contact with patients who have gonorrhea.Gonorrhea in children may be associated with a history of sexual abuse, and gonorrhea in newborns is associated with infected mothers.1

Clinical manifestations

Uncomplicated gonorrhea

Uncomplicated gonorrhea in men

Gonococcal urethritis is the most common manifestation in men,although about 10%of infected men are asymptomatic.The incubation period ranges from 2 to 10 days,with an average of 3–5 days.Urethral discharge and dysuria are the most common symptoms in symptomatic patients,with some men experiencing urgency, frequent urination, or urinary itch. The urethral discharge in some patients becomes mucinous while also decreasing in volume,and a large amount of purulent discharge may appear several days after infection. In addition, the urethra of patients with gonorrhea becomes flushed and swollen. Patients with severe symptoms may develop balanoposthitis,in which the glans and prepuce appear red and swollen with exudation,erosion, edema, or even phimosis. Urethral fistulae and sinuses are occasionally observed. A small number of patients may experience posturethritis, swelling of the perineum, and/or painful penile erection at night. Even in untreated patients, obvious symptoms and signs generally decrease gradually after 10–14 days and largely disappear after one month; however, these patients are not cured.Gonorrheal infection cancontinue tospreadtothe posterior urethra or upper genital tract and may even be accompanied by complications.1-2

Uncomplicated gonorrhea in women

About 50%of women infected with N.gonorrhoeae have no obvious symptoms,making it difficult to determine the incubation period.

Cervicitis.Vaginal discharge is increased in volume and becomes purulent. The cervix becomes red and swollen,with mucopurulent discharge at the external os of the cervix. Some women may experience dyspareunia,vulvodynia, or itching.

Urethritis. Women with gonorrhea may experience dysuria, urgency, frequency, or hematuria. The urethral orifice may become flushed and swollen. Squeezing the urethra may release a small amount of purulent discharge.

Bartholinitis. Bartholinitis is usually unilateral and is characterized by localized swelling and sensations of heat and pain in the labia major.These symptoms may progress to abscess formation,fluctuation of symptoms,and severe pain. Bartholinitis may also be accompanied by systemic symptoms and fever.

Perianal inflammation. Women with gonorrhea may experience perianal flushing, mild edema, and purulent exudate with pruritus.1-2

Gonorrhea in children

Urethritis and balanoposthitis. These symptoms often occur in boys and are accompanied by dysuria and urethral discharge. Physical examination shows that the prepuce and urethra are red and swollen, and purulent discharge may be present.

Vulvovaginitis. Vulvovaginitis may occur in girls and can manifest as vaginal pain accompanied by frequency and urgency of urination as well as purulent discharge.Physical examination shows that the vulva, vagina, and urethra are red and swollen,with purulent discharge from the vagina and urethra.1-2

Complicated gonorrhea

Complicated gonorrhea in men

Epididymitis. Epididymitis in men with gonorrhea often manifests as unilateral epididymal swelling and severe pain. Reflex pain is present on the same side of the groin and lower abdomen.Physical examination shows swelling of one side of the scrotum; edema of the scrotal skin;redness, heat, and pain of the epididymis; and purulent discharge from the urethral meatus.

Seminal vesiculitis. Men with complicated gonorrhea may experience dysuria, frequency, and urgency of urination; terminal hematuria; hemospermia; and lower abdominal pain during the acute stage of the disease.Rectal examination can reveal enlarged seminal vesicles and severe tenderness.

Prostatitis. Men with complicated gonorrhea may experience chills, fever, dysuria, frequency and urgency of urination,terminal hematuria,purulent discharge from the urethral meatus,pain or discomfort in the perineumor suprapubic region, and rectal tenesmus during the acute stage of the disease. Rectal examination shows enlargement and tenderness of the prostate. Severely infected patients may experience acute urinary retention and/or prostatic abscesses.

Parafrenular gland (Tyson gland) inflammation or paraurethritis and abscesses. These symptoms are rare,observed in<1%of infected patients.1-2They are characterized by painful swelling on one or both sides of the frenulum and pus discharge through the glandular lumen.

Cowper gland inflammation and abscess. This complication is also rare, manifesting as perineal pain, acute urinary retention, and a tender mass on digital rectal examination.

Cellulitis and abscesses around the urethra. These symptoms are also rare, manifesting as pain and swelling on the side of the abscess and rupture to form a fistula around the urethra. Physical examination can reveal fluctuating,tender masses that may appear in the navicular fossa.

Urethral stricture. Urethral strictures are rare and caused by cellulitis,abscess,or fistulae around the urethra.This complication manifests as urinary tract infarction(difficulty urinating and dysuria), greater frequency of urination, and urinary retention.1-2

Complicated gonorrhea in women

Gonococcal cervicitis can lead to pelvic inflammation,including endometritis, salpingitis, ovarian cysts, pelvic peritonitis, pelvic abscesses, or perihepatitis. Gonococcal pelvic inflammation can cause infertility,ectopic pregnancy, chronic pelvic pain, and other adverse consequences.

Pelvic inflammatory disease.The clinical manifestations of this condition may be nonspecific, including systemic symptoms such as chills,fever(>38°C),anorexia,nausea,and vomiting. Patients may also experience lower abdominal pain,irregular vaginal bleeding,and abnormal vaginal discharge. Abdominal and pelvic examinations may show lower abdominal tenderness, cervical motion tenderness, adnexal tenderness, pelvic masses, and purulent discharge at the cervical os.

Perihepatitis. Perihepatitis is characterized by sudden pain in the upper abdomen,which may become aggravated by deep breathing and coughing. It may be accompanied by fever,nausea,vomiting,and other systemic symptoms.Palpation shows obvious tenderness in the right upper abdomen,and chest radiographs show a small amount of pleural effusion on the right side.1-2

Gonorrhea at other sites

Conjunctivitis

Gonococcal conjunctivitis often manifests as acute suppurative conjunctivitis. In newborns, gonococcal conjunctivitis appears 2–21 days after birth, and symptoms are usually bilateral.Inadults,gonococcalconjunctivitis canbeunilateral orbilateral.Inthiscondition,theconjunctivaiscongestedand edematous, with large amounts of purulent discharge; the sclera has clouding-like congestive erythema;and the cornea is turbid and foggy,with ulcers or perforations.

Pharyngitis

Gonococcal pharyngitis may occur via oral–genital intercourse. More than 90% of patients have no obvious symptoms, while others experience discomfort, burning,or pain in the pharynx.3Physical examination shows congestion of the pharyngeal mucosa with mucus or purulent discharge in the posterior pharyngeal wall.

Proctitis

Gonococcal proctitis may be due to anal–genital intercourse;in women,however,it may also be caused by anal contact with vaginal discharge. Most patients have no obvious symptom,although some may experience pruritus and burning of the anus, a mucinous or mucopurulent discharge from the anus, or a small amount of rectal bleeding. Severely infected patients have obvious symptoms of proctitis, including rectal pain, tenesmus, and bloody stool. Physical examination shows congestion,edema, and erosion of the anal and rectal mucosa.1-2

Disseminated gonorrhea

Disseminated gonorrhea in adults

This condition is rare in clinical settings.Affected patients often experience fever, chills, and general malaise, and arthritis–dermatitis syndrome is common. Patients with disseminated gonorrhea may develop a hemorrhagic or pustular skin rash at the extremities, often involving the small joints of the fingers,wrists,and ankles.Some patients may experience joint pain, tenosynovitis, or suppurative arthritis, and some may develop gonococcal meningitis,endocarditis, pericarditis, or myocarditis.4-5

Neonatal disseminated gonorrhea

This condition is also rare. Neonates with disseminated gonorrhea may develop gonococcal septicemia, arthritis,or meningitis.4-5

Laboratory examinations

Microscopy

Gram-stained male urethral discharge smears that show gram-negative diplococci inside polymorphonuclear cells is diagnostic for uncomplicated gonorrhea in men, with a sensitivity of ≥95% and a specificity of 97%. Gram staining is not recommended for the diagnosis of other types of gonococcal infection, including pharyngeal and rectal infection in men and women and cervical infection in women.6-7

Culture

Culture is the test of choice for the diagnosis of gonorrhea.It is suitable for the examination of all clinical specimens except urine in both men and women.N.gonorrhoeae can be preliminarily identified by colony patterns, Gram staining of cultures, and oxidase tests; identification can be confirmed by sugar fermentation and chemical reactions if necessary. Culture methods have a specificity of 100% and a sensitivity of 85%–95%. Moreover,cultured gonococcal isolates can be preserved for antimicrobial sensitivity tests.6-7

Nucleic acid tests

Nucleic acid tests have higher sensitivity than culturing and are thus appropriate for the detection of various types of clinical specimens. N. gonorrhoeae DNA and RNA can be detected by polymerase chain reaction.8These tests should be performed in specific nucleic acid amplification laboratories approved by relevant authorities.

Diagnostic classification

The diagnostic classification of gonorrhea should be based on a comprehensive analysis of the patient’s epidemiological history, clinical manifestations, and laboratory test results.Caution should be exercised,however,in making a diagnosis.

Patients with suspected gonorrhea

Patients suspected of having gonorrhea are those with an appropriate epidemiological history and clinical manifestations.

Patients with confirmed gonorrhea

Patients confirmed as having gonorrhea are those with an appropriate epidemiological history and clinical manifestations who also have positive results on one or more laboratory tests.

Treatment

General principles of treatment

The general principles of treatment include timely,sufficient, and regular administration of medications;the use of regimens recommended for specific manifestations in individual patients; follow-up after treatment;and notification and treatment of each patient’s sexual partners. Patients should also be told to avoid sexual contact before they or their partners complete their treatment courses. Attention should be paid to infection with multiple pathogens. Generally, patients with gonorrhea should be tested for Chlamydia trachomatis infection or administered agents to treat C. trachomatis, since coinfection with C. trachomatis is detected in 10%–40%of people with gonorrhoea.9–13Patients should also undergo serological testing for syphilis and human immunodeficiency virus, and they should be counseled about the risks of these diseases.

Recommended treatment regimens

Uncomplicated gonorrhea

Patients with gonococcal urethritis,cervicitis,and proctitis should receive a single dose of 1g ceftriaxone administered intramuscularly or intravenously, or a single dose of 2g spectinomycin(4g for patients with gonococcal cervicitis)administered intramuscularly. Alternative treatments include a single intramuscular dose of 1g cefotaxime or another third-generation cephalosporin.If C.trachomatis infection cannot be excluded, an additional anti-C.trachomatis treatment is warranted.1,14-15

In recent years, strains of gonococci with decreased sensitivity to broad-spectrum cephalosporins and greater antimicrobial resistance have emerged in many regions worldwide.16-17Gonorrhea treatment guidelines of the World Health Organization and the United States Centers for Disease Control and Prevention as well as guidelines in Europe have recommended treatment with both ceftriaxone and azithromycin.14-15,18Because surveillance data showed that 18.6%of N.gonorrhoeae isolates from 2013 to 2016 were resistant to azithromycin, this agent is no longer recommended for first-line treatment in China. In addition,10.8%of isolates showed decreased sensitivity to ceftriaxone, and cephalosporin-resistant N. gonorrhoeae isolates (ST1407 and FC428) were also identified in China.19-20Therefore, it is important to monitor the epidemiology of antimicrobial resistance and the clinically curative effects of various antimicrobials and to adjust treatment regimens to prevent treatment failure.21–28Because nonresponse to the recommended dose of ceftriaxone may indicate reinfection or treatment failure,antimicrobial sensitivity should be tested. Patients confirmed to have undergone failed treatment can be treated with an increased dose of ceftriaxone (consisting of 1–2g injected intramuscularly or administered intravenously for three days). Alternatively, patients can be switched to spectinomycin treatment or administered a single intramuscular injection of 240,000 IU of gentamicin.29-30

Gonorrhea in children

Children weighing≥45kg should be treated as adults.Children weighing<45kg should be treated with a single intramuscular injection of 25–50mg/kg of ceftriaxone(maximum dose not exceeding the adult dose) or a single intramuscular injection of 40mg/kg spectinomycin(maximum dose of 2g). If Chlamydia infection cannot be excluded, an additional anti-C. trachomatis treatment is warranted.

Gonococcal epididymitis, prostatitis, and seminal vesiculitis

Patients with these conditions should be administered 1g ceftriaxone intramuscularly or intravenously once daily for 10 days. Alternatively, these patients can be treated with 1g cefotaxime intramuscularly once daily for 10 days. If C. trachomatis infection cannot be excluded,patients should also be administered 100mg oral doxycycline twice daily for 10–14 days.

Gonococcal pelvic inflammatory diseases

The regimen recommended for outpatients is administration of 1g ceftriaxone intramuscularly or intravenously once daily for 10 days plus 100mg doxycycline orally twice daily for 14 days and 400mg metronidazole orally twice daily for 14 days.

Several inpatient treatment regimens have been recommended for patients with severe illness. Recommended Regimen A for hospitalized patients includes 1g ceftriaxone,injected intramuscularly or intravenously once every 24hours, or 2g cefotetan, injected intravenously once every 12hours, plus100mg doxycycline, administered intravenously or orally every 12hours.Note:If the patient can tolerate it,doxycycline should be administered orally.The duration of cefotetan treatment should not be less than one week, as long as the patient’s condition allows.Patients who show improvements in clinical symptoms within 72hours after treatment should discontinue parenteral treatment during the first week.These patients should be treated with 100mg oral doxycycline twice daily plus 400mg oral metronidazole twice daily for a total of 14 days of treatment.

Recommended Regimen B includes 900mg clindamycin injected intravenously once every 8hours, plus a loading dose of 2mg/kg gentamicin injected intravenously or intramuscularly, followed by a maintenance dose of 1.5mg/kg gentamicin once every 8hours or once a day.Please note that patients who show improvements in clinical symptoms within 24hours can stop parenteral treatment;they should then be treated by oral administration of 100mg doxycycline twice daily or 450mg clindamycin four times daily for 14 consecutive days. Intravenous doxycycline may induce pain at the injection site and has no advantage over oral doxycycline in patients who tolerate the latter. Pregnant and lactating women should avoid tetracycline and doxycycline, and metronidazole should be avoided during the first trimester of pregnancy.1,31

Gonorrhea at other sites

Gonorrheal conjunctivitis

Newborns should be treated with 25–50mg/kg intravenous or intramuscular ceftriaxone once daily for three consecutive days, with the total dose not exceeding 125 mg.Children weighing <45kg should be treated with 50 mg/kg ceftriaxone administered intramuscularly or intravenously once daily for three days,with a maximum dose of 1g. Children weighing ≥45kg should be treated with the regimen for adults, consisting of 1g ceftriaxone administered intramuscularly or intravenously once daily for three days or 2g intramuscular spectinomycin once daily for three days.The eyes should be washed every hour with normal saline. Spectinomycin should not be administered to newborns.Mothers of infected newborns should be examined,and those with gonorrhea should be treated.Newborns should be hospitalized and checked for disseminated infection.

Gonorrheal pharyngitis

Patients with gonococcal pharyngitis should be treated with a single dose of 1g ceftriaxone administered intramuscularly or intravenously or a single dose of 1g cefotaxime administered intramuscularly.If C.trachomatis infection cannot be excluded, additional anti-C.trachomatis treatment is warranted. Spectinomycin is not recommended because of its poor efficacy in patients with gonococcal pharyngitis.

Disseminated gonorrhea

Newborns should be treated with 25–50mg/kg/day ceftriaxone administered intravenously or intramuscularly once daily for 7–10 days;if meningitis is present,treatment should continue for up to 14 days.Children weighing<45 kg are treated for gonococcal arthritis with 50mg/kg ceftriaxone administered intramuscularly or intravenously once daily for 7–10 days. Children weighing <45kg are treated for gonococcal meningitis or endocarditis with 25 mg/kg ceftriaxone administered intramuscularly or intravenously twice daily for 14 days (meningitis) or 28 days(endocarditis). Children weighing >45mg are treated similarly as adults. Hospitalization is recommended to check for endocarditis or meningitis.Treatment consists of 1g ceftriaxone administered intramuscularly or intravenously once daily for at least 10 days. Patients with gonococcal meningitis should be treated for about two weeks,and those with gonococcal endocarditis should be treated for more than four weeks. If C. trachomatis infection cannot be excluded, additional anti-C. trachomatis treatment is warranted.Note:Open drainage is not necessary for patients with gonococcal arthritis except for those with gonococcal arthritis of the hip joint. Joint exudates, however, should be repeatedly aspirated. Antibiotics should not be directly injected into joint cavities.Nonsteroidal anti-inflammatory drugs can relieve pain and help prevent recurrent joint exudate.

Gonorrhea during pregnancy

Treatment regimens in pregnant women are dependent on the type of infection,although erythromycin or amoxicillin is recommended for pregnant women with suspected or confirmed C. trachomatis coinfection. Pregnant women should never be treated with fluoroquinolones or tetracycline32

Follow-up

Following treatment with the recommended regimens,patients with uncomplicated gonorrhea in the genitourinary tract should be screened by gonococcus culture if they experience persistent symptoms or signs of gonorrhea,gonococcal infection of the pharynx,pelvic inflammatory disease or disseminated gonococcus infection,or infection during pregnancy. Patients who have sexual contact with untreated sexual partners should also be screened, as should all children who have been treated for gonorrhea.N.gonorrhoeae cultures should be performed at least five days after the completion of treatment, and nucleic acid amplification tests should be performed at least three weeks after treatment completion. Treatment failure or infection with antimicrobial-resistant strains should be reported.

The diagnosis and treatment of gonococcal epididymitis should be reevaluated if the symptoms do not improve significantly within three days after treatment. Patients with gonococcal pelvic inflammatory disease should be followed up within three days after treatment, although patients with fever should be followed up within 24hours.If their condition does not improve, they should be admitted to the hospital. Patients should experience obvious clinical improvement within three days (abatement of fever, abdominal or adnexal tenderness, or cervical motion tenderness).Patients who do not improve within three days may need to be admitted to the hospital for treatment, other diagnostic tests,or surgical consultation.Patients with gonococcal meningitis and endocarditis should be referred to an appropriate specialist.

Sexual partner management

Adult patients with gonorrhea are required to have their sexual partners checked and treated for gonorrhea. All individuals who had sexual contact with the patient before the onset of symptoms or within two months before diagnosis should be notified and examined for N.gonorrhoeae and C. trachomatis. Patients should be instructed to avoid sexual intercourse before treatment is completed or when they and their partners still have symptoms.When a neonate is diagnosed with gonococcal infection, the mother of the infant and all of her sexual partners within two months before delivery should be examined and treated.Men who have sexual contact with women who have gonococcal pelvic inflammatory disease within two months before the appearance of symptoms should be examined and treated, even if they are asymptomatic.

Source of funding

This study was supported by the Union Innovation Project of the Chinese Academy of Medical Sciences (No. 2016-I2M-3021)and the National Natural Science Foundation of China (No. 81772209 and No. 81601804).