Disseminated gonococcal infection

INTRODUCTION — Disseminated gonococcal infection (DGI) results from bacteremic spread of the sexually transmitted pathogen, Neisseria gonorrhoeae, which can lead to a variety of clinical symptoms and signs, such as arthritis or arthralgias, tenosynovitis, and multiple skin lesions.

This topic will discuss the epidemiology, pathophysiology, clinical manifestations, diagnosis, and treatment of DGI. The clinical manifestations, diagnosis, and treatment of uncomplicated gonococcal infection (eg, cervicitis and urethritis) are discussed elsewhere. (See "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents" and "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents" and "Epidemiology and pathogenesis of Neisseria gonorrhoeae infection".)

EPIDEMIOLOGY — Disseminated gonococcal infection (DGI) is estimated to occur in 0.5 to 3 percent of patients infected with N. gonorrhoeae [1-3].

Most patients with DGI are younger than 40 years of age, although DGI can occur in any age group. Historically, DGI occurred more frequently in females than males; however, that sex ratio may be reversing, with increases in gonococcal infection in general among males, and because DGI might be more common among individuals with HIV (of whom males comprise the majority in North America and Western Europe) [1,4-11].

DGI is considered a common cause of acute polyarthralgias, polyarthritis, or oligoarthritis in young, otherwise healthy patients. Although Staphylococcus aureus is the most common cause of monomicrobial septic arthritis overall, among sexually active adults, N. gonorrhoeae is the most common causative organism [12]. Nevertheless, the overall proportion of septic arthritis cases that are due to N. gonorrhoeae is low. In case studies from Europe during the 1990s, N. gonorrhoeae was the causative organism in 1.7 percent in a series from France [13], 0.6 percent in a series from the United Kingdom [14], and 0 percent from a three-year prospective community-based study in the Netherlands [15]. In a retrospective study of 34 cases of musculoskeletal infections among intravenous drug users in Spain, N. gonorrhoeae was the causative agent in 2.9 percent [16]. The prevalence of gonococcal arthritis may be higher in the United States than in the United Kingdom [17]. Gonococcal arthritis appears to be more prevalent in more resource-limited settings, although there are limited epidemiologic studies from such regions [6].

PATHOPHYSIOLOGY AND PREDISPOSING FACTORS — The probability that a localized gonococcal infection will spread to joints and other tissues depends upon specific host, microbial, and possibly immune factors.

Host factors — A history of recent symptomatic genital infection is uncommon in individuals with disseminated gonococcal infection (DGI); asymptomatic mucosal infection is thought to increase the risk of dissemination due to delayed diagnosis, resulting in delays in antibiotic treatment [6,18]. Other risk factors for DGI include the following:

●Recent menstruation – The association between menstruation and DGI may be due to several factors [19]:

•Menses is associated with phenotypic changes of N. gonorrhoeae from opaque strains to transparent strains (those with altered membrane protein expression) [20]. Transparent strains may be less sensitive to lysis by trypsin, less adherent to neutrophils [21], and may also be more adherent to fallopian tubes [22].

•Genital secretions during menses are more alkaline, which may facilitate gonococcal growth [23].

•Increased concentrations of transferrin and heme at mucosal surfaces during menstruation may be used as a source of iron by N. gonorrhoeae [24].

●Pregnancy or the immediate postpartum state [25,26] – The risk of DGI associated with pregnancy is postulated to result from normal immunological changes during pregnancy, such as alterations in cell-mediated immunity and increased vascularity, which may predispose to N gonorrhoeae invasion [27,28].

●Congenital or acquired complement deficiencies (C5, C6, C7, or C8) [27,29] – Select complement deficiencies predispose to DGI as a result of decreased complement-mediated killing of N. gonorrhoeae; up to 50 percent of patients with C6, C7, or C8 complement deficiencies may develop bacteremia with pathogenic Neisseria species [29]. Further, among patients with DGI, there is a notable prevalence of complement deficiency, with estimates between 4 and 13 percent [18,30]. Complement deficiencies also predispose to recurrent, and perhaps subacute or even chronic infections [31].

●Systemic lupus erythematosus (SLE) – SLE may predispose to DGI; however, conflicting reports exist [32,33]. Mechanisms that could potentially explain an association between SLE and DGI include complement depletion as a result of immune complex deposition [34], a possible association between SLE and inherited complement deficiencies [35], and use of immunosuppressive medications [36]. Given that the range of symptoms seen with DGI and SLE flares overlap, a high index of suspicion for DGI is warranted in patients with SLE [36,37]. (See 'Clinical suspicion' below.)

●Eculizumab – Eculizumab is a monoclonal antibody to C5 that is used in certain conditions, such as complement-mediated hemolytic uremic syndrome, and has been associated with severe meningococcal infections. Theoretically, eculizumab could also increase the risk of DGI given the risk with other acquired complement deficiencies. There have been sporadic reports of DGI among patients treated with eculizumab [38-40]. Between 2004 and 2017, eight such cases were reported to the US Food and Drug Administration from the United States, Canada, and Europe [40]. Seven patients had positive blood cultures.

Microbial factors — N. gonorrhoeae contain a variety of virulence and growth factors associated with an increased propensity to cause DGI:

●Porins – Porins are outer membrane structures. Porin B isoform 1A (PorB_1a) differs from the other existing isoform (PorB_1b), and the presence of PorB_1a has been associated with increased serum resistance and a capacity to cause DGI under low-phosphate conditions [41-43]. The exchange of arginine for histidine at locus 92 is highly conserved among PorB_1a isolates, and not among PorB_1b isolates; PorB_1b isolates thus have a serine residue with resulting loss of the invasive phenotype [44]. A proposed mechanism for the increased invasive capacity of PorB_1a involves regulatory complement factor H (fH) and C4 binding protein with preferential binding to strains expressing PorB_1a, which correlates with an increased conversion of C3b to iC3b and, thus, decreased complement-mediated killing. Furthermore, fH binds sialylated lipopolysaccharide and is responsible for further inactivation of C3b and alternative pathway-mediated killing [42,45-47]. Additional work has shown that N. gonorrhoeae invades epithelial cells via the scavenger receptor expressed by endothelial cells (SREC-I) in a manner that is dependent on PorB_1a [48]. That invasion, and potentially a starting point for dissemination, is further dependent on host cell membrane rafts [49].

●Auxotype – Strains of N. gonorrhoeae requiring arginine, hypoxanthine, and uracil (AHU auxotype) have been associated with DGI [50,51]. That association may be due to increased resistance to complement-mediated killing, thus conferring serum resistance. Importantly, strains with that auxotype may be clonal, and thus with varying distributions across the world [52,53]. Additionally, the PorB_1a isoform is found in most strains with the AHU auxotype [41,54].

●Genetic island with virulence factors – A genetic island unique to N. gonorrhoeae has been described, which can exist in different forms. One form contains a gene known as sac-4 and a peptidoglycan hydrolase gene (atlA). Isolates with genetic islands containing both sac-4 and atlA have been found preferentially in strains that cause dissemination. It is thought that sac-4 may augment the ability of N. gonorrhoeae to survive in the blood stream, and atlA may increase DNA exportation facilitating transformation and/or may increase the level of cytotoxic peptidoglycan fragments, potentially augmenting the immune response [55]. Notably, in that study, the presence of sac-4 correlated with the AHU auxotype.

●Colony opacity proteins – N. gonorrhoeae express colony opacity (OpaCEA) proteins, which bind to carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), resulting in colony formation at mucosal surfaces [56]. CEACAM-3 in particular, however, is expressed on human granulocytes and is responsible for uptake and subsequent destruction of N. gonorrhoeae organisms expressing OpaCEA [57-59]. Analysis of N. gonorrhoeae isolated from patients with disseminated infection revealed expected CEACAM binding, with the exception of CEACAM-3, indicating another potential source for immune evasion [60]. Similarly, another study found that transmigration of the epithelial cell layer by N. gonorrhoeae was limited by Opa protein expression, and that bacteria without Opa proteins expressed were able to invade [61].

●Lipid A – Lipid A is a component of lipooligosaccharide (LOS), a potent stimulator of the host immune response; the addition of phosphoethanolamine to lipid A is associated with resistance to innate host serum defenses and to polymyxin B [62].

●Pili variation – Pili are filamentous structures on the surface of Neisseria species. Genetic variation among pili is important for immune evasion and may contribute to tissue tropism [63,64]. Pilin galactosyl transferase (pgtA) can have two forms, one with a poly-G tract, which can undergo phase variation, while the second type does not have poly-G tract and is expressed constitutively without any variation. According to one study, most uncomplicated infections lack the poly-G in pgtA. Isolates with a poly-G tract (ie, those that can undergo phase variation), have been highly associated with DGI [65]. The mechanism by which a phase-variable pgtA gene increases the propensity for dissemination may involve: 1) immune evasion by turning off expression of pgtA, thus reducing antigenic exposure to serum antibodies; 2) increased molecular mimicry of variable pgtA proteins [65]; and 3) microcolony destabilization of local infection [49]. Importantly, a subsequent study in a larger, more diverse set of gonococcal isolates was unable to reproduce those findings [66], thus making the role of pgtA on N. gonorrhoeae dissemination uncertain. Work on porins has postulated that loss of microcolony stabilizing pili via phase variation may favor invasion in a PorB_1a – SREC-I-dependent manner [49].

Immune factors — The immunopathogenesis of DGI is uncertain. The hypothesis that inflammation rather than direct microbial invasion causes the clinical findings of DGI is supported by the frequent lack of N. gonorrhoeae growth from blood, skin, and synovial fluid cultures during disseminated infection (see 'Laboratory and microbiologic testing' below). Fastidious growth requirements of N. gonorrhoeae could explain the sterile cultures, and more sensitive testing methods (such as immunofluorescence or molecular techniques) have identified organisms in synovial and skin samples that were culture negative [67-71]. Nevertheless, persistent synovitis in DGI can occur in culture and PCR-negative joints, and organisms can often be cultured from the genitourinary tract or other local sites in most cases of DGI, despite negative cultures elsewhere [72,73]. Thus, the sterile synovitis, tenosynovitis, and dermatitis associated with DGI may not always require viable N. gonorrhoeae, and other inflammatory mechanisms may be important.

Immune complex deposition may play a role; however, studies attempting to identify immune complexes among patients with DGI report conflicting results [74-76]. The observation that N. gonorrhoeae cell wall components can induce inflammation and arthritis in animal studies also supports an immune component to DGI [77]. Components of the cell wall and membrane stimulate the immune response and may remain as soluble factors that perpetuate inflammatory mediators with the potential to combat the infection and damage protective mucosa, perhaps facilitating bacterial invasion and dissemination [78].

CLINICAL MANIFESTATIONS

Spectrum of findings — Most patients with disseminated gonococcal infection (DGI) report feeling well up to the onset of the illness. Upon presentation, a range of clinical findings associated with DGI has been described (table 1) [5,18]. Those can be divided into two groups:

●A triad of tenosynovitis, dermatitis, and polyarthralgia without purulent arthritis (also called the "arthritis-dermatitis syndrome"). Those findings occur frequently in patients with DGI [6]. (See 'Tenosynovitis, dermatitis, polyarthralgia (also called arthritis-dermatitis syndrome)' below.)

●Purulent arthritis with or without associated findings. Fewer than 50 percent of patients with DGI present with actual arthritis [6]. (See 'Purulent arthritis' below.)

Those two classic forms may represent a spectrum of DGI [79]. Most patients who develop suppurative arthritis have not had preceding polyarthralgia or skin lesions, although patients with the polyarthralgia syndrome can develop purulent arthritis later in the disease course if not recognized and treated [23]. The pathogenic mechanism responsible for the strikingly different clinical presentations is poorly understood, although it may in part depend upon differences in the infecting strain of the organism.

Patients with either of the above clinical syndromes usually do not simultaneously manifest signs and symptoms of a gonococcal infection involving mucous membranes, even though localized infection of the urethra, cervix, rectum, or pharynx typically precedes the onset of DGI.

Other manifestations, such as endocarditis [80,81], myopericarditis [82], meningitis [26,83,84], osteomyelitis [85], abscesses [86,87], and vasculitis [88], can also occur. Those can occur either in isolation or in addition to the more typical manifestations of DGI. However, those complications are so rare that they will not be discussed in this topic review.

Tenosynovitis, dermatitis, polyarthralgia (also called arthritis-dermatitis syndrome) — This form of DGI generally occurs within two to three weeks of the primary infection and is characterized by the following features [18,89]:

●Fever, chills, and generalized malaise – These occur in the acute phase of infection. Fever may spontaneously disappear or diminish in magnitude as the disorder progresses, and so is not uniformly observed. As an example, in a study of 112 women with DGI, approximately 60 percent had a temperature >100.4°F (>38°C) on presentation [5].

●Polyarthralgia – This can involve small or large joints. Several joints can be affected, but symmetric joint involvement is uncommon. A distinguishing feature is the migratory nature of the arthralgias compared with other causes of septic arthritis [18,90].

●Tenosynovitis – This is a relatively common finding that is unique to DGI and is unusual in other forms of infectious arthritis [18,90]. It often involves multiple tendons simultaneously, particularly at the wrist, fingers, ankle, and toes [90]. (See "Infectious tenosynovitis", section on 'Clinical manifestations'.)

●Dermatitis – Skin findings are common and occur in approximately 75 percent of cases [23]. Typical lesions are painless, and patients may be unaware of them. Lesions are usually pustular or vesiculopustular (picture 1 and picture 2 and picture 3) [91], although hemorrhagic macules, papules, bullae, or nodules rarely occur. Rarely, patients with DGI can develop lesions that are urticarial or that resemble erythema nodosum or erythema multiforme [23]. It is common to find between 2 and 10 lesions in an individual patient; there are rarely more than 40 lesions. They typically occur on the distal extremities and are rarely present on the face [23]. Pustular or vesicular skin lesions are often transient and often last for only three to four days, even without treatment. (See "Cutaneous manifestations of gonorrhea", section on 'Disseminated gonococcal infection'.)

Purulent arthritis — Patients with this form of DGI typically present with abrupt onset of mono- or oligoarthritis, with pain and swelling in one or more joints. Gonococcal arthritis generally involves distal joints, with knees, wrists, and ankles the most commonly involved joints [6,23]. Axial involvement is rare, although cases with glenohumeral joint and sternoclavicular joint involvement have been reported [25,85,92-96]. Polyarthritis, when present, is typically asymmetric. Most patients are afebrile.

As noted above, a small number of patients with purulent arthritis may also have tenosynovitis or skin lesions. (See 'Tenosynovitis, dermatitis, polyarthralgia' below.)

EVALUATION

Clinical suspicion — The possibility of disseminated gonococcal infection (DGI) should be considered in sexually active individuals (particularly those younger than 40 years, those with multiple partners, and all men who have sex with men) who present with arthralgias or joint pain concerning for septic arthritis. A low threshold for suspicion is important since not all patients will report sexual activity, and DGI has been reported in older adults [97], whom providers may assume not to be sexually active.

Accompanying skin lesions, particularly pustular or vesiculopustular lesions, and/or tenosynovitis (tenderness along the flexor sheath or pain with passive extension) should heighten suspicion for DGI.

Given that the range of symptoms seen with DGI and systemic lupus erythematosus (SLE) flares overlap and that some reports suggest an increased risk of DGI among patients with SLE, a high index of suspicion for DGI is warranted in patients with SLE.

History and physical examination — Patients suspected of having DGI should undergo a complete history and physical examination. In addition to evaluating for the typical clinical manifestations of joint involvement with or without skin findings discussed above (see 'Clinical manifestations' above), a thorough sexual history should be performed. Most patients with DGI have a history of recent sexual activity, although this may not be elicited in all, which highlights the importance of patient-provider trust and a nonjudgmental attitude. Furthermore, only a minority of patients report having recently had a sexually transmitted infection (STI), but some may report a more remote STI diagnosis. Among women, the timing of the last menstrual period and the possibility of pregnancy should be assessed.

A careful physical examination is often needed to detect the characteristic skin lesions of DGI (picture 1 and picture 2 and picture 3). Typical lesions may be mistakenly dismissed as unimportant furuncles or pimples by the patient or clinician. (See "Cutaneous manifestations of gonorrhea", section on 'Disseminated gonococcal infection'.)

Careful evaluation of the joints is also important. It is not unusual to see patients with only one or two joints that are involved. Small or large joints may be affected, and symmetric joint involvement is uncommon [92]. Tenosynovitis is often visible to the examining clinician, with redness and warmth along the tendon sheath. Its presence can usually be confirmed by eliciting pain along the tendon sheath with active or passive joint movement.

In addition, signs suggestive of rare DGI complications, such as meningitis or endocarditis should be sought, with further testing (eg, lumbar puncture or echocardiography) in patients with concerning findings on exam. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

The general approach to history and physical examination in patients with joint pain is discussed in further detail elsewhere. (See "Evaluation of the adult with polyarticular pain", section on 'History' and "Evaluation of the adult with polyarticular pain", section on 'Physical signs'.)

Laboratory and microbiologic testing — Several specimens are collected for testing in patients with suspected DGI; culture of blood, synovial fluid, and skin lesions are frequently negative.

●Blood cultures – At least two sets of blood cultures should be obtained. Cultures are diagnostic when positive and are also helpful in separating DGI from other conditions, such as septic arthritis due to Neisseria meningitidis or S. aureus, both of which may mimic the clinical features of DGI. The reported frequency of blood culture positivity in various case series ranges from 4 to 70 percent of cases [4,18,98,99]. Patients with the tenosynovitis, dermatitis, and polyarthralgia form of DGI may be more likely to have positive blood cultures, as such symptoms may reflect an earlier, bacteremic stage of disease [18,99].

●Specimens from mucosal sites – Patients with the clinical features of DGI should have urogenital, rectal, and pharyngeal specimens submitted for microbiologic testing for N. gonorrhoeae. Often, patients with DGI have evidence of infection at urogenital, rectal, or pharyngeal sites despite lack of symptoms at these sites [4,23]. Nucleic acid amplification testing (NAAT) is the preferred diagnostic test [100]. If culture is used, any specimens submitted for culture should be processed on Thayer-Martin media. The optimal urogenital specimen depends on the type of testing performed. Urine (for men) and self-collected vaginal swabs (for women) are the preferred specimens for NAAT, and urethral and cervical swabs are the preferred specimens for culture. (See "Clinical manifestations and diagnosis of Neisseria gonorrhoeae infection in adults and adolescents", section on 'Diagnostic techniques'.)

If associated urethritis is simultaneously present, a Gram stain of the urethral exudate should be obtained and examined for the presence of the gram-negative diplococci characteristic of N. gonorrhoeae infection. (See "Urethritis in adult males", section on 'Diagnosis'.)

●Synovial fluid – Synovial fluid should be sent for analysis in all patients with suspected DGI who have an accessible joint effusion. Synovial fluid is generally sent for cell count, differential, Gram stain, and bacterial culture, and the laboratory should be alerted that gonococcal infection is a consideration so that the specimen can be processed and plated appropriately. For those with purulent arthritis, cultures for N. gonorrhoeae may only be positive in approximately 50 percent of cases or less [4,18,98]. Cultures are even less likely to be positive for those who present with the tenosynovitis, dermatitis, and polyarthralgia, even if synovial fluid can be obtained. NAAT appears more sensitive than culture of synovial fluid in patients with gonococcal arthritis [68,69], and should also be performed if available. However, in certain settings, even if available for other specimens, NAAT may not be verified for use on synovial fluid.

The mean synovial fluid leukocyte count in septic arthritis is typically around 50,000 cells/microL [101,102]; in some cases of gonococcal arthritis, however, lower counts can be observed (approximately 20,000 cells/microL) (table 2). Chemistry studies of the joint fluid, such as the concentrations of glucose, lactate dehydrogenase (LDH), or protein, have only limited value; a reduction in glucose concentration and elevation of LDH are consistent with a bacterial infection but are not diagnostic or particularly sensitive [103]. (See "Synovial fluid analysis".)

●Skin lesion specimens – Laboratory testing of skin lesion samples is not typically part of the workup for DGI. Many associated skin lesions are not amenable to drainage and sampling. If pustular skin lesions are present, specimens from these lesions can be sent for Gram stain and gonococcal culture, but the yield of these is often low; in one study, culture was positive in 10 percent [98]. NAAT has also been used successfully on skin specimens [71], but this test may not be widely available for this type of specimen.

If N. gonorrhoeae is isolated on culture from any specimen, antimicrobial susceptibility testing should also be performed.

Screening for other sexually transmitted infections — In addition, all patients with known or suspected DGI should undergo testing for other sexually transmitted infections, such as HIV infection, hepatitis B infection, Chlamydia trachomatis, and syphilis, since coexistent infection with other sexually transmitted pathogens is common. (See "Screening for sexually transmitted infections".)

DIAGNOSIS — The definite diagnosis of disseminated gonococcal infection is made by identification of N. gonorrhoeae (either through nucleic acid testing or culture) on a specimen of blood, synovial fluid or tissue, skin lesion, or other non-mucosal site. If those specimens are negative, the presumptive diagnosis can be made in a patient with microbiologic evidence of N. gonorrhoeae from mucosal (urogenital, rectal, or pharyngeal) specimens and a clinical presentation consistent with disseminated infection.

In cases where all microbiologic tests are negative, the diagnosis is assumed based on a consistent clinical presentation, absence of alternative cause, and response to appropriate therapy.

DIFFERENTIAL DIAGNOSIS — An array of other infectious and noninfectious diseases may mimic disseminated gonococcal infection (DGI).

●Septic arthritis – Acute purulent arthritis due to other bacteria (such as S. aureus) can occur in young, sexually active patients, particularly if they have underlying risk factors, such as injection drug use. Those infections may present with monoarthritis or oligoarthritis, fever, and chills. Identification of an organism on bacterial culture of synovial fluid should distinguish those infections from DGI. (See "Septic arthritis in adults".)

Primary purulent arthritis caused by N. meningitidis is uncommon [104-106], but its presentation may be near identical to that of DGI, and the organisms cannot be differentiated on Gram stain. However, meningococcal infection is usually a more severe disease than DGI, and most patients with meningococcal arthritis also have clinical signs of sepsis or concurrent meningitis.

●Sexually transmitted infections – Patients with suspected DGI should be considered at risk for other sexually transmitted infections (STIs), some of which can present with similar symptoms. Since those STIs can coexist with DGI, STI screening should be performed even if the diagnosis has been established. (See 'Screening for other sexually transmitted infections' above.)

•Hepatitis B virus (HBV) infection – Patients with acute HBV infection may develop fever, chills, polyarthritis, tenosynovitis, and rash. However, the associated rash is typically urticarial, and synovial fluid analysis usually shows noninflammatory fluid. Furthermore, the arthritis associated with HBV is more often polyarticular and symmetric. In addition to those clinical features, patients with HBV infection can usually be distinguished from those with DGI by the presence of elevated serum aminotransaminases and evidence of acute HBV infection on serologic testing.

•HIV – Patients with acute HIV infection can develop rash, fever, chills, and arthralgias. However, joint effusions are uncommon in acute HIV infection, the rash is usually generalized, and mucous membrane involvement is often a dominant finding. All patients with suspected DGI should also be tested for HIV infection. (See "Acute and early HIV infection: Clinical manifestations and diagnosis".)

•Syphilis – Secondary syphilis may occasionally be confused with DGI. However, the rash of secondary syphilis usually consists of generalized, maculopapular lesions. Involvement of the palms and soles and generalized lymphadenopathy are also clues to the presence of syphilis. (See "Syphilis: Screening and diagnostic testing".)

•Herpes simplex virus (HSV) – Primary HSV infection with genital and extragenital lesions can mimic the skin lesions that occur in DGI [107]. Those can be distinguished by direct viral testing of the lesions. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Diagnosis'.)

●Mpox – In the context of the 2022 global mpox (previously referred to as monkeypox) outbreak, in which person-to-person transmission among men who have sex with men has been a primary means of infection, individuals at risk for DGI may also be at risk for mpox. The prodromal systemic symptoms and skin lesions associated with mpox are similar to those that can occur with DGI. The possibility of mpox should be suspected in individuals being evaluated or treated for DGI because of skin lesions if they have a potential epidemiologic link to mpox (eg, through travel, direct exposure, or potential exposure through a social network) or if they do not respond to empiric therapy for DGI (or other STIs) [108]. Clinical suspicion and evaluation for mpox are discussed in detail elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of mpox (monkeypox)", section on 'Evaluation and diagnosis'.)

●Other infections

•Patients with infective endocarditis may present with myalgias, arthralgias, fever, chills, and back pain symptoms that are possible to confuse with DGI. However, most patients with infective endocarditis have prominent cardiac abnormalities, and the majority have blood cultures positive for the infecting organism. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

•A number of viral infections, including parvovirus B19, measles, rubella, and arboviral infections (eg, chikungunya, dengue and Zika viruses), can also cause rash and arthritis. They can usually be distinguished from DGI by the epidemiologic setting, the character and evolution of the rash, and the presence of other associated findings. Those are discussed in detail elsewhere. (See "Viral arthritis: Causes and approach to evaluation and management".)

•Early Lyme disease, with its characteristic erythema chronicum migrans rash, can often be differentiated from DGI by other clinical characteristics and the timing of the appearance and evolution of the rash. A monoarthritis can be seen in late Lyme disease, and serologic testing can help confirm the diagnosis. (See "Musculoskeletal manifestations of Lyme disease".)

●Other arthritides

•Acute rheumatic fever (poststreptococcal arthritis) may present with polyarthritis and rash in young adults. However, the rash of acute rheumatic fever is quite rarely seen, and if observed, it is usually transient and virtually never pustular or vesiculopustular. The diagnosis of acute rheumatic fever is based upon a constellation of findings that include microbiologic or serologic evidence of a recent streptococcal infection and the presence of carditis or neurologic symptoms. Most patients with poststreptococcal arthritis have a characteristically rapid response to salicylates or other anti-inflammatory drugs. (See "Acute rheumatic fever: Clinical manifestations and diagnosis".)

•Reactive arthritis, rheumatoid arthritis, and psoriatic arthritis may be confused with DGI (table 3). In particular, DGI might be suspected in patients with the constellation of reactive arthritis, tenosynovitis, and urethritis, but unlike with typical DGI, such patients also often have one or more of the following: conjunctivitis, circinate balanitis, or keratoderma blenorrhagicum. Clinical and radiologic evidence of sacroiliitis is also very suggestive of reactive arthritis or spondyloarthritis. In addition, a therapeutic trial of antibiotics can help to differentiate between those disorders. Patients with reactive arthritis characteristically do not respond to treatment for N. gonorrhoeae, whereas response to treatment in DGI is usually rapid and unequivocal. (See "Reactive arthritis".)

•Gout and other crystal-induced forms of arthritis may cause an acute monoarthritis with fever and chills. That form of monoarthritis is usually distinguished from DGI by synovial fluid analysis and the epidemiologic setting. (See "Clinical manifestations and diagnosis of gout".)

•Lupus arthritis can have a similar presentation to that of gonococcal arthritis [36]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations'.)

MANAGEMENT — Controlled trials evaluating the treatment regimens and duration of disseminated gonococcal infection (DGI) have not been performed. Management recommendations are extrapolated from treatment studies on uncomplicated gonorrhea and based on expert opinion. Initial management in the inpatient setting and in consultation with an expert in infectious diseases is strongly advised [109]. Because of the increasing problem of antimicrobial-resistant gonococcal infections, specimens for microbiologic testing should be collected prior to antimicrobial treatment. (See 'Laboratory and microbiologic testing' above.)

As with other gonococcal infections, treatment of DGI has evolved over time because of emergent antibiotic resistance [4,52,110-112]. (See "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents", section on 'Antibiotic resistance'.)

Initial antimicrobial therapy — Parenteral therapy with ceftriaxone 1 g intravenously every 24 hours is our preferred initial regimen for DGI. Ceftriaxone can also be administered intramuscularly, if necessary, but for patients with purulent arthritis, most experts typically administer ceftriaxone intravenously. Presumptive treatment for chlamydia is also given at the same time unless chlamydial coinfection has been excluded. (See 'Treatment of Chlamydia coinfection' below.)

The duration of therapy depends on the specific clinical syndrome, as discussed below. (See 'Definitive therapy and duration' below.)

Alternatives to ceftriaxone include intravenous cefotaxime and ceftizoxime, each given as a 1 g dose every eight hours.

These treatment regimens are consistent with recommendations from the United States Centers for Disease Control and Prevention (CDC) [109].

Agents other than third-generation cephalosporins are less useful given the widespread resistance of N. gonorrhoeae to various drug classes. Decreased susceptibility of N. gonorrhoeae to the oral third-generation cephalosporin cefixime and clinical treatment failures have been reported in Asia and Canada [113-115]. Thus, oral cefixime should only be used with caution for initial therapy. The issue of drug resistance is discussed in detail elsewhere. (See "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents", section on 'Antibiotic resistance'.)

Definitive therapy and duration

Tenosynovitis, dermatitis, polyarthralgia — Patients with the triad of tenosynovitis, dermatitis, and arthralgia or synovitis, who have small or absent joint effusions, typically respond dramatically and quickly to treatment. We agree with the United States Centers for Disease Control and Prevention guidelines to continue antibiotic therapy for at least seven days as long as the clinical signs of infection are gone or nearly gone [109]. Once initial clinical improvement with ceftriaxone 1 g daily (or one of the alternative initial therapies discussed above) is noted for 24 to 48 hours, the treatment course can be completed with intramuscular ceftriaxone (500 mg for individuals <150 kg or 1 g for individuals ≥150 kg) every 24 hours.

If susceptibility testing demonstrates full sensitivity to cefixime, patients who lack septic arthritis and who respond promptly to parenteral therapy can complete their seven-day course of therapy with oral cefixime (400 mg twice daily) [23,109]. Alternately, in cases in which an isolate of N. gonorrhoeae has been identified and susceptibility to fluoroquinolones, penicillin, and/or tetracycline has been demonstrated, oral therapy with ciprofloxacin (500 mg twice daily), amoxicillin (500 mg four times daily), or doxycycline (100 mg twice daily) can also be used. However, many labs do not have the capability to perform N. gonorrhoeae culture and susceptibility testing. In the absence of such testing, the course should be completed with a parenteral cephalosporin. (See "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents", section on 'Antibiotic resistance'.)

Purulent arthritis — We generally treat patients with purulent arthritis with intravenous ceftriaxone (or one of the alternative initial therapies discussed above) until there is good evidence of response (eg, improvement in joint pain and effusion) (see 'Initial antimicrobial therapy' above). Clinical improvement and cure of purulent arthritis often require at least 7 to 14 days of parenteral therapy. The precise duration of treatment depends on the overall health status of the patient, including the presence of an immunocompromising condition and the rate of response to therapy. A duration longer than 14 days is appropriate for those with such comorbidities or slow rate of response.

Patients with purulent arthritis should generally also undergo joint drainage. That can be accomplished either with repeated needle aspirations or arthroscopically. Open surgical or arthroscopic drainage should be utilized for patients in whom needle aspirate is not successful or adequate (as assessed by continuing effusions, leukocytosis, fever, or severe joint pain). (See "Septic arthritis in adults".)

Patients with beta-lactam allergy — Because of the lack of alternate effective agents for N. gonorrhoeae, it is important to overcome potential barriers to administration of ceftriaxone (or an alternative parenteral cephalosporin).

Many patients with a history of an IgE-mediated penicillin allergy can use a ceftriaxone or other third-generation cephalosporins safely, in some cases with skin testing or graded challenge (test dosing). This is discussed in detail elsewhere. (See "Choice of antibiotics in penicillin-allergic hospitalized patients".)

Those patients with a documented IgE-mediated hypersensitivity reaction to beta-lactams that would otherwise preclude the use of a third-generation parenteral cephalosporin should undergo desensitization to allow its administration.

For patients who have other serious, non-IgE-mediated reactions that would preclude the use of a third-generation parenteral cephalosporin (eg, Stevens-Johnson syndrome), consultation with an infectious diseases specialist is warranted.

OTHER MANAGEMENT ISSUES

Treatment of Chlamydia coinfection — If concurrent C. trachomatis infection has not been excluded with nucleic acid testing, presumptive treatment for chlamydia should be given at the same time as treatment for N. gonorrhoeae. We agree with United States Centers for Disease Control and Prevention (CDC) recommendations to use doxycycline (100 mg orally twice daily for seven days) for presumptive treatment of chlamydia in nonpregnant individuals with gonococcal infection [116]. This is discussed elsewhere. (See "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents", section on 'Presumptive treatment for chlamydia' and "Treatment of Chlamydia trachomatis infection".)

Partner management — Optimal patient management includes ensuring that a patient’s recent sex partners are treated for gonorrhea. Whenever possible, partners who have had sexual contact with patients with disseminated gonococcal infection (DGI) within the 60 days prior to diagnosis should be contacted, offered testing, and be presumptively treated for N. gonorrhoeae. Treatment consists of a single intramuscular dose of ceftriaxone (500 mg for individuals <150 kg or 1 g for individuals ≥150 kg) [116]. If chlamydia coinfection has not been excluded in the patient, sex partners should also be treated for chlamydia. (See 'Treatment of Chlamydia coinfection' above.)

Cefixime 800 mg orally through expedited partner treatment (in addition to presumptive therapy for chlamydia if not excluded in the patient) is an alternative when parental ceftriaxone is not feasible. (See "Treatment of uncomplicated gonorrhea (Neisseria gonorrhoeae infection) in adults and adolescents", section on 'Management of sexual partners'.)

PROGNOSIS — Data are limited regarding the prognosis of gonococcal arthritis or DGI. With the early identification of infection and the timely initiation of treatment, the prognosis is generally excellent with few or no long-term sequelae.

RECURRENT INFECTION — Patients who have more than one episode of disseminated gonococcal infection should be screened for the presence of a deficiency in one of the terminal components of complement by obtaining an assay for total hemolytic complement activity [23]. (See "Overview and clinical assessment of the complement system", section on 'Complement measurement'.)

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".)

SUMMARY AND RECOMMENDATIONS

●Clinical features – Disseminated gonococcal infection (DGI) results from bacteremic spread of the sexually transmitted pathogen, Neisseria gonorrhoeae. DGI usually presents as one of two syndromes (see 'Clinical manifestations' above):

•A triad of tenosynovitis, dermatitis, and polyarthralgias without frank arthritis – These patients often have systemic symptoms such as fever, chills, and malaise.

•Purulent arthritis alone – The knees, wrists, or ankles are usually involved without any systemic symptoms. When present, polyarthritis is typically asymmetric.

●Clinical suspicion – The possibility of DGI should be considered in individuals (particularly those younger than 40 years or sexually active with multiple partners) who present with acute polyarthralgias, polyarthritis, or joint pain concerning for septic arthritis. Accompanying skin lesions, particularly pustular or vesiculopustular lesions and/or tenosynovitis (tenderness along the tendon sheath or pain with passive or active joint movement), should heighten suspicion for DGI. Most patients do not have a recent history of urogenital gonorrhea. (See 'Clinical suspicion' above and 'History and physical examination' above.)

●Microbiologic evaluation – Patients with clinical features of DGI should have blood cultures performed and synovial, skin, rectal, pharyngeal, and urethral or cervical specimens submitted for microbiological testing. Nucleic acid amplification tests (NAATs) are the preferred diagnostic tests for mucosal specimens (urogenital, rectal, and pharyngeal) and may be more sensitive than culture on synovial fluid. Specimens submitted for gonococcal culture should be processed on specific (Thayer-Martin) media. (See 'Laboratory and microbiologic testing' above.)

●Diagnosis –The diagnosis is made by identification of N. gonorrhoeae (either through nucleic acid testing or culture) in a nonmucosal site (blood, synovial fluid, skin). If microbiologic tests are positive only at mucosal sites, the diagnosis is also made if the clinical presentation is consistent with disseminated infection. If all microbiologic tests are negative, the diagnosis is assumed based on a consistent clinical presentation and response to appropriate therapy. All patients with DGI should be tested for HIV infection, hepatitis B infection, syphilis, and chlamydia. (See 'Diagnosis' above and 'Screening for other sexually transmitted infections' above.)

●Treatment – For initial therapy of DGI, we suggest ceftriaxone (1 g intravenously [or, if needed, intramuscularly] every 24 hours) (Grade 2C). For patients without septic arthritis, treatment is generally continued for seven days; once clinical improvement has occurred, the course can be completed either with a lower dose of ceftriaxone (500 mg intramuscularly daily as long as the patient weight is <150 kg) or, if susceptibility testing was performed, with an active oral agent. Patients with septic arthritis usually require ceftriaxone for 7 to 14 days along with joint drainage. (See 'Initial antimicrobial therapy' above and 'Definitive therapy and duration' above.)

●Chlamydia coinfection – Chlamydia trachomatis is a frequent copathogen with N. gonorrhoeae and should be empirically treated if not specifically excluded with microbiologic testing. (See 'Treatment of Chlamydia coinfection' above and "Treatment of Chlamydia trachomatis infection", section on 'Doxycycline as preferred agent'.)

●Partner management – All sex partners within the past 60 days of patients with DGI should be notified and offered treatment for gonococcal infection. (See 'Partner management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lao-Tzu Allan-Blitz, MD, who contributed to a revision of this topic review. The UpToDate editorial staff also acknowledges Daniel Sexton, MD, and Don Goldenberg, MD, who contributed to an earlier version of this topic review.