The Brief Case: Disseminated Neisseria gonorrhoeae in an 18-Year-Old Female

DISCUSSION

Neisseria gonorrhoeae is the 4th most common sexually transmitted infection in the United States. As the majority of infections are asymptomatic, routine screening for N. gonorrhoeae (and C. trachomatis) via NAAT is recommended for sexually active females under the age of 25, while risk-based screening is recommended for women over the age of 24 and sexually active males (1). The most frequent clinical manifestations of N. gonorrhoeae infection include cervicitis and pelvic inflammatory disease in females and urethritis and epididymitis in males. Extragenital infections are common, and clinical manifestations include pharyngitis, proctitis, and conjunctivitis, dependent on the site of inoculation. Only 0.5 to 3% of N. gonorrhoeae infections from any site lead to dissemination. Females are at a 4-fold-higher risk for dissemination than males, particularly if they are menstruating or pregnant. Individuals with a complement deficiency are also at increased risk. DGI classically presents with arthritis and dermatitis early in the course of disease. Skin lesions can be seen in more than 40% of patients with DGI paired with migratory arthritis and/or tenosynovitis and/or fever (2). If untreated, progression to pyogenic septic arthritis occurs in less than a third of patients. Despite a large degree of clinical overlap with common causes of septic arthritis, involvement of distal joints and polyarticular arthritis are specific to DGI septic arthritis and can help steer the differential. Further, synovial fluid cell counts tend to be an order of magnitude lower in cases of N. gonorrhoeae septic arthritis than in cases of other common bacterial causes (2), consistent with the case presented. While DGI is reported as the leading cause of infectious arthritis in sexually active young adults without preexisting joint disease, unpublished data from our institution show Lyme disease (Borrelia burgdorferi) to be at least 5-fold-more common in this age group, as we are in an area of Lyme endemicity. Nonetheless, DGI should always be considered in adolescents presenting with joint pain with no alternative explanation (i.e., trauma). The lack of consideration of DGI during the patient's first and second hospital visits led to a delayed diagnosis, significant joint impairment, and, as a result, a lengthened hospital stay.

Laboratory testing for DGI is limited to indirect testing of urogenital (and/or rectal and/or pharyngeal) sites of primary mucosal infection by NAAT and, if possible, Gram staining and culture from sites of dissemination. Blood cultures have less than 10% sensitivity, with slightly higher yields during the early stages of dissemination (2). This is likely partially due to the blood culture anticoagulant additive sodium polyanethole sulfonate (SPS), which is well known to inhibit the growth of Neisseria species (3) and may have more impact when bacteremia levels are low during later stages. In the case presented, 2 sets of blood cultures drawn 12 to 13 days after symptom onset were negative. Culture of the implicated joint's (or joints') synovial fluid is maximally 50% sensitive for DGI septic arthritis, and the corresponding Gram stain is estimated to be less than 10% sensitive. Despite evidence that N. gonorrhoeae directly invades the skin, manifesting in lesions, culture of punch-biopsied material is not recommended, as the yield is close to 0% (4).

NAAT for N. gonorrhoeae, via any of the FDA-cleared platforms, is not approved for synovial fluid or blood. There are few reports of laboratory-developed molecular testing for N. gonorrhoeae from synovial fluid, as the matrix is thought to be inhibitory to amplification. One study used a nested-PCR approach to increase sensitivity, with a reported 78.6% sensitivity when 10 culture-negative samples were tested from patients with probable DGI (5). As FDA-cleared platforms do not employ nested PCR, it is difficult to extrapolate these findings to commonly used NAAT platforms for N. gonorrhoeae. Thus, NAAT testing should be performed on FDA-cleared or validated sources, such as urine, vaginal swabs, and pharyngeal and/or rectal swabs, as supportive evidence for DGI and to rule out coinfection with C. trachomatis. Importantly, rectal and pharyngeal sources are also not yet FDA cleared by any of the commercially available platforms but have been validated by numerous clinical laboratories for the detection of C. trachomatis/N. gonorrhoeae.

Neisseria gonorrhoeae grows readily on chocolate agar and even some formulations of blood agar (Fig. 2). Specialized agar for the selection of Neisseria species should be included for culture, particularly from nonsterile sources (Fig. 2). This medium is referred to as modified Thayer-Martin or Martin-Lewis agar and typically includes vancomycin, colistin, trimethorprim, and anisomycin or nystatin to inhibit normal flora and most nonpathogenic (saprophytic) Neisseria species. Care should be taken with positive growth from pharyngeal cultures, as Neisseria meningitidis can be incidentally isolated. Colonies suspicious for Neisseria gonorrhoeae (oxidase-positive, Gram-negative diplococci) require confirmation by biochemical and/or enzymatic analyses. Testing should be performed from colonies isolated on the Neisseria selective agar mentioned above to limit possible false-positive interpretations for N. gonorrhoeae. More than one method of confirmation may be necessary, as no test is 100% specific. The carbohydrate utilization test analyzes differential fermentation between 4 sugars: glucose, maltose, lactose, and sucrose. N. gonorrhoeae should ferment only glucose, while other Neisseria species should ferment 2 or more sugars. Enzymatic testing looks for the presence of proline-iminopeptidase, which should be specific for N. gonorrhoeae. Identification of N. gonorrhoeae by matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectrometry may be validated by individual laboratories but is not currently FDA approved/cleared for commercially available systems as a stand-alone identification. Molecular confirmation of isolated colonies by one of the NAAT platforms used for primary specimen screening has also been reported. Finally, sequencing of the first 500 bp of the 16S ribosomal gene, widely used for bacterial identification, may not provide enough resolution to call an isolate of Neisseria to the species level, and results should be interpreted with caution.

Despite limited sensitivity compared to that of molecular testing, culture is still recommended to generate isolates for susceptibility testing (and for medicolegal purposes). While routine susceptibility testing is not recommended, it may be useful in cases of treatment failure and dissemination. The majority of clinical isolates are resistant to penicillin, tetracyclines, and fluoroquinolones; thus, these drugs are no longer recommended for treatment (6). Susceptibility testing now focuses on emerging resistance to cephalosporins and azithromycin. In 2012, the CDC revised treatment recommendations, due to increasing oral cephalosporin resistance, to now recommend only dual therapy with 1 injection of high-dose ceftriaxone (250 mg) plus a single dose of azithromycin. For disseminated infections, treatment with parenteral ceftriaxone (1 g) for a duration of 7 to 14 days is recommended along with a single dose of azithromycin for combination therapy and to treat possible C. trachomatis coinfection (6). In these cases, treatment may be switched to an oral 3rd-generation cephalosporin, such as cefixime or cefpodoxime, if susceptibility can be confirmed. Most clinical laboratories do not have the capacity to perform susceptibility testing on N. gonorrhoeae isolates, as agar dilution is the gold standard. Clinical laboratories should contact their public health laboratory to coordinate testing as needed.