Читать книгу Cases in Medical Microbiology and Infectious Diseases - Melissa B. Miller - Страница 41

1. The organism seen on Gram stain is a Gram-negative, intracellular diplococcus consistent with Neisseria gonorrhoeae. In males with symptomatic urethritis, a Gram stain of a urethral discharge is a highly reliable test for diagnosis of N. gonorrhoeae urethral infection. The Gram stain will be positive for Gram-negative, intracellular diplococci in approximately 95 to 100% of infected male patients. Gram stains of vaginal specimens are positive in only 50 to 60% of females and there are specificity concerns because of the presence of saprophytic Neisseria spp. in the vaginal microbiota, making direct Gram stain an unreliable test for women suspected of having a gonococcal infection. A number of FDA-approved nucleic acid amplification tests (NAATs), including ones that use PCR and transcription-mediated amplification, are commercially available. In males, these assays can be performed on either urine or urethral swabs. In females, the assays can be performed on endocervical swabs, vaginal swabs, or urine. Less is known about the performance of these methods in throat or rectal specimens. These methods are more sensitive than culture in part due to the fastidious nature of the organism. Historically, false-positive results have been reported in some NAATs for closely related but saprophytic Neisseria spp. The NAATs that are now in use have a greater specificity than did the earlier NAATs. As clinical laboratories become more centralized in the era of managed care, the NAATs are replacing N. gonorrhoeae culture. The reason for this changing diagnostic approach is that maintaining the viability of this fastidious organism for culture is difficult when specimens have to travel significant distances to a central laboratory. Bacterial nucleic acid, on the other hand, is comparatively stable, making transport of these specimens for molecular amplification much easier and the detection of gonococci theoretically more sensitive. Given the potential implications of a false-positive result, due to either the presence of saprophytic Neisseria spp. or laboratory contamination, it is important for health care providers to understand the issues surrounding the specificity of the particular amplification assay that is being used in the diagnostic laboratory.

There is an important distinction between the use of a NAAT in a patient with signs and symptoms that are strongly suggestive of gonorrhea, as is the case here, and the use of this testing to screen a population of patients. In 2002, the Centers for Disease Control and Prevention (CDC) recommended additional testing to improve the positive predictive value of NAAT screening tests for sexually transmitted infections, particularly in low-prevalence settings. Based on data that demonstrated >90% agreement between initial and confirmatory testing, the CDC no longer recommends routine repeat testing for Chlamydia trachomatis, and additional testing for N. gonorrhoeae should only be performed when a NAAT is used that cross-reacts with other Neisseria spp. However, if a positive test would lead to substantial adverse medical, social, psychological, or legal impact for a patient, additional testing may be warranted.

2. In patients with gonococcal urethritis, white blood cells wash from the urethra during urination. The white blood cells can be detected in urine by dipstick testing for leukocyte esterase (an enzyme produced by leukocytes) or by microscopic examination. N. gonorrhoeae is generally not recovered on urine culture because of the media and incubation conditions used (usually sheep blood agar and media selective for enteric Gram-negative rods, with incubation times usually <48 hours and incubation under ambient air). N. gonorrhoeae requires an enriched medium such as chocolate agar and incubation times of at least 36 to 48 hours in 5% CO₂ for growth to be detected visibly. Therefore, a negative urine culture is consistent with the patient’s disease. A patient with positive urinalysis for leukocytes who does not have an organism recovered on urine culture is said to have “sterile pyuria.” N. gonorrhoeae is a common cause of sterile pyuria, as is C. trachomatis.

3. Obtaining an accurate sexual history, especially from adolescents, may be difficult. The individual may not recognize signs and symptoms of sexually transmitted infections or may be too embarrassed or ashamed to seek medical care for them. However, given an incubation time of approximately 2 to 5 days for N. gonorrhoeae and an acute symptomatic history of 24 hours, it is most likely that this patient was recently infected. If the patient was “serially monogamous” (that is, sexually active exclusively with only one partner for varying lengths of time), it is likely that he was infected by one of his recent partners and that his previous partners had not been infected. A significant percentage of infected women may be infected asymptomatically, and it is possible that the sexual partner who infected him was asymptomatic.

Complications of N. gonorrhoeae infection are more common in women because of increased rates of asymptomatic infections. These complications tend to be severe. The major complication seen in women infected with N. gonorrhoeae is pelvic inflammatory disease (PID). PID can cause fallopian tube scarring and obstruction, which may result in infertility. Ectopic pregnancy is also more common in women with a history of PID. Though it is uncommon, both men and women can have disseminated gonococcal infection, which can present with a rash and septic arthritis.

4. N. gonorrhoeae induces an intense inflammatory response, which is manifested clinically in males as exudate from the urethra. Two virulence factors are important in this process: pili and lipooligosaccharide. Pili mediate attachment and stimulate nonspecific phagocytosis by epithelial cells in the urethra. Lipooligosaccharide (endotoxin) can stimulate an inflammatory reaction to these phagocytized organisms.

5. This individual is at increased risk for a number of sexually transmitted infections. Coinfections with C. trachomatis are common. Less frequent but still problematic would be syphilis (Treponema pallidum), herpes simplex virus, human papillomavirus, and HIV. Because of his history of multiple sexual partners and the diagnosis of a sexually transmitted infection, this individual is at increased risk for becoming infected with HIV. Sexually active teenagers are one of the populations in which HIV is most rapidly spreading in the United States. Emergency rooms are often hectic, with physicians needing to see many patients as rapidly as possible. This physician did not feel he could adequately counsel and get consent for HIV serologic testing in such an environment. The physician asked the patient to return to the clinic so appropriate counseling and HIV testing could be done. This patient did not return.

6. The current CDC guidelines for treating uncomplicated gonococcal urethritis are to administer a single dose of an oral cephalosporin (cefixime) or an intramuscular injection of ceftriaxone, plus doxycycline or azithromycin to treat a presumed coinfection with C. trachomatis. Many centers, especially in areas of high HIV incidence, have abandoned intramuscular administration of antimicrobial agents for treatment of gonococcal disease in favor of oral therapy. The reason is concern among health professionals over needlestick injuries after injection of patients who are at high risk for HIV infection. Why not treat both the gonococcal and C. trachomatis infections with doxycycline? There are two reasons. First, CDC surveillance data in 1997 showed that 26% of gonococcal isolates were resistant to doxycycline. Second, compliance when antimicrobial agents must be taken twice daily for 7 days is often poor.

In addition to resistance to the tetracyclines, gonococcal resistance to penicillin therapy has become so widespread in the past 25 years that penicillin is no longer a reasonable therapeutic option for treating infections with this organism. Initially, penicillin resistance was due to a plasmid-encoded β-lactamase; β-lactamase is an enzyme that degrades the β-lactam ring in penicillin, inactivating the drug. Subsequently, isolates were recovered that had chromosomal mutations that encoded modification in penicillin-binding proteins, making the binding of penicillin to the gonococci much less efficient. This decreased binding resulted in resistance to penicillin. Additionally, by 2008, gonococcal antimicrobial susceptibility surveillance studies showed widespread resistance to the fluoroquinolones, a first-line drug class in the 2002 CDC guidelines. As a result, it is no longer recommended for treatment of gonococcal infection. This is not surprising, since single mutations resulting in fluoroquinolone resistance have been reported in other organisms. However, this is a significant setback for public health efforts to control gonococcal infections since fluoroquinolones such as ciprofloxacin are inexpensive and easy to administer as a single oral dose.

With resistance to different classes of antimicrobials becoming increasingly widespread, how do we monitor drug resistance development in the few antimicrobials to which the gonococci remain susceptible? Molecular methods that are increasingly used for diagnosis of gonococcal infections do not determine the antimicrobial resistance pattern of these organisms. Therefore, the CDC surveillance studies of gonococcal resistance are critical for the recognition of when increased resistance to cefixime and ceftriaxone emerges. Examples of either in vitro resistance or treatment failures with these antimicrobials have already been recognized. Public health experts are concerned that we are reaching a time when only more complex and expensive treatment regimens will be effective against this organism. Right now both spectinomycin, which is expensive, and azithromycin are available for treatment of gonococcal infection in patients who have cephalosporin treatment failure, infection with a cephalosporin-resistant organism, or cephalosporin allergies. However, low-level azithromycin resistance is widespread in Europe and high-level azithromycin isolates have been found in the United States.

7. The most successful bacterial vaccines elicit an immune response against either toxins produced by the organism (tetanus and diphtheria) or surface components of the bacteria (Haemophilus influenzae type b capsular polysaccharide or filamentous hemagglutinin in the acellular pertussis vaccine). Since the gonococcus does not produce a conventional exotoxin, the obvious target would be a surface component. Unfortunately, surface components of gonococci such as pili can undergo rapid antigenic variation because of frequent rearrangement of the pilin genes, making it impossible to produce a reliably protective vaccine antigen. Conserved and phenotypically stable determinants on the surface of the gonococcus have not yet been used in vaccine development. Whether they will be efficacious in providing mucosal immunity is beyond the scope of this discussion.