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.
REFERENCES
1. Bolan GA, Sparling PF, Wasserheit JN. 2012. The emerging threat of untreatable gonococcal infection. N Engl J Med 366:485–487.
2. Cole MJ, Unemo M, Hoffman S, Chisholm SA, Ison CA, van de Laar MJ. 2011. The European gonococcal antimicrobial surveillance programme, 2009. Euro Surveill 16(42): pii=19995. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19995.
3. Katz AR, Komeya AY, Soge OO, Kiaha MI, Lee MV, Wasserman GM, Maningas EV, Whelen AC, Kirkcaldy RD, Shapiro SJ, Bolan GA, Holmes KK. 2012. Neisseria gonorrhoeae with high-level resistance to azithromycin: case report of the first isolate identified in the United States. Clin Infect Dis 54:841–843.
4. Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). 2010. Sexually transmitted disease treatment guidelines, 2010. MMWR Recomm Rep 59:1–110.
CASE 3
This 16-year-old female presented to the emergency room of an urban medical center with complaints of crampy abdominal pain for days and vaginal bleeding. She denied symptoms of urinary tract infection or abnormal vaginal discharge and had not noted any chills or fever. She had no nausea or vomiting. The pain increased in the 24 hours prior to presentation, and at the time of examination she also noted pain in the right upper quadrant. She was sexually active with one male partner in the preceding 3 months and claimed to use condoms as a method of birth control. She is the mother of one child.
On examination, her temperature was 38.3°C, and there was exquisite tenderness in the right upper quadrant as well as the left lower quadrant. No rebound tenderness or guarding was noted. On pelvic exam, cervical motion tenderness was present, as well as right and left adnexal tenderness. No masses were palpated.
1 1. Clinically, this patient was believed to have pelvic inflammatory disease (PID) and was admitted to the hospital for antibiotic treatment. What bacteria have been associated with PID?
2 2. An endocervical swab was collected from this patient, and a nucleic acid amplification test (NAAT) was performed for Chlamydia trachomatis and Neisseria gonorrhoeae. Why have NAATs become the method of choice for diagnosis of these two organisms? What are strengths and weaknesses of this method?
3 3. The NAAT was positive for the more common cause of PID of the two. What was the organism? Why does PID occur in a limited proportion of women who have genital infections with this organism? What serious consequence can PID have for the infected individual?
4 4. Briefly describe the life cycle of the organism infecting this patient. Why was this organism once classified as a virus?
5 5. In addition to PID, in which this organism may well have a significant role, in what other clinical situations might this organism be expected to be recovered?
6 6. How effective are β-lactam antibiotics in treating infections caused by this organism? What is the rationale for using a β-lactam in addition to doxycycline in this patient’s therapy? What else should be done epidemiologically in cases of PID?
7 7. What type of screening strategy has been used successfully to prevent PID? What populations have a high prevalence of chlamydial infection? What are the potential consequences of PID?
CASE 3 CASE DISCUSSION
1. PID, which includes any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis, has been associated with the sexually transmitted bacterial agents Neisseria gonorrhoeae and Chlamydia trachomatis. In addition, normal vaginal flora, including anaerobes and facultative aerobes, may be isolated from patients with PID who either have no documented gonococcal or chlamydial infection or have an infection documented with one of these pathogens. Knowledge about the role of Mycoplasma and Ureaplasma species in the pathogenesis of PID is evolving, but both genera have been found in patients with PID in the absence of N. gonorrhoeae and C. trachomatis.
2. NAATs are the preferred method for diagnosing sexually transmitted infections due to N. gonorrhoeae and C. trachomatis owing to their increase in sensitivity, decreased time to result (compared with culture), and ease of specimen transport. For the routine diagnosis of sexually transmitted infections in adults by NAAT, a vaginal or endocervical swab should be used for women and a urine or urethral swab for men. In addition, the Centers for Disease Control and Prevention (CDC) recommends routine screening of rectal and oral swabs from men who have sex with men. However, it should be noted that there are no NAATs currently FDA approved for rectal