Common Sexually Transmissible Diseases (STDs): Diagnosis and Treatment of Uncomplicated Gonococcal and Chlamydial Infections
Authors: Charles Stewart, MD, FACEP, Emergency Physician, Colorado Springs, CO; and Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Medicine, Yale University School of Medicine, New Haven, CT; Associate Clinical Professor, Oregon Health Sciences University.
Peer Reviewer: Raghavan Chari, MD, FACEP, Emergency Medicine Physician, Carolina Hospital System, Florence, SC; Emergency Medicine Physician, Wyoming Valley Health Care System, Wilkes Barre, PA; Chair- man, Conquest Health Associates.
Despite aggressive public education programs and a well-documented association between infection with common sexually transmissible diseases (STDs) and facilitation of HIV transmission, STDs are on the rise, and are frequently encountered in the emergency department setting.(See Table 1.) Prompt diagnosis and outcome-effective management of common STDs will reduce the incidence of complications (i.e., pelvic inflammatory disease [PID]) associated with gonococcal and chlamydial infections. The Centers for Disease Control and Prevention (CDC) publishes treatment recommendations for these conditions, and emergency physicians must be familiar with the range of treatment options and the precise indications for initiating therapy.
| Table 1. Some Sexually Transmissible Diseases | |
| Disease | Implicated organism |
| Gonorrhea | Neisseria gonorrhea |
| Chlamydia | Chlamydia trachomatis |
| Syphilis | Treponema pallidum |
| Chancroid | Hemophilus Ducreyi |
| Lymphogranuloma venereum | Calymmatobacterium granulomatis |
| Gardnerella | Gardnerella vaginalis |
| Genital herpes | Herpes simplex virus |
| Cytomegalovirus | |
| Hepatitis virus A and B | |
| AIDS | HIV |
| Genital condylomata | Human papilloma virus |
| Trichomonas | Trichomonas vaginalis |
| Giardia | Giardia lamblia |
| Scabies | Sarcoptes scabiei |
| Pediculosis | Pedicululs pubis |
As a rule, uncomplicated gonorrhea is treated with single-dose therapy. There are a variety of effective drug regimens based on quinolones, cephalosporins, and the macrolides; treatment options vary considerably in cost—a factor that may dictate usage patterns in specific hospital environments. Although only one infectious agent may be involved, empiric treatment of chlamydia is required when gonococcal disease is suspected, and conversely, antimicrobial coverage of Neisseria gonorrhoeae is required when chlamydial infection is the most likely etiology.
The importance of effective communication for the purpose of enhancing compliance with medication regimens cannot be overemphasized. Because significant noncompliance has been reported with doxycycline, one-dose therapeutic modalities (e.g., azithromycin 1 g po once for uncomplicated chlamydial infection and a choice of several agents for uncomplicated gonococcal infection (GC) are generally preferred.
With an estimated annual cost of up to $5 billion to treat primary chlamydial infection and related complications (PID, infertility, chronic pelvic pain), it has become abundantly clear that the chlamydia problem deserves special attention. From an emergency therapeutics perspective, it should be stressed that, to a significant degree, the chlamydia epidemic has grown significantly because of poor patient compliance with the traditional, seven-day course of bid doxycycline. Although this regimen is highly effective for uncomplicated chlamydia when it is taken in its entirety, noncompliance with the drug regimen has been identified as a potential weak link between the emergency physician’s prescription pad and optimal clinical outcomes.1
For example, in one real world study that followed patients from the time of diagnosis to prescription generation to antibiotic pill consumption, only 65% of all patients prescribed a seven-day course of doxycycline therapy reported sufficient intake of the antimicrobial to achieve expected clinical cure of their chlamydial infection.1-3 When this degree of noncompliance occurs, a significant percentage of patients will return for retreatment because of therapeutic failures. In addition, these patients increase the chances of infecting their present and future sexual partners, who will then have to access the healthcare system for treatment.
The end result of noncompliance-mediated therapeutic failures, as well as failure to diagnose these conditions, is "turnstile STDs," a phenomenon in which pharmacologic reservicing for STDs is required because of therapeutic failures associated with inadequate adherence to medication regimens. These observations strongly support the use of single-dose therapy that is administered under clinical supervision, on site, in the ED or clinic for treatment of uncomplicated chlamydial infections. Finally, it should be stressed that emerging resistance to quinolones among certain gonococcal species may affect decisions regarding antimicrobial treatment.
The purpose of this review is to update the emergency physician on current advances in the diagnosis and management of common, uncomplicated STDs (complications of STDs, such as PID, were covered in the previous issue). New diagnostic modalities are highlighted and outcome-effective treatment options are provided.
— The Editor
Gonococcal Infection
Life Cycle. Neisseria gonorrhoeae is a facultative, intracellular parasite that contains a typical, gram-negative cell wall. It is characteristic of gonococcal infection that these microbes are able to invade and divide inside epithelial cells. Interestingly, some strains of gonorrhea are "auxotrophs," infectious variants which, because they are unable to synthesize certain amino acids, must acquire these nutrients from the host organism in order to permit propagation. N. gonorrhoeae divides by binary fission every 20 to 30 minutes. To a great degree, intracellular replication allows the organism to evade host immune defenses. Local tissue damage is the result of a toxin produced by the gonococcal organisms. Although it is speculated that the majority of tissue damage is toxin-mediated, immune response mechanisms may also play a role.
Spectrum of Disease. Transmission of gonorrhea requires physical contact with the infected tissue. It is estimated that about 50% of patients harboring N. gonorrhoeae are asymptomatic (i.e., they are colonized with the organism and potentially infectious). The remaining 50% of patients will have characteristic symptoms, 20% of which will have local complications. Overall, about 1-2% of patients will have disseminated gonococcal infection (DGI), which may be symptomatic. Variations in presentation, from asymptomatic to severely symptomatic, reinforce the importance of definitive treatment in all patients suspected of having infection, as well as treatment of their sexual partners.
The vectors for transmission have been well studied. Male to female transmission of N. gonorrhoeae is the most efficient transport vector, although there is strong evidence that receptive anal intercourse is also an efficient vector. It should stressed that although oral transmission occurs, this vector is less efficient in transmitting infection than sexual intercourse. (See Table 2.)
| Table 2. Clinical Manifestations of Gonorrhea | ||
| 50% of men and women may be asymptomatic | ||
| Patient | Syndrome | Frequency |
| Men | Conjunctivitis | Rare |
| Gonococcal urethritis | 85-90% of cases | |
| Epididymitis | Most common cause | |
| Prostatitis | Common | |
| Proctitis (anal intercourse) | Uncommon | |
| Pharyngitis | Uncommon | |
| Disseminated disease | Rare | |
| Women | Conjunctivitis | Rare |
| Cervicitis | Common, 10-20% | |
| Acute urethral syndrome | Up to 50% of cases | |
| Salpingitis | 20-25% of cases | |
| Perihepatitis | Uncommon | |
| Proctitis | Common | |
| Pharyngitis | Common | |
| Disseminated disease | Rare | |
| Neonates | 25-50% of exposed | |
| Conjunctivitis | infants | |
| (May also develop disease in any exposed mucous membrane surface) | ||
Urethritis. Urethritis is the most common manifestation of N. gonorrhoeae infection in men. The incubation period ranges from 3-7 days, and the disease usually manifests symptoms within 10-14 days after the exposure. Characteristic symptoms include a purulent urethral discharge and dysuria. The urethral discharge ranges in color from clear to yellow and, therefore, although not diagnostic, all urethral discharges in men should be presumed to be gonococcal in origin unless culture results suggest otherwise. The majority of cases of gonococcal urethritis in men are symptomatic, with 85-90% of men developing symptoms of an acute infection. Moreover, the more pronounced the discharge, the more likely it is that gonorrhea is present.
From an emergency management perspective, it must be emphasized that chlamydial and gonococcal infections frequently coexist, a clinical finding that explains why treatment protocols including antimicrobial agents directed at both organisms have become standard. For example, if a patient has documented chlamydial infection, the chance of co-infection with gonorrhea is between 25-50%. Overall, the ratio of men with non-gonococcal urethritis (NGU) to men with gonococcal urethritis in most geographical areas is about 4:1. Although the diagnosis of gonococcal urethritis is usually straightforward in men, in women gonococcal urethritis may mimic a urinary tract infection (UTI). As might be expected, dysuria and frequency of urination are common symptoms of gonococcal urethritis in women. Consequently, the presence of pyuria in the absence of bacteriuria in a sexually active female should direct the physician toward evaluation of gonococcal disease.
In young women, acute cystitis and urethritis occur in the absence of classical criteria for bacteriuria (105 bacteria per mL of urine) in as many as 50% of cases.4-6 The constellation of dysuria, frequency of urination, and pyuria in the absence of "significant" bacteriuria has been termed the acute urethral syndrome. In many cases, this syndrome is caused by low-level infections with Escherichia coli (102-104 organisms per mL) or with a sexually transmitted pathogen such as Chlamydia trachomatis.
The modern standard for a positive urine culture in a patient with dysuria is now widely accepted to be 102 rather than 105 organisms per mL. Sexually transmitted pathogens can cause urethritis, vaginitis, and prostatitis, conditions that can clinically mimic the infections of classic uropathogens such as E. coli. Microorganisms, including Trichomonas vaginalis, N. gonorrhoeae, C. trachomatis, and Ureaplasma urealyticum, are common offenders. Urethritis and epididymitis caused by sexually transmitted pathogens are increasingly common among promiscuous males, and UTI may be associated with HIV or herpes virus infection.
Cervicitis. Approximately 10-20% of women who are infected with N. gonorrhoeae will present with acute cervicitis. Nevertheless, clinicians should be aware that about 50% of patients with clinical cervicitis will have no complaints, even though they harbor the infection and can transmit the organism. The presence of a purulent cervical exudate in conjunction with cervical friability characterizes the clinical presentation of gonococcal cervicitis. As many as 50% of women infected with gonorrhea will have gonococcal urethritis, although this diagnosis frequently is missed in the female population.7 In addition, women who have had a hysterectomy can still become infected with gonorrhea; in these individuals, urethral cultures may be necessary to confirm the diagnosis. Although the classical literature on the subject suggests that clinical symptoms tend to follow menstruation, the precise incubation period is not well established for this disease. Typically, however, symptoms generally occur within 10 days of exposure and typically may include the following: 1) vaginal discharge; 2) dysuria; 3) increased frequency of urination; 4) abnormal uterine bleeding; and 5) lower abdominal pain with or without PID.
Epididymitis. Epididymitis is probably the most common and severe complication of gonococcal infection encountered in men. Symptoms include swelling of the epididymal gland next to the testis and accompanying pain in the epididymis. Chlamydia and gonorrhea are the most common causes of acute epididymitis in men younger than age 35. Unfortunately, this disease may be easily confused with acute testicular torsion. A differential point that may aid in diagnosis is that gonococcal epididymitis most often presents with concurrent urethritis. Evaluation of men older than 35 years is sometimes considered problematic, since the classical teaching states that epididymitis is infrequently caused by a STD (either GC or Chlamydia) in men older than age 35. Although this is true on a statistical and epidemiological basis, a STD cannot be ruled out by age of the patient alone. The most common causes for epididymitis are insertive anal intercourse or iatrogenic instrumentation of the urethra.
Proctitis. In the male population, this disease is associated with receptive anorectal sex. Interestingly, about 33-50% of women who have cervical gonorrhea may acquire anorectal infection; in this population, gonococcal proctitis is not related to anorectal intercourse.7 Of special clinical importance is the fact that 80% of patients who have gonococcal proctitis will have no symptoms, which means the physician must have a high index of suspicion and perform anal cultures when the diagnosis is entertained. As is the case with urethritis, this condition may be due to either gonorrhea or Chlamydia. The most common symptoms include the following: 1) anal irritation; 2) rectal bleeding; 3) rectal discharge; 4) rectal itching (pruritus ani); 5) painful defecation; 6) constipation; and 7) tenesmus. Treatment must include screening for repeat and recurrent infection. The initial treatment course fails in up to 35% of cases.8
Pharyngitis. Gonorrheal pharyngitis is transmitted by oral sex. As many as 10-20% of women who have cervical gonorrhea have positive pharyngeal cultures.9 From a detection point of view, ED physicians should be aware that 90-95% of patients with oral gonorrhea are asymptomatic. When present, symptoms may include oropharyngeal erythema, uvular erythema, and tonsillitis. Chlamydia also may cause occasional cases of pharyngitis; clinical symptoms are mild if present. Because GC pharyngitis is often resistant to usual therapy, close follow-up is mandatory.
Conjunctivitis. Gonococcal ophthalmia used to be a problem affecting newborns in the United States. In the current environment, it is occurring with increasing frequency among sexually active adults. The most common cause is autoinoculation. The condition is characterized by a rapidly developing purulent exudate, and ulceration that may cause perforation of the globe. It usually appears 2-3 days after delivery and can be prevented by instillation of silver nitrate, tetracycline, or erythromycin eye drops after delivery. Although gonococcal conjunctivitis has a more acute onset and produces a more purulent exudate than Chlamydia, these findings are not specific enough to be useful for clinical differentiation.
Pregnancy. Pregnancy does not provide protection from gonococcal infection. In fact, clinically apparent gonococcal infection occurs in pregnant women as frequently as it does in non-pregnant women. From the standpoint of evaluating the pregnant patient, it should be pointed out that there is an increased rate of oropharyngeal gonorrhea in pregnant women. The higher rate of oropharyngeal infection is partially offset by a decreased rate of PID in pregnancy.
Septic abortion, premature delivery, and disseminated gonococcal infection (DGI) all occur in pregnancy. Perinatal GC can also produce pharyngeal, vaginal, or rectal infections in the newborn. Ophthalmia neonatorum is a serious systemic disease, which is now more common in Third World countries.
Disseminated Gonococcal Infection. DGI is the most common systemic complication of acute gonorrhea and occurs in 0.5-3.0% of patients with untreated mucosal infection.7 For reasons that are not entirely clear, DGI is more common in women than in men. Disseminated gonococcal infection is a complex syndrome characterized by a pustular rash and joint findings; it may also be called arthritis-dermatitis syndrome. Specifically, the following manifestations are encountered in the accompanying percentage of cases: 1) joint and skin findings (69%); 2) joints only (23%); 3) skin only (7%); and 4) endocarditis (1%).
The incubation period for DGI ranges from about 7-30 days and the rash typically is detectable about seven days after menses. Gonorrhea still is the most common cause of septic arthritis in patients younger than 45 years.10 The usual sites of involvement include the distal joints and the extremities. Rarely, endocarditis can result from hematogenous dissemination of the gonococcal organism.
Diagnosis of Gonorrhea
Although patients usually are treated empirically with antibiotics for suspected gonococcal infection, it is important to establish the diagnosis and report confirmed cases to public health authorities. Diagnostic confirmation of disease will also guide treatment of sexual partners and permit follow-up in patients with resistant strains, complications, or difficult-to-treat clinical subgroups.
Culture. Culture of the organism remains the "gold standard" for diagnosis of gonorrhea. Routine culture for the organism is mandatory even when the diagnosis is evident, since culture results permit evaluation of the strain of N. gonorrhoeae, monitoring of antimicrobial susceptibility, and epidemiological surveillance. The full complement of information required to characterize epidemiological patterns and generate organism- and region-specific treatment recommendations can be obtained only from culture results.
The culture technique that is selective for gonorrhea is modified Thayer-Martin medium. The sensitivity rate of bacterial culture using Thayer-Martin medium is about 96-98%, with a turnaround time of about 48 hours. Specimens should be obtained with a Dacron swab, because cotton swabs inhibit growth. Various transport systems containing CO2 releasing devices are available and are especially useful if the laboratory is either slow to respond or is located a significant distance from the emergency department.
The usual sites of culture are urethral for males and cervical for females. It is important to do a rectal culture if the patient has engaged in receptive rectal intercourse. It is equally important to check and, when indicated, perform a culture of, the pharynx if there are symptoms or if it is a known or suspected site of exposure.
Gram Stain. Although not definitive and limited in sensitivity (especially in females), gram stain of a urethral discharge is an excellent screening and diagnostic test for males. When interpreted by an experienced individual, the test is both sensitive and specific.11 Unfortunately, there is a high false-positive rate in specimens obtained from cervical smears, so a positive test is only suggestive of GC infection in females. Although not usually performed, gram stain and culture of a female’s urethra is as sensitive as it is in males. Likewise, discharge from a Bartholin’s gland yields a high sensitivity for gonorrhea. Overall, the sensitivity rates for gram stain specimens obtained from various anatomical sites are reported to be as follows: 1) urethral (96%, either sex); 2) cervical (50%); 3) conjunctiva (95%); 4) rectal (< 50%); and 5) pharyngeal (< 50%).11
DNA Techniques. Of special diagnostic significance is the finding that DNA testing is more accurate and reliable in females than are culture results. In contrast, the opposite appeared to be true for males infected with gonorrhea (i.e., culture results appear to be more specific and sensitive).12 The extreme sensitivity of DNA-based tests in women makes it possible to detect the presence of a single gonococcal organism in samples of freshly voided urine, tampons, and distal vaginal secretions.13
Both polymerase chain reaction (PCR) and ligase chain reaction (LCR) techniques have been used for the diagnosis of gonorrhea. Commercially available DNA probe (Gen-Probe-Pace II) and LCR tests (Abbott LCR) can detect N. gonorrhoeae directly from cervical or urethral specimens. These assay systems will detect both gonorrhea and Chlamydia infections from a single swab sample.
Similar technology (the AMPLICOR N. gonorrhoeae PCR test) has been shown to detect gonorrhea in urine specimens with better accuracy than current urethral swabs (90-95% sensitivity with 98-100% specificity).14,15 When the cost of preventing a case of PID caused by GC or Chlamydia is computed, urine-based LCR screening appears to be the most cost-effective diagnostic and clinical screening strategy.16 In asymptomatic, sexually active adolescent females, using a urine-based LCR assay will prevent the greatest number of cases of PID.
Based on these findings, DNA probes are likely to become the standard test for diagnosing Chlamydia and gonorrhea in the near future. Because the tubes used for collection of specimens cause lysis of the organism, the specimen obtained cannot be used for subsequent culture.17 Moreover, bacterial culture is more expensive and may not necessarily be a more useful clinical test.
Other Diagnostic Modalities. Other confirmatory methods for culture have been used, but are not as well studied. These include antigen detection techniques such as enzyme immunoassay (EIA), nucleic acid probes, and direct fluroscein antigen (DFA). They offer rapid turnaround and office-based performance; they are inexpensive. Unfortunately, these tests are compromised by relatively poor sensitivity and specificity (60-90% sensitivity).
Treatment of Gonococcal Infection
Antimicrobial therapy for gonococcal infection has undergone a dramatic change over the past two decades. In particular, changes in therapy over time have had to account for developing resistance patterns and geographical variations related to antimicrobial resistance. When penicillin was first used for treatment of gonorrhea, the minimum inhibitory concentration was 0.003 to 0.03 mg/L. Since that time, there has been a slow but inexorable increase in the upper range of the minimum inhibitory concentration (MIC). By the 1960s, many strains of N. gonorrhoeae had developed intermediate to complete resistance to penicillin, a resistance trend that has continued until the present day.
The evolution of gonococcal resistance has challenged infectious disease experts and epidemiologists at the CDC to identify an "ideal" agent for the treatment of gonorrhea. In the best of all worlds, such a drug would be effective against all types of gonococcal resistance patterns, and all bacterial strains, regardless of geographic location and would produce clinical cure at all sites of infection. Because empiric treatment of the patient with gonorrhea also includes coverage of chlamydia, it would be advantageous for the therapeutic agent to have activity against Chlamydia, as well as incubating syphilis. If the drug could be given orally as a single dose, if its cost was sufficiently attractive, and if the the drug had minimal side effects, it would satisfy all the criteria for the perfect anti-gonococcal agent. Unfortunately, such a drug does not yet exist.
Nevertheless, a variety of newer (post-penicillin era) antibiotics are available that are effective against otherwise resistant strains of gonorrhea. These agents are reliable when administered orally, and some are reliable when given by injection. Among the classes/agents approved for treatment of gonorrhea are the cephalosporins, quinolones, and the macrolide azithromycin.
Plasmid-Mediated Resistance. There are two forms of drug resistance: plasmid-mediated and chromosome-mediated resistance. The mechanism of plasmid-mediated penicillin resistance is linked to a bacterial enzyme that breaks down the beta-lactam ring of penicillin, rendering it ineffective. This form of resistance was first described in 1976, and since that time many strains of gonorrhea have been identified that exhibit this kind of resistance. It is also a very effective mechanism of resistance to tetracycline. The abbreviation, PPNG, is used to indicate penicillinase-producing N. gonorrhoeae, whereas the abbreviation TRNG is used to indicate tetracycline resistant N. gonorrhoeae.
Chromosomal-Mediated Resistance. In this mechanism of drug resistance, there is a genetic mutation in the gonococcus strain that results in altered cell wall permeability to antibiotics. Chromosome-mediated resistant N. gonorrhoeae (CMRNG) strains are usually resistant to both tetracycline and penicillin. They may also be resistant to cefoxitin and spectinomycin. Unlike beta-lactamase-mediated antibiotic resistance, chromosomal-mediated resistance cannot be easily detected in the laboratory.18
Resistance Patterns. Nationwide, about 20-30% of gonococcal isolates in the United States exhibit some resistance to penicillin and tetracycline. About 8-10% exhibit PPNG resistance; 3-5% are TRNG; 3-5% are both PPNG and TRNG, and 10-20% demonstrate CMRNG to both penicillin and tetracycline. In addition, it should be stressed that resistance to quinolones is being encountered with increasing frequency in the Far East.19
Current Treatment Recommendations. Oral therapy consisting of a single dose of the drug, administered under supervision, with medication intake observed by medical providers, is considered to be the best available approach to therapy of uncomplicated gonococcal infection.20 This approach is associated with the lowest cost for both the patient and the institution and minimizes the possibility of noncompliance. (See Table 3 for treatment recommendations.)
| Table 3. Treatment of Uncomplicated Gonorrhea |
| URETHRAL, RECTAL, OR CERVICAL SITE |
| Cefixime a 400 mg po once |
| or |
| Ceftriaxone a 125 mg IM once |
| or |
| Ciprofloxacin bc 500 mg po once |
| or |
| Oxyfloxacin bc 400 mg po once |
| Plus |
| Azithromycin 1 g orally once d (to cover possible or presumed uncomplicated, coexisting chlamydial infection) |
| or |
| Doxycycline c 100 mg po twice a day for 7 days d |
| Alternative parenteral medication |
| Spectinomycin 2 g IM e |
| Ceftizoxime 500 mg IM one time |
| Cefotaxime 500 mg IM one time |
| Cefotetan 1 g IM once |
| Cefoxitin 2 g IM once with probenecid 1 g orally |
| Alternative quinolones |
| Enoxacin 400 mg po once f |
| Lomefloxacin 400 mg po once f |
| Norfloxacin 800 mg po once f |
| PHARYNGEAL SITE |
| GC of the pharynx is more difficult to eradicate. Few antigonococcal drugs can reliably cure pharyngeal GC infections more than 90% of the time.20 |
| Ceftriaxone a 125 mg IM once |
| or |
| Ciprofloxacin bc 500 mg po once |
| or |
| Oxyfloxacin bc 400 mg po once |
| Plus |
| Azithromycin 1 g orally once d (to cover possible or presumed uncomplicated, coexisting chlamydial infection) |
| or |
| Doxycycline c 100 mg po twice a day for 7 days d |
| Gonococcal Conjunctivitis |
| Ceftriaxone a 1 g IM once |
| or |
| Spectinomycin 2 g IM g |
| a Contraindicated if penicillin allergy |
| b Contraindicated during pregnancy |
| c Contraindicated in growing children |
| d Used for treatment of presumed coexisting Chlamydia infection |
| e Useful in treatment of patient who cannot tolerate cephalosporins and quinolones |
| f There is no advantage in use of these drugs over ciprofloxacin. |
| g Spectinomycin is unreliable for GC pharyngitis. Patients should be reevaluated 3-5 days after treatment with this drug. It should be reserved only for those with a known allergy to ceftriaxone. |
It should be emphasized that concurrent treatment for Chlamydia is still considered to be essential. It is felt that the cost of therapy is less than the cost of testing. Although this contention may no longer be valid with newer DNA probes for Chlamydia, current standard of care mandates antimicrobial coverage for chlamydia. It is also felt that dual therapy may decrease the incidence of antimicrobial-resistant GC in the United States.
Ceftriaxone is the currently recommended intramuscular drug of choice for treatment of gonococcal infection. It has a long history of excellent results and few ceftriaxone-resistant strains of gonorrhea have been reported. Ceftriaxone has the highest cure rate of all currently recommended GC drugs.20 Using lidocaine or sterile saline solution will reduce the discomfort associated with the injection.
There is still some debate and confusion about the appropriate dose of intramuscular ceftriaxone. The former recommendation for treatment of gonorrhea was 250 mg of ceftriaxone. Many authorities still feel that the currently recommended lower dose of 125 mg will lead to resistant microbes and, therefore, continue to use 250 mg IM.21 Because ceftriaxone is not presently available in a 125 mg vial, smaller facilities must either use 250 mg of the drug or discard the excess medication. This is not a problem for facilities that have a significant chance of treating more than one patient with a STD in a 24-hour period. If the patient’s sexual partner is present in the ED, then treatment using the other half of a 250 mg vial solves several problems simultaneously. Another approach is to use a recommended single-dose oral cephalosporin such as cefixime 400 mg po. Although these agents have a slightly lower cure rate than IM ceftriaxone, the cure rate with cefixime is still a very acceptable 98%.
Although CDC recommendations include quinolones as first-line agents for treatment of uncomplicated GC, this class appears to have several major drawbacks. Currently, the CDC recommendations include a single dose of either ofloxacin or ciprofloxacin. Because of reports of strains that have become increasingly resistant to quinolones, some authorities are becoming less enthusiastic about recommending quinolones for treatment of GC unless the patient has a significant allergy to cephalosporins.
In this regard, a number of factors should be considered. First, quinolones have no significant activity against syphilis, whereas the cephalosporins have substantial efficacy. Quinolones cannot be used in the pregnant patient or in patients younger than 16 years. (See Table 4.) In addition, gonorrhea can develop resistance to the quinolones relatively rapidly. This has been shown in both the laboratory and in the clinical environment. Although quinolones are currently recommended by the CDC, the reports includes a caveat about multiple reports of quinolone-resistant GC throughout the world.20
| Table 4. Treatment of Gonococcal Disease in Pregnancy |
| TREATMENT OF CHOICE |
| One of the recommended cephalosporins or spectinomycin |
| Plus |
| Erythromycin base 500 mg po qid for 7 days d |
| Patient Follow-up.It is essential to treat all contacts of the index case who have had sexual relations with the index case within 60 days. Testing and retreatment is indicated only if there is persistence of symptoms. Only ceftriaxone is effective against incubating syphilis, and therefore, testing for coexistence of syphilis is more important when other agents are used for therapy. Gonorrhea is reportable in all states. Such cases should be reported either to the local public health authorities or to the designated authority. |
| Patients should be instructed to avoid sexual intercourse until: 1) the entire course of therapy is completed; 2) their sexual partners are treated; and 3) they and their sexual partners no longer have symptoms. As noted earlier, spectinomycin is an unreliable drug for the treatment of GC pharyngitis. It should be reserved only for those patients with a known allergy to ceftriaxone.20 Patients who are treated with this drug must be re-evaluated 3-5 days after therapy. |
| d Used for treatment of presumed coexisting Chlamydia infection |
Fluoroquinolone-resistant strains account for approximately 10% of all gonococcal strains in Hong Kong and the Republic of the Philippines.22 If the patient has acquired GC in Asia, then quinolones are definitely not recommended due to the increasing incidence of quinolone-resistant gonorrhea in this geographic region. Strains of gonococci with decreased susceptibility to ciprofloxacin appear to have become endemic in Cleveland, Ohio.23 This resistance may limit the future use of the quinolones for treatment of gonorrhea in the United States.
None of the quinolones are effective as single-dose therapy against Chlamydia.24,25 This means that dual therapy for Chlamydia and gonorrhea will require either extended administration of quinolones or dual drug therapy. Of these, the dual drug therapy is both cheaper and more certain when a single-dose antibiotic such as azithromycin is employed.
Chlamydial Infection
The major problems associated with uncomplicated chlamydial infection are difficulty of detection and diagnosis and, on the treatment side, noncompliance with medications. Definitive diagnosis is not possible using any one or more clinical criteria in either the female or male.26 In women, a presentation spectrum ranges from one that is asymptomatic to one characterized by pain associated with a severely eroded, hypertrophic cervix with a mucopurulent discharge. (See Table 5.) In males, the patient may be normal or present with any of the symptoms described above for gonococcal disease.
| Table 5. Clinical Manifestations of Chlamydia | ||
| 50-75% of men and women may be asymptomatic | ||
| Patient | Syndrome | Frequency |
| Men | Conjunctivitis | Rare |
| Nongonococcal urethritis | 30-50% of cases | |
| Most common | Postgonococcal urethritis cause | |
| Epididymitis | Common | |
| Prostatitis | Very rare | |
| Proctitis (anal intercourse) | Uncommon | |
| Women | Conjunctivitis | Rare |
| Cervicitis | Very common | |
| Acute urethral syndrome | 20-25% of cases | |
| Salpingitis | 20-25% of cases | |
| Perihepatitis | Uncommon | |
| Neonates | 25-50% of | |
| Conjunctivitis | exposed infants | |
| 10-20% of | ||
| Pneumonitis | exposed infants. | |
Culture. Chlamydia cannot be identified on a gram stain. Either the Chlamydia organisms must be cultured (a difficult proposition) or the organism must be identified by other means. Culture of the organism by a competent laboratory is 100% specific, but is far from perfectly sensitive.27 Confirming the diagnosis of chlamydia by culture is currently the legal standard for sexual assault and child abuse cases. Interestingly, although culture is the "gold" standard of diagnosis, Chlamydia culture is problematic. Naturally, a positive Chlamydia culture is 100% specific, but because of problems that are inherent with live culture techniques, this test is only about 80% sensitive. Since the organism is intracellular, culture techniques must use live media; the lab requires special expertise with this culture. Smaller hospitals may simply not have the ability to adequately culture this organism well. Moreover, cultures are expensive ($50 or more each), and it takes about three days to get results.
Direct Fluroscein Antigen (DFA) Detection. In this technique, samples from swab or scrapings are incubated with fluorescein-stained, monoclonal antibody. Slides are evaluated for presence of fluorescein stain. These tests are less sensitive than tissue culture, but non-culture antigen detection methods are easier to handle than cultures and less expensive, costing about $6-12 per test. Performance depends upon the skill of the laboratory staff. Based on product literature and studies, greater than 90% sensitivity and 95% specificity is associated with Microtrak, and greater than 90% sensitivity and specificity is associated with Chlamydiazyme.
Enzyme Immunoassay. The enzyme immunoassay (EIA) test detects the presence of antigen to Chlamydia from anatomic specimens. An antibody-coated solid phase (either polystyrene beads or welled plates of membranes) are used to capture Chlamydia lipopolysaccharide antigen. The antigen is then detected by a second antibody labeled with enzymes that produce a color reaction. The change in color is read by a spectrophotometer. EIA and DFA are equally sensitive and specific when used in women for screening tests. The EIA is a rapid test that takes from 20 minutes to two hours to perform. A one-day turnaround time from most labs is not unusual. There is an office-based kit available that costs about $5-10 per test.
Nucleic Acid Probes. This technique uses DNA or RNA amplification probes to detect Chlamydia in clinical specimens, including urine, tampons, and self -collected distal vaginal secretions (AMPLICOR Chlamydia trachomatis Test; Roche Diagnostic Systems, Inc., Branchburg, N.J.).16,28 This technique has far better sensitivity and specificity than culture.29 A major advantage is that the sample can be split and tested for GC at the same time.
As noted in the section on GC, these tests are extremely sensitive and may be able to detect as little as a single organism. Indeed, they may be able to quickly monitor patients for both diagnosis and effectiveness of therapy with simply a urine specimen or a self-collected vaginal swab.30,31 The authors believe that nucleic acid probes will soon replace cultures as both the standard and the legal test in the foreseeable future. Although there are abundant papers detailing the specificity and sensitivity of cultures in infants and children, there is not a wealth of experience with the nucleic acid amplification techniques. They are not currently recommended as a legal test for rape or in child abuse cases. As more information is collected, this is likely to change.
Cytology. Although cytology is sometimes recommended, it is generally not helpful; it has poor sensitivity and specificity. Cytologic examination looks for inclusion bodies of Chlamydia on scraping smears stained with Giemsa stain. It is a technique that works better with conjunctival scrapings than with pap smears.
Treatment of Uncomplicated Chlamydial Infection
Presumed chlamydial infection should be treated in the following circumstances and patient subgroups: 1) individuals suspected of having non-gonococcal urethritis; 2) individuals suspected of having gonococcal infection; 3) women who present with mucopurulent cervicitis; 4) women who present with a clinical picture consistent with PID; and 5) sexually active men with epididymitis. A follow-up appointment for test of cure should be considered for pregnant women, in patients in whom an "alternative" (i.e., non first-line) agent has been employed, and when there is suspected non-compliance with medications. HIV and immunosuppressed patients may be refractory to an initial treatment course and may therefore require and extended duration of treatment.
Antibiotic Regimens. In populations where noncompliance with medication is likely and when follow-up is unlikely or nonexistent, a single dose of azithromycin (1 gram), consumed by the patient under supervision on site may be more cost-effective approach to the treatment of uncomplicated chlamydial infection. (See Table 6.) In fact, when the cost of complications associated with doxycycline noncompliance and the overall outcome cost of azithromycin are compared, the total outcome costs associated with azithromycin are less than with doxycycline.33 This is despite the higher drug acquisition cost of azithromycin. Unfortunately, azithromycin is not yet approved for use in the pregnant patient and further studies are probably indicated before routine use is advisable. Rifampin and sulfonamides also have good activity against Chlamydia but these agents are not recommended by the CDC.
| Table 6. Treatment of Uncomplicated Chlamydia |
| Treatments of Choice |
| Azithromycin 1 g po, once given under supervision in the clinic or emergency department or practitioner's office, if possible. Note:This is the only single-dose therapy for Chlamydia. |
| or |
| Alternative Treatment of Choice |
| Doxycycline 100 mg bid po for 7-10 days.a |
| Alternative Treatments for Chlamydia |
| Arythromycin base 500 milligrams orally four times daily for 7 days. a |
| or |
| Erythromycin ethylsuccinate 800 mg orally four times daily for 7 days. a |
| or |
| Ofloxacin 300 mg twice a day for 7 days. (contraindicated in patients who are pregnant and/or < 16 years) a |
| Recommended Treatments for Chlamydia in the pregnant patient |
| Erythromycin base 500 milligrams orally four times daily for 7 days |
| or |
| Amoxicillin 500 mg orally three times a day for 7 days. |
| Alternative Treatments for Chlamydia in the pregnant patient |
| Erythromycin base 250 mg orally four times daily for 14 days. a |
| or |
| Erythromycin ethylsuccinate 800 mg orally four times daily for 7 days. a |
| or |
| Erythromycin ethylsuccinate 400 mg orally four times daily for 14 days. a |
| or |
| Azithromycin 1 g po, once (Many authorities feel that this drug should completely replace erythromycin even in the pregnant patient, although it does not yet carry formal approval for use in the pregnant patient. Azithromycin carries a class B pregnancy rating).32 |
| a When an extended duration medication such as doxycycline is employed, the patient should be given the entire course of medication when discharged. Compliance is often unreliable with these medications and any measure possible to improve compliance is appropriate. In one study, even when the doxycycline is given to the patient, only 25% of the patients will complete the full course of doxycycline as directed. |
As a general rule, two factors will influence choice of therapy. Treatment with most agents requires an extended treatment duration (greater than 5 days.) Although resistance to any of the customarily used antibiotics has not been clinically significant, there are some Chlamydial species that have started to exhibit increasing tolerance for tetracycline and derivatives. All of the major antimicrobial agents can cause gastrointestinal side effects. Many patients will not complete the full course of therapy because of this discomfort.
Tetracyclines are contraindicated in pregnancy and in growing children. If the patient is pregnant, an erythromycin regimen should be used. There is some evidence that if the pregnant patient has severe gastrointestinal side effects while taking erythromycin, there will be subtherapeutic levels of erythromycin.34 This would mean that another regimen would be appropriate in these pregnant patients.
All sexual contacts within the last 60 days should be treated. Timely treatment of sexual partners is essential for decreasing the risk of reinfecting the index patient and stopping the spread of infection. In most patients, a "test of cure" is not needed, unless symptoms persist. There are groups in which recurrence or reinfection is more likely. In one study, a two- to three-fold increased risk of chlamydial persistence or recurrence was observed among women who were younger than 25 years and white or who reported: 1) a recent, new partner; 2) multiple partners; 3) a partner who may have had multiple partners at the time of enrollment; or 4) that not all partners were treated during the one-month follow-up period after initiation of treatment.35 In these patients, a "test of cure" may be appropriate one month after treatment.
Finally, Chlamydia infection increases the chance of HIV transmission. In addition, HIV infection probably causes altered manifestations of Chlamydia infection. Since the two diseases are related at least in the manner in which they are transmitted, if the patient has Chlamydia or a high risk for Chlamydia, HIV testing is appropriate.
References
1. Katz BP, Zwickl BW. Compliance with antibiotic therapy for Chlamydia trachomatis and Neisseria gonorrhoeae. Sex Trans Dis 1992;6:351-354.
2. McCormack WM. Pelvic inflammatory disease. N Engl J Med 1994;330:115-119.
3. Therapy for sexually transmitted diseases. Med Lett Drugs Ther 1994;913:1-4.
4. Faro S. New considerations in treatment of urinary tract infections in adults. Urology 1992;39:1-11.
5. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993;329:753-756.
6. Arav-Boger R, et al. Urinary tract infections with low and high colony counts in young women. Spontaneous remission and single-dose vs. multiple-day treatment. Arch Int Med 1994;154:300-304.
7. Zenilman JM. Update on bacterial sexually transmitted disease. Urol Clin N Am 1992;19:25-34.
8. Wexner SD. Sexually transmitted diseases of the colon, rectum, and anus. Dis Col and Rect 1990;33:1048-1062.
9. Martien K, Emans SJ. Treatment of common genital infections in adolescents. J Adoles Health Care 1987;8:129-136.
10. Cucurull E, Espinoza LR. Gonococcal arthritis. Rheum Dis Clin North Am 1998;;24:305-322.
11. Bowie WR. Approach to men with urethritis and urologic complications of sexually transmitted diseases. Med Clin N Am 1990;74:1543-1557.
12. Carroll KC, Aldeen WE, Morrison M, et al. Evaluation of the Abbott LCx ligase chain reaction assay for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in urine and genital swab specimens from a sexually transmitted disease clinic population. J Clin Microbiol 1998;36:1630-1633.
13. Gray RH, Wawer MJ, Girdner J, et al. Use of self-collected vaginal swabs for detection of Chlamydia trachomatis infection [letter]. Sex Transm Dis 1998;25:450.
14. Chapin-Robertson K. Use of molecular diagnostics in sexually transmitted diseases. Diag Microbiol Infec Dis 1993;16:173-184.
15. Koumans EH, Johnson RE, Knapp JS, et al. Laboratory testing for Neisseria gonorrhoeae by recently introduced nonculture tests: A performance review with clinical and public health considerations. Clin Infect Dis 1998;27:1171-1180.
16. Shafer MA, Pantell RH, Schachter J. Is the routine pelvic examination needed with the advent of urine-based screening for sexually transmitted diseases? Arch Pediatr Adolesc Med 1999;153:119-125.
17. Hall GS. Probe technology for the clinical microbiology laboratory. Arch Path Lab Med 1993;117:578-583.
18. Stamm WE. Problems in the treatment of bacterial sexually transmitted diseases. Am J Med 1987;82(suppl 4A):307-310.
19. Denver STD/HIV Prevention Training Center. Sexually transmitted disease clinician's update. Feb. 4-5, 1999.
20. Centers for Disease Control and Prevention. 1998 Guidelines for treatment of sexually transmitted diseases. Morb Mortal Wkly Rep MMWR 1998;(No. RR-1).
21. Villarino ME, Shulte JM. Diagnosis and therapy for common sexually transmitted diseases. Derm Clin 1992;10:459-468.
22. Knapp JS, Fox KK, Trees DL, et al. Fluoroquinolone resistance in Neisseria gonorrhoeae. Emerg Infect Dis 1997;3:33-39.
23. Gordon SM, Carlyn CJ, Doyle LJ, et al. The emergence of Neisseria gonorrhoeae with decreased susceptibility to ciprofloxacin in Cleveland, Ohio: Epidemiology and risk factors. Ann Intern Med 1996;125:465-470.
24. Ridgway GL. Quinolones in sexually transmitted diseases. Drugs 1993;45:134-138.
25. Corrado ML. The clinical experience with ofloxacin in the treatment of sexually transmitted diseases. Am J Obstet Gynecol 1991;5:1396-1399.
26. Stewart CE. Male urinary tract infections. Emerg Med Clin North Am 1988;6:617-630.
27. Bell TA. Chlamydia infections in adolescents. Med Clin North Am 1990;74:1225-1233.
28. Stary A. Urethritis: Diagnosis of nongonococcal urethritis. Dermatol Clin 1998;16:723-726.
29. Smith IW, Morrison CL, Patrizio C, et al. Use of a commercial PCR kit for detecting Chlamydia trachomatis. J Clin Pathol 1993;46:822-285.
30. Morre SA, Sillekens PT, Jacobs MV, et al. Monitoring of Chlamydia trachomatis infections after antibiotic treatment using RNA detection by nucleic acid sequence based amplification. Mol Pathol 1998;51:149-154.
31. Polaneczky M, Quigley C, Pollock L, et al. Use of self-collected vaginal specimens for detection of Chlamydia trachomatis infection. Obstet Gynecol 1998;91:375-378.
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Physician CME Questions
25. Male to female transmission of gonorrhea is the most efficient transmission vector.
A. True
B. False
26. The incubation period for gonorrhea ranges from three to seven days, and the disease usually manifests symptoms within:
A. 7-9 days after exposure.
B. 10-14 days after exposure.
C. 15-21 days after exposure.
D. more than 21 days after exposure.
E. none of the above.
27. What percentage of people harboring gonorrhea are thought to be asymptomatic?
A. 20%
B. 30%
C. 40%
D. 50%
E. None of the above
28. The sensitivity rate for a gram stain evaluation of a cervical specimen site is about:
A. 5%.
B. 10%.
C. 15%.
D. 20%.
E. none of the above.
29. The two forms of gonococcus-mediated resistance are:
A. plasmid-mediated and chromosome-mediated resistance.
B. plasminogen-mediated and chromosome-mediated resistance.
C. plasminogen-mediated and lysosome-mediated resistance.
D. none of the above.
30. Increasing resistance to what CDC-approved antibiotic for treatment of gonococcus has been reported in Asia?
A. Cephalosporins
B. Azithromycin
C. Quinolones
D. Macrolides
E. None of the above
31. A one-dose treatment for uncomplicated chlamydial infection is:>
A. tetracycline.
B. cefixime.
C. ciprofloxacin.
D. azithromycin.
E. none of the above.
32. Chlamydia infection increases the risk of HIV infection.
A. True
B. False
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