Biomedical subjects
Publications and source records attributed to H H Handsfield.
It is likely that up to 50% of the U.S. population will acquire a sexually transmitted disease by age 30 to 35. In industrialized countries, herpes simplex virus is by far the most common pathogen. The major public health impact of HSV infection is its brutal legacy to newborns. Half of the affected infants die at birth, and many of the survivors have severe neurodevelopmental disabilities.
Chancroid is a mucocutaneous infection caused by Haemophilus ducreyi that produces ulcerative lesions and enhances the efficiency of transmission of human immunodeficiency virus (HIV). Confirmation of infection by culture of H. ducreyi is essential in therapeutic trials. Minimal inhibitory concentrations of antibiotics for the isolate should be determined by agar dilution. Patients should be evaluated by appropriate laboratory tests for syphilis, infection with herpes simplex virus, gonorrhea, and (in North America) infection with Chlamydia trachomatis. The clinical history of the disease should be recorded and ulcers, buboes, and lymphadenitis mass described. Whenever possible, study participants also should be tested for HIV infection. Randomized, prospective, double-blind, active-control comparative clinical trials are preferred for evaluation of the safety and efficacy of new anti-infective drugs. Otherwise-healthy men and women should be enrolled in these studies. Patients with active syphilis or genital herpes should be excluded. Microbiological and clinical outcomes are paramount.
The three major vaginal infections are yeast vulvovaginitis, Trichomonas vaginalis vaginitis, and bacterial vaginosis. In terms of signs and symptoms, these disorders overlap substantially with one another and with other infections. Therefore, the diagnosis of candidiasis and trichomoniasis requires isolation of the responsible pathogen. For the diagnosis of bacterial vaginosis, all other potential causes of vaginal infection must be excluded and specified laboratory criteria must be met. Clinical trials must be carefully designed to control for coexisting pathogens, for potential efficacy of treatment against more than one microbe, and for variable end points used to define clinical response. Prospective, randomized, double-blind, active-control comparative studies are preferred. Follow-up evaluations 5-7 days and 4-6 weeks after the completion of therapy are required for the assessment of outcome. Laboratory studies of vaginal fluid (culture and/or microscopic examination) are paramount in the final appraisal of outcome.
Gonorrhea is among the most common sexually transmitted diseases. Treatment for uncomplicated gonorrhea should be efficacious in > or = 95% of cases. Because patients with gonococcal infections often have other sexually transmitted diseases concurrently, individuals enrolled in clinical trials of therapy for gonorrhea should also be evaluated for infection with Chlamydia trachomatis and for syphilis. Testing for other pathogens should be considered in light of the clinical presentation. The presence of gonococcal infection is defined by a positive culture of a specimen obtained from an appropriate mucosal site. Patients enrolled in clinical trials should be otherwise-healthy adults who agree to return for follow-up assessment. These patients should be stratified by gender and anatomic site of infection. The preferred study design is a prospective, randomized, double-blind, active-control comparison. In some circumstances, however, historical controls may suffice. The study drug must have an efficacy rate of > or = 95% in genital and rectal infections. Microbiological eradication, demonstrated by negative cultures of samples from all potentially infected mucosal sites at follow-up, is the sole determinant of efficacy.
This guideline addresses clinical trials of new antimicrobial agents in the treatment of uncomplicated genital infections caused by Chlamydia trachomatis and of syndromes resembling chlamydial infections. The most common clinical manifestations of chlamydial infection are urethritis in men and mucopurulent cervicitis in women. However, many chlamydial infections are not associated with inflammatory symptoms or signs. Culture is the diagnostic standard for defining the presence of C. trachomatis, although nonculture tests may be used in screening patients for enrollment in clinical trials. Susceptibility testing for C. trachomatis is laborious and difficult to standardize; only a few clinical isolates need to be tested in vitro. Prospective, randomized, double-blind, active-control comparative studies are recommended. Eradication of C. trachomatis defines both microbiological success and overall cure for chlamydial infection, but clinical and nonmicrobiological laboratory criteria are paramount in assessing the therapeutic response in nonchlamydial urethritis or cervicitis.
Syphilis is caused by Treponema pallidum, a spirochetal bacterium pathogenic only for humans. The clinical course of disease is divided into three stages interspersed by periods of latency. Penicillin remains the treatment of choice for all stages of infection; tetracycline or erythromycin may be used as therapeutic alternatives in defined circumstances. Patients enrolled in clinical trials should be evaluated clinically, microscopically, and serologically for the presence of the spirochete. All participants, after undergoing counseling and giving informed consent, should be tested for infection with human immunodeficiency virus. Specific criteria exist for diagnosis of syphilis and response to therapy. It may be desirable to perform a small, uncontrolled, open trial of a new anti-infective drug for the collection of preliminary evidence of efficacy. A larger-scale, randomized, active-control comparative clinical trial is necessary to prove efficacy.
Several special issues arise in relation to clinical trials of therapy for sexually transmitted diseases. These issues include the desirability of including adolescents and both pregnant and nonpregnant women in the trial, the use of unapproved control regimens, problems with antimicrobial susceptibility testing due to inadequate methodology and the need for prompt treatment, the need to assess agents for treatment of syndromes of unknown microbial etiology, toxicity considerations related to the use of single-dose regimens, management of the sexual partners of the participants in the trial, analysis of data despite the high frequency of minor protocol violations, sexual reexposure to infection during the trial, and the potential for loss, alteration, or falsification of data because of the relative simplicity of the usual protocol design and the diagnostic reliance on specimens that are routinely discarded.
This guideline addresses clinical trials of new therapies for genital infections due to herpes simplex virus (HSV). Of the two types of virus, HSV-2 is the more common pathogen. Both HSV-1 and HSV-2 become latent in sacral nerve root ganglia and intermittently reactivate. Patients who have frequent recurrences (more than four per year) may be candidates for long-term suppressive therapy. In both first-episode and recurrent genital HSV infections, lesions should be cultured for HSV. Testing for human immunodeficiency virus is encouraged but not required. Serum antibodies to HSV-1 and HSV-2 should be quantitated at enrollment and 3-5 weeks thereafter. Randomized, double-blind, active-control comparative studies are generally recommended. Placebo-controlled trials may be appropriate for recurrent genital herpes or for suppression of recurrences. Final evaluation should generally take place 10-15 days after the completion of therapy.
Case reports suggest that the course of syphilis is altered in patients infected with human immunodeficiency virus (HIV). To investigate this issue, a model of syphilis in rhesus macaques with and without simian immunodeficiency virus (SIV) was developed. After intradermal inoculation with Treponema pallidum, 2 SIV-infected monkeys had persistent ulcerative primary lesions and 1 developed secondary syphilis. Two SIV-uninfected controls developed transient nonulcerative primary lesions. Only the controls showed consistent VDRL antibody responses. In contrast, reciprocal antibody titers to T. pallidum detected by microhemagglutination were higher in SIV-infected animals (greater than or equal to 20,480) than controls (greater than or equal to 1280). All 4 animals developed a full range of T. pallidum antigen-specific antibodies shown by immunoblot and had similar peak lymphocyte proliferative responses to T. pallidum antigens. These results support the contention that retrovirus-induced immunodeficiency delays clearance of T. pallidum from sites of infection and may impair the humoral immune response to syphilis.
BACKGROUND: Because of the widespread existence of Neisseria gonorrhoeae resistant to penicillin or tetracycline, ceftriaxone is now recommended for the treatment of gonorrhea. There is, however, a need for effective antibiotics that can be administered orally as an alternative to ceftriaxone, which requires intramuscular administration. Cefixime is an orally absorbed cephalosporin that is active against resistant gonococci and has pharmacokinetic activity suitable for single-dose administration. METHODS AND RESULTS: In a randomized, unblinded multicenter study of 209 men and 124 women with uncomplicated gonorrhea, we compared three single-dose treatment regimens: 400 mg or 800 mg of cefixime, administered orally, and 250 mg of ceftriaxone administered intramuscularly. The overall cure rates were 96 percent for the 400-mg dose of cefixime (89 of 93 patients) (95 percent confidence interval, 93.5 percent to 97.8 percent); 98 percent for the 800-mg dose of cefixime (86 of 88 patients) (95 percent confidence interval, 94.6 percent to 100 percent); and 98 percent for ceftriaxone (92 of 94 patients) (95 percent confidence interval, 94.9 to 100 percent). The cure rates were similar in men and women, and pharyngeal infection was eradicated in 20 of 22 patients (91 percent). Thirty-nine percent of 303 pretreatment gonococcal isolates had one or more types of antimicrobial resistance; the efficacy of all three regimens was independent of the resistance pattern. Chlamydia trachomatis infection persisted in at least half the patients infected in each treatment group. All three regimens were well tolerated. CONCLUSIONS: In the treatment of uncomplicated gonorrhea, a single dose of cefixime (400 or 800 mg) given orally appears to be as effective as the currently recommended regimen of ceftriaxone (250 mg given intramuscularly).
Bacterial pathogens account for a significant portion of the current STD epidemic in the United States. Gonorrhea, syphilis, and chancroid are especially rife in the nation's poverty pockets. Chlamydial infection, the most common bacterial STD, is prevalent at all socioeconomic levels. A recurrent theme in these diseases is coexisting infection, sometimes involving HIV.
BACKGROUND: Despite a declining incidence during the AIDS era, gonorrhea remains the most frequently reported communicable disease in the United States. METHODS: During 1986 and 1987 we supplemented gonorrhea case reporting with laboratory surveillance in King County, Washington. Incidence rates were correlated with demographic variables. RESULTS: Overall incidence of gonorrhea was similar for men and women, but highest for 16- to 21-year-old females and urban Seattle residents. Incidence rates by ethnicity were Blacks, 3033; Native Americans, 843; Hispanics, 617; Asians, 190; and Whites, 121. Census tracts representing the lowest socioeconomic status (SES) quartile accounted for 58% of reported gonorrhea. Black female teenagers residing in the lowest SES urban areas had highest incidence rates: aged 14 to 15, 3.4%; 16 to 17, 10.4%; 18, 17.0%; and 19, 15.4%. Rates in female teenagers were even higher after adjustment for estimated proportion of those who were sexually experienced. CONCLUSIONS: Gonorrhea incidence is associated with age, gender, ethnicity, SES, and residence. Identification of populations at highest risk for gonorrhea can direct interventions against all sexually transmitted diseases. Clearly, interventions to alter high-risk behaviors must be initiated in early adolescence.
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To evaluate prospectively the relationship between current and past sexual practices and seroprevalence of cytomegalovirus (CMV) in adult women, 1481 women (1101 white, 301 black, 79 other) attending a sexually transmitted disease clinic underwent a standardized interview and genital examination. CMV seroprevalence was higher in black (78%) than in white (59%) women. In logistic regression models that adjusted for age and years of education, CMV seropositivity in white women was associated with younger sexual debut (P = .001), more lifetime sex partners (P = .025), recent new partner(s) (P = .003), and parity (P = .002), and was inversely associated with use of barrier contraception (P = .006). In black women, after adjustment for demographic characteristics, CMV antibody was associated with greater numbers of recent sex partners (P = .007), new sex partners (P = .04), and with cervical infection with Chlamydia trachomatis (P = .05). This study confirms that sexual activity is an important determinant of CMV infection in both white and black women; however, the relative contributions of sexual and nonsexual transmission of CMV apparently vary and require further investigation.
Endocervical infections due to Chlamydia trachomatis remain difficult to diagnose due to the lack of an inexpensive, rapid, and accurate test. We evaluated an alternative strategy for diagnosis in which initial screening was performed with an enzyme immunoassay (Chlamydiazyme) followed by a direct fluorescent antibody (DFA) test on specimens in which the Chlamydiazyme optical density (OD) reading fell in an intermediate zone. Lowering the Chlamydiazme OD ratio (specimen to control) used to define a positive test from 1.0 (the ratio suggested by the manufacturer) to 0.3 raised the sensitivity of Chlamydiazyme from 73 to 83%. Confirmation of those specimens having OD ratios of 0.3 to 0.99 by DFA testing increased the specificity of Chlamydiazyme from 95 to 100%. This strategy necessitated performance of the DFA test on 5% of the specimens. Lowering the cutoff OD ratio below 0.3 increased the sensitivity even further but required DFA testing on greater than 25% of the specimens. Use of an adjusted positive cutoff value for defining positive enzyme immunoassays followed by DFA confirmation for intermediate-zone readings may be a feasible approach for some laboratories that lack cell culture facilities.
A multicenter, randomized, investigator-blind controlled trial was conducted to compare the safety and efficacy of a single, whole-body application of 5% permethrin cream with that of 1% lindane lotion for the treatment of scabies in 467 patients. At 14 +/- 3 days after treatment, the mean active lesion count decreased from pretreatment levels of 85 (range, 4 to 600) in both treatment groups to 14 (range, 0 to 133) in the permethrin group and to 15 lesions (range, 0 to 500) in the lindane group. At 28 +/- 7 days after treatment, complete resolution had occurred in 181 (91%) of 199 patients treated with permethrin and in 176 (86%) of 205 patients given lindane. Pruritus due to scabies persisted at 28 +/- 7 days in 14% of the permethrin group and in 25% of the lindane group. The most frequent adverse effects were new or increased pruritus and mild, transient burning or stinging; the latter was slightly more frequent following permethrin treatment and appeared to be related to severity of infestation. Because of a lower potential for neurologic toxicity, permethrin may be preferable to lindane for the treatment of scabies particularly in children.
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In King County, Washington, penicillinase-producing Neisseria gonorrhoeae infections increased from 0.8% of reported cases of gonorrhea in 1986 to 6.8% of cases in the third quarter of 1987, then stabilized at 2.7% to 3.6% of cases. Of 268 penicillinase-producing N gonorrhoeae isolates tested, 159 (59%) belonged to a single clone, as evidenced by auxotyping, protein-I serotyping, plasmid analysis, and antimicrobial susceptibility testing. As this strain spread, the predominance of cases shifted from whites to blacks and from men to equal numbers of men and women. The proportion of cases associated with illicit drug use rose steadily from 19% in the first quarter of 1987 to 82% in the fourth quarter. Sixty percent of cases occurred in prostitutes or recent sexual contacts of prostitutes. These results suggest that core gonorrhea transmitters in King County are predominantly black illicit drug users, prostitutes, and their sexual partners. These are priority target populations for behavioral intervention and other measures to control the spread of all sexually transmitted diseases, including human immunodeficiency virus infection.