Kimberly A. Workowski

Sexually transmitted diseases treatment guidelines.

Sexually transmitted diseases (STDs) are a major health problem for adolescents. Health care providers for adolescents play a critical role in preventing and treating STDs. In May 2002, the Centers for Disease Control and Prevention published the Sexually Transmitted Diseases Treatment Guidelines 2002. These evidence-based guidelines are based on a systematic literature review focusing on information that had become available since the 1998 Guidelines for Treatment of STDs. This article reviews the new STD treatment guidelines for gonorrhea, chlamydia, bacterial vaginosis, trichomonas, vulvovaginal candidiasis, pelvic inflammatory disease, genital warts, herpes simplex virus infection, syphilis, and scabies. Although these guidelines emphasize treatment, prevention strategies and diagnostic recommendations also are discussed.

Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression.

ABSTRACT The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T-cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the coinhibitory molecule PD-1 predicts CD8+ antiviral T-cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8+ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8+ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, express not only high levels of PD-1 but also decreased interleukin-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1

BACKGROUND Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).

CDC Sexually Transmitted Diseases Treatment Guidelines

Sexually transmitted diseases (STDs) constitute an epidemic of tremendous magnitude, with an estimated 15 million persons acquiring a new STD each year [1]. Effective clinical management of STDs represents a strategic element in prevention of HIV infection and in efforts to improve reproductive and sexual health. Clinicians who evaluate persons with STDs or those at risk for STDs should be aware of the current national guidelines for STD treatment. The 2002 Centers for Disease Control (CDC) guidelines for the treatment of STDs provide clinical guidance in the appropriate assessment and management of STDs [2]. The scope and content of these guidelines continues to evolve, reflecting changes not only in clinical experience and epidemiology but also in changes in the health care environment and the circumstances under which clinical services are delivered. The 2002 guidelines for the treatment of sexually transmitted diseases were developed in consultation with publicand private-sector professionals knowledgeable in the management of STDs, using an evidence-based approach. A systematic literature review was performed that focused on peer-reviewed journal articles and published abstracts that have become available since publication of the 1998 guidelines. On the basis of this review process, background papers were developed, and the available evidence was evaluated during a meeting of consultants in September 2000. A draft report was then circulated to professional associations, STD treatment experts, and other agencies,

Multiple Drug-Resistant Chlamydia trachomatis Associated with Clinical Treatment Failure

In vitro susceptibility testing and genotyping were done on urogenital isolates of Chlamydia trachomatis from 3 patients, 2 of whom showed evidence of clinical treatment failure with azithromycin and one of whom was the wife of a patient. All 3 isolates demonstrated multidrug resistance to doxycycline, azithromycin, and ofloxacin at concentrations >4.0 microg/mL. Recurrent disease due to relapsing infection with the same resistant isolate was documented on the basis of identical genotypes of both organisms. This first report of clinically significant multidrug-resistant C. trachomatis causing relapsing or persistent infection may portend an emerging problem to clinicians and public health officials.

Repeat infection with chlamydia and gonorrhea among females: a systematic review of the literature.

Determining the magnitude of chlamydia and gonorrhea reinfection is critical to inform evidence-based clinical practice guidelines related to retesting after treatment. PubMed was used to identify peer-reviewed English language studies published in the past 30 years that estimated reinfection rates among females treated for chlamydia or gonorrhea. Included in this analysis were original studies conducted in the United States and other industrialized countries that reported data on chlamydia or gonorrhea reinfection in females. Studies were stratified into 3 tiers based on study design. Reinfection rates were examined in relation to the organism, study design, length of follow-up, and population characteristics. Of the 47 studies included, 16 were active cohort (Tier 1), 15 passive cohort (Tier 2), and 16 disease registry (Tier 3) studies. The overall median proportion of females reinfected with chlamydia was 13.9% (n = 38 studies). Modeled chlamydia reinfection within 12 months demonstrated peak rates of 19% to 20% at 8 to 10 months. The overall median proportion of females reinfected with gonorrhea was 11.7% (n = 17 studies). Younger age was associated with higher rates of both chlamydia and gonorrhea reinfection. High rates of reinfection with chlamydia and gonorrhea among females, along with practical considerations, warrant retesting 3 to 6 months after treatment of the initial infection. Further research should investigate effective interventions to reduce reinfection and to increase retesting.

Emerging Antimicrobial Resistance in Neisseria gonorrhoeae: Urgent Need to Strengthen Prevention Strategies

Neisseria gonorrhoeae infection can cause cervicitis, urethritis, proctitis, pelvic inflammatory disease with long-term sequelae (infertility, ectopic pregnancy, chronic pelvic pain), adverse outcomes of pregnancy, and increased susceptibility to and transmission of HIV infection (1, 2). Neisseria gonorrhoeae infection is the second most common notifiable disease in the United States, with 358366 cases reported in 2006 (3). However, reported cases probably represent an underestimate of the actual disease burden because of underdiagnosis and underreporting; it is estimated that there were approximately 718000 incident gonorrhea cases in 2000 (4). After national implementation of gonorrhea control activities in the 1970s, the incidence of gonorrhea in the United States declined markedly, with a 74% reduction in rates from 1975 to 1997. Although rates have remained relatively stable over the past decade, in 2006 the national gonorrhea case rate (120.9 cases per 100000 population) increased for the second consecutive year, particularly in the western United States (3, 5). Rates of gonorrhea remain high in the South and among African Americans, adolescents, young adults, and men who have sex with men. Recent reports have also documented high rates of gonorrhea among HIV-infected men who have sex with men (3). Because of increased infection rates, high burden of disease, and the reproductive and economic implications of gonorrhea infection, prevention and control of gonorrhea is an important public health concern (6, 7). As current therapeutic options become more limited, we describe the emergent challenges to maintaining antimicrobial effectiveness and a comprehensive approach to gonorrhea control. Historical Perspective on Antimicrobial Resistance An essential element in gonorrhea control is the availability and provision of appropriate, effective antimicrobial therapy. Effective treatment not only eradicates infection in the affected individual and prevents the development of complications, it also has an important public health benefit of shortening the duration of infection, thus decreasing transmission and eliminating reservoirs of infection. However, over the past 60 years N. gonorrhoeae has developed resistance to multiple classes of antimicrobials (Appendix Figure). Sulfanilamides were used for gonococcal treatment after their introduction in 1936, but their efficacy was short-lived because of the rapid emergence of resistance by 1945 (8). Penicillin became the recommended antimicrobial regimen for the next 40 years. The progressive decline in susceptibilityinitially associated with chromosomally mediated resistance (exhibited by a stepwise increase in resistance) and later by the acquisition and spread of plasmids containing genes for penicillinase productionrequired serial increases in the recommended dose of intramuscular procaine penicillin (with probenecid) from 50000 units in 1945 to 4.8 million units by the early 1970s (9). In 1985, because of emerging penicillin resistance, ceftriaxone became a recommended regimen for the treatment of uncomplicated gonococcal infections (10). At the same time, tetracycline resistance (both plasmid and chromosomally mediated) was spreading to the extent that tetracycline was no longer a viable treatment option. By 1989, resistance to penicillin was sufficiently widespread that penicillin was no longer effective. Ceftriaxone then became the recommended regimen for gonorrhea therapy, with ciprofloxacin as an alternative treatment option (11). By 1993, on the basis of data regarding high efficacy, safety, and convenience as single-dose therapies, oral fluoroquinolones (ciprofloxacin, ofloxacin) were recommended as oral regimens for gonorrhea treatment, as was the oral third-generation cephalosporin cefixime (12). Appendix Figure. Historical perspective on antimicrobial resistance in the United States. QRNG = quinolone-resistant Neisseria gonorrhoeae; MSM = men who have sex with men. In 1986, concerns about emerging gonococcal antimicrobial resistance lead to the development of the Gonococcal Isolate Surveillance Project (GISP), a national sentinel surveillance system that monitors antimicrobial susceptibility in the United States. Each year, approximately 6000 urethral gonococcal isolates from men attending 25 to 30 sexually transmitted disease (STD) clinics throughout the country are collected and analyzed to provide national data that help guide treatment recommendations. The GISP findings of notable importance include the continued high prevalence of penicillin and tetracycline resistance, which has remained greater than 15%; the increasing prevalence of isolates with decreased susceptibility to macrolides; the appearance of a limited number of multidrug-resistant isolates with decreased susceptibility to cefixime (3); and most important, the dramatic spread of quinolone-resistant N. gonorrhoeae. Based in part on data from GISP, the emergence of quinolone-resistant N. gonorrhoeae was first identified in Hawaii in 1991, at about same time that it was recognized as a problem in Asia (13). Thereafter, sporadic occurrences of quinolone-resistant N. gonorrhoeae were noted in the United States throughout the 1990s. By 2000, quinolone-resistant N. gonorrhoeae was increasingly observed in persons who became infected in Asia, the Pacific Islands (including Hawaii), or California. As a result, fluoroquinolones were no longer recommended for treating gonorrhea acquired in those locales (14, 15). Over the next several years, GISP identified increased rates of quinolone-resistant N. gonorrhoeae among men who have sex with men. This finding prompted an advisory in 2004 that fluoroquinolones were no longer recommended for treating gonorrhea in men who have sex with men, regardless of locale (16). Most recently, data from GISP indicate that quinolone-resistant N. gonorrhoeae is widely dispersed in the United States and that in 2006 the infection accounted for 39% of gonococcal isolates in men who have sex with men and 7% in heterosexual men. On the basis of these cumulative data, the Centers for Disease Control and Prevention (CDC) announced that fluoroquinolones are no longer recommended for treating gonococcal infections and associated conditions, such as pelvic inflammatory disease or epididymitis, in any population in the United States (17). The antimicrobial resistance data from GISP have provided a rational basis for recommended gonococcal treatment regimens. However, data from this sentinel surveillance system have limitations. The GISP data may not be representative of the total population with gonorrhea in the United States, because the current national surveillance system oversamples West Coast locations (where new resistant strains have been first detected), evaluates only male urethral isolates obtained from STD clinics, and samples only a minority of reported gonococcal infections. Dramatic differences in quinolone-resistant N. gonorrhoeae prevalence by geographic location and sexual orientation illustrate the challenge of achieving accurate representation (18). The rapid spread throughout the United States of quinolone-resistant N. gonorrhoeae in heterosexual men, as well as among men who have sex with men, makes defining remaining pockets of continued susceptibility of N. gonorrhoeae problematic. These limitations highlight the difficulty of defining an appropriate sentinel population and a frequency of sampling with sufficient representation to assure susceptibility in a particular locale. Thus, there is a need to monitor antimicrobial resistance at the local level, which would provide a more in-depth understanding of resistance trends and contribute to decisions that affect treatment recommendations in various locations (19, 20). Evolution of Criteria for Gonorrhea Treatment Recommendations The epidemiology of antimicrobial resistance guides decisions about gonococcal treatment recommendations. As discussed, data from GISP are critical when evaluated along with other relevant data, such as those provided by the Gonococcal Antimicrobial Surveillance Program of the Western Pacific Regional Office of the World Health Organization (WHO) in Southeast Asia and the Pacific region. The CDC and the WHO have recommended a change in the treatment regimen when the prevalence of antimicrobial resistance exceeds 5% for a specific antibiotic, while taking into account the prevalence of gonorrhea in the community, the cost of diagnostic and treatment regimens, and the availability of antimicrobial susceptibility data (2123). An accepted definition of gonococcal treatment efficacy requires a cure rate of over 95% with a lower bound of the 95% CI of at least 90% (24). At the time this criterion was proposed, many antimicrobial regimens met this standard, but in an attempt to reduce the risk for therapeutic failure and development of antimicrobial resistance, more stringent criteria were proposed by Moran and colleagues (25). Their criteria specified that efficacy exceed 95% in summed clinical trials, but required that the lower bound of the 95% CI also be at least 95%. In addition to efficacy data, decisions regarding treatment recommendations involve consideration of other factors. These include administration of at least twice the minimum dose to ensure therapeutic reserve, documentation that susceptibility is not lower among organisms recovered after treatment, and evidence that the serum or plasma concentration with the recommended dose is at least 4 times the minimum inhibitory concentration required to inhibit 90% of strains (MIC90) for 10 hours after the concentration peak (25). These stringent clinical efficacy criteria (95% efficacy with 95% CI) were used to determine the gonorrhea treatment regimens recommended in the CDC STD Treatment Guidelines since 1993. However, it was recently suggested that these criteria be modified, given the propensity of N. gonorrhoeae to develo

Update on the Management of Gonorrhea in Adults in the United States

Gonorrhea, the second most commonly reported notifiable disease, is an important cause of cervicitis, urethritis, and pelvic inflammatory disease. The selection of appropriate therapy for gonorrhea (i.e., safe, highly effective, single dose, and affordable) is complicated by the ability of Neisseria gonorrhoeae to develop resistance to antimicrobial therapies. This article reviews the key questions and data that informed the 2006 gonorrhea treatment recommendations of the Centers for Disease Control and Prevention. Key areas addressed include the criteria used to select effective treatment for gonorrhea, the level of antimicrobial resistance at which changing treatment regimens is recommended, the epidemiology of resistance, and the use of quinolones, cephalosporins, and other classes of antimicrobials for the treatment of uncomplicated gonorrhea.

Treatment of abnormal vaginal flora in early pregnancy with clindamycin for the prevention of spontaneous preterm birth: a systematic review and metaanalysis

The purpose of this study was to determine whether the administration of clindamycin to women with abnormal vaginal flora at <22 weeks of gestation reduces the risk of preterm birth and late miscarriage. We conducted a systematic review and metaanalysis of randomized controlled trials of the early administration of clindamycin to women with abnormal vaginal flora at <22 weeks of gestation. Five trials that comprised 2346 women were included. Clindamycin that was administered at <22 weeks of gestation was associated with a significantly reduced risk of preterm birth at <37 weeks of gestation and late miscarriage. There were no overall differences in the risk of preterm birth at <33 weeks of gestation, low birthweight, very low birthweight, admission to neonatal intensive care unit, stillbirth, peripartum infection, and adverse effects. Clindamycin in early pregnancy in women with abnormal vaginal flora reduces the risk of spontaneous preterm birth at <37 weeks of gestation and late miscarriage. There is evidence to justify further randomized controlled trials of clindamycin for the prevention of preterm birth. However, a deeper understanding of the vaginal microbiome, mucosal immunity, and the biology of BV will be needed to inform the design of such trials.

Pathology of hyalohyphomycosis caused by Scedosporium apiospermum (Pseudallescheria boydii): An emerging mycosis

The genus Scedosporium contains two medically significant species of emerging mycotic agents, S. apiospermum and S. prolificans, which have received scant attention. Scedosporium apiospermum is the anamorph, or asexual state, of the cosmopolitan fungus Pseudallescheria boydii, with both sharing the same risk factors for infection, clinical spectrum, and histopathologic features. Scedosporium prolificans is a recently recognized agent of bone, soft tissue, and joint infections that occurs with highest frequency in children and young adults. S. prolificans may also cause potentially fatal disseminated infections in immunocompromised persons. The drug sensitivities of both Scedosporium species are significantly different from those of most other fungi, and thus identification of these organisms is important. Unfortunately, the pathological features of Scedosporium infections may be easily confused with other mycotic agents, resulting in delayed or inappropriate medical therapy. Because many pathologists and clinicians are unfamiliar with the significance of Scedosporium spp. infection, this communication describes three persons with differing clinical and pathological presentations of S. apiospermum infection. In one patient with sickle cell disease and chronic mycotic sinusitis, fungal colonies of S. apiospermum removed from the sinuses showed a pattern of alternating zones of mycelial hypercellularity and hypocellularity associated with conidiation, similar to a previous report of P. boydii infection. The clinicopathologic features of an immunocompetent person with S. apiospermum osteomyelitis, and a patient with S. apiospermum infection of the brain after bone marrow transplantation, are also described.