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Kimberly A Workowski - Top 30 Publications

Developing a Public Health Response to Mycoplasma genitalium.

Although Mycoplasma genitalium is increasingly recognized as a sexually transmitted pathogen, at present there is no defined public health response to this relatively newly identified sexually transmitted infection. Currently available data are insufficient to justify routinely screening any defined population for M. genitalium infection. More effective therapies, data on acceptability of screening and its impact on clinical outcomes, and better information on the natural history of infection will likely be required before the value of potential screening programs can be adequately assessed. Insofar as diagnostic tests are available or become available in the near future, clinicians and public health agencies should consider integrating M. genitalium testing into the management of persons with sexually transmitted infection (STI) syndromes associated with the infection (ie urethritis, cervicitis, and pelvic inflammatory disease) and their sex partners. Antimicrobial-resistant M. genitalium is a significant problem and may require clinicians and public health authorities to reconsider the management of STI syndromes in an effort to prevent the emergence of ever more resistant M. genitalium infections.

Mycoplasma genitalium From Basic Science to Public Health: Summary of the Results From a National Institute of Allergy and Infectious Disesases Technical Consultation and Consensus Recommendations for Future Research Priorities.

This article lays out the research priorities for Mycoplasma genitalium research agreed upon by the participants in a 2016 National Institutes of Allergy and Infectious Diseases-funded Technical Consultation focused on this organism. The state of current knowledge concerning the microbiology, epidemiology, clinical manifestations of infection, treatment, and public health significance of M. genitalium reviewed at the meeting is described in detail in the individual articles included in this supplemental edition of the Journal of Infectious Diseases. Here we summarize the points made in these articles most relevant to the formulation of the research priorities listed in this article. The most important recommendation resulting from this Technical Consultation is the initiation of clinical trials designed to determine definitively whether screening for and treatment of M. genitalium infections in women and their sexual partners improve reproductive health in women and/or prevent human immunodeficiency virus transmission.

Estimation of State-Level Prevalence of Hepatitis C Virus Infection, US States and District of Columbia, 2010.

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States and a leading cause of morbidity and mortality. Previous analyses of the US National Health and Nutrition Examination Survey (NHANES) indicated approximately 3.6 million noninstitutionalized persons with antibody to HCV (anti-HCV). However, state-level prevalence remains less understood and cannot be estimated reliably from NHANES alone.

Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials.

Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir).

Factors Associated With Primary Care Physician Knowledge of the Recommended Regimen for Treating Gonorrhea.

The recommended regimen for treating uncomplicated gonorrhea has changed over time, due to the emergence of antimicrobial resistance. We assessed physician knowledge of the recommendation for treating uncomplicated urogenital gonorrhea in adolescents and adults using ceftriaxone and azithromycin dual therapy.

Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype.

Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semiallogeneic fetus. The restoration of these systems after childbirth is poorly understood. We reasoned that enhanced innate immune activation may extend beyond gestation while adaptive immunity recovers. To test this hypothesis, the transcriptional profiles of total peripheral blood mononuclear cells following delivery in healthy women were compared with those of nonpregnant control subjects. Interestingly, interferon-stimulated genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as well as signaling proteins such as STAT1, STAT2, and MAVS, were enriched postpartum. Antiviral genes were primarily expressed in CD14(+) cells and could be stratified according to genetic variation at the interferon-λ3 gene (IFNL3, also named IL28B) SNP rs12979860. Antiviral gene expression was sustained beyond 6 mo following delivery in mothers with a CT or TT genotype, but resembled baseline nonpregnant control levels following delivery in mothers with a CC genotype. CT and TT IFNL3 genotypes have been associated with persistent elevated ISG expression in individuals chronically infected with hepatitis C virus. Together, these data suggest that postpartum, the normalization of the physiological rheostat controlling IFN signaling depends on IFNL3 genotype.

A Review of Evidence-Based Care of Symptomatic Trichomoniasis and Asymptomatic Trichomonas vaginalis Infections.

Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection, affecting an estimated 3.7 million women and men in the United States. Health disparities are prominent in the epidemiology of this infection, which affects 11% of women aged ≥40 years and a disproportionately high percentage of black women. Particularly high prevalences have been identified among sexually transmitted disease (STD) clinic patients and incarcerated individuals. This article reviews and updates scientific evidence in key topic areas used for the development of the 2015 STD Treatment Guidelines published by the Centers for Disease Control and Prevention. Current evidence is presented regarding conditions associated with Trichomonas vaginalis infection, including human immunodeficiency virus (HIV) and pregnancy complications such as preterm birth. Nucleic acid amplification tests and point-of-care tests are newly available diagnostic methods that can be conducted on a variety of specimens, potentially allowing highly sensitive testing and screening of both women and men at risk for infection. Usually, trichomoniasis can be cured with single-dose therapy of an appropriate nitroimidazole antibiotic, but women who are also infected with HIV should receive therapy for 7 days. Antimicrobial resistance is an emerging concern.

Management of Gonorrhea in Adolescents and Adults in the United States.

Gonorrhea is the second most commonly reported notifiable disease in the United States and is associated with serious health sequelae, including pelvic inflammatory disease, infertility, and ectopic pregnancy. Treatment for gonorrhea has been complicated by antimicrobial resistance. Neisseria gonorrhoeae has developed resistance to each of the antimicrobials that were previously recommended as first-line treatment regimens, and current treatment options are severely limited. This article summarizes the key questions and data that were discussed at the Sexually Transmitted Diseases (STD) Treatment Guidelines Expert Consultation meeting in April 2013, and the rationale for the 2015 Centers for Disease Control and Prevention STD treatment guidelines for gonococcal infections in adolescents and adults. Key issues addressed include whether to change the dosage of ceftriaxone and azithromycin used in the recommended dual treatment regimen, whether to continue to list dual treatment with cefixime and azithromycin as an alternative treatment regimen, and management of gonococcal infections in persons with severe cephalosporin allergy or suspected treatment failure.

Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines.

Sexually transmitted diseases treatment guidelines, 2015.

These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR-12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs.

Unusual presentation of chikungunya virus infection with concomintant erysipelas in a returning traveler from the Caribbean: a case report.

Chikungunya fever is a mosquito-borne febrile illness caused by Chikungunya virus (CHIKV), an alphavirus from the Togaviridae family. It is transmitted by primarily Aedes aegytpi and Aedes albopictus mosquitos [1]. Once of little importance in the Americas, local transmission was identified in the Caribbean in late 2013. More than 1000 travelers returning to the continental United States have been diagnosed with CHIKV. More importantly, there have been 9 documented cases of autochthonous disease in Florida as of September 16, 2014 [2].

Acquired macrolide-resistant Treponema pallidum after a human bite.

Syphilis is a systemic disease caused by the spirochete Treponema pallidum that is usually acquired through sexual exposure.

Neglected parasitic infections in the United States: trichomoniasis.

Trichomonas vaginalis is one of the most common human parasitic infections in the United States, as well as the most prevalent non-viral sexually transmitted infection. However, it has long received much less consideration than other parasitic and sexually transmitted diseases. Much of this inattention can be attributed to a poor understanding of the public health impact of trichomoniasis. Increasing recognition of the sequelae of infection, including increased risk of infection with human immunodeficiency virus and adverse outcomes of pregnancy, has led to increased interest in T. vaginalis. Recent innovations include development of diagnostic tests that could improve detection of the parasite. A number of important questions, such as the epidemiology among men and women, the true public health burden of symptomatic and asymptomatic T. vaginalis infections, and whether current treatments will be adequate to reduce the substantial health disparities and costs associated with trichomoniasis, need consideration to remedy neglect of this important disease.

Clinical update in sexually transmitted diseases-2014.

Sexually transmitted diseases (STDs) and their associated syndromes are extremely common in clinical practice. Early diagnosis, appropriate treatment, and partner management are important to ensure sexual, physical, and reproductive health in our patients.

Provider barriers prevent recommended sexually transmitted disease screening of HIV-infected men who have sex with men.

HIV-infected men who have sex with men (MSM) are at increased risk for transmitting and acquiring sexually transmitted diseases (STDs). Guidelines recommend at least annual screening of HIV-infected MSM for syphilis and for chlamydia and gonorrhea at exposed anatomical sites, to protect their health and their sexual partners' health. Despite these guidelines, STD screening has been suboptimal, with very low nongenital chlamydia and gonorrhea testing rates. Our objective was to better understand barriers encountered by HIV care providers in adhering to STD screening guidelines for HIV-infected MSM.

Trichomonas vaginalis antimicrobial drug resistance in 6 US cities, STD Surveillance Network, 2009-2010.

Nitroimidazoles (metronidazole and tinidazole) are the only recommended drugs for treating Trichomonas vaginalis infection, and previous samples that assessed resistance of such isolates have been limited in geographic scope. We assessed the prevalence of in vitro aerobic metronidazole and tinidazole resistance among T. vaginalis isolates from multiple geographic sites in the United States. Swab specimens were obtained from women who underwent routine pelvic examinations at sexually transmitted disease clinics in 6 US cities. Cultured T. vaginalis isolates were tested for nitroimidazole resistance (aerobic minimum lethal concentration [MLC] >50 µg/mL). Of 538 T. vaginalis isolates, 23 (4.3%) exhibited low-level in vitro metronidazole resistance (minimum lethal concentrations 50-100 µg/mL). No isolates exhibited moderate- to high-level metronidazole resistance or tinidazole resistance. Results highlight the possibility that reliance on a single class of antimicrobial drugs for treating T. vaginalis infections may heighten vulnerability to emergence of resistance. Thus, novel treatment options are needed.

Sexually transmitted infections and HIV: diagnosis and treatment.

Accurate assessment, diagnosis, and treatment of sexually transmitted infections (STIs) in HIV-infected persons can identify sexual risk behaviors and specific STIs that may increase transmission of STIs and HIV. HIV-infected men and women should be screened annually for syphilis and urogenital gonorrhea and chlamydia. Serologic testing for hepatitis A, B, and C viruses should also be performed. Women should be tested for trichomoniasis and undergo a cervical Papanicolaou test annually. Men who report receptive anal intercourse with men during the preceding year should be screened for rectal gonorrhea and chlamydia. Men who report receptive oral intercourse with men during the preceding year should be screened for oropharyngeal gonorrhea. More frequent screening at 3- to 6-month intervals may be indicated for men who have sex with men who have numerous or anonymous partners. STIs may have unusual presentations in HIV-infected patients. Aspects of diagnosis and management of common STIs will be discussed in this article. This article summarizes a presentation by Kimberly A. Workowski, MD, at the IAS-USA live continuing medical education course held in New York City in October 2011.

Low rates of hepatitis screening and vaccination of HIV-infected MSM in HIV clinics.

HIV-infected men who have sex with men (MSM) are at increased risk of viral hepatitis because of similar behavioral risk factors for acquisition of these infections. Our objective was to estimate adherence to HIV management guidelines that recommend screening HIV-infected persons for hepatitis A, B, and C infection, and vaccinating for hepatitis A and B if susceptible.

Centers for Disease Control and Prevention Sexually Transmitted Disease Treatment Guidelines.

Trichomonas vaginalis genital infections: progress and challenges.

Trichomonas vaginalis (TV) infection is the most prevalent curable sexually transmitted infection in the United States and worldwide. Most TV infections are asymptomatic, and the accurate diagnosis of this infection has been limited by lack of sufficiently sensitive and specific diagnostic tests, particularly for men. To provide updates for the 2010 Centers for Disease Control and Prevention's Sexually Transmitted Diseases Treatment Guidelines, a PubMed search was conducted of all TV literature published from 9 January 2004 through 24 September 2008. Approximately 175 pertinent abstracts and articles were reviewed and discussed with national experts. This article describes advances in TV diagnostics which have led to an improved understanding of the epidemiology of this pathogen, as well as potential biologic and epidemiological interactions between TV and human immunodeficiency virus (HIV). New data on treatment outcomes, metronidazole-resistant TV, management of nitroimidazole-allergic patients, frequency of recurrent TV infection following treatment, and screening considerations for TV in certain populations are also presented.

Updates on human papillomavirus and genital warts and counseling messages from the 2010 Sexually Transmitted Diseases Treatment Guidelines.

In April 2009, experts on sexually transmitted diseases (STDs) were convened to review updates on STD prevention and treatment in preparation for the revision of the Centers for Disease Control and Prevention (CDC) STD Treatment Guidelines. At this meeting, there was a discussion of important updates on human papillomavirus (HPV), genital warts, and cervical cancer screening.

Management of adult syphilis.

There are several important unanswered key questions in the management of adult syphilis. A systematic literature review was conducted and tables of evidence were constructed to answer these important questions. A single dose of 2.4 million units of benzathine penicillin G remains the drug of choice for managing early syphilis. Enhanced antibiotic therapy has not been shown to improve treatment outcomes, regardless of human immunodeficiency virus (HIV) status. Although additional data on the efficacy of azithromycin in treating early syphilis have emerged, reported increases in the prevalence of a mutation associated with azithromycin resistance precludes a recommendation for its routine use. Cerebrospinal fluid (CSF) examination should be performed in all persons with serologic evidence of syphilis infection and neurologic symptoms. In those persons with early syphilis who do not achieve a ≥ 4-fold serologic decline in their rapid plasma reagin (RPR) titers 6-12 months after adequate therapy and those with late latent infection who do not achieve a similar decline within 12-24 months, CSF examination should be considered. Among HIV-infected persons, CSF examination among all those with asymptomatic late latent syphilis is not recommended owing to lack of evidence that demonstrates clinical benefit. HIV-infected persons with syphilis of any stages whose RPR titers are ≥ 1:32 and/or whose CD4 cell counts are <350 cells/mm(3) may be at increased risk for asymptomatic neurosyphilis. If CSF pleocytosis is evident at initial CSF examination, these examinations should be repeated every 6 months until the cell count is normal. Several important questions regarding the management of syphilis remain unanswered and should be a priority for future research.

Utility of antimicrobial susceptibility testing in Trichomonas vaginalis-infected women with clinical treatment failure.

Antimicrobial resistance is one of the causes of treatment failure in women after standard nitroimidazole therapy for Trichomonas vaginalis infections. The Centers for Disease Control and Prevention provides drug susceptibility testing and guidance for treatment failures but the efficacy of the alternate recommendations has not been assessed.

Sexually transmitted diseases treatment guidelines, 2010.

These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 18-30, 2009. The information in this report updates the 2006 Guidelines for Treatment of Sexually Transmitted Diseases (MMWR 2006;55[No. RR-11]). Included in these updated guidelines is new information regarding 1) the expanded diagnostic evaluation for cervicitis and trichomoniasis; 2) new treatment recommendations for bacterial vaginosis and genital warts; 3) the clinical efficacy of azithromycin for chlamydial infections in pregnancy; 4) the role of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis and treatment-related implications; 5) lymphogranuloma venereum proctocolitis among men who have sex with men; 6) the criteria for spinal fluid examination to evaluate for neurosyphilis; 7) the emergence of azithromycin-resistant Treponema pallidum; 8) the increasing prevalence of antimicrobial-resistant Neisseria gonorrhoeae; 9) the sexual transmission of hepatitis C; 10) diagnostic evaluation after sexual assault; and 11) STD prevention approaches.

Aspergillus endocarditis: a review of the literature.

We present a case of cardiac device-related Aspergillus endocarditis in a patient with a pacemaker and an allogeneic bone marrow transplant to segue into a review of the Aspergillus endocarditis literature. Aspergillus endocarditis should be suspected in patients with underlying immunosuppression, negative cultures, and a vegetation on echocardiography. Diagnosis ultimately requires confirmation by tissue histology and culture. The optimal treatment approach often requires aggressive surgical debridement in conjunction with prolonged antifungal therapy.

Transient CD86 expression on hepatitis C virus-specific CD8+ T cells in acute infection is linked to sufficient IL-2 signaling.

Costimulatory signals via B7/CD28 family molecules (signal 2) are critical for effective adaptive CD8(+) T cell immune responses. In addition to costimulatory signals, B7/CD28 family coinhibitory receptor/ligands that modulate immune responses have been identified. In acute hepatitis C virus (HCV) infection, programmed death receptor 1, an inhibitory receptor in the CD28 family, is highly expressed on virus-specific CD8(+) T cells, yet vigorous immune responses often develop. We hypothesized that other costimulatory signals present during the acute phase of HCV infection would be important to counter this negative signaling. In this study, we found that CD86 was highly expressed on HCV-specific CD8(+) T cells early in acute HCV infection and was lost on transition to chronic HCV infection; the expression of CD86 was different from other activation markers, because expression was delayed after in vitro TCR stimulation and required sufficient IL-2 signaling; and HCV-specific CD8(+) T cells in the liver of patients with chronic HCV infection were highly activated (CD69, CD38, and HLA-DR expression), but only a minority expressed CD86 or showed evidence of recent IL-2 signaling (low basal phosphorylated STAT5), despite persistent viremia. Our study identified B7 ligand expression on HCV-specific CD8(+) T cells as a distinct marker of effective T cell stimulation with IL-2 signaling in acute HCV infection. Expression of costimulatory molecules, such as CD86, early in HCV infection may be essential in overcoming inhibitory signals from the high level of programmed death receptor 1 expression also seen at this phase of infection.

Pharyngeal gonorrhea: an important reservoir of infection?

Dilemmas in the management of syphilis: a survey of infectious diseases experts.

We surveyed infectious diseases consultants to determine how they manage syphilis when there are insufficient data to guide management or when guidelines cannot be followed because of a lack of available definitive diagnostic tests. Most providers did not have access to dark-field microscopy. We found variation in management of syphilis, especially for patients with human immunodeficiency virus infection.

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.

Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection.

A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8(+) T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8(+) T cells during the acute and chronic stages of infection. Although HCV-specific CD8(+) T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8(+) T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8(+) T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the "death phase" of HCV-specific CD8(+) T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.