Pennan M. Barry

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

The use of cephalosporins for gonorrhea: The impending problem of resistance

Gonorrhea remains an important clinical and public health problem throughout the world. Gonococcal infections have historically been diagnosed by Gram stain and culture but are increasingly diagnosed through nucleic acid tests, thereby eliminating the opportunity for antimicrobial susceptibility testing. Gonococcal infections are typically treated with single-dose therapy with an agent found to cure > 95% of cases. Unfortunately, the gonococcus has repeatedly developed resistance to antimicrobials including sulfonamides, penicillin, tetracyclines and fluoroquinolones. This has now left third-generation cephalosporins as the lone class of antimicrobials recommended as first-line therapy for gonorrhea in some regions. However, resistance to oral third-generation cephalosporins has emerged and spread in Asia, Australia and elsewhere. The mechanism of this resistance seems to be associated with a mosaic penicillin binding protein (penA) in addition to other chromosomal mutations previously found to confer resistance to β-lactam antimicrobials (ponA, mtrR, penB, pilQ). Few good options exist or are in development for treating cephalosporin-resistant isolates, as most have had multidrug resistance. Preventing the spread of resistant isolates will depend on ambitious antimicrobial management programs, strengthening and expanding surveillance networks, and through effective sexually transmitted disease control and prevention.

Chlamydia trachomatis and Neisseria gonorrhoeae Transmission from the Oropharynx to the Urethra among Men who have Sex with Men

BACKGROUND Limited data exist on the risk of Chlamydia trachomatis and Neisseria gonorrhoeae transmission from oropharynx to urethra. We examined urethral C. trachomatis and N. gonorrhoeae positivity among men who have sex with men (MSM) seen at San Francisco City Clinic (San Francisco, CA) during 2007. METHODS All patients who sought care at the San Francisco City Clinic (the only municipal sexually transmitted disease clinic in San Francisco) received a standardized interview conducted by clinicians. We estimated urethral C. trachomatis and N. gonorrhoeae positivity for 2 groups of visits by MSM who visited during 2007: (1) men who reported their only urethral exposure was receiving fellatio in the previous 3 months and (2) men who reported unprotected insertive anal sex in the previous 3 months. Additionally, urethral C. trachomatis and N. gonorrhoeae positivity was estimated, stratified by human immunodeficiency virus infection status, urogenital symptom history, and whether the patient had been a contact to a sex partner with either chlamydia or gonorrhea. RESULTS Among MSM who reported only receiving fellatio, urethral C. trachomatis and N. gonorrhoeae positivity were 4.8% and 4.1%, respectively. These positivity estimates were similar to positivity found among MSM who reported unprotected insertive anal sex. CONCLUSIONS A more complete understanding of the risks of transmission of C. trachomatis and N. gonorrhoeae from oropharynx to urethra will help inform prevention and screening programs.

Mosaic Penicillin-Binding Protein 2 in Neisseria gonorrhoeae Isolates Collected in 2008 in San Francisco, California

ABSTRACT Using a real-time PCR assay specific for a mosaic penA allele that has been associated with oral cephalosporin resistance in Asia, 54 available Neisseria gonorrhoeae isolates collected in San Francisco, CA, from January to October 2008 were analyzed. Five isolates tested positive for the mosaic penA gene by real-time PCR. DNA sequencing revealed two mosaic penA alleles (SF-A and SF-B). Isolates with SF-A and SF-B alleles possessed elevated MICs for the oral cephalosporins cefpodoxime and cefixime.

Invasive pneumococcal disease in a cohort of HIV-infected adults: incidence and risk factors, 1990-2003.

Objective:To investigate the association between the introduction of HAART and invasive pneumococcal disease (IPD) in HIV-infected patients. Methods:Incidence of IPD was determined from 1990 to 2003 in a cohort of HIV-infected individuals and a nested case–control study assessed risk factors of IPD. Results:There were 72 cases over 19 020 person-years of follow-up (overall IPD rate, 379/100 000 person-years). In the calendar periods 1990–1995, 1995–1998, and 1998–2003, the IPD incidence per 100 000 person-years was 279 [95% confidence interval (CI), 150–519], 377 (95% CI, 227–625) and 410 (95% CI, 308–545), respectively (P = 0.516). CD4 cell count < 200 cells/μl [odds ratio (OR), 3.0; 95% CI, 1.2–7.6), HIV RNA > 50 000 copies/ml (OR, 2.8; 95% CI, 1.2–6.5), hepatitis C (OR, 4.9; 95% CI, 1.7–14.9), serum albumin (OR, 0.1; 95% CI, 0.04–0.5), injection drug use in women (OR, 3.8; 95% CI, 1.6–8.8), and education beyond high school (OR, 0.2; 95% CI, 0.05–0.8) were significantly associated with IPD in multivariate analysis. No treatment factor, including HAART (OR, 0.7; 95% CI, 0.3–1.5) and pneumococcal vaccination (OR, 0.9; 95% CI, 0.5–1.6), was associated with IPD. Conclusions:IPD incidence did not change significantly during the widespread dissemination of HAART in this cohort. IPD risk was associated with several sociodemographic and clinical factors.

Real-Time PCR Assay for Detection of Quinolone-Resistant Neisseria gonorrhoeae in Urine Samples

ABSTRACT A need exists for the development of applicable surveillance tools to detect fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) in urine samples. We describe here a real-time PCR assay for detecting mutations in the Ser91 codon of the gyrA gene of N. gonorrhoeae in urine specimens. We tested 96 urine samples collected along with Gonorrhea Isolate Surveillance Project (GISP) urethral swab samples and compared the results with matched MICs of ciprofloxacin, as reported by the regional GISP laboratory. We then tested 100 urine specimens, known to be gonorrhea positive by nucleic acid amplification testing, provided by females to challenge the real-time PCR assay with urine specimens containing potentially less target DNA content than specimens from symptomatic males. With an MIC threshold of 0.125 μg of ciprofloxacin/ml, our assay correctly identified resistance in 41 of 44 (93.2%; 95% confidence interval [CI] = 81.3 to 98.6%) corresponding resistant culture specimens and correctly identified 51 of 51 (100%; 95% CI = 93.0 to 100%) susceptible specimens. One specimen did not amplify. The assay successfully amplified the gyrA amplicon and determined a susceptibility genotype in 72 of 100 (72%) urine specimens collected from female patients. We developed an assay for detecting QRNG in urine specimens that correlated well with MIC results of cultured specimens and had moderate sensitivity with urine specimens. This methodology might fulfill the need for a QRNG detection system for urine specimens, a useful characteristic in the age of nucleic acid amplification testing for gonococcal infection.

Results of a program to test women for rectal chlamydia and gonorrhea.

OBJECTIVE: To analyze whether rectal testing among women increased chlamydia and gonorrhea case-finding and whether reported receptive anal intercourse was a risk factor for rectal infection. METHODS: From March 2007 to August 2008, women receiving pelvic examinations at the San Francisco sexually transmitted disease clinic were tested for rectal gonorrhea and chlamydia by using a transcription-mediated amplification assay. Results of testing and clinical and demographic data were analyzed using a cross-sectional study design. RESULTS: Of 1,308 women with both rectal and vaginal tests, test results were positive for 79 patients (6.0%) for rectal chlamydia or gonorrhea and 88 patients (6.7%) for genital chlamydia or gonorrhea. Test results were positive for 13 patients (1.0%) at the rectum only, increasing detection from 88 to 101 patients (14.8%; 95% confidence interval 8.1–23.9). No correlation existed between reported anal sex and rectal chlamydia (P=.74); however, 50% of women with rectal gonorrhea reported anal sex compared with 21% of women without rectal gonorrhea (P=.002). CONCLUSION: Sexually transmitted disease clinics might improve chlamydia and gonorrhea case-finding through rectal testing of women, but more study is needed to determine the effects of finding and treating such infections. Reporting anal intercourse did not predict rectal chlamydial infection among women tested at both the rectum and the vagina. LEVEL OF EVIDENCE: II

Is Jail Screening Associated With a Decrease in Chlamydia Positivity Among Females Seeking Health Services at Community Clinics?-San Francisco, 1997-2004

Background: Young adults entering jail are at increased risk for sexually transmitted diseases (STD) such as chlamydia, are released quickly, and are unlikely to be tested for STDs elsewhere. San Francisco jails performed targeted chlamydia screening and treatment since 1996. Goal: To determine this program’s impact on chlamydia positivity among females attending neighborhood medical clinics. Study Design: During 1997–2004, jail testing density, a measure of the proportion of persons from year 2000 census blocks that were tested in jail, was compared by neighborhood. Chlamydia positivity among females aged 15 to 25 years were compared at 2 clinics serving areas with different jail testing densities. Results: Of persons offered screening at intake, 89% accepted. A total of 42,952 tests were performed among 23,561 persons in jail (45% black, 73% male). A total of 2765 (6.4%) tests were positive for chlamydia; 81% of chlamydial infections were treated. Jail testing density significantly correlated with neighborhood female chlamydia rates. Mean jail testing density at Clinic S, calculated by using the residence of persons tested for chlamydia, was 7 times greater than that at Clinic O. Chlamydia positivity declined at Clinic S from 16.1% to 7.8% (Ptrend <0.001). No significant change occurred at Clinic O in chlamydia (4.7% in 1997 and 2004, Ptrend = 0.81). Conclusions: In San Francisco, screening young adults in jail focused testing on persons from neighborhoods with high chlamydia rates. Jail screening started immediately before chlamydia declines among young females at a clinic serving neighborhoods with high jail testing density. These programs might help reduce community prevalence and racial/ethnic disparities in STDs.

Genome Sequencing of a Neisseria gonorrhoeae Isolate of a Successful International Clone with Decreased Susceptibility and Resistance to Extended-Spectrum Cephalosporins

ABSTRACT The recent emergence of Neisseria gonorrhoeae strains with decreased susceptibility to extended-spectrum cephalosporins is a major concern globally. We sequenced the genome of an N. gonorrhoeae multiantigen sequence typing (NG-MAST) ST1407 isolate (SM-3) with decreased susceptibility and resistance to oral extended-spectrum cephalosporins. The isolate was cultured in 2008 in San Francisco, CA, and possessed mosaic penA allele XXXIV, which is associated with an international clone that possesses decreased susceptibility as well as resistance to oral extended-spectrum cephalosporins globally. The genome sequence of strain NCCP11945 was used as a scaffold, and our assembly resulted in 91 contigs covering 2,029,064 bp (91%; >150× coverage) of the genome. Numerous instances of suspected horizontal genetic transfer events with other Neisseria species were identified, and two genes, opa and txf, acquired from nongonococcal Neisseria species, were identified. Strains possessing mosaic penA alleles (n = 108) and nonmosaic penA alleles (n = 169) from the United States and Europe (15 countries), cultured in 2002 to 2009, were screened for the presence of these genes. The opa gene was detected in most (82%) penA mosaic-containing isolates (mainly from 2007 to 2009) but not in any penA nonmosaic isolates. The txf gene was found in all strains containing opa but also in several (18%) penA nonmosaic strains. Using opa and txf as genetic markers, we identified a strain that possesses mosaic penA allele XXXIV, but the majority of its genome is not genetically related to strain SM-3. This implies that penA mosaic allele XXXIV was transferred horizontally. Such isolates also possessed decreased susceptibility and resistance to oral extended-spectrum cephalosporins. These findings support that genetic screening for particular penA mosaic alleles can be a valuable method for tracking strains with decreased susceptibility as well as resistance to oral extended-spectrum cephalosporins worldwide and that screening using only NG-MAST may not be sufficient.

Chlamydia trachomatis and Neisseria gonorrhoeae transmission from the female oropharynx to the male urethra.

In a sexually transmitted disease clinic-based sample of men who have sex with women, positivity for urethral Chlamydia trachomatis and Neisseria gonorrhoeae was 3.5% and 3.1%, respectively, among patients whose only urethral exposure in the previous 3 months was receiving fellatio from a woman. Urethral infections acquired by fellatio might contribute to ongoing disease spread.