CROI 2016 Abstract eBook

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Oral Abstracts

157 HIV-Associated XDR TB Is Transmitted in Households and Hospitals in South Africa Sara C. Auld 1 ; James C. Brust 2 ; Barun Mathema 3 ;Thuli Mthiyane 4 ; Nazir Ismail 5 ; Pravi Moodley 6 ; Darius McDaniel 7 ; Salim Allana 8 ; Neel Gandhi 7 ; N. Sarita Shah 9 1 Emory Univ, Atlanta, GA, USA; 2 Albert Einstein Coll of Med, Bronx, NY, USA; 3 Columbia Univ Mailman Sch of PH, New York, NY, USA; 4 Univ of KwaZulu-Natal, Westville, South Africa; 5 Natl Inst for Communicable Diseases, Johannesburg, South Africa; 6 Univ of KwaZulu-Natal, Durban, South Africa; 7 Emory Univ Rollins Sch of PH, Atlanta, GA, USA; 8 Rollins Sch of PH, Emory Univ, Atlanta, GA, USA; 9 CDC, Atlanta, GA, USA Background: Transmission of drug-resistant TB threatens gains in global TB and HIV control, particularly in high-burden settings such as South Africa. Recent data suggests the majority of drug-resistant cases worldwide arise due to transmission, however, studies are needed to characterize the nature (e.g., location, timing) of transmission. In KwaZulu- Natal province, South Africa, we have demonstrated that up to 83% of XDR TB cases are genotypically-clustered, using IS6110 RFLP and targeted gene sequencing, suggesting person-to-person transmission is driving the XDR TB epidemic in this high-HIV prevalence setting. In the current study, we employed social network analysis to further characterize patterns of transmission. Methods: We enrolled patients diagnosed with XDR TB by culture and drug-susceptibility testing in KwaZulu-Natal from 2010–2014. Patients were interviewed at the time of diagnosis about their social networks at home, work, and other community locations, as well as about hospitalizations in the five years preceding their XDR TB diagnosis. An epidemiologic link was defined as two participants having either a social network connection or overlapping admission at the same hospital. Results: Among 404 patients with XDR TB, the median age was 34 (IQR 28–43) and 58%were female. 311 (77%) patients were HIV-infected, with a median CD4 count of 255 cells/mm3 (IQR 117–431); 177 (57%) were on ART at the time of their XDR TB diagnosis and 155 (88%) had an undetectable viral load. Epidemiologic links were identified for 287 (71%) patients. 83 (21%) patients were linked as social network contacts; of these, 92% lived in the same home, 4%worked together, and 4% spent time together in a congregate setting (e.g., church, bar). 267 (66%) patients overlapped with other XDR TB patients in the hospital, 66 of whomwere hospitalized at more than one hospital. There were 63 (16%) patients with both hospital and social network links to other XDR TB patients, four of whom are depicted in Figure 1. Conclusions: The XDR TB epidemic in this high HIV prevalence setting in South Africa is being driven by direct transmission of drug-resistant TB strains in both hospitals and households. Social network analysis has provided valuable insights into the multitude of interactions associated with transmission. This more comprehensive understanding is important for designing interventions that both limit exposure in hospitals and focus contact tracing efforts to households where the majority of transmission is occurring.

Oral Abstracts

158LB Beta-Lactams Against TB: Teaching a New Trick to an Old Dog Andreas H. Diacon 1 ; Lize van der Merwe 2 ; Marinus Barnard 2 ; FlorianVon Groote-Bidlingmaier 2 ; Christoph Lange 3 ; Alberto L. García-Basteiro 4 ; Esperança Sevene 5 ; Lluís Ballell 6 ; David Barros-Aguirre 6 1 Stellenbosch Univ, Bellville, South Africa; 2 Task Applied Science, Bellville, South Africa; 3 Rsr Cntr Borstel, Borstel, Germany; 4 Barcelona Inst for Global Hlth, Barcelona, Spain; 5 Manhiça Hlth Rsr Cntr (CISM), Manhiça, Mozambique; 6 Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain Background: It is generally accepted that ß-lactam antibiotics are ineffective against Mycobacterium tuberculosis . Carbapenems are relatively resistant to mycobacterial ß-lactamases in vitro . We investigated whether the carbapenems meropenem and faropenem combined with amoxicillin and clavulanic acid (A/CA) have antituberculosis activity in humans. Methods: Groups of 15 patients with newly diagnosed, smear-positive, drug-sensitive pulmonary tuberculosis received one of three treatments for 14 days: meropenem 2g intravenously or faropenem 600mg orally, both combined with oral A/CA 500mg/125mg, all given three times per day, or standard antituberculosis treatment as control. We collected sputum overnight for colony forming unit (CFU) counting on solid agar plates and for assessing time to culture positivity (TTP) in liquid medium. Full pharmacokinetic profiling was performed on day 14. Patients were hospitalised for daily safety assessments. Results: The viable mycobacterial sputum load was significantly reduced with standard treatment (validating the laboratory assays) and with meropenem A/CA but not with faropenem A/CA (Table). Meropenem exposures were much higher than faropenem exposures (Table). AUC and C max were significantly associated with meropenem activity measured by CFU (r 2 =0.62; p=0.002 and r 2 =0.49; p=0.066, respectively). Mild intermittent diarrhea was reported by >50% of patients in both carbapenem groups and was probably related to A/CA. Conclusions: The combination of intravenous meropenem and oral A/CA has antituberculosis activity in humans of similar magnitude as previously reported for rifampin (10mg/kg), pyrazinamide, bedaquiline and PA-824 over the first 2 weeks of treatment. This establishes ß-lactams as a class with clinical antituberculosis activity. Oral faropenem combined with A/CA was ineffective owing to insufficient exposure. Both treatments were safe. Meropenem A/CA should be considered for all patients with highly resistant tuberculosis in whom intravenous treatment is feasible.

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CROI 2016