SummaryBackgroundStaphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FindingsBetween Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.
In many settings, adults with active or latent tuberculosis will also be coinfected with helminths. Our study aimed to investigate how anthelmintic treatment modulates antimycobacterial immunity, in a setting where helminth reinfection should not occur. Additional supporting information may be found in the online version of this article at the publisher's web-site We investigated the potential impact of helminth infection on immune responses to Mycobacterium tuberculosis (Mtb) in patients with latent Mtb infection with or without helminth infection (Strongyloides orSchistosoma IntroductionMycobacterium tuberculosis (Mtb) infects a third of the world's population, causing 1.5 million deaths a year [1,2]. In addi- Correspondence:Frederic Toulza e-mail: Frederic.Toulza@lshtm.ac.uk tion, helminth infections are estimated to affect 1.5 billion people worldwide, with the majority of these infections concentrated in developing countries where tuberculosis (TB) is endemic [3,4]. Helminth infections are reported to induce Th2 type immune responses in the host [5], and evidence suggests that Th2 cytokines may play a critical role in reducing the Th1 immune response to other infections. Protection against TB is not well understood, but Th1 T-cell responses involving interferon gamma (IFN-γ), tumor C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 752-761 Clinical immunology 753 necrosis factor alpha (TNF-α), and interleukin 2 (IL-2) are induced in the immune response to Mtb [6]. IFN-γ is thought to play an important role in the protective immune response against TB as indicated by the susceptibility of humans with IFN-γ signaling pathway deficiencies to TB disease [7,8]. A number of studies have previously investigated the immunomodulatory effect of helminth infection on antimycobacterial immunity (reviewed in [9] [22,23] and in patients with active TB [24]. A recent study showed that in children in Gabon, the proportion of Tregs decreased with anthelmintic treatment [25].There have been only a few studies that investigated the impact of helminth infections on T-cell immunity in patients with latent TB infection. Filaria infections were shown to reduce Th1 responses in Indian patients with latent Mtb infection (LTBI), that were increased with blockage of CTLA-4 or PD-1 [26], while anthelminth treatment increased TLR2 and TLR9 expression with an associated increase in production of proinflammatory cytokines. In Indian patients with LTBI, coincident hookworm infection reduced Mtb-specific Th1 and Th17 CD4 T cells [14]. Indian pulmonary TB patients with Wucheria or Stronglyoides also showed reduced CD4 and CD8 T-cell responses to mycobacterial antigens, which could be partly blocked with anti-IL-10 neutralizing antibodies [27].In this study, we measured the impact of anthelmintic treatment on the immune response to Mtb in LTBI in a migrant cohort in London. As United Kingdom is not a helminth endemic area, reinfection is not likely in this setting. This provides a unique opport...
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