Showing papers in "Lancet Infectious Diseases in 2011"
TL;DR: The presence of NDM-1 β-lactamase-producing bacteria in environmental samples in New Delhi has important implications for people living in the city who are reliant on public water and sanitation facilities.
Abstract: Summary Background Not all patients infected with NDM-1-positive bacteria have a history of hospital admission in India, and extended-spectrum β-lactamases are known to be circulating in the Indian community. We therefore measured the prevalence of the NDM-1 gene in drinking water and seepage samples in New Delhi. Methods Swabs absorbing about 100 μL of seepage water (ie, water pools in streets or rivulets) and 15 mL samples of public tap water were collected from sites within a 12 km radius of central New Delhi, with each site photographed and documented. Samples were transported to the UK and tested for the presence of the NDM-1 gene, bla NDM-1 , by PCR and DNA probing. As a control group, 100 μL sewage effluent samples were taken from the Cardiff Wastewater Treatment Works, Tremorfa, Wales. Bacteria from all samples were recovered and examined for bla NDM-1 by PCR and sequencing. We identified NDM-1-positive isolates, undertook susceptibility testing, and, where appropriate, typed the isolates. We undertook Inc typing on bla NDM-1 -positive plasmids. Transconjugants were created to assess plasmid transfer frequency and its relation to temperature. Findings From Sept 26 to Oct 10, 2010, 171 seepage samples and 50 tap water samples from New Delhi and 70 sewage effluent samples from Cardiff Wastewater Treatment Works were collected. We detected bla NDM-1 in two of 50 drinking-water samples and 51 of 171 seepage samples from New Delhi; the gene was not found in any sample from Cardiff. Bacteria with bla NDM-1 were grown from 12 of 171 seepage samples and two of 50 water samples, and included 11 species in which NDM-1 has not previously been reported, including Shigella boydii and Vibrio cholerae . Carriage by enterobacteria, aeromonads, and V cholera was stable, generally transmissible, and associated with resistance patterns typical for NDM-1; carriage by non-fermenters was unstable in many cases and not associated with typical resistance. 20 strains of bacteria were found in the samples, 12 of which carried bla NDM-1 on plasmids, which ranged in size from 140 to 400 kb. Isolates of Aeromonas caviae and V cholerae carried bla NDM-1 on chromosomes. Conjugative transfer was more common at 30°C than at 25°C or 37°C. Interpretation The presence of NDM-1 β-lactamase-producing bacteria in environmental samples in New Delhi has important implications for people living in the city who are reliant on public water and sanitation facilities. International surveillance of resistance, incorporating environmental sampling as well as examination of clinical isolates, needs to be established as a priority. Funding European Union.
1,119 citations
TL;DR: The discovery of a strain of S aureus isolated from bulk milk that was phenotypically resistant to meticillin but tested negative for the mecA gene is reported and new diagnostic guidelines for the detection of MRSA should consider the inclusion of tests for mecALGA251.
Abstract: Summary Background Animals can act as a reservoir and source for the emergence of novel meticillin-resistant Staphylococcus aureus (MRSA) clones in human beings. Here, we report the discovery of a strain of S aureus (LGA251) isolated from bulk milk that was phenotypically resistant to meticillin but tested negative for the mecA gene and a preliminary investigation of the extent to which such strains are present in bovine and human populations. Methods Isolates of bovine MRSA were obtained from the Veterinary Laboratories Agency in the UK, and isolates of human MRSA were obtained from diagnostic or reference laboratories (two in the UK and one in Denmark). From these collections, we searched for mecA PCR-negative bovine and human S aureus isolates showing phenotypic meticillin resistance. We used whole-genome sequencing to establish the genetic basis for the observed antibiotic resistance. Findings A divergent mecA homologue ( mecA LGA251 ) was discovered in the LGA251 genome located in a novel staphylococcal cassette chromosome mec element, designated type-XI SCC mec . The mecA LGA251 was 70% identical to S aureus mecA homologues and was initially detected in 15 S aureus isolates from dairy cattle in England. These isolates were from three different multilocus sequence type lineages (CC130, CC705, and ST425); spa type t843 (associated with CC130) was identified in 60% of bovine isolates. When human mecA -negative MRSA isolates were tested, the mecA LGA251 homologue was identified in 12 of 16 isolates from Scotland, 15 of 26 from England, and 24 of 32 from Denmark. As in cows, t843 was the most common spa type detected in human beings. Interpretation Although routine culture and antimicrobial susceptibility testing will identify S aureus isolates with this novel mecA homologue as meticillin resistant, present confirmatory methods will not identify them as MRSA. New diagnostic guidelines for the detection of MRSA should consider the inclusion of tests for mecA LGA251 . Funding Department for Environment, Food and Rural Affairs, Higher Education Funding Council for England, Isaac Newton Trust (University of Cambridge), and the Wellcome Trust.
839 citations
TL;DR: Augmented adherence of the strain to intestinal epithelium might facilitate systemic absorption of Shiga toxin and could explain the high progression to haemolytic uraemic syndrome.
Abstract: Summary Background In an ongoing outbreak of haemolytic uraemic syndrome and bloody diarrhoea caused by a virulent Escherichia coli strain O104:H4 in Germany (with some cases elsewhere in Europe and North America), 810 cases of the syndrome and 39 deaths have occurred since the beginning of May, 2011. We analysed virulence profiles and relevant phenotypes of outbreak isolates recovered in our laboratory. Methods We analysed stool samples from 80 patients that had been submitted to the National Consulting Laboratory for Haemolytic Uraemic Syndrome in Munster, Germany, between May 23 and June 2, 2011. Isolates were screened with standard PCR for virulence genes of Shiga-toxin-producing E coli and a newly developed multiplex PCR for characteristic features of the outbreak strain ( rfb O104 , fliC H4 , stx 2 , and terD ). Virulence profiles of the isolates were determined with PCR targeting typical virulence genes of Shiga-toxin-producing E coli and of other intestinal pathogenic E coli . We sequenced stx with Sanger sequencing and measured Shiga-toxin production, adherence to epithelial cells, and determined phylogeny and antimicrobial susceptibility. Findings All isolates were of the HUSEC041 clone (sequence type 678). All shared virulence profiles combining typical Shiga-toxin-producing E coli ( stx 2 , iha, lpf O26 , lpf O113 ) and enteroaggregative E coli ( aggA, aggR, set1, pic, aap ) loci and expressed phenotypes that define Shiga-toxin-producing E coli and enteroaggregative E coli , including production of Shiga toxing 2 and aggregative adherence to epithelial cells. Isolates additionally displayed an extended-spectrum β-lactamase phenotype absent in HUSEC041. Interpretation Augmented adherence of the strain to intestinal epithelium might facilitate systemic absorption of Shiga toxin and could explain the high progression to haemolytic uraemic syndrome. This outbreak demonstrates that blended virulence profiles in enteric pathogens, introduced into susceptible populations, can have extreme consequences for infected people. Funding German Federal Ministry of Education and Research, Network Zoonoses.
717 citations
TL;DR: An increasing number of sporadic cases of invasive fungal infections by non-neoformans cryptococci have been reported in immunocompromised hosts, especially for patients with advanced HIV infection or cancer who are undergoing transplant.
Abstract: A growing population of immunosuppressed patients has resulted in increasingly frequent diagnoses of invasive fungal infections, including those caused by unusual yeasts. The incidence of non-albicans species of Candida is increasing compared with that of Candida albicans, and several species, such as Candida glabrata and Candida krusei, may be resistant to azole antifungal therapy. Trichosporon species are the second most common cause of fungaemia in patients with haematological malignant disease and are characterised by resistance to amphotericin and echinocandins and poor prognosis. Rhodotorula species belong to the family Cryptococcaceae, and are a cause of catheter-related fungaemia, sepsis, and invasive disease in severely immunosuppressed patients. An increasing number of sporadic cases of invasive fungal infections by non-neoformans cryptococci have been reported in immunocompromised hosts, especially for patients with advanced HIV infection or cancer who are undergoing transplant. Other uncommon yeasts that can cause invasive disease in severely immunosuppressed patients include Geotrichum, Hansenula, Malassezia, and Saccharomyces. Host immune status is a crucial determinant of the type of invasive fungal infection a patient is at risk for. Diagnosis can be challenging and relies heavily on traditional cultures of blood and other sterile sites, although serum (1,3)-β-D-glucan testing might have an adjunctive role. Although rare yeasts are emerging as opportunistic human pathogens, diagnosis remains challenging and treatment suboptimal.
708 citations
TL;DR: Non-prescription antimicrobial and antituberculosis use is common outside of North America and northern Europe and must be accounted for in public health efforts to reduce antimicrobial resistance.
Abstract: In much of the world antimicrobial drugs are sold without prescription or oversight by health-care professionals. The scale and effect of this practice is unknown. We systematically reviewed published works about non-prescription antimicrobials from 1970-2009, identifying 117 relevant articles. 35 community surveys from five continents showed that non-prescription use occurred worldwide and accounted for 19-100% of antimicrobial use outside of northern Europe and North America. Safety issues associated with non-prescription use included adverse drug reactions and masking of underlying infectious processes. Non-prescription use was common for non-bacterial disease, and antituberculosis drugs were available in many areas. Antimicrobial-resistant bacteria are common in communities with frequent non-prescription use. In a few settings, control efforts that included regulation decreased antimicrobial use and resistance. Non-prescription antimicrobial and antituberculosis use is common outside of North America and northern Europe and must be accounted for in public health efforts to reduce antimicrobial resistance.
699 citations
TL;DR: Despite much serotype replacement, a substantial reduction in invasive pneumococcal disease in young children can be achieved with PCV7 vaccination, with some indirect benefit in older age groups.
Abstract: Summary Background The seven-valent pneumococcal conjugate vaccine (PCV7) has reduced vaccine-type (VT) invasive pneumococcal disease but increases in non-vaccine-type (NVT) disease have varied between countries. We assess the effect of the PCV7 vaccination on VT and NVT disease in England and Wales. Methods The study cohort was the population of England and Wales from July, 2000, to June, 2010. We calculated incidence rate ratios (IRRs) to compare incidences of VT and NVT disease before (2000–06) and after (2009–10) the introduction of PCV7. We used data from the national surveillance database. Cases included in our analysis were restricted to those confirmed by culture linked with isolates referred for serotyping at the national reference centre by laboratories in England and Wales. We adjusted for potential bias from missing data (serotype and age of patient) and changes in case ascertainment rates during the study period. Findings 5809 cases of invasive pneumococcal disease were reported in 2009–10, giving an incidence of 10·6 per 100 000 population in 2009–10, which, when compared with the adjusted average annual incidence of 16·1 in 2000–06, gives an overall reduction of 34% (95% CI 28–39). VT disease decreased in all age groups, with reductions of 98% in individuals younger than 2 years and 81% in those aged 65 years or older. NVT disease increased by 68% in individuals younger than 2 years and 48% in those aged 65 years or older, giving an overall reduction in invasive pneumococcal disease of 56% in those younger than 2 years and 19% in those aged 65 years or older. After vaccine introduction, more NVT serotypes increased in frequency than decreased, which is consistent with vaccine-induced replacement. Key serotypes showing replacement were 7F, 19A, and 22F. Increases in NVT invasive pneumococcal disease were not associated with antimicrobial resistance. Interpretation Despite much serotype replacement, a substantial reduction in invasive pneumococcal disease in young children can be achieved with PCV7 vaccination, with some indirect benefit in older age groups. Further reductions should be achievable by use of higher valency vaccines. Robust surveillance data are needed to properly assess the epidemiological effect of multivalent pneumococcal disease vaccines. Funding Health Protection Agency.
613 citations
TL;DR: The spread of metallo-β-lactamases presents a major challenge both for treatment of individual patients and for policies of infection control, exposing the substantial unpreparedness of public health structures in facing up to this emergency.
Abstract: Summary Metallo-β-lactamases are resistance determinants of increasing clinical relevance in Gram-negative bacteria. Because of their broad range, potent carbapenemase activity and resistance to inhibitors, these enzymes can confer resistance to almost all β-lactams. Since the 1990s, several metallo-β-lactamases encoded by mobile DNA have emerged in important Gram-negative pathogens (ie, in Enterobacteriaceae, Pseudomonas aeruginosa , and Acinetobacter baumannii ). Some of these enzymes (eg, VIM-1 and NDM-1) have been involved in the recent crisis resulting from the international dissemination of carbapenem-resistant Klebsiella pneumoniae and other enterobacteria. Although substantial knowledge about the molecular biology and genetics of metallo-β-lactamases is available, epidemiological data are inconsistent and clinical experience is still lacking; therefore, several unsolved or debatable issues remain about the management of infections caused by producers of metallo-β-lactamase. The spread of metallo-β-lactamases presents a major challenge both for treatment of individual patients and for policies of infection control, exposing the substantial unpreparedness of public health structures in facing up to this emergency.
576 citations
TL;DR: Physicians in urban environments in developing and developed countries need to be aware of the changes in infectious diseases associated with urbanisation to ensure urbanisation works to reduce the burden of infectious diseases in the future.
Abstract: Summary The world is becoming urban. The UN predicts that the world's urban population will almost double from 3·3 billion in 2007 to 6·3 billion in 2050. Most of this increase will be in developing countries. Exponential urban growth is having a profound effect on global health. Because of international travel and migration, cities are becoming important hubs for the transmission of infectious diseases, as shown by recent pandemics. Physicians in urban environments in developing and developed countries need to be aware of the changes in infectious diseases associated with urbanisation. Furthermore, health should be a major consideration in town planning to ensure urbanisation works to reduce the burden of infectious diseases in the future.
517 citations
TL;DR: Triple antiretroviral prophylaxis during pregnancy and breastfeeding is safe and reduces the risk of HIV transmission to infants and serious adverse events in mothers and babies.
Abstract: BACKGROUND: Breastfeeding is essential for child health and development in low-resource settings but carries a significant risk of transmission of HIV-1 especially in late stages of maternal disease. We aimed to assess the efficacy and safety of triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis in pregnant women infected with HIV. METHODS: Pregnant women with WHO stage 1 2 or 3 HIV-1 infection who had CD4 cell counts of 200-500 cells per muL were enrolled at five study sites in Burkina Faso Kenya and South Africa to start study treatment at 28-36 weeks gestation. Women were randomly assigned (1:1) by a computer generated random sequence to either triple antiretroviral prophylaxis (a combination of 300 mg zidovudine 150 mg lamivudine and 400 mg lopinavir plus 100 mg ritonavir twice daily until cessation of breastfeeding to a maximum of 6.5 months post partum) or zidovudine and single-dose nevirapine (300 mg zidovudine twice daily until delivery and a dose of 600 mg zidovudine plus 200 mg nevirapine at the onset of labour and after a protocol amendment in December 2006 1 week post-partum zidovudine 300 mg twice daily and lamivudine 150 mg twice daily). All infants received a 0.6 mL dose of nevirapine at birth and from December 2006 4 mg/kg twice daily of zidovudine for 1 week after birth. Patients and investigators were not masked to treatment. The primary endpoints were HIV-free infant survival at 6 weeks and 12 months; HIV-free survival at 12 months in infants who were ever breastfed; AIDS-free survival in mothers at 18 months; and serious adverse events in mothers and babies. Analysis was by intention to treat. This trial is registered with Current Controlled Trials ISRCTN71468401. FINDINGS: From June 2005 to August 2008 882 women were enrolled 824 of whom were randomised and gave birth to 805 singleton or first liveborn infants. The cumulative rate of HIV transmission at 6 weeks was 3.3% (95% CI 1.9-5.6%) in the triple antiretroviral group compared with 5.0% (3.3-7.7%) in the zidovudine and single-dose nevirapine group and at 12 months was 5.4% (3.6-8.1%) in the triple antiretroviral group compared with 9.5% (7.0-12.9%) in the zidovudine and single-dose nevirapine group (p=0.029). The cumulative rate of HIV transmission or death at 12 months was 10.2% (95% CI 7.6-13.6%) in the triple antiretroviral group compared with 16.0% (12.7-20.0%) in the zidovudine and single-dose nevirapine group (p=0.017). In infants whose mothers declared they intended to breastfeed the cumulative rate of HIV transmission at 12 months was 5.6% (95% CI 3.4-8.9%) in the triple antiretroviral group compared with 10.7% (7.6-14.8%) in the zidovudine and single-dose nevirapine group (p=0.02). AIDS-free survival in mothers at 18 months will be reported in a different publication. The incidence of laboratory and clinical serious adverse events in both mothers and their babies was similar between groups. INTERPRETATION: Triple antiretroviral prophylaxis during pregnancy and breastfeeding is safe and reduces the risk of HIV transmission to infants. Revised WHO guidelines now recommend antiretroviral prophylaxis (either to the mother or to the baby) during breastfeeding if the mother is not already receiving antiretroviral treatment for her own health. FUNDING: Agence nationale de recherches sur le sida et les hepatites virales Department for International Development European and Developing Countries Clinical Trials Partnership Thrasher Research Fund Belgian Directorate General for International Cooperation Centers for Disease Control and Prevention Eunice Kennedy Shriver National Institute of Child Health and Human Development and UNDP/UNFPA/World Bank/WHO Special Programme of Research Development and Research Training in Human Reproduction. Copyright (c) 2011 Elsevier Ltd. All rights reserved.
375 citations
TL;DR: The decrease in frequency of genital warts in young Australian women resulting from the high coverage of HPV vaccination might provide protective effects in heterosexual men through herd immunity.
Abstract: Background Quadrivalent human papillomavirus (HPV) vaccine has high efficacy in clinical trials but no reports describe its effects at a population level. From July, 2007, Australia was the first country to fund a vaccination programme for all women aged 12-26 years. We established a national surveillance network in Australia and aimed to identify trends in diagnoses of genital warts in 2004-09. Methods We obtained standardised data for demographic factors, frequency of genital warts, HPV vaccination status, and sexual behaviour for new patients attending eight sexual health services in Australia between January, 2004, and December, 2009. We used χ² analysis to identify significant trends in proportions of patients diagnosed with warts in periods before and after vaccination began. Our primary group of interest was female Australian residents who were eligible for free vaccination, although data were assessed for patients ineligible for free vaccination, including women older than 26 years of age, non-resident women, and men. Findings Among 112 083 new patients attending sexual health services, we identified 9867 (9%) cases of genital warts. Before the vaccine programme started, there was no change in proportion of women or heterosexual men diagnosed with genital warts. After vaccination began, a decline in number of diagnoses of genital warts was noted for young female residents (59%, p(trend) Interpretation The decrease in frequency of genital warts in young Australian women resulting from the high coverage of HPV vaccination might provide protective effects in heterosexual men through herd immunity. Funding CSL Biotherapies.
371 citations
TL;DR: Health-care-associated bloodstream infections and pneumonia greatly increase mortality and pneumonia increase length of stay in intensive-care units; the additional effect of the most common antimicrobial resistance patterns is comparatively low.
Abstract: Summary Background Patients admitted to intensive-care units are at high risk of health-care-associated infections, and many are caused by antimicrobial-resistant pathogens. We aimed to assess excess mortality and length of stay in intensive-care units from bloodstream infections and pneumonia. Methods We analysed data collected prospectively from intensive-care units that reported according to the European standard protocol for surveillance of health-care-associated infections. We focused on the most frequent causative microorganisms. Resistance was defined as resistance to ceftazidime ( Acinetobacter baumannii or Pseudomonas aeruginosa ), third-generation cephalosporins ( Escherichia coli ), and oxacillin ( Staphylococcus aureus ). We defined 20 different exposures according to infection site, microorganism, and resistance status. For every exposure, we compared outcomes between patients exposed and unexposed by use of time-dependent regression modelling. We adjusted results for patients' characteristics and time-dependency of the exposure. Findings We obtained data for 119 699 patients who were admitted for more than 2 days to 537 intensive-care units in ten countries between Jan 1, 2005, and Dec 31, 2008. Excess risk of death (hazard ratio) for pneumonia in the fully adjusted model ranged from 1·7 (95% CI 1·4–1·9) for drug-sensitive S aureus to 3·5 (2·9–4·2) for drug-resistant P aeruginosa . For bloodstream infections, the excess risk ranged from 2·1 (1·6–2·6) for drug-sensitive S aureus to 4·0 (2·7–5·8) for drug-resistant P aeruginosa . Risk of death associated with antimicrobial resistance (ie, additional risk of death to that of the infection) was 1·2 (1·1–1·4) for pneumonia and 1·2 (0·9–1·5) for bloodstream infections for a combination of all four microorganisms, and was highest for S aureus (pneumonia 1·3 [1·0–1·6], bloodstream infections 1·6 [1·1–2·3]). Antimicrobial resistance did not significantly increase length of stay; the hazard ratio for discharge, dead or alive, for sensitive microorganisms compared with resistant microorganisms (all four combined) was 1·05 (0·97–1·13) for pneumonia and 1·02 (0·98–1·17) for bloodstream infections. P aeruginosa had the highest burden of health-care-acquired infections because of its high prevalence and pathogenicity of both its drug-sensitive and drug-resistant strains. Interpretation Health-care-associated bloodstream infections and pneumonia greatly increase mortality and pneumonia increase length of stay in intensive-care units; the additional effect of the most common antimicrobial resistance patterns is comparatively low. Funding European Commission (DG Sanco).
French Institute of Health and Medical Research1, University of Zurich2, Imperial College London3, Medical Research Council4, University of Siena5, University of Minnesota6, The Catholic University of America7, Robert Koch Institute8, Copenhagen University Hospital9, Université Bordeaux Segalen10, Goethe University Frankfurt11, University College London12, University of Copenhagen13, Autonomous University of Barcelona14
TL;DR: Findings confirm present treatment guidelines for HIV, which state that the initial treatment choice should be based on resistance testing in treatment-naive patients, that the effect of TDR on outcome in the first year of cART is confirmed.
Abstract: Summary Background The effect of transmitted drug resistance (TDR) on first-line combination antiretroviral therapy (cART) for HIV-1 needs further study to inform choice of optimum drug regimens. We investigated the effect of TDR on outcome in the first year of cART within a large European collaboration. Methods HIV-infected patients of any age were included if they started cART (at least three antiretroviral drugs) for the first time after Jan 1, 1998, and were antiretroviral naive and had at least one sample for a genotypic test taken before the start of cART. We used the WHO drug resistance list and the Stanford algorithm to classify patients into three resistance categories: no TDR, at least one mutation and fully-active cART, or at least one mutation and resistant to at least one prescribed drug. Virological failure was defined as time to the first of two consecutive viral load measurements over 500 copies per mL after 6 months of therapy. Findings Of 10 056 patients from 25 cohorts, 9102 (90·5%) had HIV without TDR, 475 (4·7%) had at least one mutation but received fully-active cART, and 479 (4·8%) had at least one mutation and resistance to at least one drug. Cumulative Kaplan-Meier estimates for virological failure at 12 months were 4·2% (95% CI 3·8–4·7) for patients in the no TDR group, 4·7% (2·9–7·5) for those in the TDR and fully-active cART group, and 15·1% (11·9–19·0) for those in the TDR and resistant group (log-rank p Interpretation These findings confirm present treatment guidelines for HIV, which state that the initial treatment choice should be based on resistance testing in treatment-naive patients. Funding European Community's Seventh Framework Programme FP7/2007-2013 and Gilead.
TL;DR: In this paper, the authors review data and make recommendations for research on diagnosis, treatment, and prevention, such as further use of molecular analysis of the Mycobacterium leprae genome, implementation of BCG vaccination, and administration of chemoprophylaxis to household contacts.
Abstract: Leprosy continues to be a challenge to health worldwide, with about 250,000 new cases being detected every year. Despite widespread implementation of effective multidrug therapy, leprosy has not been eliminated. A third of newly diagnosed patients have nerve damage and might develop disabilities, although the proportion varies according to several factors, including level of self-care. Women who develop leprosy continue to be especially disadvantaged, with rates of late diagnosis and disability remaining high in this subgroup. Leprosy was not a specified disease in the Millennium Development Goals, but improvements in the other areas they cover, such as education and levels of poverty, will help leprosy patients and services. We review data and make recommendations for research on diagnosis, treatment, and prevention, such as further use of molecular analysis of the Mycobacterium leprae genome, implementation of BCG vaccination, and administration of chemoprophylaxis to household contacts. We also suggest development of tools for early diagnosis and detection of infection and nerve damage, and formulation of strategies to manage the chronic complications of leprosy, such as immune-mediated reactions and neuropathy.
TL;DR: The MRKAd5 HIV- 1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping the trial early probably compromised the ability to draw conclusions.
Abstract: Summary Background The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. Methods We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. Findings 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76–2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20 483 copies per mL (n=33) in the vaccine group and 34 032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. Interpretation The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine. Funding The US National Institute of Allergy and Infectious Disease and Merck and Co Inc.
TL;DR: Increasing pyrethroid resistance of A gambiae and increasing susceptibility of older children and adults, probably due to decreasing immunity, caused the rebound and age shift of malaria morbidity.
Abstract: Summary Background Substantial reductions in malaria have been reported in several African countries after distribution of insecticide-treated bednets and the use of artemisinin-based combination therapies (ACTs). Our aim was to assess the effect of these policies on malaria morbidity, mosquito populations, and asymptomatic infections in a west African rural population. Methods We did a longitudinal study of inhabitants of Dielmo village, Senegal, between January, 2007, and December, 2010. We monitored the inhabitants for fever during this period and we treated malaria attacks with artesunate plus amodiaquine. In July, 2008, we offered longlasting insecticide (deltamethrin)-treated nets (LLINs) to all villagers. We did monthly night collections of mosquitoes during the whole study period, and we assessed asymptomatic carriage from cross-sectional surveys. Our statistical analyses were by negative binomial regression, logistic regression, and binomial or Fisher exact test. Findings There were 464 clinical malaria attacks attributable to Plasmodium falciparum during 17 858 person-months of follow-up. The incidence density of malaria attacks averaged 5·45 (95% CI 4·90–6·05) per 100 person-months between January, 2007, and July, 2008, before the distribution of LLINs. Incidence density decreased to 0·41 (0·29–0·55) between August, 2008, and August, 2010, but increased back to 4·57 (3·54–5·82) between September and December, 2010—ie, 27–30 months after the distribution of LLINs. The rebound of malaria attacks were highest in adults and children aged 10 years or older: 45 (63%) of 71 malaria attacks recorded in 2010 compared with 126 (33%) of 384 in 2007 and 2008 (p Anopheles gambiae mosquitoes were resistant to deltamethrin in 2010, and the prevalence of the Leu1014Phe kdr resistance mutation increased from 8% in 2007 to 48% in 2010 (p=0·0009). Interpretation Increasing pyrethroid resistance of A gambiae and increasing susceptibility of older children and adults, probably due to decreasing immunity, caused the rebound and age shift of malaria morbidity. Strategies to address the problem of insecticide resistance and to mitigate its effects must be urgently defined and implemented. Funding Institut de Recherche pour le Developpement and the Pasteur Institute of Dakar.
TL;DR: MTB/RIF testing of two induced sputum specimens is warranted as the first-line diagnostic test for children with suspected pulmonary tuberculosis.
Abstract: Summary Background WHO recommends that Xpert MTB/RIF replaces smear microscopy for initial diagnosis of suspected HIV-associated tuberculosis or multidrug-resistant pulmonary tuberculosis, but no data exist for its use in children. We aimed to assess the accuracy of the test for the diagnosis of pulmonary tuberculosis in children in an area with high tuberculosis and HIV prevalences. Methods In this prospective, descriptive study, we enrolled children aged 15 years or younger who had been admitted to one of two hospitals in Cape Town, South Africa, with suspected pulmonary tuberculosis between Feb 19, 2009, and Nov 30, 2010. We compared the diagnostic accuracy of MTB/RIF and concentrated, fluorescent acid-fast smear with a reference standard of liquid culture from two sequential induced sputum specimens (primary analysis). Results 452 children (median age 19·4 months, IQR 11·1–46·2) had at least one induced sputum specimen; 108 children (24%) had HIV infection. 27 children (6%) had a positive smear result, 70 (16%) had a positive culture result, and 58 (13%) had a positive MTB/RIF test result. With mycobacterial culture as the reference standard, MTB/RIF tests when done on two induced sputum samples detected twice as many cases (75·9%, 95% CI 64·5–87·2) as did smear microscopy (37·9%, 25·1–50·8), detecting all of 22 smear-positive cases and 22 of 36 (61·1%, 44·4–77·8) smear-negative cases. For smear-negative cases, the incremental increase in sensitivity from testing a second specimen was 27·8% for MTB/RIF, compared with 13·8% for culture. The specificity of MTB/RIF was 98·8% (97·6–99·9). MTB/RIF results were available in median 1 day (IQR 0–4) compared with median 12 days (9–17) for culture (p Interpretation MTB/RIF testing of two induced sputum specimens is warranted as the first-line diagnostic test for children with suspected pulmonary tuberculosis. Funding National Institutes of Health, the National Health Laboratory Service Research Trust, the Medical Research Council of South Africa, and Wellcome Trust.
Harvard University1, Karolinska Institutet2, Memorial Sloan Kettering Cancer Center3, University of California, Los Angeles4, University of Texas MD Anderson Cancer Center5, Oregon Health & Science University6, University of Minnesota7, Loyola University Chicago8, Katholieke Universiteit Leuven9, University of Ulm10, University of Würzburg11, Université catholique de Louvain12, ViroPharma13, Fred Hutchinson Cancer Research Center14
TL;DR: Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment and may not be sufficient to show improvements in cytomeGalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment.
Abstract: Summary Background Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients. Methods In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645. Findings Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0·90; 95% CI 0·42–1·92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26·4%) than in the placebo group (34·8%; OR 0·67; 0·47–0·95), but not when measured by plasma cytomegalovirus DNA PCR (27·8% vs 30·4%; OR 0·88; 0·62–1·25), nor by initiation of treatment against cytomegalovirus (30·6% vs 37·4%; OR 0·73, 0·52–1·03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo). Interpretation Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials. Funding ViroPharma Incorporated.
TL;DR: The higher prevalence of primary drug resistance in Uganda than in other African countries is probably related to the earlier start of ART roll-out in Uganda.
Abstract: Summary Background There are few data on the epidemiology of primary HIV-1 drug resistance after the roll-out of antiretroviral treatment (ART) in sub-Saharan Africa. We aimed to assess the prevalence of primary resistance in six African countries after ART roll-out and if wider use of ART in sub-Saharan Africa is associated with rising prevalence of drug resistance. Methods We did a cross-sectional study in antiretroviral-naive adults infected with HIV-1 who had not started first-line ART, recruited between 2007 and 2009 from 11 regions in Kenya, Nigeria, South Africa, Uganda, Zambia, and Zimbabwe. We did population-based sequencing of the pol gene on plasma specimens with greater than 1000 copies per mL of HIV RNA. We identified drug-resistance mutations with the WHO list for transmitted resistance. The prevalence of sequences containing at least one drug-resistance mutation was calculated accounting for the sampling weights of the sites. We assessed the risk factors of resistance with multilevel logistic regression with random coefficients. Findings 2436 (94.1%) of 2590 participants had a pretreatment genotypic resistance result. 1486 participants (57.4%) were women, 1575 (60.8%) had WHO clinical stage 3 or 4 disease, and the median CD4 count was 133 cells per μL (IQR 62–204). Overall sample-weighted drug-resistance prevalence was 5.6% (139 of 2436; 95% CI 4.6–6.7), ranging from 1.1% (two of 176; 0.0–2.7) in Pretoria, South Africa, to 12.3% (22 of 179; 7.5–17.1) in Kampala, Uganda. The pooled prevalence for all three Ugandan sites was 11.6% (66 of 570; 8.9–14.2), compared with 3.5% (73 of 1866; 2.5–4.5) for all other sites. Drug class-specific resistance prevalence was 2.5% (54 of 2436; 1.8–3.2) for nucleoside reverse-transcriptase inhibitors (NRTIs), 3.3% (83 of 2436; 2.5–4.2) for non-NRTIs (NNRTIs), 1.3% (31 of 2436; 0.8–1.8) for protease inhibitors, and 1.2% (25 of 2436; 0.7–1.7) for dual-class resistance to NRTIs and NNRTIs. The most common drug-resistance mutations were K103N (43 [1.8%] of 2436), thymidine analogue mutations (33 [1.6%] of 2436), M184V (25 [1.2%] of 2436), and Y181C/I (19 [0.7%] of 2436). The odds ratio for drug resistance associated with each additional year since the start of the ART roll-out in a region was 1.38 (95% CI 1.13–1.68; p=0.001). Interpretation The higher prevalence of primary drug resistance in Uganda than in other African countries is probably related to the earlier start of ART roll-out in Uganda. Resistance surveillance and prevention should be prioritised in settings where ART programmes are scaled up. Funding Ministry of Foreign Affairs of the Netherlands.
TL;DR: This analysis showed a beneficial effect of oral antiseptic use in prevention of ventilator-associated pneumonia and Clinicians should take these findings into account when providing oral care to intubated patients.
Abstract: Summary Background We did a systematic review and random effects meta-analysis of randomised trials to assess the effect of oral care with chlorhexidine or povidone-iodine on the prevalence of ventilator-associated pneumonia versus oral care without these antiseptics in adults. Methods Studies were identified through PubMed, CINAHL, Web of Science, CENTRAL, and complementary manual searches. Eligible studies were randomised trials of mechanically ventilated adult patients receiving oral care with chlorhexidine or povidone-iodine. Relative risks (RR) and 95% CIs were calculated with the Mantel-Haenszel model and heterogeneity was assessed with the I 2 test. Findings 14 studies were included (2481 patients), 12 investigating the effect of chlorhexidine (2341 patients) and two of povidone-iodine (140 patients). Overall, antiseptic use resulted in a significant risk reduction of ventilator-associated pneumonia (RR 0.67; 95% CI 0.50–0.88; p=0.004). Chlorhexidine application was shown to be effective (RR 0.72; 95% CI 0.55–0.94; p=0.02), whereas the effect resulting from povidone-iodine remains unclear (RR 0.39; 95% CI 0.11–1.36; p=0.14). Heterogeneity was moderate ( I 2 =29%; p=0.16) for the trials using chlorhexidine and high ( I 2 =67%; p=0.08) for those assessing povidone-iodine use. Favourable effects were more pronounced in subgroup analyses for 2% chlorhexidine (RR 0.53, 95% CI 0.31–0.91), and in cardiosurgical studies (RR 0.41, 95% CI 0.17–0.98). Interpretation This analysis showed a beneficial effect of oral antiseptic use in prevention of ventilator-associated pneumonia. Clinicians should take these findings into account when providing oral care to intubated patients. Funding None.
TL;DR: Evidence suggests that treatment supporters, directly observed therapy, mobile-phone text messages, diary cards, and food rations can effectively increase adherence in sub-Saharan Africa, but some interventions are unlikely to have large or lasting effects, and others are effective only in specific settings.
Abstract: The success of potent antiretroviral treatment for HIV infection is primarily determined by adherence. We systematically review the evidence of effectiveness of interventions to increase adherence to antiretroviral treatment in sub-Saharan Africa. We identified 27 relevant reports from 26 studies of behavioural, cognitive, biological, structural, and combination interventions done between 2003 and 2010. Despite study diversity and limitations, evidence suggests that treatment supporters, directly observed therapy, mobile-phone text messages, diary cards, and food rations can effectively increase adherence in sub-Saharan Africa. However, some interventions are unlikely to have large or lasting effects, and others are effective only in specific settings. These findings emphasise the need for more research, particularly for randomised controlled trials, to examine the effect of context and specific features of intervention content on effectiveness. Future work should assess intervention targeting and selection of interventions based on behavioural theories relevant to sub-Saharan Africa.
TL;DR: The findings define the major areas of uncertainty in the management of S aureus bacteraemia and highlight just two key principles: first, all infective foci must be identified and removed as soon as possible and second, long-term antimicrobial therapy is required for those with persistent bacteriaaemia or a deep, irremovable focus.
Abstract: Staphylococcus aureus bacteraemia is one of the most common serious bacterial infections worldwide. In the UK alone, around 12 500 cases each year are reported, with an associated mortality of about 30%, yet the evidence guiding optimum management is poor. To date, fewer than 1500 patients with S aureus bacteraemia have been recruited to 16 controlled trials of antimicrobial therapy. Consequently, clinical practice is driven by the results of observational studies and anecdote. Here, we propose and review ten unanswered clinical questions commonly posed by those managing S aureus bacteraemia. Our findings define the major areas of uncertainty in the management of S aureus bacteraemia and highlight just two key principles. First, all infective foci must be identified and removed as soon as possible. Second, long-term antimicrobial therapy is required for those with persistent bacteraemia or a deep, irremovable focus. Beyond this, the best drugs, dose, mode of delivery, and duration of therapy are uncertain, a situation compounded by emerging S aureus strains that are resistant to old and new antibiotics. We discuss the consequences on clinical practice, and how these findings define the agenda for future clinical research.
Ghent University Hospital1, Utrecht University2, University of Cologne3, Claude Bernard University Lyon 14, University of Siena5, The Catholic University of America6, Royal Free London NHS Foundation Trust7, University of Basel8, University of Erlangen-Nuremberg9, University of Rome Tor Vergata10, Carlos III Health Institute11, Karolinska University Hospital12, Katholieke Universiteit Leuven13, Erasmus University Rotterdam14
TL;DR: The European Consensus Group on clinical management of tropism testing was established to make recommendations to clinicians and clinical virologists recommended an enhanced sensitivity Trofile assay and V3 population genotyping are the recommended methods.
Abstract: Viral tropism is the ability of viruses to enter and infect specific host cells and is based on the ability of viruses to bind to receptors on those cells. Testing for HIV tropism is recommended before prescribing a chemokine receptor blocker. In most European countries, HIV tropism is identified with tropism phenotype testing. New data support genotype analysis of the HIV third hypervariable loop (V3) for the identification of tropism. The European Consensus Group on clinical management of tropism testing was established to make recommendations to clinicians and clinical virologists. The panel recommends HIV-tropism testing for the following groups: drug-naive patients in whom toxic effects are anticipated or for whom few treatment options are available; patients who have poor tolerability to or toxic effects from current treatment or who have CNS pathology; and patients for whom therapy has failed and a change in treatment is considered. In general, an enhanced sensitivity Trofile assay and V3 population genotyping are the recommended methods. Genotypic methods are anticipated to be used more frequently in the clinical setting because of their greater accessibility, lower cost, and faster turnaround time than other methods. For the interpretation of V3 loop genotyping, clinically validated systems should be used when possible. Laboratories doing HIV tropism tests should have adequate quality assurance measures. Similarly, close collaboration between HIV clinicians and virologists is needed to ensure adequate diagnostic and treatment decisions.
TL;DR: Improved understanding of generic versus specific population biological aspects will help to translate results between different studies, and allow development of a more rational basis for sustainable drug use than exists at present.
Abstract: The emergence of resistant pathogens in response to selection pressure by drugs and their possible disappearance when drug use is discontinued are evolutionary processes common to many pathogens. Population biological models have been used to study the dynamics of resistance in viruses, bacteria, and eukaryotic microparasites both at the level of the individual treated host and of the treated host population. Despite the existence of generic features that underlie such evolutionary dynamics, different conclusions have been reached about the key factors affecting the rate of resistance evolution and how to best use drugs to minimise the risk of generating high levels of resistance. Improved understanding of generic versus specific population biological aspects will help to translate results between different studies, and allow development of a more rational basis for sustainable drug use than exists at present.
TL;DR: Assessment of samples from apes and human beings with African equatorial forest ancestry has traced the origin of HIV-1 to chimpanzees, and dated its most recent common ancestor to 1908, resulting in a complex classification, worldwide spread, and intermixing of strains.
Abstract: Since the isolation of HIV, multiple transmissions are thought to have occurred between man and other old-world primates. Assessment of samples from apes and human beings with African equatorial forest ancestry has traced the origin of HIV-1 to chimpanzees, and dated its most recent common ancestor to 1908. The evolution of HIV-1 has been rapid, which has resulted in a complex classification, worldwide spread, and intermixing of strains; at least 48 circulating recombinant forms are currently identified. In addition to posing a nearly insurmountable challenge for diagnosis, treatment, vaccine development, and prevention, this extreme and divergent evolution has led to differences in virulence between HIV-1 groups, subtypes, or both. Coincidental changes in human migration in the Congo river basin also affected spread of disease. Research over the past 25 years and advances in genomic sequencing methods, such as deep DNA sequencing, have greatly improved understanding and analysis of the thousands to millions of full infectious HIV-1 genomes.
TL;DR: Recommendations for use of pertussis booster vaccinations at different ages are proposed to reduce individual morbidity and transmission from present rates and increase herd protection.
Abstract: Although the introduction of universal pertussis immunisation in infants has greatly reduced the number of reported cases in infants and young children, disease incidence has been increasing in adolescents and adults in recent years. This changing epidemiological pattern is probably largely attributable to waning immunity after natural infection or vaccination. Furthermore, improved diagnostic testing, active surveillance, changes in disease susceptibility, vaccine characteristics, and increased awareness of the disease might also be contributing factors. Susceptibility to pertussis in adolescents and adults results not only in direct morbidity in these age groups, but also poses a transmission risk to susceptible non-immune infants who are often too young to be vaccinated. Because vaccination schedules vary across Europe, we review the pertussis situation in this region and propose considerations for use of pertussis booster vaccinations at different ages to reduce individual morbidity and transmission from present rates and increase herd protection.
TL;DR: Wang et al. as mentioned in this paper used data from the national HIV epidemiology and treatment databases to identify individuals aged 15 years or older with HIV who were eligible for highly active antiretroviral therapy between 1985 and 2009.
Abstract: Summary Background Overall HIV mortality rates in China have not been reported. In this analysis we assess overall mortality in treatment-eligible adults with HIV and attempt to identify risk factors for HIV-related mortality. Methods We used data from the national HIV epidemiology and treatment databases to identify individuals aged 15 years or older with HIV who were eligible for highly active antiretroviral therapy between 1985 and 2009. Mortality rates were calculated in terms of person-years, with risk factors determined by Cox proportional hazard regression. Treatment coverage was calculated as the proportion of time that patients who were eligible for treatment received treatment, with risk factors for not receiving treatment identified by use of logistic regression. Findings Of 323 252 people reported as having HIV in China by the end of 2009, 145 484 (45%) were identified as treatment-eligible and included in this analysis. Median CD4 count was 201 cells per μL (IQR 71–315) at HIV diagnosis and 194 cells per μL (73–293) when first declared eligible for treatment. Overall mortality decreased from 39·3 per 100 person-years in 2002 to 14·2 per 100 person-years in 2009, with treatment coverage concomitantly increasing from almost zero to 63·4%. By 2009, mortality was higher and treatment coverage lower in injecting drug users (15·9 deaths per 100 person-years; 42·7% coverage) and those infected sexually (17·5 deaths per 100 person-years; 61·7% coverage), compared with those infected through plasma donation or blood transfusion (6·7 deaths per 100 person-years; 80·2% coverage). The two strongest risk factors for HIV-related mortality were not receiving highly active antiretroviral therapy (adjusted hazard ratio 4·35, 95% CI 4·10–4·62) and having a CD4 count of less than 50 cells per μL when first declared eligible for treatment (7·92, 7·33–8.57). Interpretation An urgent need exists for earlier HIV diagnosis and better access to treatment for injecting drug users and patients infected with HIV sexually, especially before they become severely immunosuppressed. Funding The National Centre for AIDS/STD Control and Prevention of the Chinese Centre for Disease Control and Prevention.
TL;DR: Tigecycline is not better than standard antimicrobial agents for the treatment of serious infections, and assessment with unpublished studies is needed to make appropriate decisions about new agents.
Abstract: Summary Background Multidrug resistance among bacteria increases the need for new antimicrobial drugs with high potency and stability. Tigecycline is one candidate drug, and a previous meta-analysis of only published randomised controlled trials suggested that it might as effective as comparator treatments; we did a meta-analysis to include new and unpublished trials to assess its efficacy for the treatment of adult patients with serious bacterial infection. Methods We searched PubMed, Cochrane Central Register, and Embase up to March 30, 2011, to identify published studies, and we searched clinical trial registries to identify completed unpublished studies, the results of which were obtained through the manufacturer. Eligible studies were randomised trials assessing the clinical efficacy, safety, and eradication efficiency of tigecycline versus other antimicrobial agents for any bacterial infection. The primary outcome was treatment success in patients who received at least one dose of the study drug, had clinical evidence of disease, and had complete follow-up (the clinically assessable population). Meta-analysis was done with random-effects models because of heterogeneity across the trials. Findings 14 randomised trials, comprising about 7400 patients, were included. Treatment success was lower with tigecycline than with control antibiotic agents, but the difference was not significant (odds ratio 0·87, 95% CI 0·74–1·02). Adverse events were more frequent in the tigecycline group than in the control groups (1·45, 1·11–1·88), with significantly more vomiting and nausea. All-cause mortality was higher in the tigecycline group than in the comparator groups, but the difference was not significant (1·28, 0·97–1·69). Eradication efficiency did not differ between tigecycline and control regimens, but the sample size for these comparisons was small. Interpretation Tigecycline is not better than standard antimicrobial agents for the treatment of serious infections. Our findings show that assessment with unpublished studies is needed to make appropriate decisions about new agents. Funding None.
Medical University of South Carolina1, University of California, San Francisco2, Johns Hopkins University3, Muhimbili University of Health and Allied Sciences4, Chiang Mai University5, College of Health Sciences, Bahrain6, Human Sciences Research Council7, Charles University in Prague8, University of California, Los Angeles9
TL;DR: CBVCT should be considered as a viable intervention to increase detection of HIV infection, especially in regions with restricted access to clinic-based VCT and support services after testing.
Abstract: Summary Background In developing countries, most people infected with HIV do not know their infection status. We aimed to assess whether HIV testing could be increased by combination of community mobilisation, mobile community-based voluntary counselling and testing (VCT), and support after testing. Methods Project Accept is underway in ten communities in Tanzania, eight in Zimbabwe, and 14 in Thailand. Communities at each site were paired according to similar demographic and environmental characteristics, and one community from each pair was randomly assigned to receive standard clinic-based VCT (SVCT), and the other community was assigned to receive community-based VCT (CBVCT) plus access to SVCT. Randomisation and assignment of communities to intervention groups was done by the statistics centre by computer; no one was masked to treatment assignment because the interventions were community based. Intervention was provided for about 3 years (2006–09). The primary endpoint of HIV incidence is pending completion of assessments after the intervention. In this interim analysis, we examined the secondary endpoint of uptake in HIV testing, differences in characteristics of clients receiving their first HIV test, and repeat testing. Analyses were limited to clients aged 16–32 years. This study is registered with ClinicalTrials.gov, number NCT00203749. Findings The proportion of clients receiving their first HIV test during the study was higher in CBVCT communities than in SVCT communities in Tanzania (2341 [37%] of 6250 vs 579 [9%] of 6733), Zimbabwe (5437 [51%] of 10 700 vs 602 [5%] of 12 150), and Thailand (7802 [69%] of 11 290 vs 2319 [23%] 10 033). The mean difference in the proportion of clients receiving HIV testing between CBVCT and SVCT communities was 40·2% (95% CI 15·8–64·7; p=0·019) across three community pairs (one per country). HIV prevalence was higher in SVCT communities than in CBVCT communities, but CBVCT detected almost four times more HIV cases than did SVCT across the three study sites (952 vs 264; p=0·003). Repeat HIV testing in CBVCT communities increased in all sites to reach 28% of all those testing for HIV by the end of the intervention period. Interpretation CBVCT should be considered as a viable intervention to increase detection of HIV infection, especially in regions with restricted access to clinic-based VCT and support services after testing. Funding US National Institute of Mental Health, HIV Prevention Trials Network (via US National Institute of Allergy and Infectious Diseases), and US National Institutes of Health.
TL;DR: Taking multiple-strain infections into account will improve the understanding of host-pathogen interactions and disease dynamics, and will provide a basis for novel control approaches.
Abstract: Summary Infections frequently contain multiple strains (genotypes) of the same pathogen, yet they are still usually treated as uniform entities. In this Review, we discuss problems with inconsistent definition of the term "strain" and review the prevalence and implications of multiple-strain infections. Up to now, multiple-strain infections have been shown unambiguously in 51 human pathogens (and 21 non-human ones) and are likely to arise in most pathogen species. In human pathogens, multiple-strain infections usually reach considerable frequencies (median 11·3%, mean 21·7% of infections), which are certainly underestimated in many cases because of technical limitations of detection. For many diseases, the importance of multiple-strain infections is still unclear, but theoretical work and experimental results from animal models suggest a broad range of clinically relevant effects. Multiple-strain infections can affect host immune responses and our ability to prevent and treat infection efficiently. Competition and mutualism between strains change pathogen and disease dynamics and promote pathogen evolution. Co-infection enables gene transfer among strains. Taking multiple-strain infections into account will improve our understanding of host-pathogen interactions and disease dynamics, and will provide a basis for novel control approaches.
TL;DR: Because adherence with empirical treatment was associated with increased mortality, it is recommended a randomised trial be done before further implementation of these guidelines.
Abstract: Summary Background The American Thoracic Society and Infectious Diseases Society of America provide guidelines for management of hospital-acquired, ventilator-associated, and health-care-associated pneumonias, consisting of empirical antibiotic regimens for patients at risk for multidrug-resistant pathogens. We aimed to improve compliance with these guidelines and assess outcomes. Methods We implemented a performance-improvement initiative in four academic medical centres in the USA with protocol-based education and prospective observation of outcomes. Patients were assessed for severity of illness and followed up until death, hospital discharge, or day 28. We included patients in intensive-care units who were at risk for multidrug-resistant pneumonia and were treated empirically. Findings 303 patients at risk for multidrug-resistant pneumonia were treated empirically, and prescribed treatment was guideline compliant in 129 patients and non-compliant in 174 patients. 44 (34%) patients died before 28 days in the compliance group and 35 (20%) died in the non-compliance group. Five patients in the compliance group and seven in the non-compliance group were lost to follow-up after day 14. Kaplan-Meier estimated survival to 28 days was 65% in the compliance group and 79% in the non-compliance group (p=0·0042). This difference persisted after adjustment for severity of illness. Median length of stay and duration of mechanical ventilation did not differ between groups. Compliance failures included non-use of dual treatment for Gram-negative pathogens in 154 patients and absence of meticillin-resistant Staphylococcus aureus coverage in 24 patients. For patients in whom pathogens were subsequently identified, empirical treatment was active in 79 (81%) of 97 of patients receiving compliant therapy compared with 109 (85%) of 128 of patients receiving non-compliant therapy. Interpretation Because adherence with empirical treatment was associated with increased mortality, we recommend a randomised trial be done before further implementation of these guidelines. Funding Pfizer, US Medical.