register interest

Professor Heiman Wertheim

Research Area: Microbiology
Scientific Themes: Tropical Medicine & Global Health
Keywords: tuberculosis, pneumonia, meningitis, Klebsiella pneumoniae, antibiotic resistance
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Heiman Wertheim, MD PhD, is a clinical microbiologist at the Oxford University Clinical Research Unit in Hanoi, Vietnam, which is based at the National Hospital for Tropical Diseases. Currently, he is involved with several infectious disease research projects in Asia. His main research topics are central nervous sytem infections, pediatric tuberculosis, pneumonia, Klebsiella pneumoniae infections, Staphylococcus aureus infections, and antibiotic resistance. He supervises activities of the Global Antibiotic Resistance Partnership (GARP) in Vietnam, which did a situation analysis on antibiotic use and resistance in Vietnam. He recently finished a large project that studied hospital acquired infections, antibiotic resistance and antibiotic use across 16 hospitals in Vietnam (Vinares study).

There are no collaborations listed for this principal investigator.

Li R, van Doorn HR, Wertheim HF, Khue LN, Ha NT, Dat VQ, Hanh CT, Nga DT, Trang NN, Nadjm B et al. 2016. Combating antimicrobial resistance: quality standards for prescribing for respiratory infections in Vietnam. Lancet Glob Health, 4 (11), pp. e789. | Read more

Tran DN, Tran HH, Matsui M, Suzuki M, Suzuki S, Shibayama K, Pham TD, Van Phuong TT, Dang DA, Trinh HS et al. 2017. Emergence of New Delhi metallo-beta-lactamase 1 and other carbapenemase-producing Acinetobacter calcoaceticus-baumannii complex among patients in hospitals in Ha Noi, Viet Nam. Eur J Clin Microbiol Infect Dis, 36 (2), pp. 219-225. | Show Abstract | Read more

Acinetobacter baumannii is an important cause of multidrug-resistant hospital acquired infections in the world. Here, we investigate the presence of NDM-1 and other carbapenemases among carbapenem-resistant A. baumannii isolated between August 2010 and December 2014 from three large hospitals in Hanoi, Vietnam. We identified 23/582 isolates (4 %) (11 from hospital A, five from hospital B, and seven from hospital C) that were NDM-1 positive, and among them 18 carried additional carbapenemase genes, including seven isolates carrying NDM-1, IMP-1, and OXA-58 with high MICs for carbapenems. Genotyping indicated that NDM-1 carrying A. baumannii have expanded clonally in these hospitals. Five new STs (ST1135, ST1136, ST1137, ST1138, and ST1139) were identified. One isolate carried NDM-1 on a plasmid belonging to the N-repA replicon type; no NDM-1-positive plasmids were identified in the other isolates. We have shown the extent of the carbapenem resistance and the local clonal spread of A. baumannii carrying NDM-1 in these hospitals; coexistence of NDM-1 and IMP-1 is reported for the first time from Vietnam here, and this will further seriously limit future therapeutic options.

Levy Hara G, Kanj SS, Pagani L, Abbo L, Endimiani A, Wertheim HF, Amábile-Cuevas C, Tattevin P, Mehtar S, Lopes Cardoso F et al. 2016. Ten key points for the appropriate use of antibiotics in hospitalised patients: a consensus from the Antimicrobial Stewardship and Resistance Working Groups of the International Society of Chemotherapy. Int J Antimicrob Agents, 48 (3), pp. 239-246. | Show Abstract | Read more

The Antibiotic Stewardship and Resistance Working Groups of the International Society for Chemotherapy propose ten key points for the appropriate use of antibiotics in hospital settings. (i) Get appropriate microbiological samples before antibiotic administration and carefully interpret the results: in the absence of clinical signs of infection, colonisation rarely requires antimicrobial treatment. (ii) Avoid the use of antibiotics to 'treat' fever: use them to treat infections, and investigate the root cause of fever prior to starting treatment. (iii) Start empirical antibiotic treatment after taking cultures, tailoring it to the site of infection, risk factors for multidrug-resistant bacteria, and the local microbiology and susceptibility patterns. (iv) Prescribe drugs at their optimal dosing and for an appropriate duration, adapted to each clinical situation and patient characteristics. (v) Use antibiotic combinations only where the current evidence suggests some benefit. (vi) When possible, avoid antibiotics with a higher likelihood of promoting drug resistance or hospital-acquired infections, or use them only as a last resort. (vii) Drain the infected foci quickly and remove all potentially or proven infected devices: control the infection source. (viii) Always try to de-escalate/streamline antibiotic treatment according to the clinical situation and the microbiological results. (ix) Stop unnecessarily prescribed antibiotics once the absence of infection is likely. And (x) Do not work alone: set up local teams with an infectious diseases specialist, clinical microbiologist, hospital pharmacist, infection control practitioner or hospital epidemiologist, and comply with hospital antibiotic policies and guidelines.

Do NT, Ta NT, Tran NT, Than HM, Vu BT, Hoang LB, van Doorn HR, Vu DT, Cals JW, Chandna A et al. 2016. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob Health, 4 (9), pp. e633-e641. | Show Abstract | Read more

BACKGROUND: Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is difficult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. METHOD: We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1-65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecified in the protocol and the statistical analysis plan. All analyses were done on the intention-to-treat population and the analysis of the primary endpoint was repeated in the per-protocol population. This trial is registered under number NCT01918579. FINDINGS: Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics within 14 days was 581 (64%) of 902 patients in the C-reactive protein group versus 738 (78%) of 947 patients in the control group (odds ratio [OR] 0·49, 95% CI 0·40-0·61; p<0·0001). Highly significant differences were seen in both children and adults, with substantial heterogeneity of the intervention effect across the 10 sites (I(2)=84%, 95% CI 66-96). 140 patients in the C-reactive protein group and 137 patients in the routine care group missed the urine test on day 3, 4, or 5. Antibiotic activity in urine on day 3, 4, or 5 was found in 267 (30%) of 877 patients in the C-reactive protein group versus 314 (36%) of 882 patients in the routine treatment group (OR 0·78, 95% CI 0·63-0·95; p=0·015). Time to resolution of symptoms was similar in both groups. Adverse events were rare, with no deaths and a total of 14 hospital admissions (six in the C-reactive protein group and eight in the control group). INTERPRETATION: C-reactive protein point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients' recovery in primary health care in Vietnam. Health-care providers might have become familiar with the clinical picture of low C-reactive protein, leading to reduction in antibiotic prescribing in both groups, but this would have led to a reduction in observed effect, rather than overestimation. Qualitative analysis is needed to address differences in context in order to implement this strategy to improve rational antibiotic use for patients with acute respiratory infection in low-income and middle-income countries. FUNDING: Wellcome Trust, UK, and Global Antibiotic Resistance Partnership, USA.

Nguyen DN, Mai LEQ, Bryant JE, Hang NLEK, Hoa LENM, Nadjm B, Thai PQ, Duong TN, Anh DD, Horby P et al. 2016. Epidemiology and etiology of influenza-like-illness in households in Vietnam; it's not all about the kids! J Clin Virol, 82 pp. 126-132. | Show Abstract | Read more

BACKGROUND: Household studies provide opportunities to understand influenza-like-illness (ILI) transmission, but data from (sub)tropical developing countries are scarce. OBJECTIVE: To determine the viral etiology and epidemiology of ILI in households. STUDY DESIGN: ILI was detected by active case finding amongst a cohort of 263 northern Vietnam households between 2008 and 2013. Health workers collected nose and throat swabs for virus detection by multiplex real-time RT-PCR. RESULTS: ILI was detected at least once in 219 (23.7%) of 945 household members. 271 (62.3%) of 435 nose/throat swabs were positive for at least one of the 15 viruses tested. Six viruses predominated amongst positive swabs: Rhinovirus (28%), Influenza virus (17%), Coronavirus (8%), Enterovirus (5%), Respiratory syncytial virus (3%), Metapneumovirus virus (2.5%) and Parainfluenza virus 3 (1.8%). There was no clear seasonality, but 78% of episodes occurred in Winter/Spring for Influenza compared to 32% for Rhinovirus. Participants, on average, suffered 0.49 ILI, and 0.29 virus-positive ILI episodes, with no significant effects of gender, age, or household size. In contrast to US and Australian community studies, the frequency of ILI decreased as the number of household members aged below 5 years increased (p=0.006). CONCLUSION: The findings indicate the need for tailored ILI control strategies, and for better understanding of how local childcare practices and seasonality may influence transmission and the role of children.

Yacoub S, Lam PK, Vu LEHM, Le TL, Ha NT, Toan TT, Van NT, Quyen NT, Le Duyen HT, Van Kinh N et al. 2016. Association of Microvascular Function and Endothelial Biomarkers With Clinical Outcome in Dengue: An Observational Study. J Infect Dis, 214 (5), pp. 697-706. | Show Abstract | Read more

BACKGROUND: The hallmark of severe dengue is increased microvascular permeability, but alterations in the microcirculation and their evolution over the course of dengue are unknown. METHODS: We conducted a prospective observational study to evaluate the sublingual microcirculation using side-stream dark-field imaging in patients presenting early (<72 hours after fever onset) and patients hospitalized with warning signs or severe dengue in Vietnam. Clinical findings, microvascular function, global hemodynamics assessed with echocardiography, and serological markers of endothelial activation were determined at 4 time points. RESULTS: A total of 165 patients were enrolled. No difference was found between the microcirculatory parameters comparing dengue with other febrile illnesses. The proportion of perfused vessels (PPV) and the mean flow index (MFI) were lower in patients with dengue with plasma than those without leakage (PPV, 88.1% vs 90.6% [P = .01]; MFI, 2.1 vs 2.4 [P = .007]), most markedly during the critical phase. PPV and MFI were correlated with the endothelial activation markers vascular cell adhesion molecule 1 (P < .001 for both) and angiopoietin 2 (P < .001 for both), negatively correlated. CONCLUSIONS: Modest microcirculatory alterations occur in dengue, are associated with plasma leakage, and are correlate with molecules of endothelial activation, angiopoietin 2 and vascular cell adhesion molecule 1.

Vu BN, Jafari AJ, Aardema M, Tran HK, Nguyen DN, Dao TT, Nguyen TV, Tran TK, Nguyen CK, Fox A et al. 2016. Population structure of colonizing and invasive Staphylococcus aureus strains in northern Vietnam. J Med Microbiol, 65 (4), pp. 298-305. | Show Abstract | Read more

Staphylococcus aureus is an important global health problem worldwide. There is still scarce information on the population structure of S. aureus strains in Asia, where the majority of the world population lives. This study characterizes the diversity of S. aureus strains in northern Vietnam through multilocus sequence typing (MLST). 85 carriage isolates from community and 77 invasive isolates from the clinical setting were selected and tested for methicillin resistance and the presence of Panton-Valentine Leukocidin (PVL). MLST was performed on these isolates, of which CC59 (25.4%), CC188 (17.3%), and CC45 (16.7%) were the predominant clonal complexes (CC). CC59-carriage isolates were significantly lower in rates of MRSA than their corresponding clinical group isolates (32% vs. 83%). There were no significant differences in rates of MRSA between carriage isolates and clinical isolates of CC45 and CC188. CC59-carriage isolates were significantly lower in rates of PVL+ than CC59-clinical isolates (32% vs. 83%), but the converse was shown in CC45 isolates (14% vs. 0% respectively). This study reveals vast differences in the molecular epidemiology and population structure of S. aureus in community and clinical settings in Vietnam. Nevertheless, the data underline the spread of virulent and/or resistant strains (MRSA and/or PVL+) in the community, suggesting the necessity of further surveillance to determine the reasoning of transmission of these strains (i.e. MRSA/PVL+) outside clinical settings.

Phu VD, Wertheim HF, Larsson M, Nadjm B, Dinh QD, Nilsson LE, Rydell U, Le TT, Trinh SH, Pham HM et al. 2016. Burden of Hospital Acquired Infections and Antimicrobial Use in Vietnamese Adult Intensive Care Units. PLoS One, 11 (1), pp. e0147544. | Show Abstract | Read more

BACKGROUND: Vietnam is a lower middle-income country with no national surveillance system for hospital-acquired infections (HAIs). We assessed the prevalence of hospital-acquired infections and antimicrobial use in adult intensive care units (ICUs) across Vietnam. METHODS: Monthly repeated point prevalence surveys were systematically conducted to assess HAI prevalence and antimicrobial use in 15 adult ICUs across Vietnam. Adults admitted to participating ICUs before 08:00 a.m. on the survey day were included. RESULTS: Among 3287 patients enrolled, the HAI prevalence was 29.5% (965/3266 patients, 21 missing). Pneumonia accounted for 79.4% (804/1012) of HAIs Most HAIs (84.5% [855/1012]) were acquired in the survey hospital with 42.5% (363/855) acquired prior to ICU admission and 57.5% (492/855) developed during ICU admission. In multivariate analysis, the strongest risk factors for HAI acquired in ICU were: intubation (OR 2.76), urinary catheter (OR 2.12), no involvement of a family member in patient care (OR 1.94), and surgery after admission (OR 1.66). 726 bacterial isolates were cultured from 622/1012 HAIs, most frequently Acinetobacter baumannii (177/726 [24.4%]), Pseudomonas aeruginosa (100/726 [13.8%]), and Klebsiella pneumoniae (84/726 [11.6%]), with carbapenem resistance rates of 89.2%, 55.7%, and 14.9% respectively. Antimicrobials were prescribed for 84.8% (2787/3287) patients, with 73.7% of patients receiving two or more. The most common antimicrobial groups were third generation cephalosporins, fluoroquinolones, and carbapenems (20.1%, 19.4%, and 14.1% of total antimicrobials, respectively). CONCLUSION: A high prevalence of HAIs was observed, mainly caused by Gram-negative bacteria with high carbapenem resistance rates. This in combination with a high rate of antimicrobial use illustrates the urgent need to improve rational antimicrobial use and infection control efforts.

Carrique-Mas JJ, Tue NT, Bryant JE, Saylors K, Cuong NV, Hoa NT, An NN, Hien VB, Lao PV, Tu NC et al. 2015. The baseline characteristics and interim analyses of the high-risk sentinel cohort of the Vietnam Initiative on Zoonotic InfectiONS (VIZIONS). Sci Rep, 5 (1), pp. 17965. | Show Abstract | Read more

The Vietnam Initiative for Zoonotic Infections (VIZIONS) includes community-based 'high-risk sentinel cohort' (HRSC) studies investigating individuals at risk of zoonotic infection due to occupational or residential exposure to animals. A total of 852 HRSC members were recruited between March 2013 and August 2014 from three provinces (Ha Noi, Dak Lak, and Dong Thap). The most numerous group (72.8%) corresponded to individuals living on farms, followed by slaughterers (16.3%) and animal health workers (8.5%). Nasal/pharyngeal and rectal swabs were collected from HRSC members at recruitment and after notifying illness. Exposure to exotic animals (including wild pigs, porcupine, monkey, civet, bamboo rat and bat) was highest for the Dak Lak cohort (53.7%), followed by Ha Noi (13.7%) and Dong Thap (4.0%). A total of 26.8% of individuals reported consumption of raw blood over the previous year; 33.6% slaughterers reported no use of protective equipment at work. Over 686 person-years of observation, 213 episodes of suspect infectious disease were notified, equivalent of 0.35 reports per person-year. Responsive samples were collected from animals in the farm cohort. There was noticeable time and space clustering of disease episodes suggesting that the VIZIONS set up is also suitable for the formal epidemiological investigation of disease outbreaks.

Bode LG, van Rijen MM, Wertheim HF, Vandenbroucke-Grauls CM, Troelstra A, Voss A, Verbrugh HA, Vos MC, Kluytmans JA. 2016. Long-term Mortality After Rapid Screening and Decolonization of Staphylococcus Aureus Carriers: Observational Follow-up Study of a Randomized, Placebo-controlled Trial. Ann Surg, 263 (3), pp. 511-515. | Show Abstract | Read more

OBJECTIVE: To identify patients who benefit most from Staphylococcus aureus screening and decolonization treatment upon admission. BACKGROUND: S. aureus carriers are at increased risk of developing surgical-site infections with S. aureus. Previously, we demonstrated in a randomized, placebo-controlled trial (RCT) that these infections can largely be prevented by detection of carriage and decolonization treatment upon admission. In this study, we analyzed 1- and 3-year mortality rates in both treatment arms of the RCT to identify patient groups that should be targeted when implementing the screen-and-treat strategy. METHODS: Three years after enrolment in the RCT, mortality dates of all surgical patients were checked. One- and 3-year mortality rates were calculated for all patients and for various subgroups. RESULTS: After 3 years, 44 of 431 (10.2%) and 43 of 362 (11.9%) patients had died in the mupirocin/chlorhexidine and placebo groups, respectively. No significant differences in mortality rates were observed between the treatment groups or the subgroups according to type of surgery. In the subgroup of patients with clean procedures (382 cardiothoracic, 167 orthopedic, 61 vascular, and 56 other), mupirocin/chlorhexidine reduced 1-year mortality: 11 of 365 (3.0%) died in the mupirocin/chlorhexidine versus 21 of 301 (7.0%) in the placebo group [hazard ratio = 0.38 (95% CI: 0.18-0.81)]. CONCLUSIONS: Detection and decolonization of S. aureus carriage not only prevents S. aureus surgical-site infections but also reduces 1-year mortality in surgical patients undergoing clean procedures. Such patients with a high risk of developing S. aureus infections should therefore be the primary target when implementing the screen-and-treat strategy in clinical practice.

Hoang TT, Nguyen NV, Dinh SN, Nguyen HB, Cobelens F, Thwaites G, Nguyen HT, Nguyen AT, Wright P, Wertheim HF. 2015. Challenges in detection and treatment of multidrug resistant tuberculosis patients in Vietnam. BMC Public Health, 15 (1), pp. 980. | Show Abstract | Read more

BACKGROUND: Vietnam is ranked 14(th) among 27 countries with high burden of multidrug-resistant tuberculosis (MDR-TB). In 2009, the Vietnamese government issued a policy on MDR-TB called Programmatic Management of Drug-resistant Tuberculosis (PMDT) to enhance and scale up diagnosis and treatment services for MDR-TB. Here we assess the PMDT performance in 2013 to determine the challenges to the successful identification and enrollment for treatment of MDR-TB in Vietnam. METHODS: In 35 provinces implementing PMDT, we quantified the number of MDR-TB presumptive patients tested for MDR-TB by Xpert MTB/RIF and the number of MDR-TB patients started on second-line treatment. In addition, existing reports and documents related to MDR-TB policies and guidelines in Vietnam were reviewed, supplemented with focus group discussions and in-depth interviews with MDR-TB key staff members. RESULTS: 5,668 (31.2 %) of estimated 18,165 MDR-TB presumptive cases were tested by Xpert MTB/RIF and second-line treatment was provided to 948 out of 5100 (18.7 %) of MDR-TB patients. Those tested for MDR-TB were 340/3224 (10.5 %) of TB-HIV co-infected patients and 290/2214 (13.1 %) of patients who remained sputum smear-positive after 2 and 3 months of category I TB regimen. Qualitative findings revealed the following challenges to detection and enrollment of MDR-TB in Vietnam: insufficient TB screening capacity at district hospitals where TB units were not available and poor communication and implementation of policy changes. Instructions for policy changes were not always received, and training was inconsistent between training courses. The private sector did not adequately report MDR-TB cases to the NTP. CONCLUSIONS: The proportion of MDR-TB patients diagnosed and enrolled for second-line treatment is less than 20 % of the estimated total. The low enrollment is largely due to the fact that many patients at risk are missed for MDR-TB screening. In order to detect more MDR-TB cases, Vietnam should intensify case finding of MDR-TB by a comprehensive strategy to screen for MDR-TB among new cases rather than targeting previously treated cases, in particular those with HIV co-infection and contacts of MDR-TB patients, and should engage the private sector in PMDT.

Rabaa MA, Tue NT, Phuc TM, Carrique-Mas J, Saylors K, Cotten M, Bryant JE, Nghia HD, Cuong NV, Pham HA et al. 2015. The Vietnam Initiative on Zoonotic Infections (VIZIONS): A Strategic Approach to Studying Emerging Zoonotic Infectious Diseases. Ecohealth, 12 (4), pp. 726-735. | Show Abstract | Read more

The effect of newly emerging or re-emerging infectious diseases of zoonotic origin in human populations can be potentially catastrophic, and large-scale investigations of such diseases are highly challenging. The monitoring of emergence events is subject to ascertainment bias, whether at the level of species discovery, emerging disease events, or disease outbreaks in human populations. Disease surveillance is generally performed post hoc, driven by a response to recent events and by the availability of detection and identification technologies. Additionally, the inventory of pathogens that exist in mammalian and other reservoirs is incomplete, and identifying those with the potential to cause disease in humans is rarely possible in advance. A major step in understanding the burden and diversity of zoonotic infections, the local behavioral and demographic risks of infection, and the risk of emergence of these pathogens in human populations is to establish surveillance networks in populations that maintain regular contact with diverse animal populations, and to simultaneously characterize pathogen diversity in human and animal populations. Vietnam has been an epicenter of disease emergence over the last decade, and practices at the human/animal interface may facilitate the likelihood of spillover of zoonotic pathogens into humans. To tackle the scientific issues surrounding the origins and emergence of zoonotic infections in Vietnam, we have established The Vietnam Initiative on Zoonotic Infections (VIZIONS). This countrywide project, in which several international institutions collaborate with Vietnamese organizations, is combining clinical data, epidemiology, high-throughput sequencing, and social sciences to address relevant one-health questions. Here, we describe the primary aims of the project, the infrastructure established to address our scientific questions, and the current status of the project. Our principal objective is to develop an integrated approach to the surveillance of pathogens circulating in both human and animal populations and assess how frequently they are exchanged. This infrastructure will facilitate systematic investigations of pathogen ecology and evolution, enhance understanding of viral cross-species transmission events, and identify relevant risk factors and drivers of zoonotic disease emergence.

Le Viet T, Choisy M, Bryant JE, Vu Trong D, Pham Quang T, Horby P, Nguyen Tran H, Tran Thi Kieu H, Nguyen Vu T, Nguyen Van K et al. 2015. A dengue outbreak on a floating village at Cat Ba Island in Vietnam. BMC Public Health, 15 (1), pp. 940. | Show Abstract | Read more

BACKGROUND: A dengue outbreak in an ecotourism destination spot in Vietnam, from September to November 2013, impacted a floating village of fishermen on the coastal island of Cat Ba. The outbreak raises questions about how tourism may impact disease spread in rural areas. METHODS: Epidemiological data were obtained from the Hai Phong Preventive Medical Center (PMC), including case histories and residential location from all notified dengue cases from this outbreak. All household addresses were geo-located. Knox test, a spatio-temporal analysis that enables inference dengue clustering constrained by space and time, was performed on the geocoded locations. From the plasma available from two patients, positive for Dengue serotype 3 virus (DENV3), the Envelope (E) gene was sequenced, and their genetic relationships compared to other E sequences in the region. RESULTS: Of 192 dengue cases, the odds ratio of contracting dengue infections for people living in the floating villages compared to those living on the island was 4.9 (95 % CI: 3.6-6.7). The space-time analyses on 111 geocoded dengue residences found the risk of dengue infection to be the highest within 4 days and a radius of 20 m of a given case. Of the total of ten detected clusters with an excess risk greater than 2, the cluster with the highest number of cases was in the floating village area (24 patients for a total duration of 31 days). Phylogenetic analysis revealed a high homology of the two DENV3 strains (genotype III) from Cat Ba with DENV3 viruses circulating in Hanoi in the same year (99.1 %). CONCLUSIONS: Our study showed that dengue transmission is unlikely to be sustained on Cat Ba Island and that the 2013 epidemic likely originated through introduction of viruses from the mainland, potentially Hanoi. These findings suggest that prevention efforts should be focused on mainland rather than on the island.

Holt KE, Wertheim H, Zadoks RN, Baker S, Whitehouse CA, Dance D, Jenney A, Connor TR, Hsu LY, Severin J et al. 2015. Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc Natl Acad Sci U S A, 112 (27), pp. E3574-E3581. | Show Abstract | Read more

Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats.

Tran HH, Ehsani S, Shibayama K, Matsui M, Suzuki S, Nguyen MB, Tran DN, Tran VP, Tran DL, Nguyen HT et al. 2015. Common isolation of New Delhi metallo-beta-lactamase 1-producing Enterobacteriaceae in a large surgical hospital in Vietnam. Eur J Clin Microbiol Infect Dis, 34 (6), pp. 1247-1254. | Show Abstract | Read more

This study sought to monitor the presence of carbapenem-resistant Enterobacteriaceae (CRE) and the proportion New Delhi metallo-beta-lactamase 1 (NDM-1)-producing bacteria between August 2010 and December 2012 in a surgical hospital in Vietnam. We identified 47 CRE strains from a total of 4,096 Enterobacteriaceae isolates (1.1 %) that were NDM-1-positive from 45 patients admitted to 11 different departments, with the majority being from the urology department. The NDM-1 gene was found in seven different species. Genotyping revealed limited clonality of NDM-1-positive isolates. Most of the isolates carried the NDM-1 gene on a plasmid and 17.8 % (8/45) of those were readily transferable. We found five patients at admission and one patient at discharge with NDM-1-positive bacteria in their stool. From 200 screening environmental hospital samples, five were confirmed to be NDM-1-positive and included Acinetobacter species (n = 3) and Enterobacter aerogenes (n = 2). The results reveal that NDM-1-producing Enterobacteriaceae are commonly isolated in patients admitted to a Vietnamese surgical hospital and are also detected in the hospital environment.

Wertheim HF, Nadjm B, Thomas S, Agustiningsih A, Malik S, Diep NN, Vu TV, Kinh NV, Chau NV, Liem NT et al. 2015. Viral and atypical bacterial aetiologies of infection in hospitalised patients admitted with clinical suspicion of influenza in Thailand, Vietnam and Indonesia. Influenza Other Respir Viruses, 9 (6), pp. 315-322. | Show Abstract | Read more

BACKGROUND: Influenza constitutes a leading cause of morbidity and mortality worldwide. There is limited information about the etiology of infection presenting clinically as influenza in hospitalized adults and children in Southeast Asia. Such data are important for future management of respiratory infections. OBJECTIVES: To describe the etiology of infection presenting clinically as influenza in those hospitalized in Southeast Asia METHODS: Respiratory specimens archived from July 2008 to June 2009 from patients hospitalised with suspected influenza from (Indonesia, Thailand and Vietnam were tested for respiratory viruses and atypical bacteria by polymerase chain reaction. RESULTS: A total of 1222 patients' samples were tested. 776/1222 (63.5%) patients were under the age of 5. Viruses detected included rhinoviruses in 229/1222 patients (18.7%), bocaviruses in 200/1222 (16.4%), respiratory syncytial viruses in 144 (11.8%), parainfluenzaviruses in 140 (11.5%; PIV1: 32; PIV2: 12; PIV3: 71;PIV4: 25), adenovirus in 102 (8.4%), influenza viruses in 93 (7.6%; influenza A: 77; influenza B: 16), coronaviruses in 23 (1.8%; OC43: 14; E229: 9). Bacterial pathogens were: Mycoplasma pneumoniae (n=33, 2.7%), Chlamydophila psittaci (n=2), C. pneumoniae (n=1), Bordetella pertussis (n=1), and Legionella pneumophila (n=2). Overall in-hospital case fatality rate was 29/1222 (2.4%). CONCLUSION: Respiratory viruses were the most commonly detected pathogens in patients hospitalized with a clinical suspicion of influenza. Rhinovirus was the most frequently detected virus, and M. pneumoniae the most common atypical bacterium. The low number of detected influenza viruses demonstrate a low benefit for empirical oseltamivir therapy, unless during an influenza outbreak. This article is protected by copyright. All rights reserved.

Taylor WR, Fox A, Pham KT, Le HN, Tran NT, Tran GV, Nguyen BT, Nguyen MV, Nguyen LT, Yacoub S et al. 2015. Dengue in adults admitted to a referral hospital in Hanoi, Vietnam. Am J Trop Med Hyg, 92 (6), pp. 1141-1149. | Show Abstract | Read more

Knowledge of adult dengue virus (DENV) infection from Hanoi, Vietnam, is limited. In 2008, we prospectively studied 143 (77 male) confirmed (nonstructural 1 antigen enzyme-linked immunosorbent assay [ELISA], DENV polymerase chain reaction, paired serology) adult dengue patients of median age 23.5 (range 16-72) years. They were admitted to the National Hospital for Tropical Diseases, Hanoi, on median illness day (D) 5 (range 1-8). By D8, 141 (98.6%) were afebrile. Platelet counts and hematocrit (median, interquartile range [IQR]) nadired and peaked on D5 and D4, respectively: 40,000/μL (10,000-109,000/μL), 43.4% (34.9-49.7%). Four (2.8%) patients had severe dengue: 1) D10 shock (N = 1) and 2) aspartate aminotransferase (AST) ≥ 1,000 IU/L (N = 3, D5 and D7). Of 143 patients, 118 (82.5%) had ≥ 1 warning sign (World Health Organization [WHO] 2009 criteria): mucosal bleeding 66/143 (46.1%), soft tissue edema 54/143 (37.7%), and ultrasound detected plasma leakage (pleural effusions/ascites) 30/129 (23.25%). 138 (96.5%) patients received intravenous (IV) fluids: 3 L (IQR: 0.5-8.5 L). Most patients had non-severe dengue with warning signs. High rates of edema and plasma leakage may be explained partly by liberal use of IV fluids. Studies are needed on optimizing fluid management in non-severe adult dengue.

Wyres KL, Gorrie C, Edwards DJ, Wertheim HF, Hsu LY, Van Kinh N, Zadoks R, Baker S, Holt KE. 2015. Extensive Capsule Locus Variation and Large-Scale Genomic Recombination within the Klebsiella pneumoniae Clonal Group 258. Genome Biol Evol, 7 (5), pp. 1267-1279. | Show Abstract | Read more

Klebsiella pneumoniae clonal group (CG) 258, comprising sequence types (STs) 258, 11, and closely related variants, is associated with dissemination of the K. pneumoniae carbapenemase (KPC). Hospital outbreaks of KPC CG258 infections have been observed globally and are very difficult to treat. As a consequence, there is renewed interest in alternative infection control measures such as vaccines and phage or depolymerase treatments targeting the K. pneumoniae polysaccharide capsule. To date, 78 immunologically distinct capsule variants have been described in K. pneumoniae. Previous investigations of ST258 and a small number of closely related strains suggested that capsular variation was limited within this clone; only two distinct ST258 capsule polysaccharide synthesis (cps) loci have been identified, both acquired through large-scale recombination events (>50 kb). In contrast to previous studies, we report a comparative genomic analysis of the broader K. pneumoniae CG258 (n = 39). We identified 11 different cps loci within CG258, indicating that capsular switching is actually common within the complex. We observed several insertion sequences (IS) within the cps loci, and show further intraclone diversification of two cps loci through IS activity. Our data also indicate that several large-scale recombination events have shaped the genomes of CG258, and that definition of the complex should be broadened to include ST395 (also reported to harbor KPC). As only the second report of extensive intraclonal cps variation among Gram-negative bacterial species, our findings alter our understanding of the evolution of these organisms and have key implications for the design of control measures targeting K. pneumoniae capsules.

Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. 2015. Microvascular and endothelial function for risk prediction in dengue: an observational study. Lancet, 385 Suppl 1 pp. S102. | Show Abstract | Read more

BACKGROUND: Dengue infection can result in a wide spectrum of disease. The defining feature of severe disease is increased capillary permeability, which can lead to hypovolaemic shock. Microvascular and endothelial dysfunction might underlie hypovolaemic shock, but they have not been assessed clinically. We aimed to investigate the use of microvascular assessment as a prognostic method in dengue. METHODS: This is an ongoing prospective observational study that aims to recruit 300 participants: children over the age of 3 years and adults presenting to two outpatient departments in Vietnam with fever of less than 72 h duration and suspected dengue, and patients admitted to hospital with warning signs or severe disease. Participants are being clinically assessed daily for 6 days, and 2 weeks later. Microvascular imaging using sublingual sidestream darkfield imaging (SDF) and endothelial function testing using peripheral artery tonometry are being performed at enrolment, defervescence, and follow-up FINDINGS: To date, 167 patients have been recruited (92 outpatient arm, 75 inpatient arm, median age 27 years [IQR 21-33], 78 male [47%]). Dengue has been confirmed in 67 individuals in the outpatient arm, of whom 29 (43%) developed warning signs, three (4%) developed severe disease, and 35 had uncomplicated dengue; the other 25 outpatients (27%) were diagnosed as other febrile illness. At enrolment, the reactive hyperaemic index, a marker of endothelial function, was lowest in the patients who went on to develop severe dengue (median 1·54, IQR 1·36-1·77) followed by those who developed warning signs (1·78, 1·43-2·36) and then uncomplicated dengue (2·18, 1·65-2·24). Initial SDF results showed a lower proportion of perfused vessels and mean flow index during the febrile phase of dengue compared with follow-up, and were worst in the severe group at defervescence. INTERPRETATION: This study of vascular function at serial timepoints in dengue is, to our knowledge, the first and most comprehensive. Our preliminary results suggest that microvascular and endothelial dysfunction are associated with severity of dengue, and occur before the appearance of severe clinical manifestations. These techniques might be useful in risk prediction in dengue. A limitation is that a formal sample size could not be calculated because no previous microvascular data in dengue exist. FUNDING: Wellcome Trust.

Le T, Cash-Goldwasser S, Tho PV, Lan NP, Campbell JI, van Doorn HR, Lam NT, Trung NV, Trinh DT, Van Kinh N, Wertheim HF. 2015. Diagnosing Rhodococcus equi infections in a setting where tuberculosis is highly endemic: a double challenge. J Clin Microbiol, 53 (4), pp. 1431-1433. | Show Abstract | Read more

Rhodococcus equi infection is increasing in regions with high HIV prevalence worldwide. The microbiological features and clinical mimicry of tuberculosis infection pose diagnostic challenges in high-tuberculosis-incidence settings. We present two HIV-associated cases of R. equi infection from Vietnam and discuss the unique diagnostic challenges in such settings.

Pham DK, Chu J, Do NT, Brose F, Degand G, Delahaut P, De Pauw E, Douny C, Nguyen KV, Vu TD et al. 2015. Monitoring Antibiotic Use and Residue in Freshwater Aquaculture for Domestic Use in Vietnam. Ecohealth, 12 (3), pp. 480-489. | Show Abstract | Read more

Vietnam is an important producer of aquaculture products, and aquatic products are essential to the Vietnamese diet. However, Vietnam also has very little enforced regulation pertaining to antibiotic usage in domestic aquaculture, which raises concerns for antibiotic resistance in pathogenic bacteria. In this study, analysis was conducted on the presence of antibiotic residues in domestically sold fish and shrimp raised in freshwater farms in Vietnam, and an assessment of farmers' knowledge of proper antibiotics usage was performed. The results indicated that a quarter of tested aquaculture products were antibiotic screening test positive, and there is a general lack of knowledge about the purpose and proper usage of antibiotics by aquaculture producers. Farmers' decision-making processes about antimicrobial use are influenced by biased sources of information, such as drug manufacturers and sellers, and by financial incentives.

Huong VT, Thanh LV, Phu VD, Trinh DT, Inui K, Tung N, Oanh NT, Trung NV, Hoa NT, Bryant JE et al. 2016. Temporal and spatial association of Streptococcus suis infection in humans and porcine reproductive and respiratory syndrome outbreaks in pigs in northern Vietnam. Epidemiol Infect, 144 (1), pp. 35-44. | Show Abstract | Read more

Porcine reproductive and respiratory syndrome (PRRS) outbreaks in pigs are associated with increased susceptibility of pigs to secondary bacterial infections, including Streptococcus suis - an important zoonotic pathogen causing bacterial meningitis in humans. This case-control study examined the association between human S. suis infection and PRRS outbreaks in pigs in northern Vietnam. We included 90 S. suis case-patients and 183 non-S. suis sepsis controls from a referral hospital in Hanoi in 2010, a period of major PRRS epizootics in Vietnam. PRRS exposure was determined using data from the National Centre of Veterinary Diagnosis. By univariate analysis, significantly more S. suis patients were reported residing in or adjacent to a PRRS district compared to controls [odds ratio (OR) 2·82, 95% confidence interval (CI) 1·35-5·89 and OR 3·15, 95% CI 1·62-6·15, respectively]. Only residency in adjacent districts remained significantly associated with risk of S. suis infection after adjusting for sex, occupation, and eating practices. SaTScan analysis showed a possible cluster of S. suis infection in humans around PRRS confirmed locations during the March-August period. The findings indicate an epidemiological association between PRRS in pigs and S. suis infections in humans. Effective strategies to strengthen control of PRRS in pigs may help reduce transmission of S. suis infection to humans.

Robinson TP, Wertheim HF, Kakkar M, Kariuki S, Bu D, Price LB. 2016. Animal production and antimicrobial resistance in the clinic. Lancet, 387 (10014), pp. e1-e3. | Read more

Mendelson M, Røttingen JA, Gopinathan U, Hamer DH, Wertheim H, Basnyat B, Butler C, Tomson G, Balasegaram M. 2016. Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries. Lancet, 387 (10014), pp. 188-198. | Show Abstract | Read more

Access to quality-assured antimicrobials is regarded as part of the human right to health, yet universal access is often undermined in low-income and middle-income countries. Lack of access to the instruments necessary to make the correct diagnosis and prescribe antimicrobials appropriately, in addition to weak health systems, heightens the challenge faced by prescribers. Evidence-based interventions in community and health-care settings can increase access to appropriately prescribed antimicrobials. The key global enablers of sustainable financing, governance, and leadership will be necessary to achieve access while preventing excess antimicrobial use.

Thi Anh Thu L, Thi Hong Thoa V, Thi Van Trang D, Phuc Tien N, Thuy Van D, Thi Kim Anh L, Wertheim HF, Truong Son N. 2015. Cost-effectiveness of a hand hygiene program on health care-associated infections in intensive care patients at a tertiary care hospital in Vietnam. Am J Infect Control, 43 (12), pp. e93-e99. | Show Abstract | Read more

BACKGROUND: The cost-effectiveness of a hand hygiene (HH) program in low- and middle-income countries (LMICs) is largely unknown. We assessed the cost-effectiveness of a HH program in a large tertiary Vietnamese hospital. METHODS: This was a before and after study of a hand hygiene program where HH compliance, incidence of hospital-acquired infections (HAIs), and costs were analyzed.The HH program was implemented in 2 intensive care and 15 critical care units. The program included upgrading HH facilities, providing alcohol-based handrub at point of care, HH campaigns, and continuous HH education. RESULTS: The HH compliance rate increased from 25.7% to 57.5% (P < .001). The incidence of patients with HAI decreased from 31.7% to 20.3% (P < .001) after the intervention. The mean cost for patients with HAI was $1,908, which was 2.5 times higher than the costs for patients without an HAI. The mean attributable cost of an HAI was $1,131. The total cost of the HH program was $12,570, which equates to a per-patient cost of $6.5. The cost-effectiveness was estimated at -$1,074 or $1,074 saved per HAI prevented. The intervention remained cost savings under various scenarios with lower HAI rates. CONCLUSION: The HH program is an effective strategy in reducing the incidence of HAIs in intensive care units and is cost-effective in Vietnam. HH programs need to be encouraged across Vietnam and other LMICs.

Hoa LN, Bryant JE, Choisy M, Nguyet LA, Bao NT, Trang NH, Chuc NT, Toan TK, Saito T, Takemae N et al. 2015. Population susceptibility to a variant swine-origin influenza virus A(H3N2) in Vietnam, 2011-2012. Epidemiol Infect, 143 (14), pp. 2959-2964. | Show Abstract | Read more

A reassortant swine-origin A(H3N2) virus (A/swine/BinhDuong/03-9/2010) was detected through swine surveillance programmes in southern Vietnam in 2010. This virus contains haemagglutinin and neuraminidase genes from a human A(H3N2) virus circulating around 2004-2006, and the internal genes from triple-reassortant swine influenza A viruses (IAVs). To assess population susceptibility to this virus we measured haemagglutination inhibiting (HI) titres to A/swine/BinhDuong/03-9/2010 and to seasonal A/Perth/16/2009 for 947 sera collected from urban and rural Vietnamese people during 2011-2012. Seroprevalence (HI ⩾ 40) was high and similar for both viruses, with 62·6% [95% confidence interval (CI) 59·4-65·7] against A/Perth/16/2009 and 54·6% (95% CI 51·4-57·8%) against A/swine/BinhDuong/03-9/2010, and no significant differences between urban and rural participants. Children aged <5 years lacked antibodies to the swine origin H3 virus despite high seroprevalence for A/Perth/16/2009. These results reveal vulnerability to infection to this contemporary swine IAV in children aged <5 years; however, cross-reactive immunity in adults would likely limit epidemic emergence potential.

Van TD, Dinh QD, Vu PD, Nguyen TV, Pham CV, Dao TT, Phung CD, Hoang HT, Tang NT, Do NT et al. 2014. Antibiotic susceptibility and molecular epidemiology of Acinetobacter calcoaceticus-baumannii complex strains isolated from a referral hospital in northern Vietnam. J Glob Antimicrob Resist, 2 (4), pp. 318-321. | Show Abstract | Read more

Acinetobacter calcoaceticus-baumannii complex is a common cause of hospital-acquired infections (HAIs) globally, remarkable for its high rate of antibiotic resistance, including to carbapenems. There are few data on the resistance of A. baumannii in Vietnam, which are essential for developing evidence-based treatment guidelines for HAIs. Antibiotic susceptibility testing was conducted by VITEK(®)2, and pulsed-field gel electrophoresis (PFGE) was performed on 66 clinical A. baumannii complex isolates recovered during 2009 at the National Hospital of Tropical Diseases (NHTD), a referral hospital in Hanoi, Vietnam. Basic demographic and clinical data were collected and analysed using descriptive statistics. Most isolates came from lower respiratory tract specimens (59; 89.4%) from intensive care unit (ICU) patients [64/65 (98.5%) with available data] who had been admitted to NHTD for ≥2 days [42/46 (91.3%) with available data]. More than 90% of the isolates were resistant to the tested β-lactamase/β-lactamase inhibitors, cephalosporins, carbapenems, fluoroquinolones and trimethoprim/sulfamethoxazole. Moreover, 25.4% (16/63) were resistant to all tested β-lactams, quinolones and aminoglycosides. All isolates remained sensitive to colistin and 58.7% were susceptible to tigecycline. Of the 66 isolates, 49 could be classified into eight PFGE types (A-H). Every PFGE type, except D, had cluster(s) of three or more isolates with a temporal relationship. In conclusion, these data suggest a significant rise in A. baumannii antibiotic resistance in Vietnam. Clustering within PFGE types supports cross-transmission of A. baumannii within the ICU at NHTD. Increased research and resources in optimising treatment, infection control and antibiotic stewardship are needed.

Nguyen DN, Nguyen TV, Dao TT, Nguyen LT, Horby P, Nguyen KV, Wertheim HF. 2014. One year experience using mycobacterial blood cultures to diagnose tuberculosis in patients with prolonged fever in Vietnam. J Infect Dev Ctries, 8 (12), pp. 1620-1624. | Show Abstract | Read more

INTRODUCTION: To evaluate the use of mycobacterial blood cultures (MBC) in diagnosing tuberculosis (TB) in patients with prolonged fever admitted to a Vietnamese referral hospital. RESULTS: MBCs from 94 patients (66% male; median age 33 years; 75% HIV positive) were evaluated: 14 were mycobacterium positive (all HIV positive), and MBC was the only positive specimen in 9 cases (41%). Three positive cases were identified as Mycobacterium avium and the remaining M. tuberculosis (one case could not be identified). CONCLUSION: MBC can be a valuable additional method to diagnose TB, particularly in immunosuppressed HIV patients when sputum cannot be collected.

Fonville JM, Wilks SH, James SL, Fox A, Ventresca M, Aban M, Xue L, Jones TC, Le NM, Pham QT et al. 2014. Antibody landscapes after influenza virus infection or vaccination. Science, 346 (6212), pp. 996-1000. | Show Abstract | Read more

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.

Day J, Imran D, Ganiem AR, Tjahjani N, Wahyuningsih R, Adawiyah R, Dance D, Mayxay M, Newton P, Phetsouvanh R et al. 2014. CryptoDex: a randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis: study protocol for a randomised control trial. Trials, 15 (1), pp. 441. | Show Abstract | Read more

BACKGROUND: Cryptococcal meningitis (CM) is a severe AIDS-defining illness with 90-day case mortality as high as 70% in sub-Saharan Africa, despite treatment. It is the leading cause of death in HIV patients in Asia and Africa.No major advance has been made in the treatment of CM since the 1970s. The mainstays of induction therapy are amphotericin B and flucytosine, but these are often poorly available where the disease burden is highest. Adjunctive treatments, such as dexamethasone, have had dramatic effects on mortality in other neurologic infections, but are untested in CM. Given the high death rates in patients receiving current optimal treatment, and the lack of new agents on the horizon, adjuvant treatments, which offer the potential to reduce mortality in CM, should be tested.The principal research question posed by this study is as follows: does adding dexamethasone to standard antifungal therapy for CM reduce mortality? Dexamethasone is a cheap, readily available, and practicable intervention. METHOD: A double-blind placebo-controlled trial with parallel arms in which patients are randomised to receive either dexamethasone or placebo, in addition to local standard of care. The study recruits patients in both Asia and Africa to ensure the relevance of its results to the populations in which the disease burden is highest. The 10-week mortality risk in the control group is expected to be between 30% and 50%, depending on location, and the target hazard ratio of 0.7 corresponds to absolute risk reductions in mortality from 30% to 22%, or from 50% to 38%. Assuming an overall 10-week mortality of at least 30% in our study population, recruitment of 824 patients will be sufficient to observe the expected number of deaths. Allowing for some loss to follow-up, the total sample size for this study is 880 patients. To generate robust evidence across both continents, we aim to recruit roughly similar numbers of patients from each continent. The primary end point is 10-week mortality. Ethical approval has been obtained from Oxford University's Tropical Research Ethics Committee (OxTREC), and as locally mandated at each site. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN59144167 26-July-2012.

Huong VT, Hoa NT, Horby P, Bryant JE, Van Kinh N, Toan TK, Wertheim HF. 2014. Raw pig blood consumption and potential risk for Streptococcus suis infection, Vietnam. Emerg Infect Dis, 20 (11), pp. 1895-1898. | Show Abstract | Read more

We assessed consumption of raw pig blood, which is a risk factor for Streptococcus suis infection in Vietnam, by using a mix-method design. Factors associated with consumption included rural residency, age, sex, occupation, income, and marital status. We identified risk groups and practices and perceptions that should be targeted by communication programs.

Nadjm B, Thuy PT, Trang VD, Ha LED, Kinh NV, Wertheim HF. 2014. Scrub typhus in the northern provinces of Vietnam: an observational study of admissions to a national referral hospital. Trans R Soc Trop Med Hyg, 108 (11), pp. 739-740. | Show Abstract | Read more

BACKGROUND: Scrub typhus is a common cause of fever in parts of South East and Southern Asia. Little is known about the disease burden in Vietnam. METHODS: A 2-year observational study of scrub typhus at a tertiary referral hospital in northern Vietnam was carried out. Diagnosis was based on a single serological test in patients with suggestive clinical symptoms. RESULTS: Scrub typhus was diagnosed in 3.5% (251/7226) of admissions. Cases occurred throughout the year, with incidence highest in the summer. Although complications were common, mortality was low (1.2%; 3/251). CONCLUSIONS: These data suggest that scrub typhus is common, with a seasonal distribution in northern Vietnam.

Fox A, Mai LEQ, Thanh LET, Wolbers M, Le Khanh Hang N, Thai PQ, Thi Thu Yen N, Minh Hoa LEN, Bryant JE, Duong TN et al. 2015. Hemagglutination inhibiting antibodies and protection against seasonal and pandemic influenza infection. J Infect, 70 (2), pp. 187-196. | Show Abstract | Read more

OBJECTIVES: Hemagglutination inhibiting (HI) antibodies correlate with influenza vaccine protection but their association with protection induced by natural infection has received less attention and was studied here. METHODS: 940 people from 270 unvaccinated households participated in active ILI surveillance spanning 3 influenza seasons. At least 494 provided paired blood samples spanning each season. Influenza infection was confirmed by RT-PCR on nose/throat swabs or serum HI assay conversion. RESULTS: Pre-season homologous HI titer was associated with a significantly reduced risk of infection for H3N2 (OR 0.61, 95%CI 0.44-0.84) and B (0.65, 95%CI 0.54-0.80) strains, but not H1N1 strains, whether re-circulated (OR 0.90, 95%CI 0.71-1.15), new seasonal (OR 0.86, 95%CI 0.54-1.36) or pandemic H1N1-2009 (OR 0.77, 95%CI 0.40-1.49). The risk of seasonal and pandemic H1N1 decreased with increasing age (both p < 0.0001), and the risk of pandemic H1N1 decreased with prior seasonal H1N1 (OR 0.23, 95%CI 0.08-0.62) without inducing measurable A/California/04/2009-like titers. CONCLUSIONS: While H1N1 immunity was apparent with increasing age and prior infection, the effect of pre-season HI titer was at best small, and weak for H1N1 compared to H3N2 and B. Antibodies targeting non-HI epitopes may have been more important mediators of infection-neutralizing immunity for H1N1 compared to other subtypes in this setting.

Van Nguyen K, Zhang T, Thi Vu BN, Dao TT, Tran TK, Thi Nguyen DN, Thi Tran HK, Thi Nguyen CK, Fox A, Horby P, Wertheim H. 2014. Staphylococcus aureus nasopharyngeal carriage in rural and urban northern Vietnam. Trans R Soc Trop Med Hyg, 108 (12), pp. 783-790. | Show Abstract | Read more

BACKGROUND: Staphylococcus aureus is a common human pathogen that can colonise the respiratory tract and cause infection. Here we investigate the risk factors associated with nasopharyngeal carriage of S. aureus (including methicillin-resistant S. aureus [MRSA]) in Vietnam. METHODS: Between February and June 2012, nasal and pharyngeal swabs for S. aureus culture, and demographic and socioeconomic data were taken from 1016 participants in urban and rural northern Vietnam, who were randomly selected from pre-specified age strata. RESULTS: Overall S. aureus prevalence was 303/1016 (29.8%; adjusted for age: 33.8%). Carriage in the main cohort was found to be associated with younger age (≤5 years [OR 3.13, CI 1.62-6.03]; 6-12 [OR 6.87, CI 3.95-11.94]; 13-19 [OR 6.47, CI 3.56-11.74]; 20-29 [OR 4.73, CI 2.40-9.31]; 30-59 [OR 1.74, CI 1.04-2.92); with ≥60 as reference), living in an urban area (OR 1.36, CI 1.01-1.83) and antibiotics use (OR 0.69, CI 0.49-0.96). MRSA was detected in 80/1016 (7.9%). Being aged ≤5 years (OR 4.84, CI 1.47-15.97); 6-12 (OR 10.21, CI 3.54-29.50); 20-29 (OR 4.01, CI 1.09-14.77) and wealth (>3/5 wealth index, OR 1.63 CI 1.01-2.62) were significant risk factors for MRSA carriage. CONCLUSIONS: Nasopharyngeal carriage of S. aureus is present in one-third of the Vietnamese population, and is more prevalent among children. Pharyngeal carriage is more common than nasal carriage. Risk factors for S. aureus (including MRSA) carriage are identified in the community.

Thanh TH, Ngoc SD, Viet NN, Van HN, Horby P, Cobelens FG, Wertheim HF. 2014. A household survey on screening practices of household contacts of smear positive tuberculosis patients in Vietnam. BMC Public Health, 14 (1), pp. 713. | Show Abstract | Read more

BACKGROUND: Close contacts of tuberculosis (TB) patients are at increased risk of developing tuberculosis. Although passive contact screening guidelines are incorporated in the national TB control program, currently it is unknown how frequent close contacts are screened for TB in Vietnam. This study assesses current contact screening practices in Vietnam and determines the proportion of household contacts screened of newly registered TB patients. METHOD: Survey of household contacts of smear-positive TB patients (index patients) registered for treatment in 2008 in three Vietnamese cities. Households were interviewed in 2010 about screening for TB since treatment registration date of the index patient. RESULTS: We interviewed 4,118 household contacts of 1,091 identified index cases. Contact screening mainly relied on self-referral by household contacts. Of the 4,118 household contacts, 474 (11.5%) self-referred for TB screening, while this screening proportion was only 5.5% among contacts under 5 years old (16/293). Sputum examinations were performed in 374 (78.9%) of the screened contacts. Contact screening identified 27 cases of pulmonary TB (0.7%; or 656 cases/100,000 contacts), of which 20 were detected by sputum smear. CONCLUSIONS: The low proportion of household TB contacts screened for TB illustrates the limitations of passive contact screening as currently practiced in Vietnam. Children under 5 years of age are particularly neglected with this approach. Active contact screening with fixed follow-up times of close contacts of newly diagnosed TB patients should be considered in Vietnam, particularly in case of young children and drug-resistant TB.

Huong VT, Ha N, Huy NT, Horby P, Nghia HD, Thiem VD, Zhu X, Hoa NT, Hien TT, Zamora J et al. 2014. Epidemiology, clinical manifestations, and outcomes of Streptococcus suis infection in humans. Emerg Infect Dis, 20 (7), pp. 1105-1114. | Show Abstract | Read more

Streptococcus suis, a bacterium that affects pigs, is a neglected pathogen that causes systemic disease in humans. We conducted a systematic review and meta-analysis to summarize global estimates of the epidemiology, clinical characteristics, and outcomes of this zoonosis. We searched main literature databases for all studies through December 2012 using the search term "streptococcus suis." The prevalence of S. suis infection is highest in Asia; the primary risk factors are occupational exposure and eating of contaminated food. The pooled proportions of case-patients with pig-related occupations and history of eating high-risk food were 38.1% and 37.3%, respectively. The main clinical syndrome was meningitis (pooled rate 68.0%), followed by sepsis, arthritis, endocarditis, and endophthalmitis. The pooled case-fatality rate was 12.8%. Sequelae included hearing loss (39.1%) and vestibular dysfunction (22.7%). Our analysis identified gaps in the literature, particularly in assessing risk factors and sequelae of this infection.

Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. 2014. Cardiovascular manifestations of the emerging dengue pandemic. Nat Rev Cardiol, 11 (6), pp. 335-345. | Show Abstract | Read more

Dengue is one of the most important emerging viral diseases globally. The majority of symptomatic infections result in a relatively benign disease course. However, a small proportion of patients develop severe clinical manifestations, including bleeding, organ impairment, and endothelial dysfunction with increased capillary permeability causing hypovolaemic shock that can lead to cardiovascular collapse. Evidence is increasing that dengue can also cause myocardial impairment, arrhythmias and, occasionally, fulminant myocarditis. No antiviral agents or vaccines are licensed for dengue, and treatment remains supportive with judicious fluid replacement for patients with severe disease. Defining the role of cardiac dysfunction in the haemodynamic compromise of severe dengue has potentially important management implications. In this Review, we will outline the current understanding of the cardiovascular manifestations of dengue, including myocardial and vascular involvement, and conclude with a discussion of the available therapeutic options and potential future research directions.

Thai PQ, Mai LEQ, Welkers MR, Hang NLEK, Thanh LET, Dung VT, Yen NT, Duong TN, Hoa LENM, Thoang DD et al. 2014. Pandemic H1N1 virus transmission and shedding dynamics in index case households of a prospective Vietnamese cohort. J Infect, 68 (6), pp. 581-590. | Show Abstract | Read more

OBJECTIVES: Influenza household transmission studies are required to guide prevention strategies but most passively recruit index cases that seek healthcare. We investigated A(H1N1)pdm09 transmission in a household-based cohort during 2009. METHODS: Health-workers visited 270 households weekly, and collected swabs from influenza-like-illness cases. If A(H1N1)pdm09 was RT-PCR-confirmed, all household members had symptoms assessed and swabs collected daily for 10-15 days. Viral RNA was quantified and sequenced and serology performed on pre-pandemic sera. RESULTS: Index cases were detected in 20 households containing 81 people. 98.5% lacked A(H1N1)pdm09 neutralizing antibodies in pre-pandemic sera. Eleven (18.6%, 95% CI 10.7-30.4%) of 59 contacts were infected. Virus genetic diversity within households was negligible and less than between households. Index and secondary cases were distributed between mothers, daughters and sons, and had similar virus-RNA shedding and symptom dynamics. Fathers were rarely infected. Five secondary cases (45%) had no apparent symptoms and three shed virus before symptoms. Secondary infection was associated with index case wet cough (OR 1.56, 95% CI 1.22-1.99). CONCLUSIONS: In this cohort of A(H1N1)pdm09 susceptible persons, virus sequencing was capable of discriminating household from community transmission. Household transmission involved mothers and children but rarely fathers. Asymptomatic or pre-symptomatic shedding was common.

Segura M, Zheng H, de Greeff A, Gao GF, Grenier D, Jiang Y, Lu C, Maskell D, Oishi K, Okura M et al. 2014. Latest developments on Streptococcus suis: an emerging zoonotic pathogen: part 2. Future Microbiol, 9 (5), pp. 587-591. | Show Abstract | Read more

First International Workshop on Streptococcus suis, Beijing, China, 12-13 August 2013. This second and final chapter of the report on the First International Workshop on Streptococcus suis follows on from Part 1, published in the April 2014, volume 9, issue 4 of Future Microbiology. S. suis is a swine pathogen and a zoonotic agent afflicting people in close contact with infected pigs or pork meat. Although sporadic cases of human infections had been reported worldwide, deadly S. suis outbreaks emerged in Asia. The severity of the disease underscores the lack of knowledge on the virulence and zoonotic evolution of this human-infecting agent. The pathogenesis of the infection, interactions with host cells and new avenues for treatments were among the topics discussed during the First International Workshop on S. suis (China 2013).

Peto L, Nadjm B, Horby P, Ngan TT, van Doorn R, Van Kinh N, Wertheim HF. 2014. The bacterial aetiology of adult community-acquired pneumonia in Asia: a systematic review. Trans R Soc Trop Med Hyg, 108 (6), pp. 326-337. | Show Abstract | Read more

BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of adult mortality in Asia. Appropriate empirical treatment depends on knowledge of the pathogens commonly responsible. However, assessing the aetiological significance of identified organisms is often difficult, particularly with sputum isolates that might represent contamination with oropharyngeal flora. METHODS: A systematic review of all adult CAP aetiology studies from Asia, excluding the Middle East, published in English between 1 January 1990 and 1 March 2012 was conducted. Forty-eight studies reporting on 10 423 patients were included, representing data from China, India, Indonesia, Japan, Malaysia, The Philippines, Singapore, South Korea, Taiwan, Thailand and Vietnam. Data from large parts of Asia were unavailable and there was substantial heterogeneity in methodology. RESULTS: As in western studies, Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella spp. and Haemophilus influenzae were all significant pathogens. However, compared with western studies, S. pneumoniae was of less relative importance. Gram-negative bacilli and Mycobacterium tuberculosis were more important, and in northeast Thailand Burkholderia pseudomallei was a major pathogen. CONCLUSION: These data have major implications for diagnostic strategies and empirical treatment. Narrow-spectrum antibiotics targeting S. pneumoniae may be inappropriate in many Asian settings, and agents active against TB may lead to partial response and delayed TB diagnosis.

Segura M, Zheng H, de Greeff A, Gao GF, Grenier D, Jiang Y, Lu C, Maskell D, Oishi K, Okura M et al. 2014. Latest developments on Streptococcus suis: an emerging zoonotic pathogen: part 1. Future Microbiol, 9 (4), pp. 441-444. | Show Abstract | Read more

First International Workshop on Streptococcus suis, Beijing, China, 12-13 August 2013 The first international workshop on Streptococcus suis, which is an important swine pathogen and emerging zoonotic agent, took place in Beijing, jointly organized by the Faculty of Veterinary Medicine, University of Montreal, Canada and the National Institute for Communicable Disease Control and Prevention, China CDC. The aim of the meeting was to gather together, for the first time, more than 80 researchers working on S. suis, from countries including China, Canada, Japan, The Netherlands, Germany, Thailand, the UK and Vietnam. This article, the first of a two-part report on this First International Workshop, reviews current aspects of the epidemiology and population genomics of S. suis, covers public health concerns and discusses questions about S. suis serotyping and molecular diagnostics.

Fox A, Whitehead S, Anders KL, Hoa LENM, Mai LEQ, Thai PQ, Yen NT, Duong TN, Thoang DD, Farrar J et al. 2014. Investigation of dengue and Japanese encephalitis virus transmission in Hanam, Viet Nam. Am J Trop Med Hyg, 90 (5), pp. 892-896. | Show Abstract | Read more

This study investigated whether a large dengue epidemic that struck Hanoi in 2009 also affected a nearby semirural area. Seroconversion (dengue virus-reactive immunoglobulin G enzyme-linked immunosorbent assay) was high during 2009 compared with 2008, but neutralization assays showed that it was caused by both dengue virus and Japanese encephalitis virus infections. The findings highlight the importance of continued Japanese encephalitis virus vaccination and dengue surveillance.

Nga DOTT, Chuc NT, Hoa NP, Hoa NQ, Nguyen NT, Loan HT, Toan TK, Phuc HD, Horby P, Van Yen N et al. 2014. Antibiotic sales in rural and urban pharmacies in northern Vietnam: an observational study. BMC Pharmacol Toxicol, 15 (1), pp. 6. | Show Abstract | Read more

BACKGROUND: The irrational overuse of antibiotics should be minimized as it drives the development of antibiotic resistance, but changing these practices is challenging. A better understanding is needed of practices and economic incentives for antibiotic dispensing in order to design effective interventions to reduce inappropriate antibiotic use. Here we report on both quantitative and qualitative aspects of antibiotic sales in private pharmacies in northern Vietnam. METHOD: A cross-sectional study was conducted in which all drug sales were observed and recorded for three consecutive days at thirty private pharmacies, 15 urban and 15 rural, in the Hanoi region in 2010. The proportion of antibiotics to total drug sales was assessed and the revenue was calculated for rural and urban settings. Pharmacists and drug sellers were interviewed by a semi-structured questionnaire and in-depth interviews to understand the incentive structure of antibiotic dispensing. RESULTS: In total 2953 drug sale transactions (2083 urban and 870 rural) were observed. Antibiotics contributed 24% and 18% to the total revenue of pharmacies in urban and rural, respectively. Most antibiotics were sold without a prescription: 88% in urban and 91% in rural pharmacies. The most frequent reported reason for buying antibiotics was cough in the urban setting (32%) and fever in the rural area (22%). Consumers commonly requested antibiotics without having a prescription: 50% in urban and 28% in rural area. The qualitative data revealed that drug sellers and customer's knowledge of antibiotics and antibiotic resistance were low, particularly in rural area. CONCLUSION: Over the counter sales of antibiotic without a prescription remains a major problem in Vietnam. Suggested areas of improvement are enforcement of regulations and pricing policies and educational programs to increase the knowledge of drug sellers as well as to increase community awareness to reduce demand-side pressure for drug sellers to dispense antibiotics inappropriately.

Hoang LT, Tolfvenstam T, Ooi EE, Khor CC, Naim AN, Ho EX, Ong SH, Wertheim HF, Fox A, Van Vinh Nguyen C et al. 2014. Patient-based transcriptome-wide analysis identify interferon and ubiquination pathways as potential predictors of influenza A disease severity. PLoS One, 9 (11), pp. e111640. | Show Abstract | Read more

BACKGROUND: The influenza A virus is an RNA virus that is responsible for seasonal epidemics worldwide with up to five million cases of severe illness and 500,000 deaths annually according to the World Health Organization estimates. The factors associated with severe diseases are not well defined, but more severe disease is more often seen among persons aged >65 years, infants, pregnant women, and individuals of any age with underlying health conditions. METHODOLOGY/PRINCIPAL FINDINGS: Using gene expression microarrays, the transcriptomic profiles of influenza-infected patients with severe (N = 11), moderate (N = 40) and mild (N = 83) symptoms were compared with the febrile patients of unknown etiology (N = 73). We found that influenza-infected patients, regardless of their clinical outcomes, had a stronger induction of antiviral and cytokine responses and a stronger attenuation of NK and T cell responses in comparison with those with unknown etiology. More importantly, we found that both interferon and ubiquitination signaling were strongly attenuated in patients with the most severe outcomes in comparison with those with moderate and mild outcomes, suggesting the protective roles of these pathways in disease pathogenesis. CONCLUSION/SIGNIFICANCES: The attenuation of interferon and ubiquitination pathways may associate with the clinical outcomes of influenza patients.

Wertheim HF, Schultsz C. 2014. [Antibiotics in low- and middle-income countries]. Ned Tijdschr Geneeskd, 158 pp. A8049. | Show Abstract

In this paper we summarize and discuss the problem of the antibiotic resistance issue and potential intervention strategies in low- and middle-income countries (LMILs). In Europe and North America surveillance data are available and research networks are active, however, these are still largely lacking in LMILs. In recent years some initiatives have been set up for LMIL, such as 'Action on Antibiotic Resistance' (ReACT) and the 'Global Antibiotic Resistance Partnership' (GARP). While better data on antibiotic resistance and its causes in LMILs are needed, there is a more urgent need for affordable interventions to turn the tide. Unlike programs aimed at combatting bacterial antibiotic resistance, there are already strong global programs to tackle resistance in HIV/AIDS, tuberculosis and malaria. We should learn from these programs to improve efforts to control and treat resistant bacterial infections.

Dao TT, Liebenthal D, Tran TK, Ngoc Thi Vu B, Ngoc Thi Nguyen D, Thi Tran HK, Thi Nguyen CK, Thi Vu HL, Fox A, Horby P et al. 2014. Klebsiella pneumoniae oropharyngeal carriage in rural and urban Vietnam and the effect of alcohol consumption. PLoS One, 9 (3), pp. e91999. | Show Abstract | Read more

INTRODUCTION: Community acquired K. pneumoniae pneumonia is still common in Asia and is reportedly associated with alcohol use. Oropharyngeal carriage of K. pneumoniae could potentially play a role in the pathogenesis of K. pneumoniae pneumonia. However, little is known regarding K. pneumoniae oropharyngeal carriage rates and risk factors. This population-based cross-sectional study explores the association of a variety of demographic and socioeconomic factors, as well as alcohol consumption with oropharyngeal carriage of K. pneumoniae in Vietnam. METHODS AND FINDINGS: 1029 subjects were selected randomly from age, sex, and urban and rural strata. An additional 613 adult men from a rural environment were recruited and analyzed separately to determine the effects of alcohol consumption. Demographic, socioeconomic, and oropharyngeal carriage data was acquired for each subject. The overall carriage rate of K. pneumoniae was 14.1% (145/1029, 95% CI 12.0%-16.2%). By stepwise logistic regression, K. pneumoniae carriage was found to be independently associated with age (OR 1.03, 95% CI 1.02-1.04), smoking (OR 1.9, 95% CI 1.3-2.9), rural living location (OR 1.6, 95% CI 1.1-2.4), and level of weekly alcohol consumption (OR 1.7, 95% CI 1.04-2.8). CONCLUSION: Moderate to heavy weekly alcohol consumption, old age, smoking, and living in a rural location are all found to be associated with an increased risk of K. pneumoniae carriage in Vietnamese communities. Whether K. pneumoniae carriage is a risk factor for pneumonia needs to be elucidated.

Le VT, de Jong MD, Nguyen VK, Nguyen VT, Taylor W, Wertheim HF, van der Ende A, van der Hoek L, Canuti M, Crusat M et al. 2014. Limited geographic distribution of the novel cyclovirus CyCV-VN. Sci Rep, 4 (1), pp. 3967. | Show Abstract | Read more

A novel cyclovirus, CyCV-VN, was recently identified in cerebrospinal fluid (CSF) from patients with central nervous system (CNS) infections in central and southern Vietnam. To explore the geographic distribution of this novel virus, more than 600 CSF specimens from patients with suspected CNS infections in northern Vietnam, Cambodia, Nepal and The Netherlands were screened for the presence of CyCV-VN but all were negative. Sequence comparison and phylogenetic analysis between CyCV-VN and another novel cyclovirus recently identified in CSF from Malawian patients indicated that these represent distinct cycloviral species, albeit phylogenetically closely related. The data suggest that CyCV-VN has a limited geographic distribution within southern and central Vietnam. Further research is needed to determine the global distribution and diversity of cycloviruses and importantly their possible association with human disease.

Nguyen KV, Thi Do NT, Chandna A, Nguyen TV, Pham CV, Doan PM, Nguyen AQ, Thi Nguyen CK, Larsson M, Escalante S et al. 2013. Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam. BMC Public Health, 13 (1), pp. 1158. | Show Abstract | Read more

BACKGROUND: Antimicrobial resistance is a major contemporary public health threat. Strategies to contain antimicrobial resistance have been comprehensively set forth, however in developing countries where the need for effective antimicrobials is greatest implementation has proved problematic. A better understanding of patterns and determinants of antibiotic use and resistance in emerging economies may permit more appropriately targeted interventions.Viet Nam, with a large population, high burden of infectious disease and relatively unrestricted access to medication, is an excellent case study of the difficulties faced by emerging economies in controlling antimicrobial resistance. METHODS: Our working group conducted a situation analysis of the current patterns and determinants of antibiotic use and resistance in Viet Nam. International publications and local reports published between 1-1-1990 and 31-8-2012 were reviewed. All stakeholders analyzed the findings at a policy workshop and feasible recommendations were suggested to improve antibiotic use in Viet Nam.Here we report the results of our situation analysis focusing on: the healthcare system, drug regulation and supply; antibiotic resistance and infection control; and agricultural antibiotic use. RESULTS: Market reforms have improved healthcare access in Viet Nam and contributed to better health outcomes. However, increased accessibility has been accompanied by injudicious antibiotic use in hospitals and the community, with predictable escalation in bacterial resistance. Prescribing practices are poor and self-medication is common - often being the most affordable way to access healthcare. Many policies exist to regulate antibiotic use but enforcement is insufficient or lacking.Pneumococcal penicillin-resistance rates are the highest in Asia and carbapenem-resistant bacteria (notably NDM-1) have recently emerged. Hospital acquired infections, predominantly with multi-drug resistant Gram-negative organisms, place additional strain on limited resources. Widespread agricultural antibiotic use further propagates antimicrobial resistance. CONCLUSIONS: Future legislation regarding antibiotic access must alter incentives for purchasers and providers and ensure effective enforcement. The Ministry of Health recently initiated a national action plan and approved a multicenter health improvement project to strengthen national capacity for antimicrobial stewardship in Viet Nam. This analysis provided important input to these initiatives. Our methodologies and findings may be of use to others across the world tackling the growing threat of antibiotic resistance.

Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H et al. 2013. Antibiotic resistance-the need for global solutions. Lancet Infect Dis, 13 (12), pp. 1057-1098. | Show Abstract | Read more

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

Le MQ, Horby P, Fox A, Nguyen HT, Le Nguyen HK, Hoang PM, Nguyen KC, de Jong MD, Jeeninga RE, Rogier van Doorn H et al. 2013. Subclinical avian influenza A(H5N1) virus infection in human, Vietnam. Emerg Infect Dis, 19 (10), pp. 1674-1677. | Show Abstract | Read more

Laboratory-confirmed cases of subclinical infection with avian influenza A(H5N1) virus in humans are rare, and the true number of these cases is unknown. We describe the identification of a laboratory-confirmed subclinical case in a woman during an influenza A(H5N1) contact investigation in northern Vietnam.

Quaglia A, Karlsson M, Larsson M, Taylor WR, Diep NT, Trinh DT, Trung NV, Van Kinh N, Wertheim HF. 2013. Total lactate dehydrogenase in cerebrospinal fluid for identification of bacterial meningitis. J Med Microbiol, 62 (Pt 11), pp. 1772-1773. | Read more

South East Asia Infectious Disease Clinical Research Network. 2013. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ, 346 (may30 2), pp. f3039. | Show Abstract | Read more

OBJECTIVE: To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. DESIGN: Double blind randomised trial. SETTING: Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. PARTICIPANTS: Patients aged ≥ 1 year admitted to hospital with confirmed severe influenza. INTERVENTIONS: Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). MAIN OUTCOME MEASURE: Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. RESULTS: Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found. CONCLUSIONS: There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital. REGISTRATION: Clinical Trials NCT00298233.

Limmathurotsakul D, Dance DA, Wuthiekanun V, Kaestli M, Mayo M, Warner J, Wagner DM, Tuanyok A, Wertheim H, Yoke Cheng T et al. 2013. Systematic review and consensus guidelines for environmental sampling of Burkholderia pseudomallei. PLoS Negl Trop Dis, 7 (3), pp. e2105. | Show Abstract | Read more

BACKGROUND: Burkholderia pseudomallei, a Tier 1 Select Agent and the cause of melioidosis, is a Gram-negative bacillus present in the environment in many tropical countries. Defining the global pattern of B. pseudomallei distribution underpins efforts to prevent infection, and is dependent upon robust environmental sampling methodology. Our objective was to review the literature on the detection of environmental B. pseudomallei, update the risk map for melioidosis, and propose international consensus guidelines for soil sampling. METHODS/PRINCIPAL FINDINGS: An international working party (Detection of Environmental Burkholderia pseudomallei Working Party (DEBWorP)) was formed during the VIth World Melioidosis Congress in 2010. PubMed (January 1912 to December 2011) was searched using the following MeSH terms: pseudomallei or melioidosis. Bibliographies were hand-searched for secondary references. The reported geographical distribution of B. pseudomallei in the environment was mapped and categorized as definite, probable, or possible. The methodology used for detecting environmental B. pseudomallei was extracted and collated. We found that global coverage was patchy, with a lack of studies in many areas where melioidosis is suspected to occur. The sampling strategies and bacterial identification methods used were highly variable, and not all were robust. We developed consensus guidelines with the goals of reducing the probability of false-negative results, and the provision of affordable and 'low-tech' methodology that is applicable in both developed and developing countries. CONCLUSIONS/SIGNIFICANCE: The proposed consensus guidelines provide the basis for the development of an accurate and comprehensive global map of environmental B. pseudomallei.

Hoa NT, Chieu TT, Do Dung S, Long NT, Hieu TQ, Luc NT, Nhuong PT, Huong VT, Trinh DT, Wertheim HF et al. 2013. Streptococcus suis and porcine reproductive and respiratory syndrome, Vietnam. Emerg Infect Dis, 19 (2), pp. 331-333. | Read more

Tran ST, Renschler JP, Le HT, Dang HT, Dao TM, Pham AN, Nguyen LT, Van Nguyen H, Thi Thu Nguyen T, Ngoc Le S et al. 2013. Diagnostic accuracy of microscopic Observation Drug Susceptibility (MODS) assay for pediatric tuberculosis in Hanoi, Vietnam. PLoS One, 8 (9), pp. e72100. | Show Abstract | Read more

INTRODUCTION: Microscopic [corrected] Observation Drug Susceptibility (MODS) has been shown to be an effective and rapid technique for early diagnosis of tuberculosis (TB). Thus far only a limited number of studies evaluating MODS have been performed in children and in extra-pulmonary tuberculosis. This study aims to assess relative accuracy and time to positive culture of MODS for TB diagnosis in children admitted to a general pediatric hospital in Vietnam. METHODS/PRINCIPAL FINDINGS: Specimens from children with suspected TB were tested by smear, MODS and Lowenstein-Jensen agar (LJ). 1129 samples from 705 children were analyzed, including sputum (n=59), gastric aspirate (n=775), CSF (n=148), pleural fluid (n=33), BAL (n=41), tracheal fluid (n=45), other (n=28). 113 TB cases were defined based on the "clinical diagnosis" (confirmed and probable groups) as the reference standard, in which 26% (n=30) were diagnosed as extra-pulmonary TB. Analysis by patient shows that the overall sensitivity and specificity of smear, LJ and MODS against "clinical diagnosis" was 8.8% and 100%, 38.9% and 100%, 46% and 99.5% respectively with MODS significantly more sensitive than LJ culture (P=0.02). When analyzed by sample type, the sensitivity of MODS was significantly higher than LJ for gastric aspirates (P=0.004). The time to detection was also significantly shorter for MODS than LJ (7 days versus 32 days, P<0.001). CONCLUSION: MODS [corrected] is a sensitive and rapid culture technique for detecting TB in children. As MODS culture can be performed at a BSL2 facility and is inexpensive, it can therefore be recommended as a routine test for children with symptoms suggestive of TB in resource-limited settings.

Wertheim H, Van Nguyen K, Hara GL, Gelband H, Laxminarayan R, Mouton J, Cars O. 2013. Global survey of polymyxin use: A call for international guidelines. J Glob Antimicrob Resist, 1 (3), pp. 131-134. | Show Abstract | Read more

Polymyxins (polymyxin B and colistin) are older bactericidal antibiotics that are increasingly used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacteria. However, dosing and clinical use of these drugs vary widely. This survey was undertaken to reveal how polymyxins are used worldwide. Data were collected through a structured online questionnaire consisting of 24 questions regarding colistin usage patterns and indications as well as colistin dosage for adult patients. The questionnaire was disseminated in 2011 to relevant experts worldwide and was completed by 284 respondents from 56 different countries. Respondents from 11/56 countries (20%) had no access to colistin; 58/284 respondents (20.4%) reported that in 2010 they experienced that colistin was not available when needed. Formulations of polymyxins used were reported as: colistimethate sodium (48.6%); colistin sulfate (14.1%); both (1.4%); polymyxin B (1.4%); and unknown. Intravenous formulations were used by 84.2%, aerosolised or nebulised colistin by 44.4% and oral colistin for selective gut decontamination by 12.7%. Common indications for intravenous colistin were ventilator-associated pneumonia, sepsis and catheter-related infections with MDR Gram-negative bacteria. Only 21.2% of respondents used a colistin-loading dose, mainly in Europe and North America. This survey reveals that the majority of respondents use colistin and a few use polymyxin B. The survey results show that colistin is commonly underdosed. Clear guidance is needed on indications, dosing and antibiotic combinations to improve clinical outcomes and delay the emergence of resistance. Colistin should be considered a last-resort drug and its use should be controlled. International guidelines are urgently needed.

Fox A, Hung TM, Wertheim H, Hoa LENM, Vincent A, Lang B, Waters P, Ha NH, Trung NV, Farrar J et al. 2013. Acute measles encephalitis in partially vaccinated adults. PLoS One, 8 (8), pp. e71671. | Show Abstract | Read more

BACKGROUND: The pathogenesis of acute measles encephalitis (AME) is poorly understood. Treatment with immune-modulators is based on theories that post-infectious autoimmune responses cause demyelination. The clinical course and immunological parameters of AME were examined during an outbreak in Vietnam. METHODS AND FINDINGS: Fifteen measles IgM-positive patients with confusion or Glasgow Coma Scale (GCS) score below 13, and thirteen with uncomplicated measles were enrolled from 2008-2010. Standardized clinical exams were performed and blood collected for lymphocyte and measles- and auto-antibody analysis. The median age of AME patients was 21 years, similar to controls. Eleven reported receiving measles vaccination when aged one year. Confusion developed a median of 4 days after rash. Six patients had GCS <8 and four required mechanical ventilation. CSF showed pleocytosis (64%) and proteinorrhachia (71%) but measles virus RNA was not detected. MRI revealed bilateral lesions in the cerebellum and brain stem in some patients. Most received dexamethasone +/- IVIG within 4 days of admission but symptoms persisted for ≥3 weeks in five. The concentration of voltage gated calcium channel-complex-reactive antibodies was 900 pM in one patient, and declined to 609 pM ∼ 3 months later. Measles-reactive IgG antibody avidity was high in AME patients born after vaccine coverage exceeded 50% (∼ 25 years earlier). AME patients had low CD4 (218/µl, p = 0.029) and CD8 (200/µl, p = 0.012) T-cell counts compared to controls. CONCLUSION: Young adults presenting with AME in Vietnam reported a history of one prior measles immunization, and those aged <25 years had high measles-reactive IgG avidity indicative of prior vaccination. This suggests that one-dose measles immunization is not sufficient to prevent AME in young adults and reinforces the importance of maintaining high coverage with a two-dose measles immunization schedule. Treatment with corticosteroids and IVIG is common practice, and should be assessed in randomized clinical trials.

Wertheim HF, Chandna A, Vu PD, Pham CV, Nguyen PD, Lam YM, Nguyen CV, Larsson M, Rydell U, Nilsson LE et al. 2013. Providing impetus, tools, and guidance to strengthen national capacity for antimicrobial stewardship in Viet Nam. PLoS Med, 10 (5), pp. e1001429. | Read more

Dieu Ngan TT, Thomas S, Larsson M, Horby P, Diep NN, Dat VQ, Trung NV, Ha NH, Rogier van Doorn H, Van Kinh N, Wertheim HFL. 2013. First report of human psittacosis in Vietnam Journal of Infection, 66 (5), pp. 461-464. | Read more

Hoa NT, Chieu TTB, Dung SD, Long NT, Hieu TQ, Luc NT, Nhuong PT, Huong VTL, Trinh DT, Wertheim HFL et al. 2013. Streptococcus suis and porcine reproductive and respiratory syndrome, vietnam Emerging Infectious Diseases, 19 (2), pp. 331-333. | Read more

Dieu Ngan TT, Thomas S, Larsson M, Horby P, Diep NN, Dat VQ, Trung NV, Ha NH, Rogier van Doorn H, Van Kinh N, Wertheim HF. 2013. First report of human psittacosis in Vietnam. J Infect, 66 (5), pp. 461-464. | Read more

Hai LET, Bich VT, Ngai LEK, Diep NT, Phuc PH, Hung VP, Taylor WR, Horby P, Liem NT, Wertheim HF. 2012. Fatal respiratory infections associated with rhinovirus outbreak, Vietnam. Emerg Infect Dis, 18 (11), pp. 1886-1888. | Show Abstract | Read more

During an outbreak of severe acute respiratory infections in 2 orphanages, Vietnam, 7/12 hospitalized children died. All hospitalized children and 26/43 children from outbreak orphanages tested positive for rhinovirus versus 9/40 control children (p = 0.0005). Outbreak rhinoviruses formed a distinct genetic cluster. Human rhinovirus is an underappreciated cause of severe pneumonia in vulnerable groups.

Hoang TH, Wertheim H, Minh NB, Duong TN, Anh DD, Phuong TT, Son TH, Izumiya H, Ohnishi M, Shibayama K, Hien NT. 2013. Carbapenem-resistant Escherichia coli and Klebsiella pneumoniae strains containing New Delhi metallo-beta-lactamase isolated from two patients in Vietnam. J Clin Microbiol, 51 (1), pp. 373-374. | Read more

Henk DA, Shahar-Golan R, Devi KR, Boyce KJ, Zhan N, Fedorova ND, Nierman WC, Hsueh PR, Yuen KY, Sieu TP et al. 2012. Clonality despite sex: the evolution of host-associated sexual neighborhoods in the pathogenic fungus Penicillium marneffei. PLoS Pathog, 8 (10), pp. e1002851. | Show Abstract | Read more

Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a sexual cycle is possible, this haploid fungus is thought to be genetically, as well as morphologically, asexual in nature because of its highly clonal population structure. Here we use comparative genomics, experimental mixed-genotype infections, and population genetic data to elucidate the role of recombination in natural populations of P. marneffei. Genome wide comparisons reveal that all the genes required for meiosis are present in P. marneffei, mating type genes are arranged in a similar manner to that found in other heterothallic fungi, and there is evidence of a putatively meiosis-specific mutational process. Experiments suggest that recombination between isolates of compatible mating types may occur during mammal infection. Population genetic data from 34 isolates from bamboo rats in India, Thailand and Vietnam, and 273 isolates from humans in China, India, Thailand, and Vietnam show that recombination is most likely to occur across spatially and genetically limited distances in natural populations resulting in highly clonal population structure yet sexually reproducing populations. Predicted distributions of three different spatial genetic clusters within P. marneffei overlap with three different bamboo rat host distributions suggesting that recombination within hosts may act to maintain population barriers within P. marneffei.

Wertheim HF, Ngoc DM, Wolbers M, Binh TT, Hải NT, Loan NQ, Tú PT, Sjodin A, Romanoff L, Li Z et al. 2012. Studying the effectiveness of activated carbon R95 respirators in reducing the inhalation of combustion by-products in Hanoi, Vietnam: a demonstration study. Environ Health, 11 (1), pp. 72. | Show Abstract | Read more

BACKGROUND: Urban air pollution is an increasing health problem, particularly in Asia, where the combustion of fossil fuels has increased rapidly as a result of industrialization and socio-economic development. The adverse health impacts of urban air pollution are well established, but less is known about effective intervention strategies. In this demonstration study we set out to establish methods to assess whether wearing an R95 activated carbon respirator could reduce intake of polycyclic aromatic hydrocarbons (PAH) in street workers in Hanoi, Vietnam. METHODS: In this demonstration study we performed a cross-over study in which non-smoking participants that worked at least 4 hours per day on the street in Hanoi were randomly allocated to specific respirator wearing sequences for a duration of 2 weeks. Urines were collected after each period, i.e., twice per week, at the end of the working day to measure hydroxy PAHs (OH-PAH) using gas chromatography/high resolution mass spectrometry. The primary endpoint was the urinary concentration of 1-hydroxypyrene (1-OHP). RESULTS: Forty-four participants (54.5% male, median age 40 years) were enrolled with the majority being motorbike taxi drivers (38.6%) or street vendors (34.1%). The baseline creatinine corrected urinary level for 1-OHP was much higher than other international comparisons: 1020 ng/g creatinine (IQR: 604-1551). Wearing a R95 mask had no significant effect on 1-OHP levels: estimated multiplicative effect 1.0 (95% CI: 0.92-1.09) or other OH-PAHs, except 1-hydroxynaphthalene (1-OHN): 0.86 (95% CI: 0.11-0.96). CONCLUSIONS: High levels of urine OH-PAHs were found in Hanoi street workers. No effect was seen on urine OH-PAH levels by wearing R95 particulate respirators in an area of high urban air pollution, except for 1-OHN. A lack of effect may be de to gaseous phase PAHs that were not filtered efficiently by the respirator. The high levels of urinary OH-PAHs found, urges for effective interventions. TRIAL REGISTRATION: ISRCTN74390617 (date of assignation: 04/08/2009).

Gething PW, Elyazar IR, Moyes CL, Smith DL, Battle KE, Guerra CA, Patil AP, Tatem AJ, Howes RE, Myers MF et al. 2012. A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis, 6 (9), pp. e1814. | Show Abstract | Read more

BACKGROUND: Current understanding of the spatial epidemiology and geographical distribution of Plasmodium vivax is far less developed than that for P. falciparum, representing a barrier to rational strategies for control and elimination. Here we present the first systematic effort to map the global endemicity of this hitherto neglected parasite. METHODOLOGY AND FINDINGS: We first updated to the year 2010 our earlier estimate of the geographical limits of P. vivax transmission. Within areas of stable transmission, an assembly of 9,970 geopositioned P. vivax parasite rate (PvPR) surveys collected from 1985 to 2010 were used with a spatiotemporal Bayesian model-based geostatistical approach to estimate endemicity age-standardised to the 1-99 year age range (PvPR(1-99)) within every 5×5 km resolution grid square. The model incorporated data on Duffy negative phenotype frequency to suppress endemicity predictions, particularly in Africa. Endemicity was predicted within a relatively narrow range throughout the endemic world, with the point estimate rarely exceeding 7% PvPR(1-99). The Americas contributed 22% of the global area at risk of P. vivax transmission, but high endemic areas were generally sparsely populated and the region contributed only 6% of the 2.5 billion people at risk (PAR) globally. In Africa, Duffy negativity meant stable transmission was constrained to Madagascar and parts of the Horn, contributing 3.5% of global PAR. Central Asia was home to 82% of global PAR with important high endemic areas coinciding with dense populations particularly in India and Myanmar. South East Asia contained areas of the highest endemicity in Indonesia and Papua New Guinea and contributed 9% of global PAR. CONCLUSIONS AND SIGNIFICANCE: This detailed depiction of spatially varying endemicity is intended to contribute to a much-needed paradigm shift towards geographically stratified and evidence-based planning for P. vivax control and elimination.

Larsson M, Nguyen LH, Wertheim HF, Dao TT, Taylor W, Horby P, Nguyen TV, Nguyen MH, Le T, Nguyen KV. 2012. Clinical characteristics and outcome of Penicillium marneffei infection among HIV-infected patients in northern Vietnam. AIDS Res Ther, 9 (1), pp. 24. | Show Abstract | Read more

OBJECTIVE: This study reports the clinical characteristics and outcome of HIV-associated Penicilliummarneffei infection in northern Vietnam. METHODS: We conducted a retrospective chart review of all patients with laboratory confirmed Penicilliummarneffei infection admitted to the National Hospital for Tropical Diseases in Hanoi, Vietnam, between July 2006 and September 2009. RESULTS: 127 patients with P. marneffei infection were identified. All were HIV-infected; median CD4+ T-cell count was 24 cells/μl (IQR:12-48); 76% were men. Common clinical features were fever (92.9%), skin lesions (82.6%), hepatomegaly (61.4%), lymphadenopathy (40.2%), weight loss (59.1%) and cough (49.6%). Concurrent opportunistic infections were present in 22.0%; half of those had tuberculosis. Initial treatment regimens were: itraconazole or ketoconazole capsule (77.2%), amphotericin B (20.5%), and fluconazole (1.6%). In-hospital mortality was 12.6% and showed no significant difference in patients treated with itraconazole (or ketoconazole) and amphotericin B (p = 0.43). Dyspnea, ascites, and increased LDH level were independent predictors of mortality. No seasonality was observed. CONCLUSION: The clinical features, treatments and outcomes of HIV-associated P. marneffei infection in northern Vietnam are similar to those reported in other endemic regions. Dyspnea was an important predictor of mortality. More patients were treated with itraconazole than amphotericin B and no significant difference in treatment outcome was observed. It would be of clinical value to compare the efficacy of oral itraconazole and amphotericin B in a clinical trial.

Whitehorn J, Rodriguez Roche R, Guzman MG, Martinez E, Gomez WV, Nainggolan L, Laksono IS, Mishra A, Lum L, Faiz A et al. 2012. Prophylactic platelets in dengue: survey responses highlight lack of an evidence base. PLoS Negl Trop Dis, 6 (6), pp. e1716. | Show Abstract | Read more

Dengue is the most important arboviral infection of humans. Thrombocytopenia is frequently observed in the course of infection and haemorrhage may occur in severe disease. The degree of thrombocytopenia correlates with the severity of infection, and may contribute to the risk of haemorrhage. As a result of this prophylactic platelet transfusions are sometimes advocated for the prevention of haemorrhage. There is currently no evidence to support this practice, and platelet transfusions are costly and sometimes harmful. We conducted a global survey to assess the different approaches to the use of platelets in dengue. Respondents were all physicians involved with the treatment of patients with dengue. Respondents were asked that their answers reflected what they would do if they were the treating physician. We received responses from 306 physicians from 20 different countries. The heterogeneity of the responses highlights the variation in clinical practice and lack of an evidence base in this area and underscores the importance of prospective clinical trials to address this key question in the clinical management of patients with dengue.

van Doorn HR, Kinh NV, Tuan HM, Tuan TA, Minh NN, Bryant JE, Hang VT, Uyen LETT, Thinh LEQ, Anh TT et al. 2012. Clinical validation of a point-of-care multiplexed in vitro immunoassay using monoclonal antibodies (the MSD influenza test) in four hospitals in Vietnam. J Clin Microbiol, 50 (5), pp. 1621-1625. | Show Abstract | Read more

Point-of-care (POC) diagnostic tests for influenza can considerably shorten the time to clinical decision making. An investigational POC test based on a multiplexed immunoassay was developed by Meso Scale Diagnostics, LLC (MSD), with the objective to make a more sensitive rapid test that can also subtype influenza A viruses (1977 H1, H3, and H5). Between February and November 2010, we conducted a prospective multicenter study at four hospitals in Vietnam and compared the performance of this test to that of the WHO/CDC real-time reverse transcriptase PCR (RT-PCR) on nasal and throat swab specimens from patients presenting with influenza-like illness. Five hundred sixty-three adults and children with a median age of 25 months were enrolled. Sensitivity and specificity of the test with combined results from nasal and throat swab samples were 74.0% (131/177) and 99.7% (351/352), respectively, compared to RT-PCR. The POC test was as sensitive for influenza virus B as for influenza virus A (74.4% [64/86] versus 73.6% [67/91]). The positivity rate was associated with lower cycle threshold values (a marker for higher viral loads), sample type (73.6% for nasal swab versus 52.4% for throat swab), and younger age. A total of 210 (18.7%) out of 1,126 MSD tests failed, and for 34 (6%) of patients, both test samples failed (these were excluded from the performance analysis). Subtyping could be assessed only for influenza virus A/H3N2, as 1977 H1N1 was not circulating at the time and no H5N1-infected patients were enrolled, and was successful only in 9/54 patients infected with H3 influenza virus who had a positive POC test result for influenza virus A. This novel POC test provided highly sensitive detection of influenza viruses A and B compared to the reported sensitivities of other rapid tests. However, 18.7% of tests failed for technical reasons and subtyping for H3 was poor. Drawbacks to the technology include the requirement for a dedicated reader instrument and the need for continual updating of subtyping antibodies within the test array.

Taylor WR, Nguyen K, Nguyen D, Nguyen H, Horby P, Nguyen HL, Lien T, Tran G, Tran N, Nguyen HM et al. 2012. The spectrum of central nervous system infections in an adult referral hospital in Hanoi, Vietnam. PLoS One, 7 (8), pp. e42099. | Show Abstract | Read more

OBJECTIVES: To determine prospectively the causative pathogens of central nervous system (CNS) infections in patients admitted to a tertiary referral hospital in Hanoi, Vietnam. METHODS: From May 2007 to December 2008, cerebrospinal fluid (CSF) samples from 352 adults with suspected meningitis or encephalitis underwent routine testing, staining (Gram, Ziehl-Nielsen, India ink), bacterial culture and polymerase chain reaction targeting Neisseria meningitidis, Streptococcus pneumoniae, S. suis, Haemophilus influenzae type b, Herpes simplex virus (HSV), Varicella Zoster virus (VZV), enterovirus, and 16S ribosomal RNA. Blood cultures and clinically indicated radiology were also performed. Patients were classified as having confirmed or suspected bacterial (BM), tuberculous (TBM), cryptococcal (CRM), eosinophilic (EOM) meningitis, aseptic encephalitis/meningitis (AEM), neurocysticercosis and others. RESULTS: 352 (male: 66%) patients were recruited: median age 34 years (range 13-85). 95/352 (27.3%) diagnoses were laboratory confirmed and one by cranial radiology: BM (n = 62), TBM (n = 9), AEM (n = 19), CRM (n = 5), and neurocysticercosis (n = 1, cranial radiology). S. suis predominated as the cause of BM [48/62 (77.4%)]; Listeria monocytogenese (n = 1), S. pasteurianus (n = 1) and N. meningitidis (n = 2) were infrequent. AEM viruses were: HSV (n = 12), VZV (n = 5) and enterovirus (n = 2). 5 patients had EOM. Of 262/352 (74.4%) patients with full clinical data, 209 (79.8%) were hospital referrals and 186 (71%) had been on antimicrobials. 21 (8%) patients died: TBM (15.2%), AEM (10%), and BM (2.8%). CONCLUSIONS: Most infections lacked microbiological confirmation. S. suis was the most common cause of BM in this setting. Improved diagnostics are needed for meningoencephalitic syndromes to inform treatment and prevention strategies.

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Tran HD, Alam M, vu Trung N, van Kinh N, Nguyen HH, Pham VC, Ansaruzzaman M, Rashed SM, Bhuiyan NA, Dao TT et al. 2012. Multi-drug resistant vibrio cholerae O1 variant El Tor isolated in northern Vietnam between 2007 and 2010 Journal of Medical Microbiology, 61 (3), pp. 431-437. | Read more

Fox A, Le NM, Horby P, van Doorn HR, Nguyen VT, Nguyen HH, Nguyen TC, Vu DP, Nguyen MH, Diep NT et al. 2012. Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses. PLoS One, 7 (2), pp. e31535. | Show Abstract | Read more

BACKGROUND: It is unclear why the severity of influenza varies in healthy adults or why the burden of severe influenza shifts to young adults when pandemic strains emerge. One possibility is that cross-protective T cell responses wane in this age group in the absence of recent infection. We therefore compared the acute cellular immune response in previously healthy adults with severe versus mild pandemic H1N1 infection. METHODS AND PRINCIPAL FINDINGS: 49 previously healthy adults admitted to the National Hospital of Tropical Diseases, Viet Nam with RT-PCR-confirmed 2009 H1N1 infection were prospectively enrolled. 39 recovered quickly whereas 10 developed severe symptoms requiring supplemental oxygen and prolonged hospitalization. Peripheral blood lymphocyte subset counts and activation (HLADR, CD38) and differentiation (CD27, CD28) marker expression were determined on days 0, 2, 5, 10, 14 and 28 by flow cytometry. NK, CD4 and CD8 lymphopenia developed in 100%, 90% and 60% of severe cases versus 13% (p<0.001), 28%, (p = 0.001) and 18% (p = 0.014) of mild cases. CD4 and NK counts normalized following recovery. B cell counts were not significantly associated with severity. CD8 activation peaked 6-8 days after mild influenza onset, when 13% (6-22%) were HLADR+CD38+, and was accompanied by a significant loss of resting/CD27+CD28+ cells without accumulation of CD27+CD28- or CD27-CD28- cells. In severe influenza CD8 activation peaked more than 9 days post-onset, and/or was excessive (30-90% HLADR+CD38+) in association with accumulation of CD27+CD28- cells and maintenance of CD8 counts. CONCLUSION: Severe influenza is associated with transient T and NK cell deficiency. CD8 phenotype changes during mild influenza are consistent with a rapidly resolving memory response whereas in severe influenza activation is either delayed or excessive, and partially differentiated cells accumulate within blood indicating that recruitment of effector cells to the lung could be impaired.

Tran HD, Alam M, Trung NV, Kinh NV, Nguyen HH, Pham VC, Ansaruzzaman M, Rashed SM, Bhuiyan NA, Dao TT et al. 2012. Multi-drug resistant Vibrio cholerae O1 variant El Tor isolated in northern Vietnam between 2007 and 2010. J Med Microbiol, 61 (Pt 3), pp. 431-437. | Show Abstract | Read more

Since 2007, there has been a re-emergence of cholera outbreaks in northern Vietnam. To understand the molecular epidemiological relatedness and determine the antibiotic susceptibility profiles of responsible V. cholerae O1 outbreak strains, a representative collection of 100 V. cholerae O1 strains was characterized. V. cholerae O1 strains isolated from diarrhoeal patients in northern Vietnam between 2007 and 2010 were investigated for antibiotic susceptibility and characterized by using phenotypic and genotypic tests, including PFGE analysis. Ten clinical V. cholerae O1 isolates from Bangladesh and Zimbabwe were included for comparison. The results revealed that all isolates were resistant to co-trimoxazole and nalidixic acid, 29 % were resistant to tetracycline and 1 % were resistant to azithromycin. All strains were susceptible to ampicillin-sulbactam, doxycycline, chloramphenicol and ciprofloxacin and 95 % were susceptible to azithromycin. MIC values did show reduced susceptibility to fluoroquinolones and 63 % of the strains were intermediately resistant to tetracycline. The isolates expressed phenotypic traits of both serogroup O1 Ogawa and El Tor and harboured an rstR El Tor and ctxB classical biotype. Among the outbreak isolates, only a single PFGE pattern was observed throughout the study period. This study shows that multi-drug resistant V. cholerae altered El Tor producing classical CT strains are now predominant in northern Vietnam.

Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, Kirby A, Tilley R, Török ME, Walker S, Wertheim HF, Wilson P, Llewelyn MJ, UK Clinical Infection Research Group. 2011. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis, 11 (3), pp. 208-222. | Show Abstract | Read more

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.

Amábile-Cuevas CF. 2011. “Ten commandments” for the appropriate use of antibiotics by the practicing physician in an outpatient setting Frontiers in Microbiology, 2 (NOV), | Read more

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Bode LGM, Wertheim HFL, Kluytmans JAJW, Bogaers-Hofman D, Vandenbroucke-Grauls CMJE, Roosendaal R, Troelstra A, Box ATA, Voss A, van Belkum A et al. 2011. Sustained low prevalence of meticillin-resistant Staphylococcus aureus upon admission to hospital in The Netherlands Journal of Hospital Infection, 79 (3), pp. 198-201. | Read more

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Manh BH, Clements ACA, Thieu NQ, Hung NM, Hung LX, Hay SI, Hien TT, Wertheim HFL, Snow RW, Horby P. 2011. Social and environmental determinants of malaria in space and time in Viet Nam International Journal for Parasitology, 41 (1), pp. 109-116. | Read more

Fox A, Le NM, Simmons CP, Wolbers M, Wertheim HF, Pham TK, Tran TH, Trinh TM, Nguyen TL, Nguyen VT et al. 2011. Immunological and viral determinants of dengue severity in hospitalized adults in Ha Noi, Viet Nam. PLoS Negl Trop Dis, 5 (3), pp. e967. | Show Abstract | Read more

BACKGROUND: The relationships between the infecting dengue serotype, primary and secondary infection, viremia and dengue severity remain unclear. This cross-sectional study examined these interactions in adult patients hospitalized with dengue in Ha Noi. METHODS AND FINDINGS: 158 patients were enrolled between September 16 and November 11, 2008. Quantitative RT-PCR, serology and NS1 detection were used to confirm dengue infection, determine the serotype and plasma viral RNA concentration, and categorize infections as primary or secondary. 130 (82%) were laboratory confirmed. Serology was consistent with primary and secondary infection in 34% and 61%, respectively. The infecting serotype was DENV-1 in 42 (32%), DENV-2 in 39 (30%) and unknown in 49 (38%). Secondary infection was more common in DENV-2 infections (79%) compared to DENV-1 (36%, p<0.001). The proportion that developed dengue haemorrhagic fever (DHF) was 32% for secondary infection compared to 18% for primary infection (p = 0.14), and 26% for DENV-1 compared to 28% for DENV-2. The time until NS1 and plasma viral RNA were undetectable was shorter for DENV-2 compared to DENV-1 (p≤0.001) and plasma viral RNA concentration on day 5 was higher for DENV-1 (p = 0.03). Plasma viral RNA concentration was higher in secondary infection on day 5 of illness (p = 0.046). We didn't find an association between plasma viral RNA concentration and clinical severity. CONCLUSION: Dengue is emerging as a major public health problem in Ha Noi. DENV-1 and DENV-2 were the prevalent serotypes with similar numbers and clinical presentation. Secondary infection may be more common amongst DENV-2 than DENV-1 infections because DENV-2 infections resulted in lower plasma viral RNA concentrations and viral RNA concentrations were higher in secondary infection. The drivers of dengue emergence in northern Viet Nam need to be elucidated and public health measures instituted.

Bui HM, Clements AC, Nguyen QT, Nguyen MH, Le XH, Hay SI, Tran TH, Wertheim HF, Snow RW, Horby P. 2011. Social and environmental determinants of malaria in space and time in Viet Nam. Int J Parasitol, 41 (1), pp. 109-116. | Show Abstract | Read more

The malaria burden in Viet Nam has been in decline in recent decades, but localised areas of high transmission remain. We used spatiotemporal analytical tools to determine the social and environmental drivers of malaria risk and to identify residual high-risk areas where control and surveillance resources can be targeted. Counts of reported Plasmodium falciparum and Plasmodium vivax malaria cases by month (January 2007-December 2008) and by district were assembled. Zero-inflated Poisson regression models were developed in a bayesian framework. Models had the percentage of the district's population living below the poverty line, percent of the district covered by forest, median elevation, median long-term average precipitation, and minimum temperature included as fixed effects, and terms for temporal trend and residual district-level spatial autocorrelation. Strong temporal and spatial heterogeneity in counts of malaria cases was apparent. Poverty and forest cover were significantly associated with an increased count of malaria cases but the magnitude and direction of associations between climate and malaria varied by socio-ecological zone. There was a declining trend in counts of malaria cases during the study period. After accounting for the social and environmental fixed effects, substantial spatial heterogeneity was still evident. Unmeasured factors which may contribute to this residual variation include malaria control activities, population migration and accessibility to health care. Forest-related activities and factors encompassed by poverty indicators are major drivers of malaria incidence in Viet Nam.

Wertheim HF, Horby P, Viet TL, Tanh TNT, Woodall J. 2010. The making of a world atlas of infectious diseases INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 14 pp. E282-E283. | Read more

van Trijp MJ, Melles DC, Snijders SV, Wertheim HF, Verbrugh HA, van Belkum A, van Wamel WJ. 2010. Genotypes, superantigen gene profiles, and presence of exfoliative toxin genes in clinical methicillin-susceptible Staphylococcus aureus isolates. Diagn Microbiol Infect Dis, 66 (2), pp. 222-224. | Show Abstract | Read more

We compared genotype and virulence gene profiles for strains from carriers with autologous invasive infection (n = 56), nasal isolates from matched carriers (n = 108), and invasive strains from noncarriers (n = 34). Superantigen gene profiles and presence of exfoliative toxin genes A and D were associated with clonal complex rather than with invasive disease.

Bode LG, Kluytmans JA, Wertheim HF, Bogaers D, Vandenbroucke-Grauls CM, Roosendaal R, Troelstra A, Box AT, Voss A, van der Tweel I et al. 2010. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med, 362 (1), pp. 9-17. | Show Abstract | Read more

BACKGROUND: Nasal carriers of Staphylococcus aureus are at increased risk for health care-associated infections with this organism. Decolonization of nasal and extranasal sites on hospital admission may reduce this risk. METHODS: In a randomized, double-blind, placebo-controlled, multicenter trial, we assessed whether rapid identification of S. aureus nasal carriers by means of a real-time polymerase-chain-reaction (PCR) assay, followed by treatment with mupirocin nasal ointment and chlorhexidine soap, reduces the risk of hospital-associated S. aureus infection. RESULTS: From October 2005 through June 2007, a total of 6771 patients were screened on admission. A total of 1270 nasal swabs from 1251 patients were positive for S. aureus. We enrolled 917 of these patients in the intention-to-treat analysis, of whom 808 (88.1%) underwent a surgical procedure. All the S. aureus strains identified on PCR assay were susceptible to methicillin and mupirocin. The rate of S. aureus infection was 3.4% (17 of 504 patients) in the mupirocin-chlorhexidine group, as compared with 7.7% (32 of 413 patients) in the placebo group (relative risk of infection, 0.42; 95% confidence interval [CI], 0.23 to 0.75). The effect of mupirocin-chlorhexidine treatment was most pronounced for deep surgical-site infections (relative risk, 0.21; 95% CI, 0.07 to 0.62). There was no significant difference in all-cause in-hospital mortality between the two groups. The time to the onset of nosocomial infection was shorter in the placebo group than in the mupirocin-chlorhexidine group (P=0.005). CONCLUSIONS: The number of surgical-site S. aureus infections acquired in the hospital can be reduced by rapid screening and decolonizing of nasal carriers of S. aureus on admission. (Current Controlled Trials number, ISRCTN56186788.)

Le QM, Wertheim HF, Tran ND, van Doorn HR, Nguyen TH, Horby P, Vietnam H1N1 Investigation Team. 2010. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med, 362 (1), pp. 86-87. | Read more

Wertheim HF, Puthavathana P, Nghiem NM, van Doorn HR, Nguyen TV, Pham HV, Subekti D, Harun S, Malik S, Robinson J et al. 2010. Laboratory capacity building in Asia for infectious disease research: experiences from the South East Asia Infectious Disease Clinical Research Network (SEAICRN). PLoS Med, 7 (4), pp. e1000231. | Read more

Fox A, Horby P, Ha NH, Hoa LENM, Lam NT, Simmons C, Farrar J, Van Kinh N, Wertheim H. 2010. Influenza A H5N1 and HIV co-infection: case report. BMC Infect Dis, 10 (1), pp. 167. | Show Abstract | Read more

BACKGROUND: The role of adaptive immunity in severe influenza is poorly understood. The occurrence of influenza A/H5N1 in a patient with HIV provided a rare opportunity to investigate this. CASE PRESENTATION: A 30-year-old male was admitted on day 4 of influenza-like-illness with tachycardia, tachypnea, hypoxemia and bilateral pulmonary infiltrates. Influenza A/H5N1 and HIV tests were positive and the patient was treated with Oseltamivir and broad-spectrum antibiotics. Initially his condition improved coinciding with virus clearance by day 6. He clinically deteriorated as of day 10 with fever recrudescence and increasing neutrophil counts and died on day 16. His admission CD4 count was 100/microl and decreased until virus was cleared. CD8 T cells shifted to a CD27+CD28- phenotype. Plasma chemokine and cytokine levels were similar to those found previously in fatal H5N1. CONCLUSIONS: The course of H5N1 infection was not notably different from other cases. Virus was cleared despite profound CD4 T cell depletion and aberrant CD8 T cell activation but this may have increased susceptibility to a fatal secondary infection.

Thanh TT, Pawestri HA, Ngoc NM, Hien VM, Syahrial H, Trung NV, van Doorn RH, Wertheim HF, Chau NV, Ha do Q et al. 2010. A real-time RT-PCR for detection of clade 1 and 2 H5N1 influenza A virus using locked nucleic acid (LNA) TaqMan probes. Virol J, 7 (1), pp. 46. | Show Abstract | Read more

BACKGROUND: The emergence and co-circulation of two different clades (clade 1 and 2) of H5N1 influenza viruses in Vietnam necessitates the availability of a diagnostic assay that can detect both variants. RESULTS: We developed a single real-time RT-PCR assay for detection of both clades of H5N1 viruses, directly from clinical specimens, using locked nucleic acid TaqMan probes. Primers and probe used in this assay were designed based on a highly conserved region in the HA gene of H5N1 viruses. The analytical sensitivity of the assay was < 0.5 PFU and 10-100 ssDNA plasmid copies. A total of 106 clinical samples (58 from patients infected with clade 1, 2.1 or 2.3 H5N1 viruses and 48 from uninfected or seasonal influenza A virus-infected individuals) were tested by the assay. The assay showed 97% concordance with initial diagnostics for H5 influenza virus infection with a specificity of 100%. CONCLUSIONS: This assay is a useful tool for diagnosis of H5N1 virus infections in regions where different genetic clades are co-circulating.

Taylor WR, Burhan E, Wertheim H, Soepandi PZ, Horby P, Fox A, Benamore R, de Simone L, Hien TT, Chappuis F. 2010. Avian influenza--a review for doctors in travel medicine. Travel Med Infect Dis, 8 (1), pp. 1-12. | Show Abstract | Read more

First identified in humans in Hong Kong, influenza A/H5N1, known commonly as avian influenza, has caused human disease in 15 countries around the world. Although the current number of confirmed patients is tiny compared to seasonal and the recently emerged H1N1 'swine' influenza, H5N1 remains a candidate for the next highly pathogenic influenza pandemic. Currently, H5N1 has very limited ability to spread from person-to-person but this may change because of mutation or reassortment with other influenza viruses leading to an influenza pandemic with high mortality. If this occurs travellers are likely to be affected and travel medicine doctors will need to consider avian influenza in returning febrile travellers. The early clinical features may be dismissed easily as 'the flu' resulting in delayed treatment. Treatment options are limited. Oral oseltamivir alone has been the most commonly used drug but mortality remains substantial, up to 80% in Indonesia. Intravenous peramivir has been filed for registration and IV zanamivir is being developed. This review will focus on the epidemiological and clinical features of influenza A/H5N1 avian influenza and will highlight aspects relevant to travel medicine doctors.

Horby P, Wertheim H, Ha NH, Trung NV, Trinh DT, Taylor W, Ha NM, Lien TT, Farrar J, Van Kinh N. 2010. Stimulating the development of national Streptococcus suis guidelines in Viet Nam through a strategic research partnership. Bull World Health Organ, 88 (6), pp. 458-461. | Show Abstract | Read more

PROBLEM: Streptococcus suis is a common cause of adult bacterial meningitis in Viet Nam, and possibly other parts of Asia, yet this disabling infection has been largely neglected. Prevention, diagnosis and treatment are relatively straightforward and affordable but, in early 2007, no national diagnostic, case management or prevention guidelines existed in Viet Nam. APPROACH: Enhanced detection of S. suis infections was established in 2007 as part of a collaborative research programme between the National Hospital for Tropical Diseases, a key national hospital with very close links to the Ministry of Health, and a research group affiliated with Oxford University based in Viet Nam. The results were reported directly to policy-makers at the Ministry of Health. LOCAL SETTING: Viet Nam is a low-income country with a health-care system that has seen considerable improvements and increased autonomy. However, parts of the system remain fairly centralized the Ministry of Health. RELEVANT CHANGES: Following the improved detection and reporting of S. suis cases, the Ministry of Health issued guidance to all hospitals in Viet Nam on the clinical and laboratory diagnosis, treatment and prevention of S. suis. A public health laboratory diagnostic service was established at the National Institute of Hygiene and Epidemiology and training courses were conducted for clinicians and microbiologists. Ministry of Health guidance on surveillance and control of communicable diseases was updated to include a section on S. suis. LESSONS LEARNT: Research collaborations can efficiently inform and influence national responses if they are well positioned to reach policy-makers.

Holtfreter S, Nguyen TT, Wertheim H, Steil L, Kusch H, Truong QP, Engelmann S, Hecker M, Völker U, van Belkum A, Bröker BM. 2009. Human immune proteome in experimental colonization with Staphylococcus aureus. Clin Vaccine Immunol, 16 (11), pp. 1607-1614. | Show Abstract | Read more

More than 20% of adults are persistently colonized with Staphylococcus aureus. When hospitalized, these carriers have increased risks of infection with their own strains. However, a recent study demonstrated a lower incidence of bacteremia-related death among carriers than among noncarriers, raising the question whether the adaptive immune system plays a protective role. In fact, S. aureus carriers mount a highly specific neutralizing antibody response against superantigens of their colonizing strains. We now used 2-dimensional immunoblotting to investigate the profiles of antibodies from healthy individuals against S. aureus extracellular proteins. Moreover, we tested whether symptom-free experimental colonization of these individuals with an S. aureus strain of low virulence, 8325-4, is sufficient to induce an antibody response. Sera obtained before and 4 weeks after colonization were screened for immunoglobulin G (IgG) antibody binding to extracellular staphylococcal proteins. At baseline, most volunteers harbored IgG directed against conserved virulence factors, including alpha-hemolysin (Hla), beta-hemolysin (Hlb), phospholipase C (Plc), staphylococcal serine protease (SspA), and cysteine protease (SspB). However, the variability of spot patterns and intensities was striking and could be important in case of infection. Experimental nasal colonization with S. aureus 8325-4 did not elicit new antibodies or boost the humoral response. Thus, the high antibody prevalence in humans is likely not induced by short-term nasal colonization, and presumably minor infections are required to trigger anti-S. aureus antibody responses.

Taylor WR, Tran GV, Nguyen TQ, Dang DV, Nguyen VK, Nguyen CT, Nguyen LT, Luong CQ, Scott T, Dang TC et al. 2009. Acute febrile myalgia in Vietnam due to trichinellosis following the consumption of raw pork. Clin Infect Dis, 49 (7), pp. e79-e83. | Show Abstract | Read more

Trichinellosis outbreaks occur occasionally in Vietnam following the consumption of undercooked pork. Diagnosing trichinella can be problematic because fever and myalgia are nonspecific, and diagnosis may be delayed. We describe 5 Vietnamese patients in whom trichinellosis was diagnosed after several weeks of illness.

Wertheim HFL, Farrar J, Horby P. 2009. Medicine and the Media Online video sharing and patients' privacy BRITISH MEDICAL JOURNAL, 339 (sep30 2), pp. b3991-b3991. | Read more

Holtfreter S, Kolata J, Bode L, Nguyen TTH, Wertheim H, Steil L, Kusch H, Truong QP, Engelmann S, Hecker M et al. 2009. The human antibody response to S. aureus colonization and sepsis INFECTION, 37 pp. 36-36.

Liem NT, Tung CV, Hien ND, Hien TT, Chau NQ, Long HT, Hien NT, Mai LEQ, Taylor WR, Wertheim H et al. 2009. Clinical features of human influenza A (H5N1) infection in Vietnam: 2004-2006. Clin Infect Dis, 48 (12), pp. 1639-1646. | Show Abstract | Read more

BACKGROUND: The first cases of avian influenza A (H5N1) in humans in Vietnam were detected in early 2004, and Vietnam has reported the second highest number of cases globally. METHODS: We obtained retrospective clinical data through review of medical records for laboratory confirmed cases of influenza A (H5N1) infection diagnosed in Vietnam from January 2004 through December 2006. Standard data was abstracted regarding clinical and laboratory features, treatment, and outcome. RESULTS: Data were obtained for 67 (72%) of 93 cases diagnosed in Vietnam over the study period. Patients presented to the hospital after a median duration of illness of 6 days with fever (75%), cough (89%), and dyspnea (81%). Diarrhea and mucosal bleeding at presentation were more common in fatal than in nonfatal cases. Common findings were bilateral pulmonary infiltrates on chest radiograph (72%), lymphopenia (73%), and increased serum transaminase levels (aspartate aminotransferase, 69%; alanine aminotransferase, 61%). Twenty-six patients died (case fatality rate, 39%; 95% confidence interval, 27%-51%) and the most reliable predictor of a fatal outcome was the presence of both neutropenia and raised alanine aminotransferase level at admission, which correctly predicted 91% of deaths and 82% of survivals. The risk of death was higher among persons aged < or =16 years, compared with older persons (P < .001), and the risk of death was higher among patients who did not receive oseltamivir treatment (P = .048). The benefit of oseltamivir treatment remained after controlling for potential confounding by 1 measure of severity (odds ratio, 0.15; 95% confidence interval, 0.026-0.893; P = .034). CONCLUSION: In cases of infection with Influenza A (H5N1), the presence of both neutropenia and raised serum transaminase levels predicts a poor outcome. Oseltamivir treatment shows benefit, but treatment with corticosteroids is associated with an increased risk of death.

van Belkum A, Verkaik NJ, de Vogel CP, Boelens HA, Verveer J, Nouwen JL, Verbrugh HA, Wertheim HF. 2009. Reclassification of Staphylococcus aureus nasal carriage types. J Infect Dis, 199 (12), pp. 1820-1826. | Show Abstract | Read more

BACKGROUND: Persistent nasal carriers have an increased risk of Staphylococcus aureus infection, whereas intermittent carriers and noncarriers share the same low risk. This study was performed to provide additional insight into staphylococcal carriage types. METHODS: Fifty-one volunteers who had been decolonized with mupirocin treatment and whose carriage state was known were colonized artificially with a mixture of S. aureus strains, and intranasal survival of S. aureus was compared between carriage groups. Antistaphylococcal antibody levels were also compared among 83 carriage-classified volunteers. RESULTS: Persistent carriers preferentially reselected their autologous strain from the inoculum mixture (P=.02). They could be distinguished from intermittent carriers and noncarriers on the basis of the duration of postinoculation carriage (154 vs. 14 and 4 days, respectively; P=.017, by log-rank test). Cultures of swab samples from persistent carriers contained significantly more colony-forming units per sample than did cultures of swab samples from intermittent carriers and noncarriers (P=.004). Analysis of serum samples showed that levels of immunoglobulin G and immunoglobulin A to 17 S. aureus antigens were equal in intermittent carriers and noncarriers but not in persistent carriers. CONCLUSIONS: Along with the previously described low risk of infection, intermittent carriers and noncarriers share similar S. aureus nasal elimination kinetics and antistaphylococcal antibody profiles. This implies a paradigm shift; apparently, there are only 2 types of nasal carriers: persistent carriers and others. This knowledge may increase our understanding of susceptibility to S. aureus infection.

Ammerlaan HS, Kluytmans JA, Wertheim HF, Nouwen JL, Bonten MJ. 2009. Eradication of methicillin-resistant Staphylococcus aureus carriage: a systematic review. Clin Infect Dis, 48 (7), pp. 922-930. | Show Abstract | Read more

A systematic review was performed to determine the effectiveness of different approaches for eradicating methicillin-resistant Staphylococcus aureus carriage. Twenty-three clinical trials were selected that evaluated oral antibiotics (7 trials), topically applied antibiotics (12 trials), or both (4 trials). Because of clinical heterogeneity, quantitative analysis of all studies was deemed to be inappropriate, and exploratory subgroup analyses were performed for studies with similar study populations, methods, and targeted bacteria. The estimated pooled relative risk of treatment failure 1 week after short-term nasal mupirocin treatment, compared with placebo, was 0.10 (range, 0.07-0.14). There was low heterogeneity between study outcomes, and effects were similar for patients and healthy subjects, as well as in studies that included only methicillin-susceptible S. aureus carriers or both methicillin-susceptible S. aureus and methicillin-resistant S. aureus carriers. The development of drug resistance during treatment was reported in 1% and 9% of patients receiving mupirocin and oral antibiotics, respectively. Short-term nasal application of mupirocin is the most effective treatment for eradicating methicillin-resistant S. aureus carriage, with an estimated success of rate of 90% 1 week after treatment and approximately 60% after a longer follow-up period.

Wertheim HF, Nguyen TQ, Nguyen KA, de Jong MD, Taylor WR, Le TV, Nguyen HH, Nguyen HT, Farrar J, Horby P, Nguyen HD. 2009. Furious rabies after an atypical exposure. PLoS Med, 6 (3), pp. e44. | Read more

Wertheim HF, Nghia HD, Taylor W, Schultsz C. 2009. Streptococcus suis: an emerging human pathogen. Clin Infect Dis, 48 (5), pp. 617-625. | Show Abstract | Read more

Streptococcus suis infection is acquired through exposure to contaminated pigs or pig meat. Over the past few years, the number of reported S. suis infections in humans has increased significantly, with most cases originating in Southeast Asia, where there is a high density of pigs. Increased awareness, improved diagnostics, and the occurrence of outbreaks have contributed to this increase. Meningitis and sepsis are the most common clinical manifestations of S. suis infection; hearing loss is a frequent complication. In this article, we provide an overview of the emergence and clinical manifestations of S. suis infection.

Wertheim HF, Nguyen HN, Taylor W, Lien TT, Ngo HT, Nguyen TQ, Nguyen BN, Nguyen HH, Nguyen HM, Nguyen CT et al. 2009. Streptococcus suis, an important cause of adult bacterial meningitis in northern Vietnam. PLoS One, 4 (6), pp. e5973. | Show Abstract | Read more

BACKGROUND: Streptococcus suis can cause severe systemic infection in adults exposed to infected pigs or after consumption of undercooked pig products. S. suis is often misdiagnosed, due to lack of awareness and improper testing. Here we report the first fifty cases diagnosed with S. suis infection in northern Viet Nam. METHODOLOGY/PRINCIPAL FINDINGS: In 2007, diagnostics for S. suis were set up at a national hospital in Hanoi. That year there were 43 S. suis positive cerebrospinal fluid samples, of which S. suis could be cultured in 32 cases and 11 cases were only positive by PCR. Seven patients were blood culture positive for S. suis but CSF culture and PCR negative; making a total of 50 patients with laboratory confirmed S. suis infection in 2007. The number of S. suis cases peaked during the warmer months. CONCLUSIONS/SIGNIFICANCE: S. suis was commonly diagnosed as a cause of bacterial meningitis in adults in northern Viet Nam. In countries where there is intense and widespread exposure of humans to pigs, S. suis can be an important human pathogen.

Wertheim HF, Farrar J, Horby P. 2009. Online video sharing and patients' privacy. BMJ, 339 pp. b3991. | Read more

van Belkum A, Melles DC, Nouwen J, van Leeuwen WB, van Wamel W, Vos MC, Wertheim HF, Verbrugh HA. 2009. Co-evolutionary aspects of human colonisation and infection by Staphylococcus aureus. Infect Genet Evol, 9 (1), pp. 32-47. | Show Abstract | Read more

Although Staphylococcus aureus is a bacterial species of medical significance, only approximately 30% of all humans carry staphylococcal cells persistently but asymptomatically in their nasopharynx and/or other body sites. This goes largely unnoticed by the host, which shows that in the natural situation the human ecosystem is hospitable or at least receptive to the bacteria and that by a process of co-evolution this has lead to a state of mutual acceptance or tolerance. However, upon disturbance of this balanced, neutral state, localized or disseminated invasive infection can occur. Unfortunately, the events leading to infection are still largely unknown and especially the causal events leading to the transition from colonization to infection are ill-defined in vivo. Whether certain genotypes of S. aureus are more prone to colonise and/or infect humans is still quite heavily debated. The genetic population structure of S. aureus has been largely solved by using a number of different DNA polymorphism-interrogating laboratory methods. However, even this major effort has not (yet) revealed major clues with respect to colonisation and infection potency of the clonal lineages that were thus identified, except for the fact that certain lineages are highly epidemic. The overall picture is that in principle all S. aureus strains can become invasive given the proper circumstances. What these, primarily host-defined circumstances are is still enigmatic. However, a large variety of staphylococcal virulence and colonization factors have been identified as well as a number of host' colonisation and infection susceptibility traits. How these are specifically involved in colonisation and infection has been experimentally substantiated in only a limited number of cases. The present review paper will explore the relevance of these and other, for instance environmental factors that define the colonisation or infection state in humans. When the nature of these states would be known in more detail, this knowledge could be used to design novel and empirical, knowledge-driven means of preventing colonisation from proceeding into S. aureus infection.

Wertheim HF, Ammerlaan HS, Bonten MJ, van den Broek PJ, Troelstra A, Vandenbroucke-Grauls CM, Vos MC, Voss A, Nouwen JL, Kluytmans JA. 2008. [Optimisation of the antibiotic policy in the Netherlands. XII. The SWAB guideline for antimicrobial eradication of MRSA in carriers]. Ned Tijdschr Geneeskd, 152 (49), pp. 2667-2671. | Show Abstract

The 'Stichting Werkgroep Antibioticabeleid' (SWAB; Dutch Working Party on Antibiotics Policy) has developed evidence-based guidelines for the antimicrobial treatment of methicillin-resistant Staphylococcus aureus (MRSA) carriers for the eradication of MRSA. A distinction was made between uncomplicated and complicated carriage depending on the presence or absence of an active MRSA infection, skin lesions, foreign body material, mupirocin resistance and/or extranasal carriage. The indication for treatment is determined by the consequences of carriage for the carrier and his/her environment, the adverse events of treatment, and the likelihood of a successful treatment. The first choice of treatment in uncomplicated carriers is a combination of mupirocin nasal ointment and disinfectant soap for 5 days, along with hygiene advice. If treatment fails, sources in the vicinity of the patient must be sought. Complicated carriers receive a combination of 2 oral antibiotics, in addition to mupirocin nasal ointment and disinfectant soap, for at least 7 days.

Phan PH, Wertheim H, Luong ST, Ngo BT, Pham HV, Nguyen TT, Le HT, Taylor W, Horby P, Liem NT. 2008. Fatal Lower Respiratory Tract Infections with Rhinovirus A in Infants in Vietnam INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 12 pp. E81-E81. | Read more

Holtfreter S, Nguyen HT, Wertheim H, Steil L, Kusch H, Truong QP, Engelmann S, van Belkum A, Voelker U, Broeker BM. 2008. Human IgG response to experimental colonization with S. aureus WIENER KLINISCHE WOCHENSCHRIFT, 120 pp. 143-143.

Taylor WR, Thinh BN, Anh GT, Horby P, Wertheim H, Lindegardh N, de Jong MD, Stepniewska K, Hanh TT, Hien ND et al. 2008. Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza. PLoS One, 3 (10), pp. e3410. | Show Abstract | Read more

In the absence of a parenteral drug, oral oseltamivir is currently recommended by the WHO for treating H5N1 influenza. Whether oseltamivir absorption is adequate in severe influenza is unknown. We measured the steady state, plasma concentrations of nasogastrically administered oseltamivir 150 mg bid and its active metabolite, oseltamivir carboxylate (OC), in three, mechanically ventilated patients with severe H5N1 (male, 30 yrs; pregnant female, 22 yrs) and severe H3N2 (female, 76 yrs). Treatments were started 6, 7 and 8 days after illness onset, respectively. Both females were sampled while on continuous venovenous haemofiltration. Admission and follow up specimens (trachea, nose, throat, rectum, blood) were tested for RNA viral load by reverse transcriptase PCR. In vitro virus susceptibility to OC was measured by a neuraminidase inhibition assay. Admission creatinine clearances were 66 (male, H5N1), 82 (female, H5N1) and 6 (H3N2) ml/min. Corresponding AUC(0-12) values (5932, 10,951 and 34,670 ng.h/ml) and trough OC concentrations (376, 575 and 2730 ng/ml) were higher than previously reported in healthy volunteers; the latter exceeded 545 to 3956 fold the H5N1 IC(50) (0.69 ng/ml) isolated from the H5N1 infected female. Two patients with follow-up respiratory specimens cleared their viruses after 5 (H5N1 male) and 5 (H3N2 female) days of oseltamivir. Both female patients died of respiratory failure; the male survived. 150 mg bid of oseltamivir was well absorbed and converted extensively to OC. Virus was cleared in two patients but two patients died, suggesting viral efficacy but poor clinical efficacy.

Le MT, Wertheim HF, Nguyen HD, Taylor W, Hoang PV, Vuong CD, Nguyen HL, Nguyen HH, Nguyen TQ, Nguyen TV et al. 2008. Influenza A H5N1 clade 2.3.4 virus with a different antiviral susceptibility profile replaced clade 1 virus in humans in northern Vietnam. PLoS One, 3 (10), pp. e3339. | Show Abstract | Read more

BACKGROUND: Prior to 2007, highly pathogenic avian influenza (HPAI) H5N1 viruses isolated from poultry and humans in Vietnam were consistently reported to be clade 1 viruses, susceptible to oseltamivir but resistant to amantadine. Here we describe the re-emergence of human HPAI H5N1 virus infections in Vietnam in 2007 and the characteristics of the isolated viruses. METHODS AND FINDINGS: Respiratory specimens from patients suspected to be infected with avian influenza in 2007 were screened by influenza and H5 subtype specific polymerase chain reaction. Isolated H5N1 strains were further characterized by genome sequencing and drug susceptibility testing. Eleven poultry outbreak isolates from 2007 were included in the sequence analysis. Eight patients, all of them from northern Vietnam, were diagnosed with H5N1 in 2007 and five of them died. Phylogenetic analysis of H5N1 viruses isolated from humans and poultry in 2007 showed that clade 2.3.4 H5N1 viruses replaced clade 1 viruses in northern Vietnam. Four human H5N1 strains had eight-fold reduced in-vitro susceptibility to oseltamivir as compared to clade 1 viruses. In two poultry isolates the I117V mutation was found in the neuraminidase gene, which is associated with reduced susceptibility to oseltamivir. No mutations in the M2 gene conferring amantadine resistance were found. CONCLUSION: In 2007, H5N1 clade 2.3.4 viruses replaced clade 1 viruses in northern Vietnam and were susceptible to amantadine but showed reduced susceptibility to oseltamivir. Combination antiviral therapy with oseltamivir and amantadine for human cases in Vietnam is recommended.

Wertheim HFL, Ammerlaan HSM, Bonten MJM, Van Den Broek PJ, Troelstra A, Vandenbroucke-Grauls CMJE, Vos MC, Voss A, Nouwen JL, Kluytmans JAJW. 2008. Optimisation of the antibiotic policy in the Netherlands. XII. The SWAB guideline for antimicrobial eradication of MRSA in carriers Nederlands Tijdschrift voor Geneeskunde, 152 (49), pp. 2667-2671.

Wertheim HF, Walsh E, Choudhurry R, Melles DC, Boelens HA, Miajlovic H, Verbrugh HA, Foster T, van Belkum A. 2008. Key role for clumping factor B in Staphylococcus aureus nasal colonization of humans. PLoS Med, 5 (1), pp. e17. | Show Abstract | Read more

BACKGROUND: Staphylococcus aureus permanently colonizes the vestibulum nasi of one-fifth of the human population, which is a risk factor for autoinfection. The precise mechanisms whereby S. aureus colonizes the nose are still unknown. The staphylococcal cell-wall protein clumping factor B (ClfB) promotes adhesion to squamous epithelial cells in vitro and might be a physiologically relevant colonization factor. METHODS AND FINDINGS: We define the role of the staphylococcal cytokeratin-binding protein ClfB in the colonization process by artificial inoculation of human volunteers with a wild-type strain and its single locus ClfB knock-out mutant. The wild-type strain adhered to immobilized recombinant human cytokeratin 10 (CK10) in a dose-dependent manner, whereas the ClfB(-) mutant did not. The wild-type strain, when grown to the stationary phase in a poor growth medium, adhered better to CK10, than when the same strain was grown in a nutrient-rich environment. Nasal cultures show that the mutant strain is eliminated from the nares significantly faster than the wild-type strain, with a median of 3 +/- 1 d versus 7 +/- 4 d (p = 0.006). Furthermore, the wild-type strain was still present in the nares of 3/16 volunteers at the end of follow-up, and the mutant strain was not. CONCLUSIONS: The human colonization model, in combination with in vitro data, shows that the ClfB protein is a major determinant of nasal-persistent S. aureus carriage and is a candidate target molecule for decolonization strategies.

van Belkum A, Emonts M, Wertheim H, de Jongh C, Nouwen J, Bartels H, Cole A, Cole A, Hermans P, Boelens H et al. 2007. The role of human innate immune factors in nasal colonization by Staphylococcus aureus. Microbes Infect, 9 (12-13), pp. 1471-1477. | Show Abstract | Read more

Staphylococcus aureus colonization of the human nares predisposes to sometimes severe auto-infection. To investigate whether genetic polymorphism affects the S. aureus carriage status, sequence variation in alpha-defensin and beta-defensin, and mannose-binding lectin (MBL) genes were determined for a group of volunteers (n=109) with known S. aureus nasal carriage status. DEFA1/3 expression was measured in a subset of the volunteers (n=32). None of the single nucleotide polymorphisms studied could clearly distinguish the (non) carriage groups. S. aureus carriers differed from non-carriers in baseline level of HNP1-3 peptide production (median: 218 versus 89mug/ml, P=0.016). No association between HNP1-3 levels and the individual sequence polymorphisms was documented. The combined copy numbers of DEFA1/A3 genes ranged from 5 to 23 per diploid genome. A linear correlation between combined copy numbers and HNP1-3 peptide concentrations in nasal secretions of non-carriers was noted (r(2)=0.8991). DEFA3 gene was absent in 25% of the individuals. MBL haplotype A was overrepresented in persistent S. aureus carriers (87% vs. 67%; P=0.038). In conclusion, defensin gene polymorphism, both in sequence and in gene copy numbers, does not seem to be involved in S. aureus carriage predisposition. However, MBL haplotypes do so significantly. Baseline HNP1-3 production is more the consequence of S. aureus colonization than a reason for the (non) carrier status.

Wertheim HF, Verbrugh HA. 2006. Global prevalence of meticillin-resistant Staphylococcus aureus. Lancet, 368 (9550), pp. 1866. | Read more

Wertheim HF, van Kleef M, Vos MC, Ott A, Verbrugh HA, Fokkens W. 2006. Nose picking and nasal carriage of Staphylococcus aureus. Infect Control Hosp Epidemiol, 27 (8), pp. 863-867. | Show Abstract | Read more

OBJECTIVE: Nasal carriage of Staphylococcus aureus is an important risk factor for S. aureus infection and a reservoir for methicillin-resistant S. aureus. We investigated whether nose picking was among the determinants of S. aureus nasal carriage. SETTING AND PARTICIPANTS: The study cohort comprised 238 patients who visited the ear, nose, and throat (ENT) disease outpatient clinic of a tertiary care hospital and did not have a nose-specific complaint (defined as ENT patients) and 86 healthy hospital employees (including medical students and laboratory personnel). MEASUREMENTS: All participants completed a questionnaire on behavior regarding the nose and were screened for S. aureus nasal carriage; only ENT patients underwent nasal examination by an ear, nose, and throat physician for clinical signs of nose picking. RESULTS: Among ENT patients, nose pickers were significantly more likely than non-nose pickers to carry S. aureus (37 [53.6%] of 69 vs 60 [35.5%] of 169 patients; relative risk, 1.51 [95% confidence interval, 1.03-2.19]). Among healthy volunteers, there was a statistically significant positive correlation between the self-perceived frequency of nose picking and both the frequency of positive culture results (R=0.31; P=.004) and the load of S. aureus present in the nose (R=0.32; P=.003). CONCLUSION: Nose picking is associated with S. aureus nasal carriage. The role of nose picking in nasal carriage may well be causal in certain cases. Overcoming the habit of nose picking may aid S. aureus decolonization strategies.

Choudhurry RS, Melles DC, Eadie K, Vos M, Wertheim HF, Verbrugh HA, van Belkum A, van Leeuwen WB. 2006. Direct detection of human Staphylococcus aureus carriage in the nose using the Lightcycler Staphylococcus kit. J Microbiol Methods, 65 (2), pp. 354-356. | Show Abstract | Read more

The Lightcycler Staphylococcus kit is a diagnostic tool for direct real-time detection of Staphylococcus aureus in clinical materials. We show here that detection of S. aureus nasal carriage using this test is hampered by competition of DNA from coagulase-negative staphylococci. However the test is well suited for species identification after culture and the identification of high-load S. aureus carriers.

van Belkum A, Melles DC, Snijders SV, van Leeuwen WB, Wertheim HF, Nouwen JL, Verbrugh HA, Etienne J. 2006. Clonal distribution and differential occurrence of the enterotoxin gene cluster, egc, in carriage- versus bacteremia-associated isolates of Staphylococcus aureus. J Clin Microbiol, 44 (4), pp. 1555-1557. | Show Abstract | Read more

The Staphylococcus aureus enterotoxin gene cluster, egc, was detected in isolates from healthy individuals and in those from patients with bacteremia. The egc genes cooccur and are slightly enriched in strains from healthy carriers (present in 63.7% of carriage-associated isolates versus 52.9% of invasive isolates; P = 0.03). Multilocus sequence typing revealed that successful staphylococcal clones usually harbor the egc locus.

Wertheim HF, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, Nouwen JL. 2005. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis, 5 (12), pp. 751-762. | Show Abstract | Read more

Staphylococcus aureus is a frequent cause of infections in both the community and hospital. Worldwide, the increasing resistance of this pathogen to various antibiotics complicates treatment of S aureus infections. Effective measures to prevent S aureus infections are therefore urgently needed. It has been shown that nasal carriers of S aureus have an increased risk of acquiring an infection with this pathogen. The nose is the main ecological niche where S aureus resides in human beings, but the determinants of the carrier state are incompletely understood. Eradication of S aureus from nasal carriers prevents infection in specific patient categories-eg, haemodialysis and general surgery patients. However, recent randomised clinical trials in orthopaedic and non-surgical patients failed to show the efficacy of eliminating S aureus from the nose to prevent subsequent infection. Thus we must elucidate the mechanisms behind S aureus nasal carriage and infection to be able to develop new preventive strategies. We present an overview of the current knowledge of the determinants (both human and bacterial) and risks of S aureus nasal carriage. Studies on the population dynamics of S aureus are also summarised.

Wertheim HF, van Leeuwen WB, Snijders S, Vos MC, Voss A, Vandenbroucke-Grauls CM, Kluytmans JA, Verbrugh HA, van Belkum A. 2005. Associations between Staphylococcus aureus Genotype, Infection, and In-Hospital Mortality: A Nested Case-Control Study. J Infect Dis, 192 (7), pp. 1196-1200. | Show Abstract | Read more

We screened 14,008 adult nonsurgical patients for Staphylococcus aureus nasal carriage at hospital admission and assessed them for invasive S. aureus disease and in-hospital mortality. Multilocus sequence typing was performed on endogenous invasive strains and nasal strains of matched asymptomatic carriers to investigate whether virulent clones could be identified in nasal carriers. Clonal complex (CC) 45 was significantly underrepresented (odds ratio [OR], 0.16 [95% confidence interval {CI}, 0.04-0.59]) and CC30 was overrepresented (not statistically significant) among invasive strains (OR, 1.91 [95% CI, 0.91-4.0]). The distribution of CCs of invasive S. aureus strains in noncarriers did not differ from that in carriers. Those infected with S. aureus strains belonging to a CC had higher mortality than those infected with strains not belonging to a CC (P<.05), which indicates the coevolution of S. aureus virulence and spread in humans.

van Leeuwen WB, Melles DC, Alaidan A, Al-Ahdal M, Boelens HA, Snijders SV, Wertheim H, van Duijkeren E, Peeters JK, van der Spek PJ et al. 2005. Host- and tissue-specific pathogenic traits of Staphylococcus aureus. J Bacteriol, 187 (13), pp. 4584-4591. | Show Abstract | Read more

Comparative genomics were used to assess genetic differences between Staphylococcus aureus strains derived from infected animals versus colonized or infected humans. A total of 77 veterinary isolates were genetically characterized by high-throughput amplified fragment length polymorphism (AFLP). Bacterial genotypes were introduced in a large AFLP database containing similar information for 1,056 human S. aureus strains. All S. aureus strains isolated from animals in close contact with humans (e.g., pet animals) were predominantly classified in one of the five main clusters of the AFLP database (cluster I). In essence, mastitis-associated strains from animals were categorized separately (cluster IVa) and cosegregated with bacteremia-associated strains from humans. Distribution of only 2 out of 10 different virulence genes differed across the clusters. The gene encoding the toxic shock syndrome protein (tst) was more often encountered among veterinary strains (P < 0.0001) and even more in the mastitis-related strains (P<0.0001) compared to human isolate results. The gene encoding the collagen binding protein (cna) was rarely detected among invasive human strains. The virulence potential, as indicated by the number of virulence genes per strain, did not differ significantly between the human- and animal-related strains. Our data show that invasive infections in pets and humans are usually due to S. aureus strains with the same genetic background. Mastitis-associated S. aureus isolated in diverse farm animal species form a distinct genetic cluster, characterized by an overrepresentation of the toxic shock syndrome toxin superantigen-encoding gene.

Wertheim HF, Vos MC. 2005. Can mupirocin prevent methicillin-resistant Staphylococcus aureus infections? Crit Care, 9 (3), pp. 257-258. | Show Abstract | Read more

In a retrospective study, Dr Muller and colleagues have assessed the efficacy of mupirocin nasal ointment alongside hygienic measures in methicillin-resistant Staphylococcus aureus (MRSA)-positive patients admitted to the intensive care unit (ICU). Their findings, which suggest that intranasal mupirocin can prevent ICU-related MRSA infections, need confirmation in a well-designed clinical trial. In general: early identification, isolation and treatment of all MRSA carriers, including health care workers, and disinfection of contaminated environments, are the main 'ingredients' of an effective MRSA 'search and destroy' program.

Wertheim HF, Verveer J, Boelens HA, van Belkum A, Verbrugh HA, Vos MC. 2005. Effect of mupirocin treatment on nasal, pharyngeal, and perineal carriage of Staphylococcus aureus in healthy adults. Antimicrob Agents Chemother, 49 (4), pp. 1465-1467. | Show Abstract | Read more

Nasal carriage of Staphylococcus aureus is an important risk factor for S. aureus infections. Mupirocin nasal ointment is presently the treatment of choice for decolonizing the anterior nares. However, recent clinical trials show limited benefit from mupirocin prophylaxis in preventing nosocomial S. aureus infections, probably due to (re)colonization from extranasal carriage sites. Therefore, we studied the effectiveness of mupirocin nasal ointment treatment on the dynamics of S. aureus nasal and extranasal carriage. Twenty noncarriers, 26 intermittent carriers, and 16 persistent carriers had nasal, throat, and perineum samples taken 1 day before and 5 weeks after mupirocin treatment (twice daily for 5 days) and assessed for growth of S. aureus. The identities of cultured strains were assessed by restriction fragment length polymorphisms of the coagulase and protein A genes. The overall carriage rate (either nasal, pharyngeal, or perineal carrier or a combination) was significantly reduced after mupirocin treatment from 30 to 17 carriers (P = 0.003). Of the 17 carriers, 10 (60%) were still colonized with their old strain, 6 (35%) were colonized with an exogenous strain, and 1 (5%) was colonized with both. Two noncarriers became carriers after treatment. The acquisition of exogenous strains after mupirocin treatment is a common phenomenon. The finding warrants the use of mupirocin only in proven carriers for decolonization purposes. Mupirocin is effective overall in decolonizing nasal carriers but less effective in decolonizing extranasal sites.

Kluytmans JA, Wertheim HF. 2005. Nasal carriage of Staphylococcus aureus and prevention of nosocomial infections. Infection, 33 (1), pp. 3-8. | Show Abstract | Read more

This review summarizes the clinically relevant aspects of nasal carriage of Staphylococcus aureus. The epidemiology, associated risk, and the effects of eradication are discussed. The main conclusions are that nasal carriage of S. aureus is a well-defined risk factor for subsequent infection in nearly all categories of hospitalized patients that have been studied. However, studies that have been performed to evaluate the effect of eradication of carriage using mupirocin nasal ointment have been inconclusive so far in most subgroups. Only in patients on hemodialysis or chronic ambulatory peritoneal dialysis (CAPD) was a significant reduction of the infection rate found. But prolonged treatment in these groups carries a risk for the development of resistance. In surgical patients two randomized studies have found an effect on the surgical site infection rate in carriers that, when those studies are combined, was close to being statistically significant (p = 0.06). In non-surgical patients a significant delay in the onset of infection was found but the overall infection rate was not significantly different. When the results of all well-designed studies that have been performed are combined, a significant reduction of the nosocomial S. aureus infections in carriers is found (approximately 50% lower). Future studies should focus on treating carriers only and consider other treatment regimens.

Wertheim HFL, Vos MC, Ott A, Voss A, Kluytmans JAJW, Vandenbroucke-Grauls CMJE, Meester MHM, Van Keulen PHJ, Verbrugh HA. 2005. Mupirocin prophylaxis for the prevention of nosocomial infections due to nasal carriers of Staphylococcus aureus is of no use in nonsurgical patients as yet Nederlands Tijdschrift voor Geneeskunde, 149 (7), pp. 350-355.

Wertheim HF, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JA, van Keulen PH, Vandenbroucke-Grauls CM, Meester MH, Verbrugh HA. 2004. Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet, 364 (9435), pp. 703-705. | Show Abstract | Read more

Staphylococcus aureus is the second most frequent cause of nosocomial blood infections. We screened 14008 non-bacteraemic, non-surgical patients for S aureus nasal carriage at admission, and monitored them for development of bacteraemia. Nosocomial S aureus bacteraemia was three times more frequent in S aureus carriers (40/3420, 1.2%) than in non-carriers (41/10588, 0.4%; relative risk 3.0, 95% CI 2.0-4.7). However, in bacteraemic patients, all-cause mortality was significantly higher in non-carriers (19/41, 46%) than in carriers (seven/40, 18%, p=0.005). Additionally, S aureus bacteraemia-related death was significantly higher in non-carriers than in carriers (13/41 [32%] vs three/40 [8%], p=0.006). S aureus nasal carriers and non-carriers differ significantly in risk and outcome of nosocomial S aureus bacteraemia. Genotyping revealed that 80% of strains causing bacteraemia in carriers were endogenous.

Wertheim HF, Vos MC, Boelens HA, Voss A, Vandenbroucke-Grauls CM, Meester MH, Kluytmans JA, van Keulen PH, Verbrugh HA. 2004. Low prevalence of methicillin-resistant Staphylococcus aureus (MRSA) at hospital admission in the Netherlands: the value of search and destroy and restrictive antibiotic use. J Hosp Infect, 56 (4), pp. 321-325. | Show Abstract | Read more

In the Netherlands, less than 1% of clinical isolates of Staphylococcus aureus are methicillin-resistant (MRSA). A national search and destroy policy prevents MRSA from becoming endemic. Some MRSA outbreaks cannot be related to patients at risk for MRSA carriage. This study was designed to measure the prevalence of MRSA among patients without risk factors for MRSA carriage at the time of admission to the hospital. In four Dutch hospitals, patients admitted to non-surgical departments in the period 1999-2000 were screened for MRSA nasal carriage. Nasal swabs were streaked on 5% sheep blood agar (BA), submerged in a selective broth, and incubated for two to three days at 35 degrees C. Colonies suspected of being S. aureus were identified with an agglutination test. Susceptibility testing was performed by an automated system and additional oxacillin disk diffusion. Methicillin resistance was confirmed by a DNA hybridization test and mecA PCR. MRSA strains were genotyped by pulsed-field gel electrophoresis (PFGE). Twenty-four percent (2332/9859) of the patients were S. aureus nasal carriers. Only three (0.03%) patients were MRSA carriers. These patients were not repatriated, nor known to be MRSA carriers before screening. Genotyping revealed that the strains were not clonally related and were not related to MRSA outbreaks in the hospital where the patients were admitted. We conclude that at routine admission to a Dutch hospital (excluding high-risk foreign admissions) the MRSA prevalence is low (0.03%), due to the Dutch search and destroy policy and restrictive antibiotic prescribing.

Wertheim HF, Vos MC, Ott A, Voss A, Kluytmans JA, Vandenbroucke-Grauls CM, Meester MH, van Keulen PH, Verbrugh HA. 2004. Mupirocin prophylaxis against nosocomial Staphylococcus aureus infections in nonsurgical patients: a randomized study. Ann Intern Med, 140 (6), pp. 419-425. | Show Abstract | Read more

BACKGROUND: Staphylococcus aureus nasal carriage is a major risk factor for nosocomial S. aureus infection. Studies show that intranasal mupirocin can prevent nosocomial surgical site infections. No data are available on the efficacy of mupirocin in nonsurgical patients. OBJECTIVE: To assess the efficacy of mupirocin prophylaxis in preventing nosocomial S. aureus infections in nonsurgical patients. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 3 tertiary care academic hospitals and 1 nonacademic hospital. PATIENTS: 1602 culture-proven S. aureus carriers hospitalized in nonsurgical departments. INTERVENTION: Therapy with mupirocin 2% nasal ointment (n = 793) or placebo ointment (n = 809), twice daily for 5 days, started 1 to 3 days after admission. MEASUREMENTS: Nosocomial S. aureus infections according to defined criteria, in-hospital mortality, duration of hospitalization, and time to nosocomial S. aureus infection. Staphylococcus aureus isolates were genotyped to assess whether infection was caused by endogenous strains. RESULTS: The mupirocin and placebo groups did not statistically differ in the rates of nosocomial S. aureus infections (mupirocin, 2.6%; placebo, 2.8%; risk difference, 0.2 percentage point [95% CI, -1.5 to 1.9 percentage points]), mortality (mupirocin, 3.0%; placebo, 2.8%; risk difference, -0.2 percentage point [CI, -1.9 to 1.5 percentage points]), or duration of hospitalization (median for both, 8 days). However, time to nosocomial S. aureus infection was decreased in the mupirocin group from 12 to 25 days (P > 0.2). A total of 77% of S. aureus nosocomial infections were endogenous. LIMITATIONS: A few infections in both groups may have been missed because investigators assessed a patient for infection only if microbiology culture results were positive for S. aureus. CONCLUSION: Routine culture for S. aureus nasal carriage at admission and subsequent mupirocin application does not provide effective prophylaxis against nosocomial S. aureus infections in nonsurgical patients.

Wertheim HFL, Vos MC, Boelens HAM, Voss A, Vandenbroucke-Grauls CMJE, Meester MHM, Kluytmans JAJW, Van Keulen PHJ, Verbrugh HA. 2004. Low prevalence of methicillin-resistant Staphylococcus aureus (MRSA) carriage at hospital admission in the Netherlands Nederlands Tijdschrift voor Geneeskunde, 148 (21), pp. 1044-1048.

Wertheim HF, Albers MJ, Piena-Spoel M, Tibboel D. 2001. The incidence of septic complications in newborns on extracorporeal membrane oxygenation is not affected by feeding route. J Pediatr Surg, 36 (10), pp. 1485-1489. | Show Abstract | Read more

PURPOSE: The aim of this study was to compare the effects of enteral and total parenteral feeding on septic complications in neonates on extracorporeal membrane oxygenation (ECMO). METHODS: Ninety-six neonates were on ECMO between January 1992 and February 1998. Matching for diagnosis and exclusion of neonates with sepsis before ECMO or undergoing surgery on ECMO left 16 enterally fed neonates (cases) and 35 parenterally fed neonates (controls) for analysis. Septic complications were scored using the criteria of the Society of Critical Care Medicine and the American College of Chest Physicians adapted to children. RESULTS: Both groups were comparable with respect to gestational age, sex, and age at initiation of ECMO. The frequency of septic complications did not differ between cases and controls: no complications, 75% versus 69%; systemic inflammatory response syndrome, 13% versus 6%; bacteremia, 6% versus 14%; sepsis, 6% versus 11%. There were no complications associated with enteral feeding. The ECMO run was significantly longer in the case group (median, 161 v. 111 hours; P =.01) and mortality rate was lower in the case group (0 v. 14%; P =.17). CONCLUSIONS: Enteral nutrition does not affect the risk of sepsis in neonates on ECMO when compared with total parenteral nutrition. Enteral nutrition is well tolerated and not associated with adverse effects.

Wertheim H, Verbrugh HA, van Pelt C, de Man P, van Belkum A, Vos MC. 2001. Improved detection of methicillin-resistant Staphylococcus aureus using phenyl mannitol broth containing aztreonam and ceftizoxime. J Clin Microbiol, 39 (7), pp. 2660-2662. | Show Abstract | Read more

We tested a phenyl mannitol broth containing ceftizoxime and aztreonam (PHMB(+)) for detection of methicillin-resistant Staphylococcus aureus (MRSA) with reference MRSA strains and, subsequently, with clinical samples (n = 1,098). All reference MRSA strains induced color change in PHMB(+) after 24 to 72 h of incubation. In a clinical setting, 40 MRSA strains were detected with PHMB(+), compared with only 23 detected with a routine method. Thus, this selective broth significantly (P < 0.001) improved the rate of MRSA detection.

Chesmel KD, Branger J, Wertheim H, Scarborough N. 1998. Healing response to various forms of human demineralized bone matrix in athymic rat cranial defects. J Oral Maxillofac Surg, 56 (7), pp. 857-863. | Show Abstract | Read more

PURPOSE: This study compared the ability of a bone autograft and four distinct forms of human demineralized bone (DBM) to elicit bone repair in a critical size cranial defect in athymic rats. MATERIALS AND METHODS: Cranial defects were created in athymic rats and then grafted with either an autograft, rat DBM particles in glycerol (rGel), or one of four forms of human DBM: 1) hGel; 2) Putty (DBM fibers in glycerol); 3) Sheet (sheet of DBM fibers); or 4) Flex (DBM fiber sheet with glycerol). Histology, histomorphometry, and radiographic density of the graft sites were evaluated at 8 weeks. RESULTS: Of the grafted defects, 29% to 58% were found to be filled with new bone. The rGel and human forms of DBM stimulated similar amounts of new bone growth in comparison with the autograft-filled defects. The fiber-based grafts produced the largest amounts of new bone. CONCLUSIONS: Human DBM in gel, putty and sheet forms were found to perform as well as an autograft in a critical size cranial defect in the athymic rat.

Wertheim HFL, Piena-Spoel M, Tibboel D. 1998. Het effect van enterale voeding bij neonaten die met Extra Corporele Membraan Oxygenatie (ECMO) worden behandeld; een case control analyse van septische complicaties Tijdschrift voor Kindergeneeskunde, 66 (SUPPL. 1), pp. 80.

Holt KE, Wertheim H, Zadoks RN, Baker S, Whitehouse CA, Dance D, Jenney A, Connor TR, Hsu LY, Severin J et al. 2015. Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. Proc Natl Acad Sci U S A, 112 (27), pp. E3574-E3581. | Show Abstract | Read more

Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats.

Robinson TP, Wertheim HF, Kakkar M, Kariuki S, Bu D, Price LB. 2016. Animal production and antimicrobial resistance in the clinic. Lancet, 387 (10014), pp. e1-e3. | Read more

Mendelson M, Røttingen JA, Gopinathan U, Hamer DH, Wertheim H, Basnyat B, Butler C, Tomson G, Balasegaram M. 2016. Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries. Lancet, 387 (10014), pp. 188-198. | Show Abstract | Read more

Access to quality-assured antimicrobials is regarded as part of the human right to health, yet universal access is often undermined in low-income and middle-income countries. Lack of access to the instruments necessary to make the correct diagnosis and prescribe antimicrobials appropriately, in addition to weak health systems, heightens the challenge faced by prescribers. Evidence-based interventions in community and health-care settings can increase access to appropriately prescribed antimicrobials. The key global enablers of sustainable financing, governance, and leadership will be necessary to achieve access while preventing excess antimicrobial use.

Huong VT, Hoa NT, Horby P, Bryant JE, Van Kinh N, Toan TK, Wertheim HF. 2014. Raw pig blood consumption and potential risk for Streptococcus suis infection, Vietnam. Emerg Infect Dis, 20 (11), pp. 1895-1898. | Show Abstract | Read more

We assessed consumption of raw pig blood, which is a risk factor for Streptococcus suis infection in Vietnam, by using a mix-method design. Factors associated with consumption included rural residency, age, sex, occupation, income, and marital status. We identified risk groups and practices and perceptions that should be targeted by communication programs.

Yacoub S, Wertheim H, Simmons CP, Screaton G, Wills B. 2014. Cardiovascular manifestations of the emerging dengue pandemic. Nat Rev Cardiol, 11 (6), pp. 335-345. | Show Abstract | Read more

Dengue is one of the most important emerging viral diseases globally. The majority of symptomatic infections result in a relatively benign disease course. However, a small proportion of patients develop severe clinical manifestations, including bleeding, organ impairment, and endothelial dysfunction with increased capillary permeability causing hypovolaemic shock that can lead to cardiovascular collapse. Evidence is increasing that dengue can also cause myocardial impairment, arrhythmias and, occasionally, fulminant myocarditis. No antiviral agents or vaccines are licensed for dengue, and treatment remains supportive with judicious fluid replacement for patients with severe disease. Defining the role of cardiac dysfunction in the haemodynamic compromise of severe dengue has potentially important management implications. In this Review, we will outline the current understanding of the cardiovascular manifestations of dengue, including myocardial and vascular involvement, and conclude with a discussion of the available therapeutic options and potential future research directions.

Nguyen KV, Thi Do NT, Chandna A, Nguyen TV, Pham CV, Doan PM, Nguyen AQ, Thi Nguyen CK, Larsson M, Escalante S et al. 2013. Antibiotic use and resistance in emerging economies: a situation analysis for Viet Nam. BMC Public Health, 13 (1), pp. 1158. | Show Abstract | Read more

BACKGROUND: Antimicrobial resistance is a major contemporary public health threat. Strategies to contain antimicrobial resistance have been comprehensively set forth, however in developing countries where the need for effective antimicrobials is greatest implementation has proved problematic. A better understanding of patterns and determinants of antibiotic use and resistance in emerging economies may permit more appropriately targeted interventions.Viet Nam, with a large population, high burden of infectious disease and relatively unrestricted access to medication, is an excellent case study of the difficulties faced by emerging economies in controlling antimicrobial resistance. METHODS: Our working group conducted a situation analysis of the current patterns and determinants of antibiotic use and resistance in Viet Nam. International publications and local reports published between 1-1-1990 and 31-8-2012 were reviewed. All stakeholders analyzed the findings at a policy workshop and feasible recommendations were suggested to improve antibiotic use in Viet Nam.Here we report the results of our situation analysis focusing on: the healthcare system, drug regulation and supply; antibiotic resistance and infection control; and agricultural antibiotic use. RESULTS: Market reforms have improved healthcare access in Viet Nam and contributed to better health outcomes. However, increased accessibility has been accompanied by injudicious antibiotic use in hospitals and the community, with predictable escalation in bacterial resistance. Prescribing practices are poor and self-medication is common - often being the most affordable way to access healthcare. Many policies exist to regulate antibiotic use but enforcement is insufficient or lacking.Pneumococcal penicillin-resistance rates are the highest in Asia and carbapenem-resistant bacteria (notably NDM-1) have recently emerged. Hospital acquired infections, predominantly with multi-drug resistant Gram-negative organisms, place additional strain on limited resources. Widespread agricultural antibiotic use further propagates antimicrobial resistance. CONCLUSIONS: Future legislation regarding antibiotic access must alter incentives for purchasers and providers and ensure effective enforcement. The Ministry of Health recently initiated a national action plan and approved a multicenter health improvement project to strengthen national capacity for antimicrobial stewardship in Viet Nam. This analysis provided important input to these initiatives. Our methodologies and findings may be of use to others across the world tackling the growing threat of antibiotic resistance.

Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H et al. 2013. Antibiotic resistance-the need for global solutions. Lancet Infect Dis, 13 (12), pp. 1057-1098. | Show Abstract | Read more

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.

Le MQ, Horby P, Fox A, Nguyen HT, Le Nguyen HK, Hoang PM, Nguyen KC, de Jong MD, Jeeninga RE, Rogier van Doorn H et al. 2013. Subclinical avian influenza A(H5N1) virus infection in human, Vietnam. Emerg Infect Dis, 19 (10), pp. 1674-1677. | Show Abstract | Read more

Laboratory-confirmed cases of subclinical infection with avian influenza A(H5N1) virus in humans are rare, and the true number of these cases is unknown. We describe the identification of a laboratory-confirmed subclinical case in a woman during an influenza A(H5N1) contact investigation in northern Vietnam.

Wertheim HF, Chandna A, Vu PD, Pham CV, Nguyen PD, Lam YM, Nguyen CV, Larsson M, Rydell U, Nilsson LE et al. 2013. Providing impetus, tools, and guidance to strengthen national capacity for antimicrobial stewardship in Viet Nam. PLoS Med, 10 (5), pp. e1001429. | Read more

Bode LG, Kluytmans JA, Wertheim HF, Bogaers D, Vandenbroucke-Grauls CM, Roosendaal R, Troelstra A, Box AT, Voss A, van der Tweel I et al. 2010. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med, 362 (1), pp. 9-17. | Show Abstract | Read more

BACKGROUND: Nasal carriers of Staphylococcus aureus are at increased risk for health care-associated infections with this organism. Decolonization of nasal and extranasal sites on hospital admission may reduce this risk. METHODS: In a randomized, double-blind, placebo-controlled, multicenter trial, we assessed whether rapid identification of S. aureus nasal carriers by means of a real-time polymerase-chain-reaction (PCR) assay, followed by treatment with mupirocin nasal ointment and chlorhexidine soap, reduces the risk of hospital-associated S. aureus infection. RESULTS: From October 2005 through June 2007, a total of 6771 patients were screened on admission. A total of 1270 nasal swabs from 1251 patients were positive for S. aureus. We enrolled 917 of these patients in the intention-to-treat analysis, of whom 808 (88.1%) underwent a surgical procedure. All the S. aureus strains identified on PCR assay were susceptible to methicillin and mupirocin. The rate of S. aureus infection was 3.4% (17 of 504 patients) in the mupirocin-chlorhexidine group, as compared with 7.7% (32 of 413 patients) in the placebo group (relative risk of infection, 0.42; 95% confidence interval [CI], 0.23 to 0.75). The effect of mupirocin-chlorhexidine treatment was most pronounced for deep surgical-site infections (relative risk, 0.21; 95% CI, 0.07 to 0.62). There was no significant difference in all-cause in-hospital mortality between the two groups. The time to the onset of nosocomial infection was shorter in the placebo group than in the mupirocin-chlorhexidine group (P=0.005). CONCLUSIONS: The number of surgical-site S. aureus infections acquired in the hospital can be reduced by rapid screening and decolonizing of nasal carriers of S. aureus on admission. (Current Controlled Trials number, ISRCTN56186788.)

Wertheim HF, Puthavathana P, Nghiem NM, van Doorn HR, Nguyen TV, Pham HV, Subekti D, Harun S, Malik S, Robinson J et al. 2010. Laboratory capacity building in Asia for infectious disease research: experiences from the South East Asia Infectious Disease Clinical Research Network (SEAICRN). PLoS Med, 7 (4), pp. e1000231. | Read more

Wertheim HF, Vos MC, Ott A, van Belkum A, Voss A, Kluytmans JA, van Keulen PH, Vandenbroucke-Grauls CM, Meester MH, Verbrugh HA. 2004. Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet, 364 (9435), pp. 703-705. | Show Abstract | Read more

Staphylococcus aureus is the second most frequent cause of nosocomial blood infections. We screened 14008 non-bacteraemic, non-surgical patients for S aureus nasal carriage at admission, and monitored them for development of bacteraemia. Nosocomial S aureus bacteraemia was three times more frequent in S aureus carriers (40/3420, 1.2%) than in non-carriers (41/10588, 0.4%; relative risk 3.0, 95% CI 2.0-4.7). However, in bacteraemic patients, all-cause mortality was significantly higher in non-carriers (19/41, 46%) than in carriers (seven/40, 18%, p=0.005). Additionally, S aureus bacteraemia-related death was significantly higher in non-carriers than in carriers (13/41 [32%] vs three/40 [8%], p=0.006). S aureus nasal carriers and non-carriers differ significantly in risk and outcome of nosocomial S aureus bacteraemia. Genotyping revealed that 80% of strains causing bacteraemia in carriers were endogenous.

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