Prof Paul Newton

Research Area: Clinical Epidemiology
Scientific Themes: Tropical Medicine & Global Health
Keywords: Laos, global health, Asia, medicine quality, scrub typhus
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Laboratories at dusk, Laos

Laboratories at dusk, Laos

We are a small clinical tropical medicine research group, the Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), based at Mahosot Hospital, Vientiane in Laos. Vientiane is a small capital city, on the banks of the Mekong River, of a country of 6 million people but of the size of the UK. We are embedded in the Microbiology Laboratory of the Hospital and linked to the Mahidol University Oxford University Research Unit (MORU) in Bangkok and the Shoklo Malaria Research Unit (SMRU) in Mae Sot, Thailand. Core funding for the research is from the Wellcome Trust (UK).

We conduct clinical research to help improve global, regional and Lao public health and to build capacity for this in Laos. Our research aims to provide global, regional organisations and the Lao Government with key data that will help make evidence-based decisions for individual patients and for health policy. The conditions we concentrate on include malaria, scrub typhus, murine typhus, melioidosis, typhoid, dengue, leptospirosis and the causes of central nervous system infections. We also investigate diseases of nutrition and poverty such as infantile beriberi and noma and build diagnostic, clinical and research capacity. Early work demonstrated the importance of local knowledge in deciding policy and the heterogeneity of infectious disease epidemiology in rural Asia. We also perform clinical trials on malaria, typhoid, murine typhus and scrub typhus treatment and evaluate locally appropriate diagnostic tests for key diseases.

With WWARN we conduct a diversity of research projects on medicine quality epidemiology, diagnostics, law and advocacy for this benighted field to be taken more seriously, especially the severe public health problem of falsified antimalarials in Asia and Africa.

That research in Laos has significant impact beyond its borders will become increasingly important as the country becomes more connected, dramatically with forthcoming transnational high-speed railways and multiple new highways. With Laos, and adjacent areas of Zomia, having great ethnic diversity, large forest tracts and wildlife trade understanding the clinical epidemiology of infectious diseases, especially zoonoses, is of great importance.

We build human medical research capacity in Laos and produce a Lao and English language medical journal – the Mahosot Microbiology Review and assist with the production of the Lao Medical Journal.

Name Department Institution Country
Prof Daniel H Paris Tropical Medicine University of Oxford United Kingdom
Prof Adrianus Dondorp Tropical Medicine University of Oxford United Kingdom
Dr Lorenz Von Seidlein Tropical Medicine University of Oxford United Kingdom
Dr Mayfong Mayxay Tropical Medicine University of Oxford United Kingdom
Prof François H Nosten Tropical Medicine University of Oxford United Kingdom
Prof Rose McGready Tropical Medicine University of Oxford United Kingdom
Prof Philippe J Guerin Tropical Medicine University of Oxford United Kingdom
Dr Paul Turner Tropical Medicine University of Oxford United Kingdom
Dr Claudia Turner Tropical Medicine University of Oxford United Kingdom
Dr Gareth Turner Tropical Medicine University of Oxford United Kingdom
Dr Yoel Lubell Tropical Medicine University of Oxford United Kingdom
Dr Direk Limmathurotsakul Tropical Medicine University of Oxford United Kingdom
Prof Guy Thwaites Tropical Medicine University of Oxford United Kingdom
Dr Stuart Blacksell Tropical Medicine University of Oxford United Kingdom
Prof Nicholas J White FRS Tropical Medicine University of Oxford United Kingdom
Prof Nicholas PJ Day FMedSci FRCP Tropical Medicine University of Oxford United Kingdom
Dr Joel Tarning Tropical Medicine University of Oxford United Kingdom
Prof Lisa J White Tropical Medicine University of Oxford United Kingdom
Dr David AB Dance Tropical Medicine University of Oxford United Kingdom
Dr Sabine Dittrich Tropical Medicine University of Oxford United Kingdom
Prof Bridget Wills Tropical Medicine University of Oxford United Kingdom

Newton PN, Tabernero P, Dwivedi P, Culzoni MJ, Monge ME, Swamidoss I, Mildenhall D, Green MD et al. 2014. Falsified medicines in Africa: all talk, no action. Lancet Glob Health, 2 (9), pp. e509-e510. | Read more

Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, Sreng S, Anderson JM et al. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med, 371 (5), pp. 411-423. Read abstract | Read more

BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.). Hide abstract

Mayxay M, Castonguay-Vanier J, Chansamouth V, Dubot-Pérès A, Paris DH, Phetsouvanh R, Tangkhabuanbutra J, Douangdala P et al. 2013. Causes of non-malarial fever in Laos: a prospective study. Lancet Glob Health, 1 (1), pp. e46-e54. Read abstract | Read more

BACKGROUND: Because of reductions in the incidence of Plasmodium falciparum malaria in Laos, identification of the causes of fever in people without malaria, and discussion of the best empirical treatment options, are urgently needed. We aimed to identify the causes of non-malarial acute fever in patients in rural Laos. METHODS: For this prospective study, we recruited 1938 febrile patients, between May, 2008, and December, 2010, at Luang Namtha provincial hospital in northwest Laos (n=1390), and between September, 2008, and December, 2010, at Salavan provincial hospital in southern Laos (n=548). Eligible participants were aged 5-49 years with fever (≥38°C) lasting 8 days or less and were eligible for malaria testing by national guidelines. FINDINGS: With conservative definitions of cause, we assigned 799 (41%) patients a diagnosis. With exclusion of influenza, the top five diagnoses when only one aetiological agent per patient was identified were dengue (156 [8%] of 1927 patients), scrub typhus (122 [7%] of 1871), Japanese encephalitis virus (112 [6%] of 1924), leptospirosis (109 [6%] of 1934), and bacteraemia (43 [2%] of 1938). 115 (32%) of 358 patients at Luang Namtha hospital tested influenza PCR-positive between June and December, 2010, of which influenza B was the most frequently detected strain (n=121 [87%]). Disease frequency differed significantly between the two sites: Japanese encephalitis virus infection (p=0·04), typhoid (p=0·006), and leptospirosis (p=0·001) were more common at Luang Namtha, whereas dengue and malaria were more common at Salavan (all p<0·0001). With use of evidence from southeast Asia when possible, we estimated that azithromycin, doxycycline, ceftriaxone, and ofloxacin would have had significant efficacy for 258 (13%), 240 (12%), 154 (8%), and 41 (2%) of patients, respectively. INTERPRETATION: Our findings suggest that a wide range of treatable or preventable pathogens are implicated in non-malarial febrile illness in Laos. Empirical treatment with doxycycline for patients with undifferentiated fever and negative rapid diagnostic tests for malaria and dengue could be an appropriate strategy for rural health workers in Laos. FUNDING: Wellcome Trust, WHO-Western Pacific Region, Foundation for Innovative New Diagnostics, US Centers for Disease Control and Prevention Hide abstract

Castonguay-Vanier J, Davong V, Bouthasavong L, Sengdetka D, Simmalavong M, Seupsavith A, Dance DA, Baker S, Le Thi Phuong T, Vongsouvath M, Newton PN. 2013. Evaluation of a simple blood culture amplification and antigen detection method for diagnosis of Salmonella enterica serovar typhi bacteremia. J Clin Microbiol, 51 (1), pp. 142-148. Read abstract | Read more

In most areas where typhoid is endemic, laboratory diagnosis is not possible due to the lack of appropriate facilities. We investigated whether the combination of blood culture amplification of Salmonella enterica serovar Typhi with an S. Typhi antigen rapid diagnostic test (RDT) could be an accurate and inexpensive tool for the accelerated diagnosis of patients with acute typhoid in Laos. For a panel of 23 Gram-negative reference pathogens, the Standard Diagnostics (catalog no. 15FK20; Kyonggi-do, South Korea) RDT gave positive results for S. Typhi NCTC 8385, S. Typhi NCTC 786 (Vi negative), Salmonella enterica serovar Enteritidis (ATCC 13076), and Salmonella enterica serovar Ndolo NCTC 8700 (all group D). In a prospective study of 6,456 blood culture bottles from 3,028 patients over 15 months, 392 blood culture bottles (6.1%) from 221 (7.3%) patients had Gram-negative rods (GNRs) seen in the blood culture fluid. The sensitivity, negative predictive value, specificity, and positive predictive value were 96.7%, 99.5%, 97.9%, and 87.9%, respectively, for patients with proven S. Typhi bacteremia and 91.2%, 98.4%, 98.9%, and 93.9% for patients with group D Salmonella. The median (range) number of days between diagnosis by RDT and reference assays was 1 (-1 to +2) day for those with confirmed S. Typhi. The use of antigen-based pathogen detection in blood culture fluid may be a useful, relatively rapid, inexpensive, and accurate technique for the identification of important causes of bacteremia in the tropics. Hide abstract

Newton PN, Fernández FM, Plançon A, Mildenhall DC, Green MD, Ziyong L, Christophel EM, Phanouvong S et al. 2008. A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia. PLoS Med, 5 (2), pp. e32. Read abstract | Read more

BACKGROUND: Since 1998 the serious public health problem in South East Asia of counterfeit artesunate, containing no or subtherapeutic amounts of the active antimalarial ingredient, has led to deaths from untreated malaria, reduced confidence in this vital drug, large economic losses for the legitimate manufacturers, and concerns that artemisinin resistance might be engendered. METHODS AND FINDINGS: With evidence of a deteriorating situation, a group of police, criminal analysts, chemists, palynologists, and health workers collaborated to determine the source of these counterfeits under the auspices of the International Criminal Police Organization (INTERPOL) and the Western Pacific World Health Organization Regional Office. A total of 391 samples of genuine and counterfeit artesunate collected in Vietnam (75), Cambodia (48), Lao PDR (115), Myanmar (Burma) (137) and the Thai/Myanmar border (16), were available for analysis. Sixteen different fake hologram types were identified. High-performance liquid chromatography and/or mass spectrometry confirmed that all specimens thought to be counterfeit (195/391, 49.9%) on the basis of packaging contained no or small quantities of artesunate (up to 12 mg per tablet as opposed to approximately 50 mg per genuine tablet). Chemical analysis demonstrated a wide diversity of wrong active ingredients, including banned pharmaceuticals, such as metamizole, and safrole, a carcinogen, and raw material for manufacture of methylenedioxymethamphetamine ('ecstasy'). Evidence from chemical, mineralogical, biological, and packaging analysis suggested that at least some of the counterfeits were manufactured in southeast People's Republic of China. This evidence prompted the Chinese Government to act quickly against the criminal traders with arrests and seizures. CONCLUSIONS: An international multi-disciplinary group obtained evidence that some of the counterfeit artesunate was manufactured in China, and this prompted a criminal investigation. International cross-disciplinary collaborations may be appropriate in the investigation of other serious counterfeit medicine public health problems elsewhere, but strengthening of international collaborations and forensic and drug regulatory authority capacity will be required. Hide abstract

Phetsouvanh R, Phongmany S, Soukaloun D, Rasachak B, Soukhaseum V, Soukhaseum S, Frichithavong K, Khounnorath S et al. 2006. Causes of community-acquired bacteremia and patterns of antimicrobial resistance in Vientiane, Laos. Am J Trop Med Hyg, 75 (5), pp. 978-985. Read abstract

There is no published information on the causes of bacteremia in the Lao PDR (Laos). Between 2000 and 2004, 4512 blood culture pairs were taken from patients admitted to Mahosot Hospital, Vientiane, Laos, with suspected community-acquired bacteremia; 483 (10.7%) cultures grew a clinically significant community-acquired organism, most commonly Salmonella enterica serovar typhi (50.9%), Staphylococcus aureus (19.0%), and Escherichia coli (12.4%). S. aureus bacteremia was common among infants (69.2%), while children 1-5 years had a high frequency of typhoid (44%). Multi-drug-resistant S. Typhi was rare (6%). On multiple logistic regression analysis, typhoid was associated with younger age, longer illness, diarrhea, higher admission temperature, and lower peripheral white blood cell count than non-typhoidal bacteremia. Empirical parenteral ampicillin and gentamicin would have some activity against approximately 88% of clinically significant isolates at a cost of US $1.4/day, an important exception being B. pseudomallei. Bacteremic infants in this setting require an anti-staphylococcal antibiotic. Hide abstract

Newton PN, Green MD, Fernández FM, Day NP, White NJ. 2006. Counterfeit anti-infective drugs. Lancet Infect Dis, 6 (9), pp. 602-613. Read abstract | Read more

The production of counterfeit or substandard anti-infective drugs is a widespread and under-recognised problem that contributes to morbidity, mortality, and drug resistance, and leads to spurious reporting of resistance and toxicity and loss of confidence in health-care systems. Counterfeit drugs particularly affect the most disadvantaged people in poor countries. Although advances in forensic chemical analysis and simple field tests will enhance drug quality monitoring, improved access to inexpensive genuine medicines, support of drug regulatory authorities, more open reporting, vigorous law enforcement, and more international cooperation with determined political leadership will be essential to counter this threat. Hide abstract

Phongmany S, Rolain JM, Phetsouvanh R, Blacksell SD, Soukkhaseum V, Rasachack B, Phiasakha K, Soukkhaseum S et al. 2006. Rickettsial infections and fever, Vientiane, Laos. Emerg Infect Dis, 12 (2), pp. 256-262. Read abstract | Read more

Rickettsial diseases have not been described previously from Laos, but in a prospective study, acute rickettsial infection was identified as the cause of fever in 115 (27%) of 427 adults with negative blood cultures admitted to Mahosot Hospital in Vientiane, Laos. The organisms identified by serologic analysis were Orientia tsutsugamushi (14.8%), Rickettsia typhi (9.6%), and spotted fever group rickettsia (2.6% [8 R. helvetica, 1 R. felis, 1 R. conorii subsp. indica, and 1 Rickettsia "AT1"]). Patients with murine typhus had a lower frequency of peripheral lymphadenopathy than those with scrub typhus (3% vs. 46%, p<0.001). Rickettsioses are an underrecognized cause of undifferentiated febrile illnesses among adults in Laos. This finding has implications for the local empiric treatment of fever. Hide abstract

Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, Bruneton C, Phanouvong S, Millet P et al. 2006. Manslaughter by fake artesunate in Asia--will Africa be next? PLoS Med, 3 (6), pp. e197. | Read more

Newton PN, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. 2003. Randomized comparison of artesunate and quinine in the treatment of severe falciparum malaria. Clin Infect Dis, 37 (1), pp. 7-16. Read abstract | Read more

A randomized, open-label comparison of artesunate and quinine was conducted in 113 adults with clinically severe falciparum malaria in western Thailand. Mortality was 12% with artesunate and 22% with quinine treatment (relative risk, 0.53; 95% confidence interval, 0.23-1.26; P=.22). Multiple logistic regression analysis found admission plasma lactate level, Glasgow Coma Scale score, and total serum bilirubin level to be independent risk factors for death. Coma recovery and times to normalize plasma lactate levels were similar, but the parasite clearance time was much shorter among artesunate-treated patients (P=.019). Fewer patients became hypoglycemic during artesunate therapy (10%) than during quinine therapy (28%) (P=.03). Artesunate is at least as effective as quinine in the treatment of adults with severe malaria. Larger trials are required to determine whether mortality is reduced among patients treated with artesunate. Hide abstract

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