Publications 2006

Stepniewska K, White NJ. 2006. Some considerations in the design and interpretation of antimalarial drug trials in uncomplicated falciparum malaria. Malar J, 5 (1), pp. 127. | Citations: 46 (Scopus) | Show Abstract | Read more

BACKGROUND: Treatments for uncomplicated falciparum malaria should have high cure rates. The World Health Organization has recently set a target cure rate of 95% assessed at 28 days. The use of more effective drugs, with longer periods of patient follow-up, and parasite genotyping to distinguish recrudescence from reinfection raise issues related to the design and interpretation of antimalarial treatment trials in uncomplicated falciparum malaria which are discussed here. METHODS: The importance of adequate follow-up is presented and the advantages and disadvantages of non-inferiority trials are discussed. The different methods of interpreting trial results are described, and the difficulties created by loss to follow-up and missing or indeterminate genotyping results are reviewed. CONCLUSION: To characterize cure rates adequately assessment of antimalarial drug efficacy in uncomplicated malaria requires a minimum of 28 days and as much as 63 days follow-up after starting treatment. The longer the duration of follow-up in community-based assessments, the greater is the risk that this will be incomplete, and in endemic areas, the greater is the probability of reinfection. Recrudescence can be distinguished from reinfection using PCR genotyping but there are commonly missing or indeterminate results. There is no consensus on how these data should be analysed, and so a variety of approaches have been employed. It is argued that the correct approach to analysing antimalarial drug efficacy assessments is survival analysis, and patients with missing or indeterminate PCR results should either be censored from the analysis, or if there are sufficient data, results should be adjusted based on the identified ratio of new infections to recrudescences at the time of recurrent parasitaemia. Where the estimated cure rates with currently recommended treatments exceed 95%, individual comparisons with new regimens should generally be designed as non-inferiority trials with sample sizes sufficient to determine adequate precision of cure rate estimates (such that the lower 95% confidence interval bound exceeds 90%).

Newton PN, Barnes KI, Smith PJ, Evans AC, Chierakul W, Ruangveerayuth R, White NJ. 2006. The pharmacokinetics of intravenous artesunate in adults with severe falciparum malaria. Eur J Clin Pharmacol, 62 (12), pp. 1003-1009. | Citations: 31 (Scopus) | Show Abstract | Read more

OBJECTIVE: Intravenous artesunate is commonly used in the emergency treatment of patients with severe falciparum malaria in Asia. The choice of doses used has been empirical. To inform dosage recommendations we assessed the pharmacokinetics of intravenous artesunate after the first dose. METHODS: As part of a clinical trial of artesunate in adults with severe falciparum malaria in western Thailand, we assayed plasma concentrations of artesunate and the principal biologically active metabolite dihydroartemisinin (DHA) in 17 patients given an initial dose of 2.4 mg/kg body weight of intravenous artesunate. Drug levels were measured using high performance liquid chromatography with mass spectroscopy-electrospray ionisation detection. RESULTS: Median (range) observed DHA Cmax was 2128 (513-5789) nmol/L, elimination half-life was 0.34 (0.14-0.87) h, and the time to the last detectable DHA was 2 h. CONCLUSION: The large inter-individual variability (10 fold) in DHA Cmax and AUC in patients with potentially lethal, severe malaria, suggests that 2.4 mg/kg should be the minimum daily dose in severe malaria.

Sayasone S, Odermatt P, Vongphrachanh P, Keoluangkot V, Dupouy-Camet J, Newton PN, Strobel M. 2006. A trichinellosis outbreak in Borikhamxay Province, Lao PDR. Trans R Soc Trop Med Hyg, 100 (12), pp. 1126-1129. | Citations: 20 (Scopus) | Show Abstract | Read more

Trichinellosis is documented in Southeast Asia, particularly in Thailand and China. Data from Lao PDR are lacking. An outbreak investigation was conducted in Borikhamxay Province after three patients with suspected trichinellosis consulted the Mahosot Hospital, Vientiane. In total, 22 trichinellosis cases were identified; 21 cases could be confirmed by Western blot. High fever (100%), muscle pain (91%), upper eyelid oedema (86%) and diarrhoea (59%) were observed. Among the 22 patients, 86% had consumed pork meat from the same source. This is the first report of an outbreak investigation in Lao PDR since 1975. It shows that the incidence of trichinellosis is much higher than currently thought.

Lindegårdh N, Giorgi F, Galletti B, Di Mattia M, Quaglia M, Carnevale D, White NJ, Mazzanti A, Day NPJ. 2006. Identification of an isomer impurity in piperaquine drug substance. J Chromatogr A, 1135 (2), pp. 166-169. | Citations: 7 (Scopus) | Show Abstract | Read more

A significant contaminant of the antimalarial drug piperaquine (1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]propane) has been identified using liquid chromatography-mass spectrometry (LC-MS) and 2D NMR spectroscopy (1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC). The impurity was identified as the positional isomer 1-[(5-chloroquinolin-4)-piperazinyl]-3-[(7-chloroquinolin-4)-piperazinyl]propane. The impurity is formed because of contamination of batches of 4,7-dichloroquinoline (a precursor in the synthesis of piperaquine) with 4,5-dichloroquinoline. The amount of impurity (peak area impurity/peak area piperaquine using LC-UV at 347 nm) in old batches of piperaquine and in Artekin (the combination of dihydroartemisinin-piperaquine) ranged from 1.5 to 5%.

Chierakul W, Wangboonskul J, Singtoroj T, Pongtavornpinyo W, Short JM, Maharjan B, Wuthiekanun V, Dance DAB, Teparrukkul P, Lindegardh N et al. 2006. Pharmacokinetic and pharmacodynamic assessment of co-amoxiclav in the treatment of melioidosis. J Antimicrob Chemother, 58 (6), pp. 1215-1220. | Citations: 12 (Scopus) | Show Abstract | Read more

OBJECTIVES: We conducted a prospective pharmacokinetic study of oral co-amoxiclav in patients with melioidosis to determine the optimal dosage and dosing interval in this potentially fatal infection. PATIENTS AND METHODS: Serial plasma concentrations were measured after administration of two 1 g tablets of Augmentin (1750 mg of amoxicillin and 250 mg of clavulanate) to 14 adult patients with melioidosis. Monte Carlo simulation was used to predict the concentration of each drug following multiple doses of co-amoxiclav at different dosages and dose intervals. The proportion of the dose-interval above MIC (T > MIC) was calculated from 10,000 simulated subject plasma concentration profiles together with chequerboard MIC data from 46 clinical isolates and four reference strains of Burkholderia pseudomallei. RESULTS: The median (range) observed maximum plasma concentrations of amoxicillin and clavulanate were 11.5 (3.3-40.2) mg/L and 5.1 (0.8-12.1) mg/L, respectively. The median (range) elimination half-lives were 94 (73-215) and 89 (57-140) min, respectively. Simulation indicated that co-amoxiclav 1750/250 mg given at 4, 6, 8 or 12 hourly dosing intervals would be associated with a T > MIC of < or = 50% in 0.7%, 2.8%, 8.6% and 33.2% of patients, respectively. Corresponding proportions for T > MIC of > or = 90% were 95.8%, 78.6%, 50.2% and 10.8%, respectively. CONCLUSIONS: The dosing interval for co-amoxiclav (750/250 mg) in melioidosis should not be greater than 6 h.

Ashley E, McGready R, Singhasivanon P, Nosten F, Carrara V, Price R. 2006. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate-mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Trop Med Int Health, 11 (12), pp. 1898-1899. | Citations: 3 (European Pubmed Central) | Read more

Sonthayanon P, Chierakul W, Wuthiekanun V, Blacksell SD, Pimda K, Suputtamongkol Y, Pukrittayakamee S, White NJ, Day NP, Peacock SJ. 2006. Rapid diagnosis of scrub typhus in rural Thailand using polymerase chain reaction. Am J Trop Med Hyg, 75 (6), pp. 1099-1102. | Citations: 38 (Scopus) | Show Abstract | Read more

The aim of this study was to evaluate the use of polymerase chain reaction (PCR) amplification of the O. tsutsugamushi 16S rRNA gene for the diagnosis of scrub typhus in rural Thailand. A prospective study of acute febrile illness in Udon Thani, northeast Thailand, identified 183 patients as having scrub typhus on the basis of immunofluorescent antibody testing (IFA) of paired sera. A further 366 febrile patients admitted concurrently with a range of other diagnoses acted as negative controls. Diagnostic sensitivity and specificity of 16S rRNA PCR was 44.8% and 99.7%, respectively, compared with IFA. PCR positivity was related to duration of symptoms and presence of eschar (P < 0.001, both cases). PCR using primers to amplify a fragment of the 56-kd gene had a sensitivity and specificity of 29.0% and 99.2%, respectively. PCR has a high specificity but low sensitivity for the rapid diagnosis of scrub typhus in this endemic setting.

Tarning J, Bergqvist Y, Day NP, Bergquist J, Arvidsson B, White NJ, Ashton M, Lindegårdh N. 2006. Characterization of human urinary metabolites of the antimalarial piperaquine. Drug Metab Dispos, 34 (12), pp. 2011-2019. | Citations: 30 (Scopus) | Show Abstract | Read more

Five metabolites of the antimalarial piperaquine (PQ) (1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane) have been identified and their molecular structures characterized. After a p.o. dose of dihydroartemisinin-piperaquine, urine collected over 16 h from two healthy subjects was analyzed using liquid chromatography (LC)/UV, LC/tandem mass spectrometry (MS/MS), Fourier transform ion cyclotron resonance (FTICR)/MS, and H NMR. Five different peaks were recognized as possible metabolites [M1, 320 m/z; M2, M3, and M4, 551 m/z (PQ + 16 m/z); and M5, 567 m/z (PQ + 32 m/z)] using LC/MS/MS with gradient elution. The proposed carboxylic M1 has a theoretical monoisotopic molecular mass of 320.1166 m/z, which is in accordance with the FTICR/MS (320.1168 m/z) findings. The LC/MS/MS results also showed a 551 m/z metabolite (M2) with a distinct difference both in polarity and fragmentation pattern compared with PQ, 7-hydroxypiperaquine, and the other 551 m/z metabolites. We suggest that this is caused by N-oxidation of PQ. The results showed two metabolites (M3 and M4) with a molecular ion at 551 m/z and similar fragmentation pattern as both PQ and 7-hydroxypiperaquine; therefore, they are likely to be hydroxylated PQ metabolites. The molecular structures of M1 and M2 were also confirmed using H NMR. Urinary excretion rate in one subject suggested a terminal elimination half-life of about 53 days for M1. Assuming formation rate-limiting kinetics, this would support recent findings that the terminal elimination half-life of PQ has been underestimated previously.

McGready R, Stepniewska K, Lindegardh N, Ashley EA, La Y, Singhasivanon P, White NJ, Nosten F. 2006. The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria. Eur J Clin Pharmacol, 62 (12), pp. 1021-1031. | Citations: 92 (Scopus) | Show Abstract | Read more

OBJECTIVE: To determine the pharmacokinetic properties of artemether and lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria. METHODS: Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood samples were taken over a 7-day period, and pharmacokinetic parameters were estimated. For lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria. RESULTS: The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and lumefantrine, and the elimination of lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults. CONCLUSION: Pregnancy is associated with reduced plasma concentrations of both artemether and lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-lumefantrine in pregnancy.

Khan AM, Miotto O, Heiny AT, Salmon J, Srinivasan KN, Nascimento EJM, Marques ETA, Brusic V, Tan TW, August JT. 2006. A systematic bioinformatics approach for selection of epitope-based vaccine targets. Cell Immunol, 244 (2), pp. 141-147. | Citations: 57 (Scopus) | Show Abstract | Read more

Epitope-based vaccines provide a new strategy for prophylactic and therapeutic application of pathogen-specific immunity. A critical requirement of this strategy is the identification and selection of T-cell epitopes that act as vaccine targets. This study describes current methodologies for the selection process, with dengue virus as a model system. A combination of publicly available bioinformatics algorithms and computational tools are used to screen and select antigen sequences as potential T-cell epitopes of supertype human leukocyte antigen (HLA) alleles. The selected sequences are tested for biological function by their activation of T-cells of HLA transgenic mice and of pathogen infected subjects. This approach provides an experimental basis for the design of pathogen specific, T-cell epitope-based vaccines that are targeted to majority of the genetic variants of the pathogen, and are effective for a broad range of differences in human leukocyte antigens among the global human population.

Barnes KI, Little F, Smith PJ, Evans A, Watkins WM, White NJ. 2006. Sulfadoxine-pyrimethamine pharmacokinetics in malaria: pediatric dosing implications. Clin Pharmacol Ther, 80 (6), pp. 582-596. | Citations: 93 (Scopus) | Show Abstract | Read more

OBJECTIVE: Our objective was to characterize the pharmacokinetic properties of sulfadoxine-pyrimethamine in African adults and children with acute falciparum malaria. Despite decades of widespread use, there are few data to inform dose recommendations. METHODS: In a prospective multicenter pharmacokinetic study in 307 patients with acute falciparum malaria, capillary blood concentrations of sulfadoxine and pyrimethamine were determined at 9 visits over a period of 42 days by mass spectrometry. RESULTS: After adjustment for dose, the area under the concentration-time curves (AUCs) of sulfadoxine and pyrimethamine in children aged 2 to 5 years were half of those in adults (median AUC, 410 microg/mL x d [interquartile range (IQR), 126-705 microg/mL x d] versus 816 microg/mL x d [IQR, 536-1150 microg/mL x d] [P = .0001] for sulfadoxine and 620 ng/mL x d [IQR, 229-1399 ng/mL x d] versus 1518 ng/mL x d [IQR, 1117-2013 ng/mL x d] for pyrimethamine). The effect of age on the AUC of sulfadoxine and pyrimethamine reflected higher clearance rates and larger apparent volumes of distribution in children aged 2 to 5 years when compared with adults (median clearance, 64.5 mL x kg(-1) x d(-1) [IQR, 46.2-132.6 mL x kg(-1) x d(-1)] versus 32.7 mL x kg(-1) x d(-1) [IQR, 22.3-52.2 mL x kg(-1) x d(-1)] for sulfadoxine [P = .0001] and 1.77 L x kg(-1) x d(-1) [IQR, 1.0-3.0 L x kg(-1) x d(-1)] versus 0.85 L x kg(-1) x d(-1) [IQR, 0.62-1.21 L x kg(-1) x d(-1)] for pyrimethamine [P = .0001]; median volume of distribution, 413 mL/kg [IQR, 299-711 mL/kg] versus 372 mL/kg [IQR, 267-488 mL/kg] for sulfadoxine [P = .0021] and 6.28 L/kg [IQR, 3.83-11.24 L/kg] versus 3.83 L/kg [IQR, 2.73-5.11 L/kg] for pyrimethamine [P = .0001]). Day 7 concentrations of both sulfadoxine and pyrimethamine provided good surrogate measures (R(2) >or= 0.72) of their respective AUCs. CONCLUSIONS: Pharmacokinetic factors may contribute to the increased risk of sulfadoxine-pyrimethamine antimalarial treatment failure in young children. The current dose recommendations need revision. We predict that children aged 2 to 5 years should be treated with 1 g sulfadoxine/50 mg pyrimethamine to achieve drug concentrations equivalent to those in adults.

Taylor WRJ, Terlouw DJ, Olliaro PL, White NJ, Brasseur P, ter Kuile FO. 2006. Use of weight-for-age-data to optimize tablet strength and dosing regimens for a new fixed-dose artesunate-amodiaquine combination for treating falciparum malaria. Bull World Health Organ, 84 (12), pp. 956-964. | Citations: 48 (Scopus) | Show Abstract | Read more

OBJECTIVE: To test a novel methodology to define age-based dosing regimens for the treatment of malaria with a new, user-friendly, blister-packaged fixed-dose combination of artesunate and amodiaquine. METHODS: A weight-for-age reference database of 88 054 individuals from sub-Saharan Africa was compiled using data from Demographic Health Surveys, observational and intervention studies, and standardized for sex, age and malaria risk. We then determined the optimal tablet strength (milligram (mg) per tablet) and age-dose categories for the combination of artesunate and amodiaquine. The proportions of patients predicted to receive doses within newly defined therapeutic ranges for amodiaquine (7-15 mg/kg/day) and artesunate (2-10 mg/kg/day), were estimated for different age categories and mg tablet strengths using models based on the weight-for-age reference database. FINDINGS: The optimal paediatric (p) and adult (a) strength tablets contained 25/67.5 and 100/270 mg artesunate/amodiaquine, respectively. A regimen with five age categories: 0-1 months (1/2 p), 2-11 months (1 p), 1-5 years (2 p), 6-13 years (1 a), and > 14 years (2 a) had an overall dosing accuracy of 83.4% and 99.9% for amodiaquine and artesunate, respectively. CONCLUSION: The proposed method to use weight-for-age reference data from countries where malaria is endemic is a useful tool for designing age-based dosing regimens for antimalarial drugs for drug registration and field use.

Ashley E, McGready R, Singhasivanon P, Nosten F, Carrara V, Price R. 2006. Untitled TROPICAL MEDICINE & INTERNATIONAL HEALTH, 11 (12), pp. 1898-1899. | Citations: 3 (Web of Science Lite) | Read more

Orr HJ, Christensen H, Smyth B, Dance DAB, Carrington D, Paul I, Stuart JM, South West Q Fever Project Group. 2006. Case-control study for risk factors for Q fever in southwest England and Northern Ireland. Euro Surveill, 11 (10), pp. 260-262. | Citations: 15 (Scopus) | Show Abstract

Q fever (Coxiella burnetti) is thought to account for 1% (700 cases) of community acquired pneumonia in the United Kingdom each year, and can result in serious complications such as endocarditis. Although outbreaks have frequently been reported worldwide, the causes are often not clearly identified and there have been few studies of risk factors in sporadic cases. We conducted a matched case-control study. Cases of acute Q fever in people aged over 15 years in southwest England and Northern Ireland were identified from January 2002 to December 2004. Controls were matched for age, sex and the general practice at which they were registered. Questionnaires asking about contact with animals, and leisure and work activities, were posted to cases and controls. Questionnaires were completed by 39/50 (78%) of the cases and 90/180 (50%) of the controls. In the single variable analysis, occupational exposure to animals or animal products was the only risk factor associated with cases at the 5% level (P=0.05, odds ratio (OR) 3.4). Long term illness appeared to be significantly protective (P=0.03, OR 0.3). In multivariable analysis the strength of association between occupational exposure and illness remained high (OR 3.6, 95% confidence interval (CI) 0.9 to 14.8) and smoking emerged as a possible risk factor. This is the first case-control study to identify occupational exposure to animals or animal products as the most likely route of infection in sporadic cases as opposed to outbreaks.

Roumagnac P, Weill F-X, Dolecek C, Baker S, Brisse S, Chinh NT, Le TAH, Acosta CJ, Farrar J, Dougan G, Achtman M. 2006. Evolutionary history of Salmonella typhi. Science, 314 (5803), pp. 1301-1304. | Citations: 225 (Scopus) | Show Abstract | Read more

For microbial pathogens, phylogeographic differentiation seems to be relatively common. However, the neutral population structure of Salmonella enterica serovar Typhi reflects the continued existence of ubiquitous haplotypes over millennia. In contrast, clinical use of fluoroquinolones has yielded at least 15 independent gyrA mutations within a decade and stimulated clonal expansion of haplotype H58 in Asia and Africa. Yet, antibiotic-sensitive strains and haplotypes other than H58 still persist despite selection for antibiotic resistance. Neutral evolution in Typhi appears to reflect the asymptomatic carrier state, and adaptive evolution depends on the rapid transmission of phenotypic changes through acute infections.

White NJ. 2006. Malaria--time to act. N Engl J Med, 355 (19), pp. 1956-1957. | Citations: 19 (Scopus) | Read more

Phetsouvanh R, Phongmany S, Soukaloun D, Rasachak B, Soukhaseum V, Soukhaseum S, Frichithavong K, Khounnorath S, Pengdee B, Phiasakha K 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. | Citations: 69 (Scopus) | Show Abstract | Read more

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.

Nantakomon D, Udomsangpetch R, Pattanapunyasat K, Looareesuwan S, White NJ, Day NP, Chotivanich K. 2006. Circulating cell-derived microparticles in malaria patients AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 45-45.

Ashley EA, Lwin KM, McGready R, Simon WH, Phaiphun L, Proux S, Wangseang N, Taylor W, Stepniewska K, Nawamaneerat W et al. 2006. An open label randomized comparison of mefloquine-artesunate as separate tablets vs. a new co-formulated combination for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. Trop Med Int Health, 11 (11), pp. 1653-1660. | Citations: 37 (Scopus) | Show Abstract | Read more

BACKGROUND: Delivering drugs in a fixed combination is essential to the success of the strategy of artemisinin-based combination therapy. This prevents one drug being taken without the protection of the other, reducing the chance of emergence and spread of drug resistant strains of Plasmodium falciparum. A lower tablet burden should also facilitate adherence to treatment. A new fixed combination of mefloquine plus artesunate has been developed. This was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. METHODS: On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. They were followed up weekly for 63 days. RESULTS: The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2-95.6) in the fixed combination group and 89.2% (85.0-93.4) in the loose tablets group (P=0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. CONCLUSION: This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.

Simpson JA, Agbenyega T, Barnes KI, Di Perri G, Folb P, Gomes M, Krishna S, Krudsood S, Looareesuwan S, Mansor S et al. 2006. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med, 3 (11), pp. e444. | Citations: 39 (Scopus) | Show Abstract | Read more

BACKGROUND: Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. METHODS AND FINDINGS: Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 (l/kg) with 96% inter-individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0-6h were observed. CONCLUSIONS: The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations.

Hall KA, Newton PN, Green MD, De Veij M, Vandenabeele P, Pizzanelli D, Mayxay M, Dondorp A, Fernandez FM. 2006. Characterization of counterfeit artesunate antimalarial tablets from southeast Asia. Am J Trop Med Hyg, 75 (5), pp. 804-811. | Citations: 67 (Scopus) | Show Abstract | Read more

In southeast Asia, the widespread high prevalence of counterfeits tablets of the vital antimalarial artesunate is of great public health concern. To assess the seriousness of this problem, we quantified the amount of active ingredient present in artesunate tablets by liquid chromatography coupled to mass spectrometry. This method, in conjunction with analysis of the packaging, classified tablets as genuine, substandard, or fake and validated results of the colorimetric Fast Red TR test. Eight (35%) of 23 fake artesunate samples contained the wrong active ingredients, which were identified as different erythromycins and paracetamol. Raman spectroscopy identified calcium carbonate as an excipient in 9 (39%) of 23 fake samples. Multivariate unsupervised pattern recognition results indicated two major clusters of artesunate counterfeits, those with counterfeit foil stickers and containing calcium carbonate, erythromycin, and paracetamol, and those with counterfeit holograms and containing starch but without evidence of erythromycin or paracetamol.

Blacksell SD, Khounsy S, Phetsouvanh R, Newton PN. 2006. A simple and inexpensive container for the transport of biological specimens in limited resource situations. Trans R Soc Trop Med Hyg, 100 (11), pp. 1084-1086. | Citations: 3 (Web of Science Lite) | Show Abstract | Read more

We describe a diagnostic specimen transport container that is appropriate for limited resource or emergency settings. The transport container is constructed from polyvinyl chloride (PVC) plumbing pipe, which is readily available and inexpensive (US$1-2, depending on size) and has wide flexibility of size due to the range of PVC pipe dimensions available. The PVC transporters are durable, water-resistant and may be easily decontaminated. They have been adapted for the transport of blood culture bottles from provincial hospitals in Laos, where, during a 2-year period, 380 PVC tubes containing blood culture bottles were transported without any leakage or breakage. We have found the PVC transporter to be a useful and cost-efficient durable alternative that meets IATA Packing Instruction 650 biological transport container requirements.

Wuthiekanun V, Langa S, Swaddiwudhipong W, Jedsadapanpong W, Kaengnet Y, Chierakul W, Day NP, Peacock SJ. 2006. Short report: Melioidosis in Myanmar: forgotten but not gone? Am J Trop Med Hyg, 75 (5), pp. 945-946. | Citations: 14 (European Pubmed Central) | Show Abstract | Read more

A serologic survey of adults resident in Myanmar was conducted to define the presence of antibodies to Burkholderia pseudomallei, the cause of melioidosis. Antibodies were detectable by indirect hemagglutination assay (IHA) in 757 (78%) of 968 adults, of whom 69 (7%) had an IHA titer > or =1:160.

Popper S, Simmons CP, Dolecek C, Chau TNB, Griffiths M, Dung NTP, Long TH, Hoang DM, Van Vinh Chau N, Thao LTT et al. 2006. Gene expression programs in adults with acute dengue infections AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 290-290.

Lampah DA, Yeo TW, Kenangalem E, Gitawati R, Waramori G, Price RN, Lopansri B, Granger D, Sly P, Tjitra E, Anstey NM. 2006. Real-time bedside measurement of nitric oxide demonstrates impaired production in adults with severe malaria in papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 47-47.

Yeo TW, Lampah DA, Kenangalem E, Gitawati R, Tjitra E, McNeil Y, Granger D, Lopansri B, Celermajer D, Price RN et al. 2006. L-arginine infusion increases no production and reverses endothelial dysfunction in adults with moderately severe falciparum malaria in Papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 98-99.

Armedy R, Hotma L, Kanagalem E, Rumaseuw R, Ebsworth EP, Anstey NM, Tjitra E, Price RN. 2006. Amodiaquine plus artesunate versus dihydroartemisinin-piperaquine for drug resistant P.falciparum and P.vivax in Papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 208-208.

Yeo TW, Lampah DA, Kenangalem E, Gitawati R, Waramori G, McNeil Y, Duffull S, Tjitra E, Price RN, Celermajer D, Anstey NM. 2006. Impaired endothelial function in adults with severe falciparum malaria in Papua, Indonesia AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 286-286.

Le MVT, Le MLN, Campbell J, Nguyen TT, Thi DN, Dolecek C, Schultsz C. 2006. High rates of carriage of drug-resistant Enterobacteriaceae in healthy volunteers in Ho Chi Minh City AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 83-83.

Jain S, Lan NTP, Tai DT, Rang NN, La TTP, Bird M, Dolecek C, Van Sach N, Bang BX, Mintz ED et al. 2006. An evaluation of a rapid serodiagnostic test for typhoid fever - An giang, Vietnam 2005-2006 AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 75 (5), pp. 314-314.

Fleming V, Feil E, Sewell AK, Day N, Buckling A, Massey RC. 2006. Agr interference between clinical Staphylococcus aureus strains in an insect model of virulence. J Bacteriol, 188 (21), pp. 7686-7688. | Citations: 33 (Scopus) | Show Abstract | Read more

Repression of virulence by Staphylococcus aureus strains from different Agr groups has been demonstrated in vitro and is proposed as a means of competitive interference. Here, using the insect Manduca sexta, we show for the first time that this interference also occurs in vivo within a mixed population.

Thwaites CL, Yen LM, Loan HT, Thuy TTD, Thwaites GE, Stepniewska K, Soni N, White NJ, Farrar JJ. 2006. Magnesium sulphate for treatment of severe tetanus: a randomised controlled trial. Lancet, 368 (9545), pp. 1436-1443. | Citations: 93 (Scopus) | Show Abstract | Read more

BACKGROUND: The most common cause of death in individuals with severe tetanus in the absence of mechanical ventilation is spasm-related respiratory failure, whereas in ventilated patients it is tetanus-associated autonomic dysfunction. Our aim was to determine whether continuous magnesium sulphate infusion reduces the need for mechanical ventilation and improves control of muscle spasms and autonomic instability. METHODS: We did a randomised, double blind, placebo controlled trial in 256 Vietnamese patients over age 15 years with severe tetanus admitted to the Hospital for Tropical Medicine, Ho Chi Minh City, Vietnam. Participants were randomly assigned magnesium sulphate (n=97) or placebo solution (n=98) intravenously for 7 days. The primary outcomes were requirement of assisted ventilation and of drugs to control muscle spasms and cardiovascular instability within the 7-day study period. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN74651862. FINDINGS: No patients were lost to follow-up. There was no difference in requirement for mechanical ventilation between individuals treated with magnesium and those receiving placebo (odds ratio 0.71, 95% CI 0.36-1.40; p=0.324); survival was also much the same in the two groups. However, compared with the placebo group, patients receiving magnesium required significantly less midazolam (7.1 mg/kg per day [0.1-47.9] vs 1.4 mg/kg per day [0.0-17.3]; p=0.026) and pipecuronium (2.3 mg/kg per day [0.0-33.0] vs 0.0 mg/kg per day [0.0-14.8]; p=0.005) to control muscle spasms and associated tachycardia. Individuals receiving magnesium were 4.7 (1.4-15.9) times less likely to require verapamil to treat cardiovascular instability than those in the placebo group. The incidence of adverse events was not different between the groups. INTERPRETATION: Magnesium infusion does not reduce the need for mechanical ventilation in adults with severe tetanus but does reduce the requirement for other drugs to control muscle spasms and cardiovascular instability.

Lindegårdh N, Hien TT, Farrar J, Singhasivanon P, White NJ, Day NPJ. 2006. A simple and rapid liquid chromatographic assay for evaluation of potentially counterfeit Tamiflu. J Pharm Biomed Anal, 42 (4), pp. 430-433. | Citations: 55 (Scopus) | Show Abstract | Read more

A simple and rapid liquid chromatographic assay for the evaluation of potentially counterfeit oseltamivir (Tamiflu has been developed and assessed. The assay uses approximately 1mg Tamiflu powder when used for authentication and content estimate. The procedure was validated using 50 replicates analysed during five independent series with a total R.S.D. of 11.2%. The assay can also be used to monitor the exact content of oseltamivir in Tamiflu capsules. One Tamiflu capsule was transferred to a 250mL volumetric flask and 150mL water was added. The flask was placed in an ultrasonic bath at 40 degrees C for 20min to dissolve the capsule. The solution was allowed to cool to room temperature before the flask was filled up to the mark (250mL). A small aliquot was centrifuged and then directly injected into the LC-system for quantification. Oseltamivir was analysed by liquid chromatography with UV detection on a Hypersil Gold column (150mmx4.6mm) using a mobile phase containing methanol-phosphate buffer (pH 2.5; 0.1M) (50:50, v/v) at a flow rate of 1.0mL/min. The assay was implemented for the analysis of Tamiflu purchased over the Internet and at local pharmacies in Thailand and Vietnam.

Siswantoro H, Ratclif A, Kenangalem E, Wuwung M, Maristela R, Rumaseuw R, Laihad F, Ebsworth P, Anstey NM, Price RN, Tjitra E. 2006. Efficacy of existing antimalarial drugs for uncomplicated malaria in Timika, Papua, Indonesia Medical Journal of Indonesia, 15 (4), pp. 251-251. | Citations: 3 (Scopus) | Show Abstract | Read more

© 2006 Faculty of Medicine, Universitas Indonesia. All rights reserved. Chloroquine resistant malaria is a serious problem in Indonesia particularly in Papua. A trial of the existing antimalarial drugs was conducted in Timika, Papua. The objective of the study was to determine the efficacy of cloroquine (CQ) ± sulfadoxine-pyrimethamine (SP). Patients with uncomplicated malaria due to Plasmodium falciparum, P. vivax, P. ovale or P. malariae were enrolled and treated with supervised CQ+SP (P. falciparum) or CQ (non-P. falciparum). Patients were followed for 28-42 days. Patients failing therapy were retreated with unsupervised quinine±doxycycline. 207 patients were enrolled in the study (88 P. falciparum, 40 P. vivax, 15 mixed infections, 50 P. malariae and 14 P. ovale). Early treatment failures occurred in 4 of 86 (5%) patients with falciparum malaria, 6 of 37 (16%) patients with vivax malaria and none of those with P. ovale or P. malariae infections. The failure rate by day 28 for P. vivax was 22 of 30 (73%) patients, with all recurrences occurring in the presence of plasma chloroquine concentration above the minimum effective concentration (MEC>15ng/ml). After correcting for reinfections the day 42 recrudescence rate for falciparum malaria was 48% [95%CI:31-65] and in 61% of cases this was in the presence of chloroquine levels above 30 ng/ml. Retreatment with unsupervised quinine±doxycycline resulted in further recurrence of malaria in 48% [95%CI:31-65] of P. falciparum infections and 70% [95%CI:37-100] of P. vivax infections. None of the patients with P. ovale or P. malariae had treatment failures within 28 days. There is a high prevalence of antimalarial drug resistance of P. falciparum and P. vivax to the existing antimalarial drugs. However chloroquine retains adequate efficacy against P. ovale and P. malariae in Papua.

Blacksell SD, Smythe L, Phetsouvanh R, Dohnt M, Hartskeerl R, Symonds M, Slack A, Vongsouvath M, Davong V, Lattana O et al. 2006. Limited diagnostic capacities of two commercial assays for the detection of Leptospira immunoglobulin M antibodies in Laos. Clin Vaccine Immunol, 13 (10), pp. 1166-1169. | Citations: 41 (Web of Science Lite) | Show Abstract | Read more

The diagnostic utility of immunochromatographic (Leptotek) and enzyme-linked immunosorbent assay (ELISA; Panbio) tests for the detection of Leptospira immunoglobulin M antibodies was assessed in febrile adults admitted in Vientiane, Laos. Both tests demonstrated poor diagnostic accuracy using admission serum (Leptotek sensitivity of 47.3% and specificity of 75.5%: ELISA sensitivity of 60.9% and specificity of 65.6%) compared to the Leptospira "gold standard" microscopic agglutination test.

Day N. 2006. Fluid resuscitation in malaria: the need for new randomised clinical trials. PLoS Clin Trials, 1 (5), pp. e24. | Citations: 4 (Web of Science Lite) | Read more

Newton PN, Green MD, Fernández FM, Day NPJ, White NJ. 2006. Counterfeit anti-infective drugs. Lancet Infect Dis, 6 (9), pp. 602-613. | Citations: 222 (Scopus) | Show 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.

Kosaisavee V, Suwanarusk R, Nosten F, Kyle DE, Barrends M, Jones J, Price R, Russell B, Lek-Uthai U. 2006. Plasmodium vivax: isotopic, PicoGreen, and microscopic assays for measuring chloroquine sensitivity in fresh and cryopreserved isolates. Exp Parasitol, 114 (1), pp. 34-39. | Citations: 36 (Scopus) | Show Abstract | Read more

In vitro susceptibility tests provide information on the intrinsic response of Plasmodium vivax to antimalarials, free from confounding factors such as host immunity or relapse. This study examined the utility of radioisotope and PicoGreen assays as alternatives to the traditional microscopic examination for assessing response of P. vivax to antimalarial drugs. There was no significant difference in the mean chloroquine IC(50) of P. vivax (n=40) as determined by the microscopic (33.4 ng/ml), isotopic (33.6 ng/ml), and PicoGreen (39.1 ng/ml) assays, respectively (F=0.239, df=2, 51, and p=0.788). However measurement of IC(50)s by the microscopic method was slightly more successful in producing valid assays (57%), compared to the isotopic (32.5%) and PicoGreen (45.5%) methods. In a paired comparison of 20 fresh and cryopreserved isolates as examined by the microscopic method, there were no significant differences between the mean IC(50) responses (T=1.58, df=15, and p=0.34). Detailed methodologies for the short time culture of field and cryopreserved P. vivax are described. Although the microscopic in vitro assay provides a useful method for characterizing the drug susceptibility phenotype of P. vivax isolates, its utility is limited by a laborious methodology and need for highly skilled microscopists. Future efforts should focus on further development of high throughput assays such as the PicoGreen assay as described in this study.

Lindegardh N, Davies GR, Tran TH, Farrar J, Singhasivanon P, Day NPJ, White NJ. 2006. Rapid degradation of oseltamivir phosphate in clinical samples by plasma esterases. Antimicrob Agents Chemother, 50 (9), pp. 3197-3199. | Citations: 39 (Scopus) | Show Abstract | Read more

The anti-influenza drug oseltamivir is an ester prodrug activated by hepatic carboxylesterases. Plasma esterases also convert up to 31.8% of the parent compound to the active metabolite after 4 h ex vivo, with wide interindividual variation. This source of error is removed by adding the esterase inhibitor dichlorvos to blood collection tubes.

Waris M, White LJ. 2006. Seasonality of respiratory syncytial virus infection. Clin Infect Dis, 43 (4), pp. 541. | Citations: 4 (European Pubmed Central) | Read more

Kim J-R, Imwong M, Nandy A, Chotivanich K, Nontprasert A, Tonomsing N, Maji A, Addy M, Day NPJ, White NJ, Pukrittayakamee S. 2006. Genetic diversity of Plasmodium vivax in Kolkata, India. Malar J, 5 (1), pp. 71. | Citations: 68 (Scopus) | Show Abstract | Read more

BACKGROUND: Plasmodium vivax malaria accounts for approximately 60% of malaria cases in Kolkata, India. There has been limited information on the genotypic polymorphism of P. vivax in this malaria endemic area. Three highly polymorphic and single copy genes were selected for a study of genetic diversity in Kolkata strains. METHODS: Blood from 151 patients with P. vivax infection diagnosed in Kolkata between April 2003 and September 2004 was genotyped at three polymorphic loci: the P. vivax circumsporozoite protein (pvcs), the merozoite surface protein 1 (pvmsp1) and the merozoite surface protein 3-alpha (pvmsp3-alpha). RESULTS: Analysis of these three genetic markers revealed that P. vivax populations in Kolkata are highly diverse. A large number of distinguishable alleles were found from three genetic markers: 11 for pvcs, 35 for pvmsp1 and 37 for pvmsp3-alpha. These were, in general, randomly distributed amongst the isolates. Among the 151 isolates, 142 unique genotypes were detected the commonest genotype at a frequency of less than 2% (3/151). The overall rate of mixed genotype infections was 10.6%. CONCLUSION: These results indicate that the P. vivax parasite population is highly diverse in Kolkata, despite the low level of transmission. The genotyping protocols used in this study may be useful for differentiating re-infection from relapse and recrudescence in studies assessing of malarial drug efficacy in vivax malaria.

Blacksell SD, Doust JA, Newton PN, Peacock SJ, Day NPJ, Dondorp AM. 2006. A systematic review and meta-analysis of the diagnostic accuracy of rapid immunochromatographic assays for the detection of dengue virus IgM antibodies during acute infection. Trans R Soc Trop Med Hyg, 100 (8), pp. 775-784. | Citations: 36 (Scopus) | Show Abstract | Read more

A meta-analysis of rapid (</=60 min) dengue diagnostic assays was conducted to determine accuracy and identify causes of between-study heterogeneity. A systematic review identified 302 potentially suitable studies, of which 11 were selected for meta-analysis. All selected studies evaluated the immunochromatographic test (ICT) manufactured by Panbio Pty Ltd. Individual study results for sensitivity ranged from 0.45 to 1.0, specificity 0.57-1.0, diagnostic odds ratio 4.5-1287, and positive:negative likelihood ratios 2.3-59 and 0.01-0.56, respectively. Results indicated that the ICT evaluated in the selected studies can both rule in and rule out disease but is more accurate when samples are collected later in the acute phase of infection. Limitations of this meta-analysis were significant between-study heterogeneity caused by inconsistencies in evaluation methodologies, and the evaluation of only the Panbio ICT. It is recommended that additional, standardized evaluations are required for other dengue ICTs.

Mayxay M, Thongpraseuth V, Khanthavong M, Lindegårdh N, Barends M, Keola S, Pongvongsa T, Phompida S, Phetsouvanh R, Stepniewska K et al. 2006. An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People's Democratic Republic (Laos). Trop Med Int Health, 11 (8), pp. 1157-1165. | Citations: 47 (Web of Science Lite) | Show Abstract | Read more

OBJECTIVE: To determine the efficacy and safety of oral dihydroartemisinin-piperaquine (DP, Artekin) in the treatment of uncomplicated Plasmodium falciparum malaria in southern Laos. METHODS: An open, randomized clinical trial of oral artesunate-mefloquine (AM) vs. DP in 220 patients with acute uncomplicated falciparum malaria in Savannakhet Province, Laos. RESULTS: The 42-day cure rates (95% CI), as determined by survival analysis and adjusted for reinfection, were excellent and similar for the two groups [99 (94-100)% and 100 (100-100)% for AM and DP, respectively]. The median (range) fever and parasite clearance times for the AM and DP groups were also similar [20 (4-63) h and 2 (1-4) days vs. 20 (7-57) and 2 (1-4) days, logrank P = 0.4 and 0.17, respectively]. There were more patients with at least one potential side effect following treatment in the AM group when compared with the DP group [64/110 (58%) vs. 48/110 (44%), respectively, P = 0.031]. CONCLUSION: Dihydroartemisinin-piperaquine did not have superior efficacy to AM for the treatment of uncomplicated falciparum malaria in Laos but was associated with fewer adverse effects.

Cooper B. 2006. Poxy models and rash decisions. Proc Natl Acad Sci U S A, 103 (33), pp. 12221-12222. | Citations: 11 (Web of Science Lite) | Read more

Vesaratchavest M, Tumapa S, Day NPJ, Wuthiekanun V, Chierakul W, Holden MTG, White NJ, Currie BJ, Spratt BG, Feil EJ, Peacock SJ. 2006. Nonrandom distribution of Burkholderia pseudomallei clones in relation to geographical location and virulence. J Clin Microbiol, 44 (7), pp. 2553-2557. | Citations: 60 (Scopus) | Show Abstract | Read more

Burkholderia pseudomallei is a soil-dwelling saprophyte and the causative agent of melioidosis, a life-threatening human infection. Most cases are reported from northeast Thailand and northern Australia. Using multilocus sequence typing (MLST), we have compared (i) soil and invasive isolates from northeast Thailand and (ii) invasive isolates from Thailand and Australia. A total of 266 Thai B. pseudomallei isolates were characterized (83 soil and 183 invasive). These corresponded to 123 sequence types (STs), the most abundant being ST70 (n=21), ST167 (n=15), ST54 (n=12), and ST58 (n=11). Two clusters of related STs (clonal complexes) were identified; the larger clonal complex (CC48) did not conform to a simple pattern of radial expansion from an assumed ancestor, while a second (CC70) corresponded to a simple radial expansion from ST70. Despite the large number of STs, overall nucleotide diversity was low. Of the Thai isolates, those isolated from patients with melioidosis were overrepresented in the 10 largest clones (P<0.0001). There was a significant difference in the classification index between environmental and disease isolates (P<0.001), confirming that genotypes were not distributed randomly between the two samples. MLST profiles for 158 isolates from Australia (mainly disease associated) contained a number of STs (96) similar to that seen with the Thai invasive isolates, but no ST was found in both populations. There were also differences in diversity and allele frequency distribution between the two populations. This analysis reveals strong genetic differentiation on the basis of geographical isolation and a significant differentiation on the basis of virulence potential.

Nosten F, Ashley E, McGready R, Price R. 2006. We still need artesunate monotherapy. BMJ, 333 (7557), pp. 45. | Citations: 9 (Scopus) | Read more

Ashley EA, Stepniewska K, Lindegårdh N, McGready R, Hutagalung R, Hae R, Singhasivanon P, White NJ, Nosten F. 2006. Population pharmacokinetic assessment of a new regimen of mefloquine used in combination treatment of uncomplicated falciparum malaria. Antimicrob Agents Chemother, 50 (7), pp. 2281-2285. | Citations: 41 (Scopus) | Show Abstract | Read more

A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.

Smithuis F, Kyaw MK, Phe O, Aye KZ, Htet L, Barends M, Lindegardh N, Singtoroj T, Ashley E, Lwin S et al. 2006. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet, 367 (9528), pp. 2075-2085. | Citations: 115 (Scopus) | Show Abstract | Read more

BACKGROUND: Artemisinin-based combinations are judged the best treatments for multidrug-resistant Plasmodium falciparum malaria. Artesunate-mefloquine is widely recommended in southeast Asia, but its high cost and tolerability profile remain obstacles to widespread deployment. To assess whether dihydroartemisinin-piperaquine is a suitable alternative to artesunate-mefloquine, we compared the safety, tolerability, efficacy, and effectiveness of the two regimens for the treatment of uncomplicated falciparum in western Myanmar (Burma). METHODS: We did an open randomised comparison of 3-day regimens of artesunate-mefloquine (12/25 mg/kg) versus dihydroartemisinin-piperaquine (6.3/50 mg/kg) for the treatment of children aged 1 year or older and in adults with uncomplicated falciparum malaria in Rakhine State, western Myanmar. Within each group, patients were randomly assigned supervised or non-supervised treatment. The primary endpoint was the PCR-confirmed parasitological failure rate by day 42. Failure rates at day 42 were estimated by Kaplan-Meier survival analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN27914471. FINDINGS: Of 652 patients enrolled, 327 were assigned dihydroartemisinin-piperaquine (156 supervised and 171 not supervised), and 325 artesunate-mefloquine (162 and 163, respectively). 16 patients were lost to follow-up, and one patient died 22 days after receiving dihydroartemisinin-piperaquine. Recrudescent parasitaemias were confirmed in only two patients; the day 42 failure rate was 0.6% (95% CI 0.2-2.5) for dihydroartemisinin-piperaquine and 0 (0-1.2) for artesunate-mefloquine. Whole-blood piperaquine concentrations at day 7 were similar for patients with observed and non-observed dihydroartemisinin-piperaquine treatment. Gametocytaemia developed more frequently in patients who had received dihydroartemisinin-piperaquine than in those on artesunate-mefloquine: day 7, 18 (10%) of 188 versus five (2%) of 218; relative risk 4.2 (1.6-11.0) p=0.011. INTERPRETATION: Dihydroartemisinin-piperaquine is a highly efficacious and inexpensive treatment of multidrug-resistant falciparum malaria and is well tolerated by all age groups. The effectiveness of the unsupervised treatment, as in the usual context of use, equalled its supervised efficacy, indicating good adherence without supervision. Dihydroartemisinin-piperaquine is a good alternative to artesunate-mefloquine.

Stuetz W, McGready R, Cho T, Prapamontol T, Biesalski HK, Stepniewska K, Nosten F. 2006. Relation of DDT residues to plasma retinol, alpha-tocopherol, and beta-carotene during pregnancy and malaria infection: a case-control study in Karen women in northern Thailand. Sci Total Environ, 363 (1-3), pp. 78-86. | Citations: 12 (Web of Science Lite) | Show Abstract | Read more

Populations living in endemic malaria areas maybe exposed simultaneously to DDT and malaria infection. DDT may impair status of vitamins, which are implicated in the immunity and pathophysiology of malaria. To explore possible interactions, DDT residues, retinol, alpha-tocopherol, beta-carotene and cholesterol were measured in plasma samples of malaria-infected pregnant women (cases, n=50) and age matched malaria-free controls (n=58). DDT residues were found in all samples: mean (sd) total DDT levels of 29.7 and 32.7 ng/ml in cases and controls, respectively. Mean (sd) p,p'-DDT was higher in the controls than the cases (13.5 vs. 9.5 ng/ml, p=0.006). Malaria infection was associated with lower mean (sd) plasma retinol (0.69 vs. 1.23 micromol/L) and cholesterol (2.62 vs. 3.48 mmol/L) compared to controls (p<0.001). Mean (sd) plasma alpha-tocopherol (7.65 vs. 15.58 micromol/L) and alpha-tocopherol/cholesterol ratio (2.3 vs. 6.7 micromol/L/mmol/L) were significantly lower among the controls (p<0.001). Mean (sd) plasma beta-carotene was low (<0.3 micromol/L) in both groups, but higher among malaria cases (0.19 vs. 0.15 micromol/L). Plasma retinol among the controls showed highly significant positive correlations with individual DDT compounds, particularly with p,p'-DDT (r=0.51, p<0.001). Plasma alpha-tocopherol and beta-carotene seemed not to be affected by DDT residues.

Wuthiekanun V, Chierakul W, Langa S, Chaowagul W, Panpitpat C, Saipan P, Thoujaikong T, Day NP, Peacock SJ. 2006. Development of antibodies to Burkholderia pseudomallei during childhood in melioidosis-endemic northeast Thailand. Am J Trop Med Hyg, 74 (6), pp. 1074-1075. | Citations: 61 (Scopus) | Show Abstract | Read more

A cross-sectional serological survey of 2,214 children living in northeast Thailand was conducted to define the antibody response to Burkholderia pseudomallei from birth to 14 years. There was a sharp rise in detectable antibodies from birth to 4 years followed by reactivity in approximately 60-70% of children thereafter.

Nosten F, Hutagalung R, Carrara VI, Ashley E, White N. 2006. Untitled AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 74 (6), pp. 940-940. | Citations: 1 (Web of Science Lite) | Read more

Price RN, Uhlemann A-C, van Vugt M, Brockman A, Hutagalung R, Nair S, Nash D, Singhasivanon P, Anderson TJC, Krishna S et al. 2006. Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis, 42 (11), pp. 1570-1577. | Citations: 197 (Scopus) | Show Abstract | Read more

BACKGROUND: Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). METHODS: On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. RESULTS: All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. CONCLUSIONS: The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.

Chotivanich K, Sattabongkot J, Udomsangpetch R, Looareesuwan S, Day NPJ, Coleman RE, White NJ. 2006. Transmission-blocking activities of quinine, primaquine, and artesunate. Antimicrob Agents Chemother, 50 (6), pp. 1927-1930. | Citations: 56 (Web of Science Lite) | Show Abstract | Read more

The infectivity of Plasmodium falciparum gametocytes after exposure in vitro to quinine, artesunate, and primaquine was assessed in Anopheles dirus, a major vector of malaria in Southeast Asia. Mature gametocytes (stage 5) of a Thai isolate of P. falciparum were exposed to the drugs for 24 h in vitro before membrane feeding to A. dirus. After 10 days, the mosquito midguts were dissected and the oocysts were counted. In this system, artesunate showed the most potent transmission-blocking activity; the mean (standard deviation [SD]) 50% and 90% effective concentrations (EC(50), and EC(90), respectively, in nanograms per milliliter) were 0.1 (0.02) and 0.4 (0.15), respectively. Transmission-blocking activity of quinine and primaquine was observed at relatively high concentrations (SDs): EC(50) of quinine, 642 (111) ng/ml; EC(50) of primaquine, 181 (23) ng/ml; EC(90) of quinine, 816 (96) ng/ml; EC(90) of primaquine, 543 (43) ng/ml. Artesunate both prevents the maturation of immature P. falciparum gametocytes and reduces the transmission potential of mature gametocytes. Both of these effects may contribute to reducing malaria transmission.

Antarasena C, Sirimujalin R, Prommuang P, Blacksell SD, Promkuntod N, Prommuang P. 2006. Tissue tropism of a Thailand strain of high-pathogenicity avian influenza virus (H5N1) in tissues of naturally infected native chickens (Gallus gallus), Japanese quail (Coturnix coturnix japonica) and ducks (Anas spp.). Avian Pathol, 35 (3), pp. 250-253. | Citations: 34 (Scopus) | Show Abstract | Read more

The tropism of a Thailand strain of highly pathogenic avian influenza H5N1 virus was demonstrated on tissues (lung, trachea, heart, liver, spleen, pancreas, rectum, kidney, brain, skeletal muscle, duodenum, and oviduct) from naturally infected native chickens (Gallus gallus), Japanese quail (Coturnix coturnix japonica) and ducks (Anas spp.) by indirect immunofluorescence assay. In chickens and quail, the distribution and localization of nucleoprotein viral antigen was similar and detected at the highest level in cardiac myocytes, at 88% (chickens) and 89% (quail), and respiratory, digestive and urinary systems all showed high levels of antigen. Antigen in duck tissues were detected at significantly lower levels (P < 0.05) with the exception of brain and skeletal muscle samples. In most cases, antigen in duck tissue was absent in the digestive organs but present in respiratory organs, which supports the hypothesis that aerosol and oral-oral transmission are the main method of highly pathogenic avian influenza virus transmission from this species.

Cheng AC, Wuthiekanun V, Limmathurosakul D, Wongsuvan G, Day NPJ, Peacock SJ. 2006. Role of selective and nonselective media for isolation of Burkholderia pseudomallei from throat swabs of patients with melioidosis. J Clin Microbiol, 44 (6), pp. 2316. | Citations: 8 (Scopus) | Read more

Cooper BS, Pitman RJ, Edmunds WJ, Gay NJ. 2006. Delaying the international spread of pandemic influenza. PLoS Med, 3 (6), pp. e212. | Citations: 175 (Scopus) | Show Abstract | Read more

BACKGROUND: The recent emergence of hypervirulent subtypes of avian influenza has underlined the potentially devastating effects of pandemic influenza. Were such a virus to acquire the ability to spread efficiently between humans, control would almost certainly be hampered by limited vaccine supplies unless global spread could be substantially delayed. Moreover, the large increases that have occurred in international air travel might be expected to lead to more rapid global dissemination than in previous pandemics. METHODS AND FINDINGS: To evaluate the potential of local control measures and travel restrictions to impede global dissemination, we developed stochastic models of the international spread of influenza based on extensions of coupled epidemic transmission models. These models have been shown to be capable of accurately forecasting local and global spread of epidemic and pandemic influenza. We show that under most scenarios restrictions on air travel are likely to be of surprisingly little value in delaying epidemics, unless almost all travel ceases very soon after epidemics are detected. CONCLUSIONS: Interventions to reduce local transmission of influenza are likely to be more effective at reducing the rate of global spread and less vulnerable to implementation delays than air travel restrictions. Nevertheless, under the most plausible scenarios, achievable delays are small compared with the time needed to accumulate substantial vaccine stocks.

Chapman SJ, Khor CC, Vannberg FO, Maskell NA, Davies CWH, Hedley EL, Segal S, Moore CE, Knox K, Day NP et al. 2006. PTPN22 and invasive bacterial disease. Nat Genet, 38 (5), pp. 499-500. | Citations: 46 (Web of Science Lite) | Read more

Ashley E, McGready R, Proux S, Nosten F. 2006. Malaria. Travel Med Infect Dis, 4 (3-4), pp. 159-173. | Citations: 44 (Scopus) | Show Abstract | Read more

Malaria is increasing worldwide due to the emergence and spread of drug resistant strains. This poses major health and economic problems for the population living in endemic areas and increases the risk of infections in travelers. The diagnosis of malaria relies on a biological proof of infection by microscopy or with a rapid test. The treatment must be initiated without delay preferably with an artemisinin containing regimen. Uncomplicated malaria can be treated with oral drugs while severe infections will be hospitalized and treated with injectables. Special attention will be given to the most susceptible groups: children and pregnant women.

McGready R, Stepniewska K, Ward SA, Cho T, Gilveray G, Looareesuwan S, White NJ, Nosten F. 2006. Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria. Eur J Clin Pharmacol, 62 (5), pp. 367-371. | Citations: 80 (Scopus) | Show Abstract | Read more

OBJECTIVE: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy. METHODS: Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. RESULTS: Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. CONCLUSION: The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.

Imwong M, Sudimack D, Pukrittayakamee S, Osorio L, Carlton JM, Day NPJ, White NJ, Anderson TJC. 2006. Microsatellite variation, repeat array length, and population history of Plasmodium vivax. Mol Biol Evol, 23 (5), pp. 1016-1018. | Citations: 80 (Scopus) | Read more

White NJ. 2006. Modelling malaria control. PLoS Med, 3 (5), pp. e111. | Citations: 3 (Web of Science Lite) | Read more

Sirigul C, Wongwit W, Phanprasit W, Paveenkittiporn W, Blacksell SD, Ramasoota P. 2006. Development of a combined air sampling and quantitative real-time PCR method for detection of Legionella spp. Southeast Asian J Trop Med Public Health, 37 (3), pp. 503-507. | Citations: 5 (Scopus) | Show Abstract

The objective of this study was to develop and optimize the combined methods of air sampling and real time polymerase chain reaction (real-time PCR) for quantifying aerosol Legionella spp. Primers and TaqMan hydrolysis probe based on 5S rRNA gene specific for Legionella spp were used to amplify a specific DNA product of 84 bp. The impinger air sampler plus T-100 sampling pump was used to collect aerosol Legionella and as low as 10 fg of Legionella DNA per reaction could detected. Preliminary studies demonstrated that the developed method could detect aerosol Legionella spp 1.5-185 organisms /500 l of air within 5 hours, in contrast to culture method, that required a minimum of 7-10 days.

Gomes MGM, White LJ, Medley GF. 2006. The reinfection threshold (vol 236, pg 111, 2005) JOURNAL OF THEORETICAL BIOLOGY, 239 (4), pp. 518-518. | Read more

Clarke SR, Brummell KJ, Horsburgh MJ, McDowell PW, Mohamad SAS, Stapleton MR, Acevedo J, Read RC, Day NPJ, Peacock SJ et al. 2006. Identification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriage. J Infect Dis, 193 (8), pp. 1098-1108. | Citations: 149 (Web of Science Lite) | Show Abstract | Read more

A spectrum of in vivo-expressed Staphylococcus aureus antigens was identified by probing bacteriophage expression libraries of S. aureus with serum samples from infected and uninfected individuals. Eleven recombinant antigenic proteins were produced, and specific antibody titers in a large collection of human serum samples were determined. Significantly increased concentrations of reactive immunoglobulin G (IgG) to 7 antigens were found in serum samples from ill individuals, compared with those in healthy individuals. Significantly higher concentrations of reactive IgG to 4 antigens, including iron-responsive surface determinant (Isd) A and IsdH, were found in serum samples from healthy individuals who were not nasal carriers of S. aureus, compared with those in healthy carriers. Vaccination of cotton rats with IsdA or IsdH protected against nasal carriage. Also, IsdA is involved in adherence of S. aureus to human desquamated nasal epithelial cells and is required for nasal colonization in the cotton rat model. Thus, vaccination with these antigens may prevent S. aureus carriage and reduce the prevalence of human disease.

Blacksell SD, Newton PN, Bell D, Kelley J, Mammen MP, Vaughn DW, Wuthiekanun V, Sungkakum A, Nisalak A, Day NPJ. 2006. The comparative accuracy of 8 commercial rapid immunochromatographic assays for the diagnosis of acute dengue virus infection. Clin Infect Dis, 42 (8), pp. 1127-1134. | Citations: 91 (Scopus) | Show Abstract | Read more

BACKGROUND: The serological diagnosis of acute dengue virus infection relies on the detection of dengue-specific immunoglobulin M (IgM) antibodies. Immunochromatographic tests are rapid diagnostic tests (RDTs) that can be performed at the bedside, but they have not been fully validated for diagnosis of dengue infection. METHODS: More than 20 RDTs for diagnosis of acute dengue infection are commercially available. Of these, 8 were selected for evaluation of performance by use of characterized dengue and nondengue serum specimens, and results were compared with those of a previously published dengue IgM/IgG enzyme-linked immunosorbent assay in conjunction with dengue virus serotyping by reverse-transcriptase polymerase chain reaction. RESULTS: Assay sensitivities were low, ranging from 6.4% (95% confidence interval [CI], 4.0%-9.7%) to 65.3% (95% CI, 59.9%-70.5%), and specificities ranged from 69.1% (95% CI, 61.4%-76.0%) to 100% (95% CI, 97.8%-100%). Of the 8 tests, only 2 had sensitivities of >50%, the level considered to be clinically useful, and, of these, 1 had relatively low specificity (69.1%). Samples collected early in the infection were less likely to test positive than those collected later. A thermal stability study demonstrated a loss in performance of some RDTs when they were stored at a high ambient temperature for 3 months. CONCLUSIONS: Users of RDTs for dengue should be aware that many of these tests have a diagnostic accuracy that falls well below the manufacturers' claims. If an acute specimen yields a negative result, a convalescent serum sample should be tested to confirm the result. No RDT adequately differentiated primary and secondary dengue infections, and the tests should not be used for this purpose.

Singtoroj T, Tarning J, Annerberg A, Ashton M, Bergqvist Y, White NJ, Lindegardh N, Day NPJ. 2006. A new approach to evaluate regression models during validation of bioanalytical assays. J Pharm Biomed Anal, 41 (1), pp. 219-227. | Citations: 41 (Web of Science Lite) | Show Abstract | Read more

The quality of bioanalytical data is highly dependent on using an appropriate regression model for calibration curves. Non-weighted linear regression has traditionally been used but is not necessarily the optimal model. Bioanalytical assays generally benefit from using either data transformation and/or weighting since variance normally increases with concentration. A data set with calibrators ranging from 9 to 10000 ng/mL was used to compare a new approach with the traditional approach for selecting an optimal regression model. The new approach used a combination of relative residuals at each calibration level together with precision and accuracy of independent quality control samples over 4 days to select and justify the best regression model. The results showed that log-log transformation without weighting was the simplest model to fit the calibration data and ensure good predictability for this data set.

Tarning J, Singtoroj T, Annerberg A, Ashton M, Bergqvist Y, White NJ, Day NPJ, Lindegardh N. 2006. Development and validation of an automated solid phase extraction and liquid chromatographic method for the determination of piperaquine in urine. J Pharm Biomed Anal, 41 (1), pp. 213-218. | Citations: 23 (Scopus) | Show Abstract | Read more

A sensitive and specific bioanalytical method for determination of piperaquine in urine by automated solid-phase extraction (SPE) and liquid chromatography (LC) has been developed and validated. Buffered urine samples (containing internal standard) were loaded onto mixed phase (cation-exchange and octylsilica) SPE columns using an ASPEC XL SPE robot. Chromatographic separation was achieved on a Chromolith Performance RP-18e (100 mm x 4.6 mm I.D.) LC column with phosphate buffer (pH 2.5; 0.1 mol/L)-acetonitrile (92:8, v/v). Piperaquine was analysed at a flow rate of 3 mL/min with UV detection at 347 nm. A linear regression model on log-log transformed data was used for quantification. Within-day precision for piperaquine was 1.3% at 5000 ng/mL and 6.6% at 50 ng/mL. Between-day precision for piperaquine was 3.7% at 5000 ng/mL and 7.2% at 50 ng/mL. Total-assay precision for piperaquine over 4 days using five replicates each day (n = 20) was 4.0%, 5.2% and 9.8% at 5000, 500 and 50 ng/mL, respectively. The lower limit of quantification (LLOQ) was set to 3 ng/mL using 1 mL of urine, which could be lowered to 0.33 ng/mL when using 9 mL of urine and an increased injection volume.

Wiersinga WJ, van der Poll T, White NJ, Day NP, Peacock SJ. 2006. Melioidosis: insights into the pathogenicity of Burkholderia pseudomallei. Nat Rev Microbiol, 4 (4), pp. 272-282. | Citations: 382 (Scopus) | Show Abstract | Read more

Burkholderia pseudomallei is a potential bioterror agent and the causative agent of melioidosis, a severe disease that is endemic in areas of Southeast Asia and Northern Australia. Infection is often associated with bacterial dissemination to distant sites, and there are many possible disease manifestations, with melioidosis septic shock being the most severe. Eradication of the organism following infection is difficult, with a slow fever-clearance time, the need for prolonged antibiotic therapy and a high rate of relapse if therapy is not completed. Mortality from melioidosis septic shock remains high despite appropriate antimicrobial therapy. Prevention of disease and a reduction in mortality and the rate of relapse are priority areas for future research efforts. Studying how the disease is acquired and the host-pathogen interactions involved will underpin these efforts; this review presents an overview of current knowledge in these areas, highlighting key topics for evaluation.

White NJ, Ashley EA, Nosten F. 2006. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol, 59 (4), pp. 725-726. | Citations: 11 (Scopus) | Read more

Thwaites CL, Yen LM, Cordon SM, Binh NT, T N, Nga N, White NJ, Soni N, MacDonald IA, Farrar JJ. 2006. Urinary catecholamine excretion in tetanus. Anaesthesia, 61 (4), pp. 355-359. | Citations: 12 (Scopus) | Show Abstract | Read more

Imperfect understanding of the pathophysiology of tetanus has limited therapeutic advances. Autonomic disturbance is a major cause of mortality and is believed to be associated with catecholamine release, predominantly norepinephrine. We measured epinephrine and norepinephrine concentrations in 24-h urine collections from tetanus and critically ill patients suffering from other severe diseases. In patients with severe tetanus, mean (SD) epinephrine was 164.18 (129.37) nmol x day(-1) compared with 45.18 (37.74) nmol x day(-1) in mild-moderate disease (p = 0.008). In the severe group, mean (SD) norepinephrine was 411.64 (208.5), and 121.00 (81.81) nmol x day(-1) in moderately ill patients (p < 0.001). Compared with critically ill control patients, median epinephrine was 331.77 in tetanus patients and 89.70 nmol x day(-1) in controls (p < 0.001). Median norepinephrine concentration was 788.02 nmol x day(-1) in tetanus and 300.05 nmol x day(-1) in control patients, p = 0.006. The study finds a novel result of increased epinephrine excretion in tetanus and confirms that catecholamine excretion in tetanus exceeds that in other critically ill patients. These results should be considered in designing more effective therapeutic strategies.

Bar-Zeev N, White N. 2006. Evidence behind the WHO guidelines: Hospital Care for Children: efficacy and safety of artemisinin derivatives in children with malaria. J Trop Pediatr, 52 (2), pp. 78-82. | Citations: 10 (Scopus) | Read more

Chantratita N, Vesaratchavest M, Wuthiekanun V, Tiyawisutsri R, Ulziitogtokh T, Akcay E, Day NPJ, Peacock SJ. 2006. Pulsed-field gel electrophoresis as a discriminatory typing technique for the biothreat agent burkholderia mallei. Am J Trop Med Hyg, 74 (3), pp. 345-347. | Citations: 11 (Scopus) | Show Abstract | Read more

Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) was used to type 21 laboratory strains of Burkholderia mallei. We demonstrated good resolution by PFGE together with clustering of some geographically related isolates, and confirmed previous observations that B. mallei is clonal as defined by MLST.

Thwaites CL, Yen LM, Glover C, Tuan PQ, Nga NTN, Parry J, Loan HT, Bethell D, Day NPJ, White NJ et al. 2006. Predicting the clinical outcome of tetanus: the tetanus severity score. Trop Med Int Health, 11 (3), pp. 279-287. | Citations: 25 (Scopus) | Show Abstract | Read more

OBJECTIVES: To create a new tetanus score and compare it with the Phillips and Dakar scores. METHODS: We used prospectively acquired data from consecutive patients admitted to the Hospital for Tropical Diseases, Ho Chi Minh City, to create the Tetanus Severity Score (TSS) with multivariate logistic regression. We compared the new score with Phillips and Dakar scores by means of resubstituted and prospective data, assessing performance in terms of sensitivity, specificity and area under receiver operator characteristic curves. RESULTS: Resubstitution testing yielded a sensitivity of 77% (298/385) and a specificity of 82% (1,183/1,437) for the TSS; 89% (342/385) and 20% (281/1,437) for the Phillips score; and 13% (49/385) and 98% (1,415/1,437) for the Dakar score. The TSS showed greatest discrimination with 0.89 area under the receiver operator characteristic curve (95% CI 0.88-0.90); this was 0.74 for the Dakar score and (95% CI 0.71-0.77) and 0.66 for the Phillips score (95% CI 0.63-0.70; P values <0.001). Prospective testing showed 65% (13/20) sensitivity and 91% (210/230) specificity for the TSS; 80% (16/20) and 51% (118/230) for the Phillips score; and 25% (5/20) and 96% (221/230) for the Dakar score. The TSS achieved the greatest area under TSS of 0.89 (95% CI 0.82-0.96), significantly greater than the Phillips score [0.74 (0.6-0.88), P = 0.049] but not the Dakar score [0.80, (0.71-0.90), P = 0.090]. CONCLUSIONS: The TSS is the first prospectively developed classification scheme for tetanus and should be adopted to aid clinical triage and management and as a basis for clinical research.

Anuntagool N, Wuthiekanun V, White NJ, Currie BJ, Sermswan RW, Wongratanacheewin S, Taweechaisupapong S, Chaiyaroj SC, Sirisinha S. 2006. Lipopolysaccharide heterogeneity among Burkholderia pseudomallei from different geographic and clinical origins. Am J Trop Med Hyg, 74 (3), pp. 348-352. | Citations: 43 (Scopus) | Show Abstract | Read more

Heterogeneous patterns were obtained for lipopolysaccharide (LPS) from 1,327 Burkholderia pseudomallei isolates by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, silver staining, and immunoblot analysis. Two LPS serotypes (A and B) possessing different ladder profiles and a rough LPS without ladder appearances were identified. All three LPS types were antigenically distinct by immunoblotting. The predominant type A (97%) produced the lowest amount of biofilm. The two less common types (smooth type B and rough type) were found more in clinical than environmental isolates and more in Australian isolates than Thai isolates. These isolates were more often associated with relapse than with primary infection.

Sharma NP, Peacock SJ, Phumratanaprapin W, Day N, White N, Pukrittayakamee S. 2006. A hospital-based study of bloodstream infections in febrile patients in Dhulikhel Hospital Kathmandu University Teaching Hospital, Nepal. Southeast Asian J Trop Med Public Health, 37 (2), pp. 351-356. | Citations: 17 (Scopus) | Show Abstract

The etiology of bloodstream infections in febrile patients remain poorly characterized in Nepal. A retrospective study of febrile patients presenting to Dhulikhel Hospital Kathmandu University Teaching Hospital from July 2002 to June 2004 was performed to evaluate the etiology of bloodstream infections and the drug sensitivity patterns of cultured organisms. The medical and laboratory records of all febrile patients with an axillary temperature > or = 38 degrees C who had a blood culture taken (n = 1,774) were retrieved and analyzed. Of these, 122 (6.9%) patients had positive blood cultures, of which 40.1% were age 11 to 20 years. The male to female ratio was 1.7:1. Antibiotics had been taken prior to hospital presentation by 39 (32%) patients. Salmonella enterica serovar Typhi and serovar Paratyphi A were isolated in 50 (41.0%) and 13 (10.7%) cases, respectively. All S. Typhi and S. Paratyphi isolates were susceptible to ceftriaxone, while susceptibility to ciprofloxacin and chloramphenicol was recorded in 94.8% and 94.5% of cases, respectively. Cephalexin and amoxicillin had the lowest rates of susceptibility (64.2% and 54.1%, respectively). Salmonella spp were usually sensitive to chloramphenicol. These findings provide clinicians in this region of Nepal with a better understanding of the spectrum of pathogens causing bloodstream infections and will help guide empiric antibiotic choice.

Hutagalung R, Htoo H, Nwee P, Arunkamomkiri J, Zwang J, Carrara VI, Ashley E, Singhasivanon P, White NJ, Nosten F. 2006. A case-control auditory evaluation of patients treated with artemether-lumefantrine. Am J Trop Med Hyg, 74 (2), pp. 211-214. | Citations: 42 (Scopus) | Show Abstract | Read more

Artemether-lumefantrine is the first registered, fixed, artemisinin-based combination treatment. Artemisinin derivatives are highly effective antimalarials with a favorable safety profile. Concerns remain over their potential neurotoxicity, although there has been no clinical evidence of this in humans. In animals (rats, dogs, and monkeys) artemether, a derivative of artemisinin is associated with an unusual toxicity pattern in specific brain nuclei involving the auditory and vestibular pathways. A recent report from Mozambique described a small but significant and irreversible hearing loss in patients exposed to artemether-lumefantrine. To explore this issue, we conducted a case-control study using tympanometry, audiometry and auditory brain-stem responses. We assessed 68 subjects who had been treated with artemether-lumefantrine within the previous five years and 68 age- and sex-matched controls living in the malarious region along the Thailand-Myanmar border. There were no differences in the test results between cases and controls. There was no neurophysiologic evidence of auditory brainstem toxicity that could be attributed to artemether-lumefantrine in this study population.

Phongmany S, Rolain J-M, Phetsouvanh R, Blacksell SD, Soukkhaseum V, Rasachack B, Phiasakha K, Soukkhaseum S, Frichithavong K, Chu V et al. 2006. Rickettsial infections and fever, Vientiane, Laos. Emerg Infect Dis, 12 (2), pp. 256-262. | Citations: 143 (Scopus) | Show 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.

McGready R, Ashley EA, Tan SO, Brabin B, Nosten F. 2006. Re: Malaria in pregnancy. BJOG, 113 (2), pp. 246. | Citations: 1 (European Pubmed Central) | Read more

Newton PN, Ward S, Angus BJ, Chierakul W, Dondorp A, Ruangveerayuth R, Silamut K, Teerapong P, Suputtamongkol Y, Looareesuwan S, White NJ. 2006. Early treatment failure in severe malaria resulting from abnormally low plasma quinine concentrations. Trans R Soc Trop Med Hyg, 100 (2), pp. 184-186. | Citations: 14 (Scopus) | Show Abstract | Read more

A patient admitted with severe Plasmodium falciparum malaria in western Thailand had an early treatment failure with quinine, despite full dosing. Plasma quinine concentrations were subtherapeutic. Abnormal quinine pharmacokinetics may explain sporadic reports of quinine treatment failures in severe malaria.

Nickerson EK, Wuthiekanun V, Day NP, Chaowagul W, Peacock SJ. 2006. Meticillin-resistant Staphylococcus aureus in rural Asia. Lancet Infect Dis, 6 (2), pp. 70-71. | Citations: 23 (Web of Science Lite) | Read more

Aguas R, Gonçalves G, Gomes MGM. 2006. Pertussis: increasing disease as a consequence of reducing transmission. Lancet Infect Dis, 6 (2), pp. 112-117. | Citations: 70 (Scopus) | Show Abstract | Read more

Since the 1980s, the occurrence of pertussis cases in developed countries has increased and shifted towards older age groups. This resurgence follows 30 years of intense mass vaccination, and has been attributed primarily to three factors: (1) more effective diagnosis of the disease, (2) waning of vaccine-induced immunity, and (3) loss of vaccine efficacy due to the emergence of new Bordetella pertussis strains. Here we develop and analyse a mathematical model to assess the plausibility of these hypotheses. We consider that exposure to B pertussis through natural infection or vaccination induces an immune response that prevents severe disease but does not fully prevent mild infections. We also assume that these protective effects are temporary due to waning of immunity. These assumptions, describing the mode of action of adaptive immunity, are combined with a standard transmission model. Two distinct epidemiological scenarios are detected: under low transmission, most infections lead to severe disease; under high transmission, mild infections are frequent, boosting clinical immunity and maintaining low levels of severe disease. The two behaviours are separated by a reinfection threshold in transmission. As a result, the highest incidence of severe disease is expected to occur at intermediate transmission intensities--near the reinfection threshold--suggesting that pertussis resurgence may be induced by a reduction in transmission, independently of vaccination. The model is extended to interpret the outcomes of current control measures and explore scenarios for future interventions.

White NJ, Dondorp AM, Nosten F, Day NPJ, Grp SEAQUAMATS. 2006. Artesunate versus quinine for severe falciparum malaria - Reply LANCET, 367 (9505), pp. 111-112. | Citations: 3 (Web of Science Lite) | Read more

Lindsay JA, Moore CE, Day NP, Peacock SJ, Witney AA, Stabler RA, Husain SE, Butcher PD, Hinds J. 2006. Microarrays reveal that each of the ten dominant lineages of Staphylococcus aureus has a unique combination of surface-associated and regulatory genes. J Bacteriol, 188 (2), pp. 669-676. | Citations: 234 (Scopus) | Show Abstract | Read more

Staphylococcus aureus is the most common cause of hospital-acquired infection. In healthy hosts outside of the health care setting, S. aureus is a frequent colonizer of the human nose but rarely causes severe invasive infection such as bacteremia, endocarditis, or osteomyelitis. To identify genes associated with community-acquired invasive isolates, regions of genomic variability, and the S. aureus population structure, we compared 61 community-acquired invasive isolates of S. aureus and 100 nasal carriage isolates from healthy donors using a microarray spotted with PCR products representing every gene from the seven S. aureus sequencing projects. The core genes common to all strains were identified, and 10 dominant lineages of S. aureus were clearly discriminated. Each lineage carried a unique combination of hundreds of "core variable" (CV) genes scattered throughout the chromosome, suggesting a common ancestor but early evolutionary divergence. Many CV genes are regulators of virulence genes or known or predicted to be expressed on the bacterial surface and to interact with the host during nasal colonization and infection. Within each lineage, isolates showed substantial variation in the carriage of mobile genetic elements and their associated virulence and resistance genes, indicating frequent horizontal transfer. However, we were unable to identify any association between lineage or gene and invasive isolates. We suggest that the S. aureus gene combinations necessary for invasive disease may also be necessary for nasal colonization and that community-acquired invasive disease is strongly dependent on host factors.

Nosten F, McGready R, d'Alessandro U, Bonell A, Verhoeff F, Menendez C, Mutabingwa T, Brabin B. 2006. Antimalarial drugs in pregnancy: a review. Curr Drug Saf, 1 (1), pp. 1-15. | Citations: 106 (Scopus) | Show Abstract | Read more

In this review we examine the available information on the safety of antimalarials in pregnancy, from both animal and human studies. The antimalarials that can be used in pregnancy include (1) chloroquine, (2) amodiaquine, (3) quinine, (4) azithromycin, (5) sulfadoxine-pyrimethamine, (6) mefloquine, (7) dapsone-chlorproguanil, (8) artemisinin derivatives, (9) atovaquone-proguanil and (10) lumefantrine. Antimalarial drugs that should not be used in pregnancy including (1) halofantrine, (2) tetracycline/doxycycline, and (3) primaquine. There are few studies in humans on the pharmacokinetics, safety and efficacy of antimalarials in pregnancy. This is because pregnant women are systematically excluded from clinical trials. The absence of adequate safety data, especially in the first trimester, is an important obstacle to developing treatment strategies. The pharmacokinetics of most antimalarial drugs are also modified in pregnancy and dosages will need to be adapted. Other factors, including HIV status, drug interactions with antiretrovirals, the influence of haematinics and host genetic polymorphisms may influence safety and efficacy. For these reasons there is an urgent need to assess the safety and efficacy of antimalarial treatments in pregnancy, including artemisinin based combination therapies.

Wuthiekanun V, Chierakul W, Rattanalertnavee J, Langa S, Sirodom D, Wattanawaitunechai C, Winothai W, White NJ, Day N, Peacock SJ. 2006. Serological evidence for increased human exposure to Burkholderia pseudomallei following the tsunami in southern Thailand. J Clin Microbiol, 44 (1), pp. 239-240. | Citations: 23 (Scopus) | Show Abstract | Read more

A serological study was performed to determine recent human exposure to Burkholderia pseudomallei (the cause of melioidosis) in residents of southern Thailand affected by the tsunami of 26 December 2004. The findings were suggestive of increased recent exposure in both tsunami survivors and uninjured bystanders. Survivors of the Thailand tsunami may be at increased risk of melioidosis.

Cheng AC, Peacock SJ, Limmathurotsakul D, Wongsuvan G, Chierakul W, Amornchai P, Getchalarat N, Chaowagul W, White NJ, Day NPJ, Wuthiekanun V. 2006. Prospective evaluation of a rapid immunochromogenic cassette test for the diagnosis of melioidosis in northeast Thailand. Trans R Soc Trop Med Hyg, 100 (1), pp. 64-67. | Citations: 26 (Scopus) | Show Abstract | Read more

A prospective study was performed to compare a rapid immunochromogenic cassette test (ICT) with the indirect haemagglutination assay (IHA) and clinical rules for the diagnosis of melioidosis in an endemic area. The sensitivity and specificity of the IgG ICT was 86% and 47%, and the IgM ICT was 82% and 47%, respectively. These were similar to the results for IHA (sensitivity 73%, specificity 64%) and clinical rules (73% and 37%). ICT lacks clinical utility as a result of high background rates of positive Burkholderia pseudomallei serology in this population. Low sensitivity and specificity of clinical rules is consistent with the protean manifestations of melioidosis and clinical difficulty in identifying patients with melioidosis.

LaRosa SP, Opal SM, Utterback B, Yan SCB, Helterbrand J, Simpson AJH, Chaowagul W, White NJ, Fisher CJ. 2006. Decreased protein C, protein S, and antithrombin levels are predictive of poor outcome in Gram-negative sepsis caused by Burkholderia pseudomallei. Int J Infect Dis, 10 (1), pp. 25-31. | Citations: 23 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Acute septicemic melioidosis is associated with systemic release of endotoxin and the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin-1, and interleukin-6. Excessive release of these cytokines may lead to endothelial injury, depletion of naturally occurring endothelial modulators, microvascular thrombosis, organ failure, and death. METHOD: Plasma samples drawn at baseline and after initial antimicrobial therapy in 30 patients with suspected acute severe melioidosis were assayed for D-dimer levels, protein C and protein S antigen levels, and antithrombin functional activities. RESULTS: Both baseline and continued deficiencies of protein C, protein S, and antithrombin were statistically associated with a poor outcome by logistic regression. Baseline D-dimer levels were significantly higher in fatal cases than survivors and correlated inversely with protein C and antithrombin, suggesting both increased fibrin deposition and fibrinolysis. CONCLUSION: The inflammatory response to systemic Burkholderia pseudomallei infection leads to depletion of the natural endothelial modulators protein C, protein S, and antithrombin. Both baseline and continued deficiency of these endothelial modulators is predictive of poor outcome in melioidosis.

Chotivanich K, Silamut K, Day NPJ. 2006. Laboratory diagnosis of malaria infection - A short review of methods Australian Journal of Medical Science, 27 (1), pp. 11-15. | Citations: 5 (Scopus) | Show Abstract

Malaria is one of the most important tropical infectious diseases. The incidence of malaria worldwide is estimated to be 300-500 million clinical cases each year with a mortality of between one and three million people worldwide annually. The accurate and timely diagnosis of malaria infection is essential if severe complications and mortality are to be reduced by early specific antimalarial treatment. This review details the methods for the laboratory diagnosis of malaria infection.

Boonbumrung K, Wuthiekanun V, Rengpipat S, Day NPJ, Peacock SJ. 2006. In vitro motility of a population of clinical Burkholderia pseudomallei isolates. J Med Assoc Thai, 89 (9), pp. 1506-1510. | Citations: 3 (European Pubmed Central) | Show Abstract

Melioidosis, a serious infection caused by Burkholderia pseudomallei, is a leading cause of community-acquired sepsis in Northeast Thailand, and the commonest cause of death from community-acquired pneumonia in the Top End of Northern Australia. The causative organism is a Gram-negative, motile bacillus that is a facultative intracellular pathogen. B. pseudomallei flagella have been proposed as a possible vaccine candidate and putative virulence determinant. Flagella expression was highly conserved for 205 clinical B. pseudomallei isolates, as defined by in vitro swim and swarm motility assays. No association was found between motility and clinical factors including bacteremia and death.

Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, Bruneton C, Phanouvong S, Millet P, Whitty CJM, Talisuna AO et al. 2006. Manslaughter by fake artesunate in Asia--will Africa be next? PLoS Med, 3 (6), pp. e197. | Citations: 141 (Scopus) | Read more

Fernández FM, Cody RB, Green MD, Hampton CY, McGready R, Sengaloundeth S, White NJ, Newton PN. 2006. Characterization of solid counterfeit drug samples by desorption electrospray ionization and direct-analysis-in-real-time coupled to time-of-flight mass spectrometry. ChemMedChem, 1 (7), pp. 702-705. | Citations: 170 (Scopus) | Show Abstract | Read more

Vacuum is not the limit: direct analysis in real time (DART), a new MS ionization method, allows probing of pharmaceuticals under atmospheric pressure, thus bypassing lengthy sample preparation steps and enhancing throughput. DART allows rapid screening of solid drugs at almost constant temperature which decreases errors in mass measurement and improves the identification of potentially harmful unknowns. This is important for identifying counterfeit drugs (fake hologram shown). © 2006 Wiley-VCH Verlag GmbH & Co. KGaA.

Taylor WRJ, Cañon V, White NJ. 2006. Pulmonary manifestations of malaria : recognition and management. Treat Respir Med, 5 (6), pp. 419-428. | Citations: 58 (Scopus) | Show Abstract | Read more

Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement. Increased alveolar capillary permeability leading to intravascular fluid loss into the lungs is the main pathophysiologic mechanism. This defines malaria as another cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).Pulmonary edema has been described most often in non-immune individuals with Plasmodium falciparum infections as part of a severe systemic illness or as the main feature of acute malaria. P.vivax and P.ovale have also rarely caused pulmonary edema.Clinically, patients usually present with acute breathlessness that can rapidly progress to respiratory failure either at disease presentation or, interestingly, after treatment when clinical improvement is taking place and the parasitemia is falling. Pregnant women are particularly prone to developing pulmonary edema. Optimal management of malaria-induced ALI/ARDS includes early recognition and diagnosis. Malaria must always be suspected in a returning traveler or a visitor from a malaria-endemic country with an acute febrile illness. Slide microscopy and/or the use of rapid antigen tests are standard diagnostic tools. Malaria must be treated with effective drugs, but current choices are few: e.g. parenteral artemisinins, intravenous quinine or quinidine (in the US only). A recent trial in adults has shown that intravenous artesunate reduces severe malaria mortality by a third compared with adults treated with intravenous quinine. Respiratory compromise should be managed on its merits and may require mechanical ventilation.Patients should be managed in an intensive care unit and particular attention should be paid to the energetic management of other severe malaria complications, notably coma and acute renal failure. ALI/ARDS may also be related to a coincidental bacterial sepsis that may not be clinically obvious. Clinicians should employ a low threshold for starting broad spectrum antibacterials in such patients, after taking pertinent microbiologic specimens. Despite optimal management, the prognosis of severe malaria with ARDS is poor.ALI/ARDS in pediatric malaria appears to be rare. However, falciparum malaria with severe metabolic acidosis or acute pulmonary edema may present with a clinical picture of pneumonia, i.e. with tachypnea, intercostal recession, wheeze or inspiratory crepitations. This results in diagnostic confusion and suboptimal treatment. Whilst this is increasingly being recognized in malaria-endemic countries, clinicians in temperate zones should be aware that malaria may be a possible cause of 'pneumonia' in a visiting or returning child.

Carrara VI, Sirilak S, Thonglairuam J, Rojanawatsirivet C, Proux S, Gilbos V, Brockman A, Ashley EA, McGready R, Krudsood S et al. 2006. Deployment of early diagnosis and mefloquine-artesunate treatment of falciparum malaria in Thailand: the Tak Malaria Initiative. PLoS Med, 3 (6), pp. e183. | Citations: 91 (Scopus) | Show Abstract | Read more

BACKGROUND: Early diagnosis and treatment with artesunate-mefloquine combination therapy (MAS) have reduced the transmission of falciparum malaria dramatically and halted the progression of mefloquine resistance in camps for displaced persons along the Thai-Burmese border, an area of low and seasonal transmission of multidrug-resistant Plasmodium falciparum. We extended the same combination drug strategy to all other communities (estimated population 450,000) living in five border districts of Tak province in northwestern Thailand. METHODS AND FINDINGS: Existing health structures were reinforced. Village volunteers were trained to use rapid diagnostic tests and to treat positive cases with MAS. Cases of malaria, hospitalizations, and malaria-related deaths were recorded in the 6 y before, during, and after the Tak Malaria Initiative (TMI) intervention. Cross-sectional surveys were conducted before and during the TMI period. P. falciparum malaria cases fell by 34% (95% confidence interval [CI], 33.5-34.4) and hospitalisations for falciparum malaria fell by 39% (95% CI, 37.0-39.9) during the TMI period, while hospitalisations for P. vivax malaria remained constant. There were 32 deaths attributed to malaria during, and 22 after the TMI, a 51.5% (95% CI, 39.0-63.9) reduction compared to the average of the previous 3 y. Cross-sectional surveys indicated that P. vivax had become the predominant species in Thai villages, but not in populations living on the Myanmar side of the border. In the displaced persons population, where the original deployment took place 7 y before the TMI, the transmission of P. falciparum continued to be suppressed, the incidence of falciparum malaria remained low, and the in vivo efficacy of the 3-d MAS remained high. CONCLUSIONS: In the remote malarious north western border area of Thailand, the early detection of malaria by trained village volunteers, using rapid diagnostic tests and treatment with mefloquine-artesunate was feasible and reduced the morbidity and mortality of multidrug-resistant P. falciparum.

Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, Bruneton C, Phanouvong S, Millet P, Whitty CJM, Talisuna AO et al. 2006. Manslaughter by fake artesunate in Asia - Will Africa be next? (vol 3, art. no. e197, 2006) PLOS MEDICINE, 3 (8), pp. 1439-1439. | Citations: 1 (Web of Science Lite) | Read more

Nosten F, Hutagalung R, Carrara VI, Ashley E, White N. 2006. Letters to the editor American Journal of Tropical Medicine and Hygiene, 74 (6), pp. 940. | Citations: 1 (Scopus)

Blacksell SD, Khounsy S, Van Aken D, Gleeson LJ, Westbury HA. 2006. Comparative susceptibility of indigenous and improved pig breeds to Classical swine fever virus infection: practical and epidemiological implications in a subsistence-based, developing country setting. Trop Anim Health Prod, 38 (6), pp. 467-474. | Citations: 11 (Web of Science Lite) | Show Abstract | Read more

This study investigated the comparative susceptibility of indigenous Moo Laat and improved Large White/Landrace pig breeds to infection with classical swine fever virus (CSFV) under controlled conditions in the Lao People's Democratic Republic (Lao PDR). The Moo Laat (ML) and Large White/Landrace cross-breed (LWC) pigs were inoculated with a standard challenge strain designated Lao/Kham225 (infectivity titre of 10(2.75) TCID50/ml). The results demonstrated that both the native breed and an improved pig breed are fully susceptible to CSFV infection and the mortality rate is high. LWC pigs demonstrated lower (or shorter) survival times (50% survival time: 11 days), earlier and higher pyrexia and earlier onset of viraemia compared to ML pigs (50% survival time: 18 days). In the context of village-based pig production, the longer time from infection to death in native ML pigs means that incubating or early sick pigs are likely to be sold once an outbreak of CSF is recognized in a village. This increased longevity probably contributes to the maintenance and spread of disease in a population where generally the contact rate is low.

Blacksell SD. 2006. Laboratory diagnosis of tropical infections Australian Journal of Medical Science, 27 (1), pp. 3.

Burford B, Blacksell SD. 2006. Diagnosis and management of tropical infections in travellers and expatriates at the Australian Embassy Clinic, Laos: Experience in a limited-resource environment Australian Journal of Medical Science, 27 (1), pp. 34-38. | Show Abstract

The Lao People's Democratic Republic (Lao PDR) is located in South East Asia bordered by Thailand, Vietnam, Cambodia, Myanmar and China. There is a large resident expatriate community as well as many foreign travellers. Health care resources available to this population are limited to a few embassy-based clinics. This review presents a perspective on managing tropical infections in the context of an expatriate clinic in the Lao PDR. Patients present with a variety of tropical infections and are often treated presumptively with minimal local laboratory support. Other laboratory tests that may be helpful to make an accurate diagnosis are detailed and discussed.

Blacksell SD. 2006. Serological and clinical diagnosis of dengue virus infection - A review of current knowledge Australian Journal of Medical Science, 27 (1), pp. 26-33. | Citations: 1 (Scopus) | Show Abstract

Dengue fever, dengue haemorrhagic fever and dengue shock syndrome are tropical diseases that cause significant disease burden. It is estimated that more than 2.5 billion people are at risk of infection and more than 100 countries have endemic dengue virus transmission. This paper reviews the available serological assays for the diagnosis of acute dengue virus infection, differentiation of primary and later infections, and their appropriate application depending on the setting. Dengue clinical syndromes and diagnostic criteria are also described.

White NJ. 2006. Editorial: clinical trials in tropical diseases: a politically incorrect view. Trop Med Int Health, 11 (10), pp. 1483-1484. | Citations: 20 (Scopus) | Read more

White NJ. 2006. Developing drugs for neglected diseases. Trop Med Int Health, 11 (4), pp. 383-384. | Citations: 3 (European Pubmed Central) | Read more

Anstey NM, Price RN, White NJ. 2006. Improving the availability of artesunate for treatment of severe malaria. Med J Aust, 184 (1), pp. 3-4. | Citations: 9 (Scopus)

Dondorp A, White N, Day N. 2006. PfHRP2 measures schizogony, not mechanical blockage - Authors' reply: Response to Ian Clark PLOS MEDICINE, 3 (1), pp. 145-145. | Read more

Low BY, Liong ML, Yuen KH, Chong WL, Chee C, Leong WS, Teh CL, Karim N, Yap HW, Cheah PY. 2006. Study of prevalence, treatment-seeking behavior, and risk factors of women with lower urinary tract symptoms in Northern Malaysia. Urology, 68 (4), pp. 751-758. | Citations: 10 (Scopus) | Show Abstract | Read more

OBJECTIVES: To determine the prevalence, severity, and quality-of-life (QOL) impact of female lower urinary tract symptoms (FLUTS); to determine the patterns, reasons, and factors contributing to the women's treatment-seeking behavior; and to describe the relationship between the social demographic characteristics and FLUTS. METHODS: A total of 2732 women older than 19 years of age were recruited by a series of FLUTS Awareness Campaigns held within Northern Malaysia from January to August 2004. Trained interviewers used surveys to collect information on social demographic characteristics, International Prostate Symptom Score, and King's Health Questionnaire to determine the prevalence, severity, QOL impact, treatment-seeking behavior, and risk factors of FLUTS. RESULTS: The prevalence of FLUTS was 19.0% (n = 519), with 88.6% having moderate and 11.4% severe FLUTS. Using the International Prostate Symptom Score QOL assessment index, 55.3% (n = 287) scored 4 or greater. Using the King's Health Questionnaire, the most affected QOL domain was sleep/energy. The patterns of treatment-seeking behavior revealed that only 23.1% (n = 120) of patients with FLUTS actively sought treatment. The major reason for those (76.9%) who failed to seek treatment was that they did not perceive FLUTS as a major health problem (29.1%). Factors that warranted treatment were the severity, bother, and QOL impact of FLUTS (all P <0.001), hematuria (P <0.001), age (P <0.005), parity, body mass index, and suprapubic pain (all P <0.05). The risk factors for FLUTS (defined as an odds ratio of 2 or more) included age 50 years or older, parity of 4 or more, illiteracy, postmenopausal status, and the presence of one or more concomitant chronic medical illness. CONCLUSIONS: Despite the high prevalence of FLUTS in Northern Malaysia (19.0%), many patients do not seek treatment, with ignorance being the major reason.

Cheah PY, Liong ML, Yuen KH, Lee S, Yang JR, Teh CL, Khor T, Yap HW, Krieger JN. 2006. Reliability and validity of the National Institutes of Health: Chronic Prostatitis Symptom Index in a Malaysian population. World J Urol, 24 (1), pp. 79-87. | Citations: 12 (Scopus) | Show Abstract | Read more

The objective of the study is to determine the short- and long-term utility of the Chinese, Malay and English versions of the National Institutes of Health--Chronic Prostatitis Symptom Index (NIH-CPSI) in our ethnically diverse population. The NIH-CPSI was translated into Chinese and Malay, and then verified by back translation into English. Subjects included 100 new chronic prostatitis/chronic pelvic pain (CP/CPPS) patients, 71 new benign prostatic hyperplasia patients and 97 healthy individuals. Reliability was evaluated with test-retest reproducibility (TR) by calculating intraclass correlation coefficients (ICC). Internal consistency was evaluated by calculating Cronbach's alpha (alpha). Validity assessments included discriminant and construct validity. (Presented in the order of Chinese, Malay then English). ICC values for short-term (1 week) TR were 0.90, 0.80 and 0.89, while ICC values for long-term (14 weeks) TR were 0.54, 0.61 and 0.61. Cronbach's alpha values were 0.63, 0.62 and 0.57. The NIH-CPSI total score discriminated CP/CPPS patients (P<0.001) from the control groups with receiver operating curve values of 0.95, 0.98 and 0.94, respectively. Construct validity, reflected by the correlation coefficient values between the International Prostate Symptom Score and the NIH-CPSI of CP/CPPS patients were 0.72, 0.49 and 0.63 (all P<0.05). The Chinese, Malay and English versions of the NIH-CPSI each proved effective in our population. Short-term TR and discriminant validity were excellent for all three versions. However, long-term TR was only moderate, which might reflect variation in patients' perceptions of symptoms over time.

Mahfouz ME, Grayson TH, Dance DAB, Gilpin ML. 2006. Characterization of the mrgRS locus of the opportunistic pathogen Burkholderia pseudomallei: temperature regulates the expression of a two-component signal transduction system. BMC Microbiol, 6 (1), pp. 70. | Citations: 8 (Web of Science Lite) | Show Abstract | Read more

BACKGROUND: Burkholderia pseudomallei is a saprophyte in tropical environments and an opportunistic human pathogen. This versatility requires a sensing mechanism that allows the bacterium to respond rapidly to altered environmental conditions. We characterized a two-component signal transduction locus from B. pseudomallei 204, mrgR and mrgS, encoding products with extensive homology with response regulators and histidine protein kinases of Escherichia coli, Bordetella pertussis, and Vibrio cholerae. RESULTS: The locus was present and expressed in a variety of B. pseudomallei human and environmental isolates but was absent from other Burkholderia species, B. cepacia, B. cocovenenans, B. plantarii, B. thailandensis, B. vandii, and B. vietnamiensis. A 2128 bp sequence, including the full response regulator mrgR, but not the sensor kinase mrgS, was present in the B. mallei genome. Restriction fragment length polymorphism downstream from mrgRS showed two distinct groups were present among B. pseudomallei isolates. Our analysis of the open reading frames in this region of the genome revealed that transposase and bacteriophage activity may help explain this variation. MrgR and MrgS proteins were expressed in B. pseudomallei 204 cultured at different pH, salinity and temperatures and the expression was substantially reduced at 25 degrees C compared with 37 degrees C or 42 degrees C but was mostly unaffected by pH or salinity, although at 25 degrees C and 0.15% NaCl a small increase in MrgR expression was observed at pH 5. MrgR was recognized by antibodies in convalescent sera pooled from melioidosis patients. CONCLUSION: The results suggest that mrgRS regulates an adaptive response to temperature that may be essential for pathogenesis, particularly during the initial phases of infection. B. pseudomallei and B. mallei are very closely related species that differ in their capacity to adapt to changing environmental conditions. Modifications in this region of the genome may assist our understanding of the reasons for this difference.

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