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Aims Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta‐lactam antibiotics for serious Gram‐negative infections. Severe melioidosis ( Burkholderia pseudomallei infection) carries a mortality over 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis. Methods Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg −1 8 hourly by bolus injection or 4 mg kg −1 h −1 by constant infusion following a 12 mg kg −1 priming dose and pharmacokinetic and pharmacodynamic parameters were compared. Results Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC 90 of B. pseudomallei was 2 mg l −1 , giving a minimum target concentration (4*MIC) of 8 mg l −1 . The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half‐lives of ceftazidime were 0.468 (0.241–0.573) l kg −1 , 0.058 (0.005–0.159) l kg −1 h −1 and 7.74 (1.95–44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely ( r = 0.71; P < 0.001) and there was no evidence of significant nonrenal clearance. Conclusions Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure, which is common in patients with meliodosis is Clearance = k * creatinine clearance where k = 0.72. Calculation of a loading dose gives median (range) values of loading dose, D L of 18.7 mg kg −1 (9.5–23) and infusion rate I = 3.5 mg kg −1 h −1 (0.4–13) (which equals 84 mg kg −1 day −1 ). A nomogram for adjustment in renal failure is given.

An open, randomised comparison of 2 or 3 days of oral ofloxacin (10 mg/kg/day) for uncomplicated typhoid fever was conducted in 235 Vietnamese children. Multi-drug-resistant Salmonella typhi was isolated from 182/202 (90%) children and 5/166 (3%) tested isolates were nalidixic acid-resistant (NaR). Eighty-nine of 116 children randomised to 2 days and 107/119 randomised to 3 days were blood culture-positive and eligible for analysis. There were 12 (13.5%) failures in the 2-day group (six clinical failures, four blood culture-positive post treatment, two relapses) compared with eight (7.5%) failures in the 3-day group (four clinical failures, one blood culture-positive post treatment, three relapses) (OR 1.9, 95% CI 0.7–5.5,p = 0.17). There were no significant differences in the mean (95% confidence interval) fever clearance times (h) [92 (82−102) vs 101 (93−110), p = 0.18] or duration of hospitalisation (d) [7.6 (7.2−8.1) vs 8.0 (7.6−8.4), p = 0.19] between the two groups. There was one failure in the four eligible children infected with an NaR isolate of S. typhi. No adverse events were attributable to the ofloxacin. These results extend previous observations on the efficacy of short courses of ofloxacin for children with uncomplicated multi-drug-resistant typhoid fever.

Additional file 7. All positions that are variant in RSA0â 3h phenotyped isolates.

<ns4:p><ns4:bold>Background:</ns4:bold> Inherited red blood cell disorders are prevalent in populations living in malaria endemic areas; G6PD deficiency is associated with oxidant-induced hemolysis and abnormal hemoglobin variants may cause chronic anemia. In pregnant women, microcytic anemia caused by hemoglobinopathies mimics iron deficiency, complicating diagnosis and treatment. Anemia during pregnancy is associated with morbidity and mortality. The aim of this study was to characterize the prevalence of G6PD deficiency, hemoglobinopathies, ABO and Rhesus blood groups among the pregnant population living along the Thailand-Myanmar border. Pregnant women attending antenatal clinics in this area belong to several distinct ethnic groups.</ns4:p><ns4:p> <ns4:bold>Methods:</ns4:bold> Data was available for 13,520 women attending antenatal care between July 2012 and September 2016. Screening for G6PD deficiency was done by fluorescent spot test routinely. G6PD genotyping and quantitative phenotyping by spectrophotometry were analyzed in a subsample of women. Hemoglobin variants were diagnosed by HPLC or capillary electrophoresis and molecular methods. Blood groups were diagnosed by agglutination test. The prevalence and distribution of inherited red blood cell disorders and blood groups was analyzed with respect to ethnicity.</ns4:p><ns4:p> <ns4:bold>Results:</ns4:bold> G6PD deficiency was common, especially in the Sgaw Karen ethnic group, in whom the G6PD Mahidol variant allele frequency was 20.7%. Quantitative G6PD phenotyping showed that 60.5% of heterozygote women have an intermediate enzymatic activity between 30% and 70% of the population median. HbE, beta-thalassemia trait and alpha-thalassemia trait were found in 31.2% of women. Only 0.15% of women were Rhesus negative.</ns4:p><ns4:p> <ns4:bold>Conclusions:</ns4:bold> Distribution of G6PD and hemoglobin variants varied among the different ethnic groups, but the prevalence was generally high throughout the cohort. These findings encourage the implementation of an extended program of information and genetic counseling to women of reproductive age and will help inform future studies and current clinical management of anemia in the pregnant population in this region.</ns4:p>

No abstract is provided for this article.

Relapse in Melioidosis: Incidence and Risk Factors Get access W. Chaowagul, W. Chaowagul Search for other works by this author on: Oxford Academic PubMed Google Scholar Y. Suputtamongkol, Y. Suputtamongkol Reprints or correspondence: Dr. Y. Suputtarnongkol, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Search for other works by this author on: Oxford Academic PubMed Google Scholar D. A. B. Dance, D. A. B. Dance Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Rajchanuvong, A. Rajchanuvong Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Pattara, J. Pattara Search for other works by this author on: Oxford Academic PubMed Google Scholar N. J. White N. J. White Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 168, Issue 5, November 1993, Pages 1181–1185, https://doi.org/10.1093/infdis/168.5.1181 Published: 01 November 1993 Article history Received: 11 March 1993 Revision received: 03 June 1993 Published: 01 November 1993

Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis.In this randomized, placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor [G-CSF], 263 mu g per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected melioidosis in Thailand.Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61-1.06; P=.2), including among patients with confirmed melioidosis (83% vs. 96%; P=.3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31-1.00; P=.05).Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having melioidosis in Thailand. We hypothesize that G-CSF may "buy time" for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis.

Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria.This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966.Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest number in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concentration (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3).Artefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs.Bill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.

There are an estimated 150 million episodes of childhood pneumonia per year, with 11-20 million hospital admissions and 1.575 million deaths. Refugee children are particularly vulnerable, with poorly defined pneumonia epidemiology.We followed a birth cohort of 955 refugee infants, born over a one-year period, until two years of age. Clinical and radiographic pneumonia were diagnosed according to WHO criteria. Detailed characteristics were collected to determine risk factors for clinical, radiological and multiple episodes of pneumonia. Investigations were taken during a pneumonia episode to help determine or to infer an aetiological diagnosis.The incidence of clinical pneumonia was 0.73 (95% CI 0.70-0.75) episodes per child year (/CY) and of radiological primary endpoint pneumonia (PEP) was 0.22/CY (95% CI 0.20-0.24). The incidence of pneumonia without severe signs was 0.50/CY (95% CI 0.48-0.53), severe pneumonia 0.15/CY (95% CI 0.13-0.17) and very severe pneumonia 0.06/CY (0.05-0.07). Virus was detected, from a nasopharyngeal aspirate, in 61.3% of episodes. A reduced volume of living space per person (IRR 0.99, 95% CI 0.99-1.0, p = 0.003) and young maternal age (IRR 1.59, 95% CI 1.12-2.27, p = 0.01) were risk factors for developing pneumonia. The risk of a child having >1 episode of pneumonia was increased by having a shorter distance to the next house (IRR 0.86, 95% CI 0.74-1.00, p = 0.04). Infants were at risk of having an episode of PEP if there was a shorter distance from stove to bed (IRR 0.89, 95% CI 0.80-0.99, p = 0.03). Raised CRP and neutrophil values were associated with PEP.There was a high incidence of pneumonia in young children in this SE Asian refugee population. Viral infections were important, however CXR and non-specific marker findings suggested that bacteria may be involved in up to a third of cases.

Author(s): Adhikari, Bipin; Phommasone, Koukeo; Pongvosa, Tiengkham; Koummarasy, Palingnaphone; Soundala, Xayaphone; Henriques, Gisela; Sirithiranont, Pasathorn; Parker, Daniel; von Seidlein, Lorenz; White, Nicholas; Day, Nicholas; Dondorp, Arjen; Newton, Paul; Cheah, Phaik; Pell, Christopher; Mayxay, Mayfong

Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose dependent haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals. G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused.We conducted a pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15 to 20 days. In Part 2, a single primaquine 45 mg dose was given.24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1 to 5.9; relative decline of 26% [range: 15 to 40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9 to 4.1; relative fall of 12% [range: 7 to 30% decrease]). The ascending dose primaquine regimens gave 7 times more drug but resulted in only double the haemoglobin decline.In patients with Southeast Asian G6PDd variants full radical cure treatment can be given in under three weeks compared with the current 8 week regimen.

Background.Tuberculous meningitis occurs more commonly in human immunodeficiency virus (HIV)–infected individuals than in HIV-uninfected individuals, but whether HIV infection alters the presentation and outcome of tuberculous meningitis is unknown MethodsWe performed a prospective comparison of the presenting clinical features and response to treatment in 528 adults treated consecutively for tuberculous meningitis (96 were infected with HIV and 432 were uninfected with HIV) in 2 tertiary-care referral hospitals in Ho Chi Minh City, Vietnam. Logistic regression was used to model variables associated independently with HIV infection, 9-month survival, and the likelihood of having a relapse or an adverse drug event. Kaplan-Meier estimates were used to compare survival rates and times to fever clearance, coma clearance, relapse, and adverse events ResultsHIV infection did not alter the neurological presentation of tuberculous meningitis, although additional extrapulmonary tuberculosis was more likely to occur in HIV-infected patients. The 9-month survival rate was significantly decreased in HIV-infected patients (relative risk of death from any cause, 2.91 [95% confidence interval, 2.14–3.96]; P<.001), although the times to fever clearance and coma clearance and the number or timing of relapses or adverse drug events were not significantly different between the groups ConclusionsHIV infection does not alter the neurological features of tuberculous meningitis but significantly reduces the survival rate