Tran Quang Binh

In vivo parasitological measures of artemisinin susceptibility.

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.

Selective high-performance liquid chromatographic determination of artesunate and α- and β-dihydroartemisinin in patients with falciparum malaria

Abstract A novel solid-phase extraction and a robust high-performance liquid chromatographic (HPLC) separation procedure for artesunate and α- and β-dihydroartemisinin, using post-column alkali decomposition and UV detection, is described. Extraction was performed with Bond-Elut Phenyl solid-phase extraction cartridges and analysis by HPLC was carried out using a Waters Symmetry C8 5-μm 150 × 3.9 mm I.D. column. The mobile phase was 50% acetonitrile in 0.1 M acetate buffer (pH 4.8) delivered at a flow-rate of 0.7 ml/min. The column eluate was mixed with 1.2 M potassium hydroxide in 90% methanol delivered at 0.3 ml/min, in a 1-ml reaction coil at 69°C, to form UV-absorbing chromophores which were detected at 290 mm. The recovery of all analytes was greater than 80%. There was no significant difference in the peak-area ratio of α- and β-dihydroartemisinin in plasma. Preliminary pharmacokinetic data from six adult Vietnamese patients who received 120 mg of artesunate by intravenous injection for the treatment of acute falciparum malaria are presented. Despite limited data, the mean half-life of artesunate was approximately 3.5 min while that for dihydroartemisinin was 34 min. These data confirm the relatively rapid clearance of both artesunate and its principal active metabolite, dihydroartemisinin.

Consensus review of the epidemiology and appropriate antimicrobial therapy of complicated urinary tract infections in Asia-Pacific region

Urinary tract infections (UTIs) are among the most prevalent infectious diseases in the general population. They cause a substantial financial burden in the community and are associated with significant morbidity and mortality, particularly in hospitals. With increased rates of antimicrobial resistance, especially in the Asia-Pacific region, treatment of complicated UTIs (cUTIs) can be challenging for clinicians. Consideration of an optimal antimicrobial agent should be based on local resistance patterns, patient-specific factors, pharmacokinetic and pharmacodynamic principles, and cost. In the Asia-Pacific region, nearly half of Escherichia coli urinary isolates were resistant (including intermediate and resistant) to levofloxacin or ciprofloxacin and ≥30% were resistant to third-generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) and cefepime. Overall, 33% of urinary E. coli isolates exhibited extended-spectrum β-lactamase (ESBL)-producing phenotypes. Prevalence of ESBL-producing urinary E. coli was highest in India (60%), followed by Hong Kong (48%) and Singapore (33%). All urinary isolates of E. coli were susceptible to both ertapenem and imipenem. All urinary isolates of Klebsiella pneumoniae were susceptible to imipenem and 4% of them were resistant to ertapenem. Care should be exercised when using trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, and cephalosporins for the empirical treatment of UTIs, particularly cUTI among moderately to severely ill patients. Empiric antimicrobial treatment for serious cUTIs in which risk factors for resistant organisms exist should include broad-spectrum antibiotics such as carbapenems (ertapenem, imipenem, meropenem, and doripenem) and piperacillin-tazobactam. Aminoglycosides, tigecycline, and polymyxins (colistin or polymyxin B) can be used for the treatment of multidrug-resistant organisms or serious cUTIs when first-line options are deemed inappropriate or patients fail therapy. Because of considerable variability in different countries, local epidemiological data is critical in the effective management of UTIs in the Asia-Pacific region.

Seroprevalence of dengue antibodies, annual incidence and risk factors among children in southern Vietnam

Dengue is highly endemic in southern Vietnam and all four serotypes of dengue virus have already been identified. To determine the age‐specific prevalence of dengue and associated risk factors, we conducted a serological study at two primary schools and assessed risk factors by analysing childrens questionnaires and household surveys. Sera were collected from 961 primary schoolchildren in Binh Thuan Province and tested for the presence of dengue virus serum antibodies using an indirect immunoglobulin G (IgG) enzyme‐linked immunosorbent assay (ELISA). The antibody prevalence of the total population was 65.7% (n = 631) which increased from 53.0 to 88.2% with age. The annual incidence of a first dengue infection, estimated by binary regression of the seroprevalence by age, was 11.7%. Interestingly, the prevalence of dengue IgG antibodies was significantly higher in children who confirmed using a pit latrine (RR 1.467, 95% CI: 1.245–1.730) and whose domestic environment contained discarded cans (RR 1.238, 95% CI: 1.042–1.470) and pigs (RR 1.228, 95% CI: 1.002–1.504). The epidemiology of dengue in southern Vietnam is stable with a constantly high annual incidence of first infections. Transmission occurs mainly peri‐domestically, which has important public health implications.

Dengue as a cause of acute undifferentiated fever in Vietnam

BackgroundDengue is a common cause of fever in the tropics but its contribution to the total burden of febrile illnesses that is presented to primary health facilities in endemic regions such as Vietnam, is largely unknown. We aimed to report the frequency of dengue as a cause of fever in Binh Thuan Province, to describe the characteristics of dengue patients, and analyze the diagnostic accuracy of the health care workers and the determinants of the diagnostic process.MethodsAll patients presenting with acute undifferentiated fever at twelve community health posts and one clinic at the provincial malaria station, Binh Thuan Province, a dengue endemic province in southern Vietnam, were included. Record forms were used to fill in patient and diseases characteristics, pre-referral treatment, signs and symptoms, provisional diagnosis and prescribed treatment, referral and final outcome. Serum samples were collected at first presentation and after 3 weeks for serologic diagnosis.Results2096 patients were included from April 2001 to March 2002. All 697 patients with paired serum samples were tested for dengue virus IgM and IgG. Acute dengue was found in 33.6% cases and past dengue virus infections were found in 57.1% cases. Acute primary infections were more common among children under 15 years old than among adults (7.7% vs. 3.5%, p value < 0.001). Younger age significantly predicted acute dengue (RR per increasing year of age (95 % CI): 0.986 (0.975–0.997, p value = 0.014). 48.9% of cases with clinical diagnosis of acute dengue were serologically confirmed and 32.5% of cases without clinical diagnosis of acute dengue were positive by serology after all (OR = 1.981, p value 0.025, 95% CI: 1.079 – 3.635). Tourniquet test was not a predictor for dengue diagnosis.ConclusionDengue is responsible for one third of the fevers presented to the public primary health services in Binh Thuan, southern Vietnam. It presents as a highly unspecific illness and is hardly recognized as a clinical entity by primary physicians.

Pharmacokinetics and pharmacodynamics of intravenous artesunate in severe falciparum malaria.

ABSTRACT To provide novel data relating to the dispositions, effects, and toxicities of the artemisinin derivatives in severe malaria, we studied 30 Vietnamese adults with slide-positive falciparum malaria treated with intravenous artesunate. Twelve patients with complications (severe; group 1) and 8 patients without complications but requiring parenteral therapy (moderately severe; group 2) received 120 mg of artesunate by injection, and 10 patients with moderately severe complications (group 3) were given 240 mg by infusion. Serial concentrations of artesunate and its active metabolite dihydroartemisinin in plasma were measured by high-performance liquid chromatography. The time to 50% parasite clearance (PCT50) was determined from serial parasite densities. Full clinical (including neurological) assessments were performed at least daily. In noncompartmental pharmacokinetic analyses, group mean artesunate half-lives (t1/2) were short (range, 2.3 to 4.3 min). The dihydroartemisinin t1/2 (range, 40 to 64 min), clearance (range, 0.73 to 1.01 liters/h/kg), and volume of distribution (range, 0.77 to 1.01 liters/kg) were also similar both across the three patient groups (P > 0.1) and to previously reported values for patients with uncomplicated malaria. Parasite clearance was prompt (group median PCT50 range 6 to 9 h) and clinical recovery was complete under all three regimens. These data indicate that the pharmacokinetics of artesunate and dihydroartemisinin are not influenced by the severity of malaria. Since the pharmacokinetic parameters for both artesunate and dihydroartemisinin were similar regardless of whether injection or infusion was used, artesunate can be considered a prodrug that is converted stoichiometrically to dhydroartemisinin. Conventional doses of artesunate are safe and effective when given to patients with complications of falciparum malaria.

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

BACKGROUND Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. METHODS In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. RESULTS The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. CONCLUSIONS Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo. (Funded by the United Kingdom Department for International Development and others through the Joint Global Health Trials program; Current Controlled Trials number, ISRCTN59144167.).

CV8 a new combination of dihydroartemisinin piperaquine trimethoprim and primaquine compared with atovaquone-proguanil against falciparum malaria in Vietnam.

Objectives  To study a new combination, based on dihydroartemisinin and piperaquine (CV8) and atovaquone/proguanil (Malarone) for treatment of uncomplicated falciparum malaria in Vietnam.

Penetration of Dihydroartemisinin into Cerebrospinal Fluid after Administration of Intravenous Artesunate in Severe Falciparum Malaria

ABSTRACT Penetration of cerebrospinal fluid (CSF) by artesunate and DHA was assessed in six adults with cerebral or severe malaria. Lumbar punctures were performed on admission and during convalescence, at 15 min (patient 1), 30 min (patient 2), 45 min (patient 3), 60 min (patient 4), 90 min (patient 5), and 120 min (patient 6) after intravenous administration of 120 mg of artesunate. No artesunate was detectable in CSF. In both studies, DHA levels in CSF increased with time while dihydroartemisinin levels in plasma fell. Dihydroartemisinin might accumulate in CSF during frequent artesunate dosing.

Seroepidemiology of leptospirosis in southern Vietnamese children.

Objective  To estimate the seroprevalence of human leptospirosis in southern Vietnam.