An open randomized controlled trial of desmopressin and pulse dexamethasone as adjunct therapy in patients with pulmonary involvement associated with severe leptospirosis.

Pulmonary involvement in leptospirosis is emerging as a common complication of severe leptospirosis. A prospective randomized controlled trial of desmopressin or high-dose (pulse) dexamethasone as adjunctive therapy in 68 patients with pulmonary involvement associated with severe leptospirosis was conducted between July 2003 and October 2006 at five hospitals in Thailand. There were 23 patients in the desmopressin group, 22 in the pulse dexamethasone group, and 23 in a control group who received standard critical care alone. The diagnosis of leptospirosis was confirmed in 52 patients (77%). There were 15 deaths (22%), of which eight patients received desmopressin, four patients received pulse dexamethasone, and three patients received critical care alone (p 0.19). Eight patients with confirmed leptospirosis died (five patients in the desmopressin group, one in the pulse dexamethasone group and two in the control group). The mortality was not significantly different in the desmopressin group or pulse dexamethasone group compared to the control group in both intention-to-treat patients, and in patients with confirmed leptospirosis. There were no serious events associated with desmopressin treatment, although pulse dexamethasone treatment was associated with a significant increase in nosocomial infection. The results of logistic regression analysis revealed that serum bilirubin level was the only significant risk factor associated with mortality (OR 0.759, 95% CI 0.598-0.965, p 0.024). The results obtained in the present study do not support the use of either pulse dexamethasone or desmopressin as adjunct therapy for pulmonary involvement associated with severe leptospirosis.

Epidemiology and clinical aspects of rickettsioses in Thailand.

Scrub typhus and murine typhus are widespread in Thailand. Clinical manifestations of both diseases are nonspecific and vary widely. Acute undifferentiated fever (AUF), with or without organ dysfunction, is a major clinical presentation of these two diseases. The epidemiology and clinical manifestations including severe complications of scrub typhus and murine typhus in Thailand are summarized. Sixteen hundred and sixty-three patients with AUF were studied in six hospitals in Thailand between 2000 and 2003. Scrub typhus and murine typhus were diagnosed in 16.1% and 1.7% of them, respectively. Clinical spectrum of murine typhus was similar to scrub typhus. Hepatic dysfunction and pulmonary involvement were common complications. Multi-organ dysfunction mimicking sepsis syndrome occurred in 11.9% of patients with scrub typhus. The mortality of severe scrub typhus varied from 2.6% to 16.7%. Awareness that scrub typhus and murine typhus are prominent causes of AUF in adults in Thailand improves the probability of an accurate clinical diagnosis. Early recognition and appropriate treatment reduces morbidity and mortality. Results from recent clinical studies from Thailand indicated that rational antimicrobial therapy would be doxycycline in mild cases and a combination of either cefotaxime or ceftriaxone and doxycycline in severe cases. Azithromycin could be considered as an alternative treatment when doxycycline allergy is suspected. This would be either curative, or have no ill effect, in the majority of instances. Failure to improve or defervesce within 48 hours would indicate the need to perform a thorough re-evaluation of clinical findings and initial laboratory investigation results, as well as a need to change antibiotic.

Detection of new genotypes of Orientia tsutsugamushi infecting humans in Thailand.

PCR screening of blood specimens taken from 195 patients with serologically confirmed scrub typhus in three Thai provinces detected the 56-kDa protein-encoding gene from Orientia tsutsugamushi in ten (5%) patients. Significant genetic diversity was found among the ten amplicons, with nine new genotypes identified that were different from those found previously in Thailand. Phylogenetically, the ten sequences obtained in the present study and sequences from 71 strains characterised previously were distributed into several clusters that included the Karp, Gilliam, Kuroki, Saitama, Kawasaki and Kato clusters. Two of the new genotypes found in the present study clearly belonged to the Karp cluster. However, the other new genotypes formed three different clusters, including one cluster that appeared to be distant from all previously known clusters, and which may therefore be representative of a previously undescribed serotype. Other genotypes formed two other clusters that may also be associated with undescribed serotypes.

Causes of acute, undifferentiated, febrile illness in rural Thailand: results of a prospective observational study.

The adult patients who, between July 2001 and June 2002, presented at any of five hospitals in Thailand with acute febrile illness in the absence of an obvious focus of infection were prospectively investigated. Blood samples were taken from all of the patients and checked for aerobic bacteria and leptospires by culture. In addition, at least two samples of serum were collected at different times (on admission and 2-4 weeks post-discharge) from each patient and tested, in serological tests, for evidence of leptospirosis, rickettsioses, dengue and influenza. The 845 patients investigated, of whom 661 were male, had a median age of 38 years and a median duration of fever, on presentation, of 3.5 days. Most (76.5%) were agricultural workers and most (68.3%) had the cause of their fever identified, as leptospirosis (36.9%), scrub typhus (19.9%), dengue infection or influenza (10.7%), murine typhus (2.8%), Rickettsia helvetica infection (1.3%), Q fever (1%), or other bacterial infection (1.2%). The serological results indicated that 103 (12.2%) and nine (1%) of the patients may have had double and triple infections, respectively. Leptospirosis and rickettsioses, especially scrub typhus, were thus found to be major causes of acute, undifferentiated fever in Thai agricultural workers.

Scrub typhus: chest radiographic and clinical findings in 130 Thai patients.

OBJECTIVE: To describe chest radiographic findings and their clinical correlation in patients with scrub typhus diagnosed in Thailand and to determine abnormalities that assist in the diagnosis of scrub typhus. MATERIAL AND METHOD: Between July 2001 and December 2002, 130 patients with scrub typhus admitted to three hospitals in the northeastern Thailand were studied. Data of clinical presentations and chest radiographic findings, reviewed by two radiologists who were unaware of the final diagnosis, were analyzed. RESULTS: There were 33 women, 97 men; age range, 11-92 years; median age, 45 years old. Pulmonary symptoms occurred in 61.5% of the patients and eschar was found in 33.1%. Hepatic dysfunction occurred in 58.5% and cardiovascular dysfunction in 33%. Pulmonary involvement was the major presentation in 41.5%. Acute respiratory distress syndrome developed in 7 patients. Overall 5 patients died. The initial radiography showed abnormalities in 64.6% of the patients. Common radiographic abnormalities included bilateral reticular opacities (48.5%), cardiomegaly (28.5%), congestive heart failure (18.5%), air space nodules (13.1%), and pleural effusion (10.8%). Significant association between chest radiographic abnormalities and hepatic and cardiovascular dysfunction were documented. CONCLUSION: Chest radiography should be included in the initial evaluation of patients with suspected scrub typhus. Bilateral reticular infiltration, with or without cardiomegaly or congestive heart failure, was the most frequent radiographic finding of scrub typhus.

Zoonotic species of Cryptosporidium are as prevalent as the anthroponotic in HIV-infected patients in Thailand.

The epidemiology of chronic diarrhoea in adults with late-stage HIV infection was investigated in a prospective study in Bangkok, Thailand. During this investigation, 34 Cryptosporidium isolates were obtained from the faeces of 36 patients, with mean CD4(+) counts of only 14 x 10(6) CD4(+) cells/litre (range = 2 x 10(6) - 53 x 10(6)/litre), who had symptomatic cryptosporidiosis. Genotyping of these isolates, by RFLP analysis and DNA sequencing of the hypervariable region of the 18S rRNA gene, indicated that only 17 (50%) were of the C. parvum human genotype. The rest were of C. meleagridis (seven), the C. parvum 'bovine' genotype (five), C. felis (three) and C. canis (two). Extensive genotypic heterogeneity was observed among the C. parvum isolates, and two other isolates, one of C. meleagridis and the other of C. felis, produced atypical restriction patterns and were only identified by sequencing. This appears to represent the first report of C. canis and the 'bovine' genotype of C. parvum in HIV-infected Thai patients.

A comparison of oral artesunate and artemether antimalarial bioactivities in acute falciparum malaria.

AIMS: Artesunate and artemether are the two most widely used artemisinin derivatives in the treatment of uncomplicated Plasmodium falciparum malaria, but there is little information on their comparative pharmacokinetics. The aim of this study was to examine the relative oral antimalarial bioavailability and pharmacokinetics of the two derivatives. METHODS: The pharmacokinetic properties of oral artesunate and artemether (4 mg kg(-1)) were compared in a randomized cross-over study of 14 adult patients in western Thailand with acute uncomplicated Plasmodium falciparum malaria. Antimalarial activity was compared using a previously validated, sensitive bioassay. RESULTS: Despite a 29% lower molar dose, oral artesunate administration resulted in significantly larger mean area under the plasma antimalarial activity time curve and median maximum plasma antimalarial activity than after oral artemether (P

Value of throat swab in diagnosis of melioidosis.

Throat swab (TS) cultures were performed for 1,011 patients with melioidosis and 3,524 healthy subjects or patients with other diseases. The specificity of TS culture for the diagnosis of melioidosis was 100%, and the overall sensitivity was 36% (24% for sputum-negative patients and 79% for sputum-positive patients). Direct plating of the TS specimen on Ashdown's medium was rapid (colonies were usually evident within 24 h) but only 63% sensitive compared to the results of primary culture in a selective broth. A throat swab should be cultured in all cases of suspected melioidosis.

Protozoan enteric infection in AIDS related diarrhea in Thailand.

The aim of this study was to determine the prevalence of enteric protozoa and other pathogens in AIDS patients with diarrhea in Bangkok, Thailand. Of 288 consecutive patients screened in the 10 month period between November 1999-August 2000 inclusive, 55 (19.2%) had Cryptosporidium spp, 13 (4.5%) had Isospora oocyst, 11 (3.8%) had Giardia lamblia, 3 (0.9%) had Entamoeba histolytica, and 1 (0.3%) had Iodamoeba butschlii infection. The prevalence of microsporidia was 11% in this study. Of 251 patients for whom stool culture for bacteria was performed, enteric bacterial pathogens isolated were Campylobacter spp in 18 (7.1%), Salmonella spp in 11 (4.3%), and Shigella spp in 1 (0.5%). Other pathogens found in these patients were Clostridium difficile in 16/102 (15.6%). Mycobacterium spp in 18/287 (6.2%), and Strongyloides stercoralis in 23/288 (8.0%). Overall, parasitic and bacterial pathogens were identified in 140 (48.6%) patients. These pathogens were identified by the routine simple wet smear technique in 32, formalin-ether concentration method in 46, culture for S. stercoralis in 5, and culture for bacteria in 30. Additional test, using modified Ziehl-Neelsen staining, identified cryptosporidial oocyst, isospora oocyst, and Mycobacterium spp in 72. The microsporidia, initially identified by modified trichrome blue staining, all were then determined to be Enterocytozoon bieneusi by thin sectioning electron microscopy. Protozoan and bacterial pathogens were confirmed to be important etiologic agents in diarrhea in AIDS in Thailand. They were all associated with increased mortality. Routine stool examination by simple wet smear detected only one-fourth of these pathogens. Therefore all diagnostic techniques for these organisms should be made more widely available in Thailand.

Protein and energy metabolism in chronic bacterial infection: studies in melioidosis.

Chronic infection is often accompanied by a wasting process, the metabolic basis of which is not fully understood. The aims of the present study were to measure protein and energy metabolism in patients with melioidosis (a serious and antibiotic-refractory Gram-negative bacterial infection which is endemic in South-East Asia) in order to define the metabolic abnormalities that might contribute to wasting. Whole-body protein turnover was measured using the [(13)C]leucine technique, both in the fasted state and while consuming a high-energy meal. Resting energy expenditure was measured by indirect calorimetry, and total energy expenditure by the bicarbonate/urea method. Results were normalized for fat-free mass, as estimated from skinfold thickness. Protein turnover was increased in melioidosis patients compared with healthy controls during fasting (170.9 compared with 124.1 micromol x kg(-1) x h(-1); P=0.04), but the net rate of catabolism (22.2 compared with 20.5 micromol x kg(-1) x h(-1); P=0.77) and the anabolic response to feeding were similar in the two groups. Resting energy expenditure was higher in melioidosis patients compared with controls (191.4 and 157.3 kJ x kg(-1) x day(-1) respectively; P=0.04), but total energy expenditure (measured in a separate group of eight patients with melioidosis) was low (192.1 kJ x kg(-1) x day(-1)). In conclusion, this study found no evidence of metabolic causative factors, such as accelerated net protein catabolism during fasting, a blunted anabolic response to feeding or increased daily energy expenditure, and therefore suggests that reduced energy intake is the prime cause of wasting. The observed normal response to feeding should encourage nutritional approaches to prevent wasting.

Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis.

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 MIC90 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, DL of 18.7 mg kg(-1) (9.5-23) and infusion rate I = 3.5 mg k(-1) h(-1) (0.4-13) (which equals 84 mg kg(-1) day(-1)). A nomogram for adjustment in renal failure is given.

Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis.

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 of 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 to perform estimation of pharmacokinetic and pharmacodynamic parameters. RESULTS: Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l-1, giving a target concentration CT, 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 these patients is Clearance = k * creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg-1 (1. 9-4.6) and infusion rate I = 0.46 mg kg h-1 (0.04-1.3) (which equals 14.8 mg kg-1 day-1). A nomogram for adjustment in renal failure is given.

Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria.

The pharmacokinetic properties of oral and intravenous artesunate (2 mg/kg of body weight) were studied in 19 adult patients with acute uncomplicated Plasmodium falciparum malaria by using a randomized crossover design. A sensitive bioassay was used to measure the antimalarial activity in plasma which results from artesunate and its principal metabolite, dihydroartemisinin. The oral study was repeated with 15 patients during convalescence. The mean absolute oral bioavailability of the antimalarial agent in patients with acute malaria was 61% (95% confidence interval [CI], 52 to 70%). The absorption and elimination of oral artesunate were rapid, with a mean elimination half-life of antimalarial activity of 43 min (95% CI, 33 to 53 min). Following oral administration to patients with acute falciparum malaria, peak antimalarial activity in plasma and the area under the plasma concentration-time curve were approximately double those during convalescence and the apparent volume of distribution and clearance were approximately half those during convalescence (P < or = 0.005). Acute malaria is associated with a significant reduction in the clearance of artesunate-associated antimalarial activity.

Prognostic value of cytokine concentrations (tumor necrosis factor-alpha, interleukin-6, and interleukin-10) and clinical parameters in severe melioidosis.

Raised serum concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, or IL-10 are associated with mortality in patients with sepsis, but it is not known whether elevated cytokine levels are independently predictive of mortality. Cytokine assays (TNF-alpha, IL-6, and IL-10) were performed on admission plasma samples from 172 adult Thai patients with severe melioidosis. Mortality was 31.4%. APACHE II score; septicemia; plasma lactate; TNF-alpha, IL-6, and IL-10 concentrations; and IL-10/TNF-alpha and IL-6/IL-10 ratios were each associated with outcome (P

A double-blind placebo-controlled study of an infusion of lexipafant (Platelet-activating factor receptor antagonist) in patients with severe sepsis.

Platelet-activating factor (PAF) is a potent endogenous proinflammatory mediator implicated in the pathogenesis of septic shock. A double-blind randomized placebo-controlled trial of an intravenous PAF receptor antagonist (lexipafant) was conducted with 131 adult Thai patients with suspected severe sepsis (66 of whom had positive blood cultures). Detailed serial clinical, biochemical, and cytokine measurements were performed. Lexipafant treatment was well tolerated. The 28-day mortality in the lexipafant group (61.4%) was similar to that in the placebo group (62.6%). There was also no evidence that lexipafant affected clinical or biochemical measures of disease severity or the profile of sequentially measured plasma cytokine levels. PAF may not have an important role in the pathogenesis of severe sepsis.

Antilipopolysaccharide II: an antibody protective against fatal melioidosis.

This was a study of IgG antibody responses to two S-type lipopolysaccharides (LPS I and LPS II) and flagellin of Burkholderia pseudomallei in patients with melioidosis. The specificity of these antibodies was 91.7%, 90.3%, and 93.8%, respectively, when compared to responses in a population where the organism is not endemic. Only the level of antibody to LPS II (anti-LPS II) was significantly higher in patients who survived than in those who died, as well as in patients with nonsepticemic vs. septicemic melioidosis. Results of logistic regression analysis, controlled for confounding factors such as duration of illness before treatment and bacteremic status, confirmed that a high level of anti-LPS II was a significant factor protective against fatal melioidosis. Thus, LPS II of B. pseudomallei would be a potentially useful component of a vaccine developed against fatal melioidosis. Further studies are in progress to determine the level of this antibody among those with asymptomatic infection in areas where melioidosis is endemic.

A comparison of chloramphenicol, trimethoprim-sulfamethoxazole, and doxycycline with doxycycline alone as maintenance therapy for melioidosis.

A prospective, open, randomized, comparative treatment trial was conducted to compare the therapeutic efficacy of the conventional four-drug combination (chloramphenicol, trimethoprim-sulfamethoxazole, and doxycycline) with that of doxycycline alone in oral maintenance treatment of melioidosis. Adult Thai patients with culture-confirmed melioidosis were randomized to receive treatment with either regimen for a minimum of 12 weeks, usually following intravenous treatment of severe disease. The main outcome measure was culture-confirmed relapse. One hundred sixteen patients were enrolled; 109 had culture-confirmed melioidosis, and 87 were considered evaluable (43 had received doxycycline). Culture-confirmed relapse occurred in one patient randomized to the conventional regimen and in 11 (25.6%) randomized to the doxycycline regimen (P = .009), and treatment failed for 8 (18.2%) versus 20 (46.5%), respectively (P = .009). Adverse effects occurred in 26% of patients overall. Doxycycline alone cannot be recommended for a first-line regimen of oral maintenance treatment of melioidosis.