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1.  Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trial 
Lancet  2014;383(9919):807-814.
Summary
Background
Melioidosis, an infectious disease caused by the Gram-negative bacillus Burkholderia pseudomallei, is difficult to cure. Antimicrobial treatment comprises intravenous drugs for at least 10 days, followed by oral drugs for at least 12 weeks. The standard oral regimen based on trial evidence is trimethoprim-sulfamethoxaxole (TMP-SMX) plus doxycycline. This regimen is used in Thailand but is associated with side-effects and poor adherence by patients, and TMP-SMX alone is recommended in Australia. We compared the efficacy and side-effects of TMP-SMX with TMP-SMX plus doxycycline for the oral phase of melioidosis treatment.
Methods
For this multi-centre, double-blind, non-inferiority, randomised placebo-controlled trial, we enrolled patients (aged ≥15 years) from five centres in northeast Thailand with culture-confirmed melioidosis who had received a course of parenteral antimicrobial drugs. Using a computer-generated sequence, we randomly assigned patients to receive TMP-SMX plus placebo or TMP-SMX plus doxycycline for 20 weeks (1:1; block size of ten, stratified by study site). We followed patients up every 4 months for 1 year and annually thereafter to the end of the study. The primary endpoint was culture-confirmed recurrent melioidosis, and the non-inferiority margin was a hazard ratio (HR) of 1·7. This study is registered with www.controlled-trials.com, number ISRCTN86140460.
Findings
We enrolled and randomly assigned 626 patients: 311 to TMP-SMX plus placebo and 315 to TMP-SMX plus doxycycline. 16 patients (5%) in the TMP-SMX plus placebo group and 21 patients (7%) in the TMP-SMX plus doxycycline group developed culture-confirmed recurrent melioidosis (HR 0·81; 95% CI 0·42–1·55). The criterion for non-inferiority was met (p=0.01). Adverse drug reactions were less common in the TMP-SMX plus placebo group than in the TMP-SMX plus doxycycline group (122 [39%] vs 167 [53%]).
Interpretation
Our findings suggest that TMP-SMX is not inferior to TMP-SMX plus doxycycline for the oral phase of melioidosis treatment, and is preferable on the basis of safety and tolerance by patients.
Funding
Thailand Research Fund, the Melioidosis Research Center, the Center of Excellence in Specific Health Problems in Greater Mekong Sub-region cluster, and the Wellcome Trust.
doi:10.1016/S0140-6736(13)61951-0
PMCID: PMC3939931  PMID: 24284287
2.  Clinical perspectives on human genetic screening to prevent nevirapine toxicity 
Personalized medicine  2012;9(7):773-782.
Nevirapine is one of the most extensively prescribed antiretroviral drugs worldwide. However, a concern is increased risk for severe toxicity when antiretroviral-naive individuals with higher CD4 T-cell counts initiate nevirapine-containing regimens. Several genetic variants are associated with nevirapine toxicities. The authors used data from a previous study to anticipate potential consequences of genetic screening to prevent nevirapine adverse events. That study enrolled cohorts of African, Asian and European descent in 11 countries, including 276 patients who had experienced severe cutaneous and/or hepatic adverse events with nevirapine-containing regimens and 587 matched nevirapine-tolerant controls. Associations were identified with HLA-Cw*04, HLA-B*35, HLA-DRB*01 and CYP2B6 516G>T (rs3745274); however, positive predictive values for these genetic markers were low, and most nevirapine-associated adverse events occurred in patients without these markers. Unless better genetic predictors are identified, nevirapine toxicity is best avoided by continuing to follow current prescribing guidelines that are based largely on CD4 T-cell criteria.
doi:10.2217/pme.12.82
PMCID: PMC3579661  PMID: 23439719
CYP2B6; HIV; HLA; nevirapine; toxicogenomics
3.  Intravenous anidulafungin followed optionally by oral voriconazole for the treatment of candidemia in Asian patients: results from an open-label Phase III trial 
BMC Infectious Diseases  2013;13:219.
Background
Candidemia is a significant cause of morbidity and mortality in hospitalized patients, particularly in Asia. Anidulafungin has been reported to be an effective treatment for candidemia in Western populations, but little is known about its efficacy in Asian patients, where the clinical presentation and epidemiology may be different.
Methods
An open-label study of anidulafungin for the treatment of candidemia was recently conducted in several Asian countries. Treatment was initiated with intravenous anidulafungin, given for at least 5 days, with the option to complete treatment with oral voriconazole. The primary endpoint was global (clinical and microbiological) response, and the primary analysis was the proportion of patients in the modified intent-to-treat population with successful global response at the end of therapy. Secondary analyses included proportion with successful global response in clinically relevant patient subgroups. The safety and tolerability profile of anidulafungin and voriconazole in this population was also investigated.
Results
Forty-three patients were studied, including 42 in the modified intent-to-treat population. Eighteen patients were > 65 years, the largest age subgroup, and 21 had central venous catheters. The most common Candida species causing infection were C. tropicalis (n = 18) and C. albicans (n = 10). In the primary analysis, 73.8% had a successful global response at end of therapy. Success rates in subgroups were: 72.2% for C. tropicalis and 71.4% for C. albicans infection, 58.8% for patients > 65 years, and 81.0% for patients with central venous catheters. Safety and tolerability were comparable with the known profiles for anidulafungin (and voriconazole).
Conclusions
Although the epidemiology of Candida infections was different in this open-label study, the efficacy of anidulafungin in Asian patients with documented candidemia was consistent with previous studies in Western populations. No new safety concerns were identified.
Trial registration
http://www.clinicaltrials.gov identifier NCT00537329
doi:10.1186/1471-2334-13-219
PMCID: PMC3659089  PMID: 23676114
Anidulafungin; Candidemia; Asia
4.  Prevalence and genotypic relatedness of carbapenem resistance among multidrug-resistant P. aeruginosa in tertiary hospitals across Thailand 
Background
Increased infection caused by multidrug resistant (MDR) Pseudomonas aeruginosa has raised awareness of the resistance situation worldwide. Carbapenem resistance among MDR (CR-MDR) P. aeruginosa has become a serious life-threatening problem due to the limited therapeutic options. Therefore, the objectives of this study were to determine the prevalence, the antibiotic susceptibility patterns and the relatedness of CR-MDR P. aeruginosa in tertiary hospitals across Thailand.
Methods
MDR P. aeruginosa from eight tertiary hospitals across Thailand were collected from 2007–2009. Susceptibility of P. aeruginosa clinical isolates was determined according to the Clinical and Laboratory Standards Institute guideline. Selected CR-MDR P. aeruginosa isolates were genetically analyzed by pulsed-field gel electrophoresis.
Results
About 261 clinical isolates were identified as MDR P. aeruginosa and approximately 71.65% were found to be CR-MDR P. aeruginosa. The result showed that the meropenem resistance rate was the highest reaching over 50% in every hospitals. Additionally, the type of hospitals was a major factor affecting the resistance rate, as demonstrated by significantly higher CR-MDR rates among university and regional hospitals. The fingerprinting map identified 107 clones with at least 95% similarity. Only 4 clones were detected in more than one hospital.
Conclusions
Although the antibiotic resistance rate was high, the spreading of CR-MDR was found locally. Specific strains of CR-MDR did not commonly spread from one hospital to another. Importantly, clonal dissemination ratio indicated limited intra-hospital transmission in Thailand.
doi:10.1186/1476-0711-11-25
PMCID: PMC3475077  PMID: 22970983
Antimicrobial susceptibility; Pulsed-field gel electrophoresis; Carbapenem resistance; Multidrug resistance; Pseudomonas aeruginosa; Epidemiology
5.  Human Streptococcus suis Endocarditis: Echocardiographic Features and Clinical Outcome 
Background:
Human Streptococcus suis endocarditis occurs infrequently and continues to be a serious illness with high mortality. However, knowledge of the echocardiographic features and clinical outcome of this disease remains unclear.
Methods:
One hundred and fourteen patients were identified in a prospective study, and hospitalized at Queen Sirikit Heart Center and Srinagarind Hospital, Khon Kaen University. Echocardiography was routinely performed in all patients.
Results:
Between January 2010 and December 2011, three cases of S. suis endocarditis were diagnosed. All cases were male and aged 27–53 years. The most common risk factor for contracting S. suis infection was eating undercooked pork. Three patients presented with congestive heart failure. Transthoracic echocardiography demonstrated large, highly mobile vegetations and severe valvular damage. Aortic valve involvement was documented in two patients, and mitral valve involvement in one. One patient presented with embolic stroke and one with arterial occlusion. All patients underwent urgent valve replacement with a good clinical outcome.
Conclusion:
The echocardiographic features of S. suis endocarditis show destructive, extensive valvular damage and early embolization with a fulminant course, needing early surgical intervention with a good clinical outcome.
doi:10.4137/CMC.S9793
PMCID: PMC3411327  PMID: 22872789
Streptococcus suis; endocarditis; echocardiography
6.  Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent 
AIDS (London, England)  2011;25(10):1271-1280.
Objective
Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults.
Design
We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy.
Methods
Cases and controls were matched 1 : 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes.
Results
We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies.
Conclusion
Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening.
doi:10.1097/QAD.0b013e32834779df
PMCID: PMC3387531  PMID: 21505298
CYP2B6; HIV; human leukocyte antigen; nevirapine; pharmacogenomics; rash; toxicogenomics
7.  Identification of a Novel 74-Kilodalton Immunodominant Antigen of Pythium insidiosum Recognized by Sera from Human Patients with Pythiosis 
Journal of Clinical Microbiology  2006;44(5):1674-1680.
The oomycetous, fungus-like, aquatic organism Pythium insidiosum is the etiologic agent of pythiosis, a life-threatening infectious disease of humans and animals that has been increasingly reported from tropical, subtropical, and temperate countries. Human pythiosis is endemic in Thailand, and most patients present with arteritis, leading to limb amputation and/or death, or cornea ulcer, leading to enucleation. Diagnosis of pythiosis is time-consuming and difficult. Radical surgery is the main treatment for pythiosis because conventional antifungal drugs are ineffective. The aims of this study were to evaluate the use of Western blotting for diagnosis of human pythiosis, to identify specific immunodominant antigens of P. insidiosum, and to increase understanding of humoral immune responses against the pathogen. We performed Western blot analysis on 16 P. insidiosum isolates using 12 pythiosis serum samples. These specimens were derived from human patients with pythiosis who had different forms of infection and lived in different geographic areas throughout Thailand. We have identified a 74-kDa immunodominant antigen in all P. insidiosum isolates tested. The 74-kDa antigen was also recognized by sera from all patients with pythiosis but not by control sera from healthy individuals, patients with thalassemia, and patients with various infectious diseases, indicating that Western blot analysis could facilitate diagnosis of pythiosis. Therefore, the 74-kDa antigen is a potential target for developing rapid serodiagnostic tests as well as a therapeutic vaccine for pythiosis. These advances could lead to early diagnosis and effective treatment, crucial factors for better prognosis for patients with pythiosis.
doi:10.1128/JCM.44.5.1674-1680.2006
PMCID: PMC1479217  PMID: 16672392

Results 1-7 (7)