Antibiotic susceptibility of clinical Burkholderia pseudomallei isolates in northeast Thailand during 2015-2018 and the genomic characterization of ß-lactam-resistant isolates.

Melioidosis is an often fatal infection in tropical regions caused by an environmental bacterium, Burkholderia pseudomallei Current recommended melioidosis treatment requires intravenous ß-lactam antibiotics such as ceftazidime (CAZ), meropenem (MEM) or amoxicillin-clavulanic acid (AMC) and oral trimethoprim-sulfamethoxazole. Emerging antibiotic resistance could lead to therapy failure and high mortality. We performed a prospective multicentre study in northeast Thailand during 2015-2018 to evaluate antibiotic susceptibility and characterize ß-lactam resistance in clinical B. pseudomallei isolates. Collection of 1,317 B. pseudomallei isolates from patients with primary and relapse infections were evaluated for susceptibility to CAZ, imipenem (IPM), MEM and AMC. ß-lactam resistant isolates were confirmed by broth microdilution method and characterized by whole genome sequence analysis, penA expression and ß-lactamase activity. The resistant phenotype was verified via penA mutagenesis. All primary isolates were IPM-susceptible but we observed two CAZ-resistant and one CAZ-intermediate resistant isolates, two MEM-less susceptible isolates, one AMC-resistant and two AMC-intermediate resistant isolates. One of 13 relapse isolates was resistant to both CAZ and AMC. Two isolates were MEM-less susceptible. Strains DR10212A (primary) and DR50054E (relapse) were multi-drug resistant. Genomic and mutagenesis analyses supplemented with gene expression and ß-lactamase analyses demonstrated that CAZ-resistant phenotype was caused by PenA variants: P167S (N=2) and penA amplification (N=1). Despite the high mortality rate in melioidosis, our study revealed that B. pseudomallei isolates had a low frequency of ß-lactam resistance caused by penA alterations. Clinical data suggest that resistant variants may emerge in patients during antibiotic therapy and be associated with poor response to treatment.

Efficacy and safety of switching to bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed Asian adults living with HIV: A pooled analysis from three international phase III randomized trials.

OBJECTIVES: Data on switching to bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) in virologically suppressed Asian people living with HIV are limited. We performed a pooled analysis of virologically suppressed Asian participants from three international phase III trials to evaluate the efficacy and safety of switching to B/F/TAF. METHODS: Virologically suppressed people living with HIV were randomized to switch to B/F/TAF or to stay on baseline regimens. The primary endpoint was the proportion of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48. We analysed the incidence of adverse events (AEs), laboratory abnormalities, and changes in relevant tolerability parameters through 48 weeks. RESULTS: Overall, 136 Asian participants were included. The proportions of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48 were low in both arms (0% for B/F/TAF vs 1.4% for those who stayed on baseline regimens). Those who switched to B/F/TAF had virological suppression rates similar to those who stayed on baseline regimens (100% vs 95.9%, p = 0.2485), with no treatment-emergent resistance. Drug-related AEs occurred in three participants in each arm; none were serious. No participants discontinued the study drug because of AEs, and no deaths were observed. No significant differences were observed between the arms in the median changes in estimated glomerular filtration rate, body weight, and most lipid parameters. Switching from tenofovir disoproxil fumarate-containing regimens to B/F/TAF resulted in a significant decrease in tubular proteinuria compared with those who stayed on baseline regimens (p < 0.01). CONCLUSIONS: Virologically suppressed Asian people living with HIV who switched to B/F/TAF maintained 100% virological suppression at week 48, with no treatment-emergent drug resistance and safety profiles comparable to those seen in people who stayed on baseline regimens. CLINICAL TRIAL NUMBER: ClinicalTrials.gov (NCT02603120, NCT02652624, and NCT02603107).

A Comparison Between 12 Versus 20 Weeks of Trimethoprim-sulfamethoxazole as Oral Eradication Treatment for Melioidosis: An Open-label, Pragmatic, Multicenter, Non-inferiority, Randomized Controlled Trial.

BACKGROUND: Treatment of melioidosis comprises intravenous drugs for at least 10 days, followed by oral trimethoprim-sulfamethoxazole (TMP-SMX) for 12 to 20 weeks. Oral TMP-SMX is recommended for 12 weeks in Australia and 20 weeks in Thailand. METHODS: For this open-label, pragmatic, multicenter, noninferiority, randomized controlled trial, we enrolled patients with culture-confirmed melioidosis who had received oral eradication treatment for 12 weeks and had no clinical evidence of active melioidosis. We randomly assigned patients to stop treatment (12-week regimen) or continue treatment for another 8 weeks (20-week regimen). The primary end point was culture-confirmed recurrent melioidosis within 1 year after enrollment. The noninferiority margin was a hazard ratio (HR) of 2.0. The secondary composite end point, combining overall recurrent melioidosis and mortality, was assessed post hoc. RESULTS: We enrolled 658 patients: 322 to the 12-week regimen and 336 to the 20-week regimen. There were 5 patients (2%) in the 12-week regimen and 2 patients (1%) in the 20-week regimen who developed culture-confirmed recurrent melioidosis (HR, 2.66; 95% confidence interval [CI], .52-13.69). The criterion for noninferiority of the primary event was not met (1-sided P = .37). However, all-cause mortality was significantly lower in the 12-week regimen group than in the 20-week regimen group (1 [.3%] vs 11 [3%], respectively; HR, 0.10; 95% CI, .01-.74). The criterion for noninferiority of the secondary composite end point, combining overall recurrent melioidosis and mortality, was met (1-sided P = .022). CONCLUSIONS: Based on the lower total mortality and noninferiority of the secondary composite end point observed, we recommend the 12-week regimen of TMP-SMX for oral eradication treatment of melioidosis. CLINICAL TRIALS REGISTRATION: NCT01420341.

Invariant Natural Killer T (iNKT) cells response in human melioidosis.

BACKGROUND: Melioidosis is an infectious disease caused by Burkholderia pseudomallei. In infected mice, IFN-γ can provide protection against B. pseudomallei infection. Invariant Natural Killer T (iNKT) cells are a subpopulation of T lymphocytes, activated by recognition of glycolipid ligands such as α-Galactosylceramide presented by CD1d, produce and secrete several cytokines, including IFN-γ and IL-4. The response of iNKT cells in human melioidosis was then investigated. OBJECTIVE: To determine the iNKT cells response in human melioidosis. METHODS: The number of human iNKT cells and its activation states were investigated in sepsis melioidosis patients compared with healthy controls using flow cytometry. The iNKT cells activation was confirmed in vitro using heatkilled B. pseudomallei with normal peripheral blood mononuclear cells. The components induced iNKT cell were also determined using different concentration of B. pseudomallei lipopolysaccharide (LPS), heat-killed B. pseudomallei treated with or without DNase, RNase, or proteinase. RESULTS: The number of human iNKT cells was significantly lower while the percentage of activated iNKT cells was higher in sepsis melioidosis when compared to control. In addition, B. pseudomallei can stimulate human iNKT cells in vitro. Heat-killed B. pseudomallei could activate iNKT cells but not relate to nucleic acid, proteins, or LPS. CONCLUSIONS: We found for the first time that the iNKT cells were activated during B. pseudomallei infection in human. However, the roles and the mechanism of iNKT cells during early state of infection needed to be further investigated.

Natural History and Evolution of Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome in Thailand and the United States.

BACKGROUND: The natural history of anti-interferon-γ (IFN-γ) autoantibody-associated immunodeficiency syndrome is not well understood. METHODS: Data of 74 patients with anti-IFN-γ autoantibodies at Srinagarind Hospital, Thailand, were collected annually (median follow-up duration, 7.5 years). Annual data for 19 patients and initial data for 4 patients with anti-IFN-γ autoantibodies at the US National Institutes of Health were collected (median follow-up duration, 4.5 years). Anti-IFN-γ autoantibody levels were measured in plasma samples. RESULTS: Ninety-one percent of US patients were of Southeast Asian descent; there was a stronger female predominance (91%) in US than Thai (64%) patients. Mycobacterium abscessus (34%) and Mycobacterium avium complex (83%) were the most common nontuberculous mycobacteria in Thailand and the United States, respectively. Skin infections were more common in Thailand (P = .001), whereas bone (P < .0001), lung (P = .002), and central nervous system (P = .03) infections were more common in the United States. Twenty-four percent of Thai patients died, most from infections. None of the 19 US patients with follow-up data died. Anti-IFN-γ autoantibody levels decreased over time in Thailand (P < .001) and the United States (P = .017), with either cyclophosphamide (P = .01) or rituximab therapy (P = .001). CONCLUSIONS: Patients with anti-IFN-γ autoantibodies in Thailand and the United States had distinct demographic and clinical features. While titers generally decreased with time, anti-IFN-γ autoantibody disease had a chronic clinical course with persistent infections and death. Close long-term surveillance for new infections is recommended.

Isavuconazole Versus Caspofungin in the Treatment of Candidemia and Other Invasive Candida Infections: The ACTIVE Trial.

BACKGROUND: Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. METHODS: Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. RESULTS: Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9--1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. CONCLUSIONS: This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. CLINICAL TRIALS REGISTRATION: NCT00413218.

Improvement of lipid profiles when switching from efavirenz to rilpivirine in HIV-infected patients with dyslipidemia.

Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor, which has better lipid profiles than efavirenz (EFV) in treatment naïve patients. However, the data on treatment experience are limited especially in dyslipidemic HIV patients; thus, we aimed to assess the change of lipid profiles after switching from EFV to RPV in these patients. In this prospective, open-label, cohort study, we enrolled HIV-1 infected adults who had received at least 6 months of EFV-based regimen, with HIV RNA <50 copies/mL for ≥6 months prior to switching. The objectives of this study were to analyze lipid changes and to evaluate the efficacy, safety, tolerability at 24 weeks after switching therapy. Fifty-three patients were enrolled and completed the study. At week 24, a significant decrease in the mean (95% confident interval, CI) total cholesterol (-28.06 mg/dL, 95%CI -35.20 to -20.91, p < 0.0001), LDL-cholesterol (-20.96 mg/dL, 95%CI -28.12 to -13.80, p < 0.0001), high-density lipoprotein (HDL)-cholesterol (-5.11 mg/dL, 95%CI -7.79 to -2.44, p < 0.0001), and triglyceride (-29.79 mg/dL. 95%CI -52.39 to -7.19, p = 0.011) levels were observed. One patient had virologic rebound with HIV RNA of 114 copies/mL at week 24. Three (5.7%) patients had grade 2 elevations of liver enzymes. None of the patients discontinued RPV during the study. Switching from EFV-based therapy to RPV-based regimen improved lipid profiles in fully suppressed HIV patients with dyslipidemia. This treatment should be considered in these patients.

Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial.

BACKGROUND: The optimal penetration of antiretroviral agents into the central nervous system may be a balance between providing adequate drug exposure to inhibit human immunodeficiency virus (HIV) replication while avoiding concentrations associated with neuronal toxicities. METHODS: Cerebrospinal fluid (CSF) exposure of efavirenz and the metabolites 7-hydroxy (7OH) and 8-hydroxy (8OH) efavirenz were assessed after at least 12 weeks of therapy in HIV-infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily. RESULTS: Of 28 subjects (14 and 14 on efavirenz 400 mg and 600 mg, respectively), CSF HIV RNA was undetectable in all. Geometric mean CSF efavirenz, 7OH-, and 8OH-efavirenz concentrations (with 90% confidence intervals [CIs]) for the 400-mg and 600-mg dosing groups were 16.5 (13-21) and 19.5 (15-25) ng/mL; 0.6 (.4-.9) and 0.6 (.4-1) ng/mL; and 5.1 (4.0-6.4) and 3.1 (2.1-4.4) ng/mL, respectively. Efavirenz concentration in CSF was >0.51 ng/mL (proposed CSF 50% maximal inhibitory concentration for wild-type virus) in all subjects, and 8OH-efavirenz concentration in CSF was >3.3 ng/mL (a proposed toxicity threshold) in 11 of 14 and 7 of 14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whereas CSF efavirenz concentration was significantly associated with plasma concentration (P < .001) and cytochrome P450 2B6 genotype (CSF efavirenz GG to GT/TT geometric mean ratio, 0.56 [90% CI, .42-.74]), CSF 8OH-efavirenz concentration was not (P = .242 for association and CSF 8OH-efavirenz GG to GT/TT geometric mean ratio, 1.52 [90% CI, .97-2.36]). CONCLUSIONS: With both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV replication, although concentrations of 8OH-efavirenz were greater than those reportedly associated with neuronal toxicity. CSF exposure of 8OH-efavirenz was not dependent on plasma exposure and, as we postulate, may be subject to saturable pharmacokinetic effects. CLINICAL TRIALS REGISTRATION: NCT01011413.

Trimethoprim-sulfamethoxazole versus trimethoprim-sulfamethoxazole plus doxycycline as oral eradicative treatment for melioidosis (MERTH): a multicentre, double-blind, non-inferiority, randomised controlled trial.

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.

Adult-onset immunodeficiency in Thailand and Taiwan.

BACKGROUND: Autoantibodies against interferon-γ are associated with severe disseminated opportunistic infection, but their importance and prevalence are unknown. METHODS: We enrolled 203 persons from sites in Thailand and Taiwan in five groups: 52 patients with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection (group 1); 45 patients with another opportunistic infection, with or without nontuberculous mycobacterial infection (group 2); 9 patients with disseminated tuberculosis (group 3); 49 patients with pulmonary tuberculosis (group 4); and 48 healthy controls (group 5). Clinical histories were recorded, and blood specimens were obtained. RESULTS: Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-γ in normal cells. High-titer anti-interferon-γ autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte-macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering. CONCLUSIONS: Neutralizing anti-interferon-γ autoantibodies were detected in 88% of Asian adults with multiple opportunistic infections and were associated with an adult-onset immunodeficiency akin to that of advanced HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research; ClinicalTrials.gov number, NCT00814827.).

Serological diagnosis of pulmonary Mycobacterium tuberculosis infection by LIPS using a multiple antigen mixture.

BACKGROUND: There is an urgent need for a simple and accurate test for the diagnosis of human Mycobacterium tuberculosis, the infectious agent causing tuberculosis (TB). Here we describe a serological test based on light emitting recombinant proteins for the diagnosis of pulmonary Mycobacterium tuberculosis infection. METHODS: Luciferase Immunoprecipitation Systems (LIPS), a fluid-phase immunoassay, was used to examine antibody responses against a panel of 24 different M. tuberculosis proteins. Three different strategies were used for generating the constructs expressing the recombinant fusion M. tuberculosis proteins with luciferase: synthetic gene synthesis, Gateway recombination cloning, and custom PCR synthesis. A pilot cohort of African pulmonary TB patients was used for initial antibody screening and confirmatory studies with selected antigens were performed with a cohort from Thailand and healthy US blood donors. In addition to testing M. tuberculosis antigens separately, a mixture that tested seven antigens simultaneously was evaluated for diagnostic performance. RESULTS: LIPS testing of a pilot set of serum samples from African pulmonary TB patients identified a potential subset of diagnostically useful M. tuberculosis antigens. Evaluation of a second independent cohort from Thailand validated highly significant antibody responses against seven antigens (PstS1, Rv0831c, FbpA, EspB, bfrB, HspX and ssb), which often showed robust antibody levels up to 50- to 1000-fold higher than local community controls. Marked heterogeneity of antibody responses was observed in the patients and the combined results demonstrated 73.5% sensitivity and 100% specificity for detection of pulmonary TB. A LIPS test simultaneously employing the seven M. tuberculosis antigen as a mixture matched the combined diagnostic performance of the separate tests, but showed an even higher diagnostic sensitivity (90%) when a cut-off based on healthy US blood donors was used. CONCLUSION: A LIPS immunoassay employing multiple M. tuberculosis antigens shows promise for the rapid and quantitative serological detection of pulmonary TB.

Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2014, Thailand.

New evidence has emerged regarding when to commence antiretroviral therapy (ART), optimal treatment regimens, management of HIV co-infection with opportunistic infections, and management of ART failure. The 2014 guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS). One of the major changes in the guidelines included recommending to initiating ART irrespective of CD4 cell count. However, it is with an emphasis that commencing HAART at CD4 cell count above 500 cell/mm(3) is for public health, in term of preventing HIV transmission and personal benefit. In tuberculosis co-infected patients with CD4 cell counts ≤50 cells/mm(3) or with CD4 cell counts >50 cells/mm(3) who have severe clinical disease, ART should be initiated within 2 weeks of starting tuberculosis treatment. The preferred initial ART regimen in treatment naïve patients is efavirenz combined with tenofovir and emtricitabine or lamivudine. Plasma HIV viral load assessment should be done twice a year until achieving undetectable results; and will then be monitored once a year. CD4 cell count should be monitored every 6 months until CD4 cell count ≥350 cells/mm(3) and with plasma HIV viral load <50 copies/mL; then it should be monitored once a year afterward. HIV drug resistance genotypic test is indicated when plasma HIV viral load >1,000 copies/mL while on ART. Ritonavir-boosted lopinavir or atazanavir in combination with optimized two nucleoside-analogue reverse transcriptase inhibitors is recommended after initial ART regimen failure. Long-term ART-related safety monitoring has also been included in the guidelines.

Pilot study of a non-return catheter valve for reducing catheter-associated urinary tract infections in critically ill patients.

OBJECTIVE: To determine the effectiveness of a non-return catheter valve vs. the standard urine bag for prevention of catheter-associated urinary tract infections (CAUTI) in critically ill patients. MATERIAL AND METHOD: This was a pilot, randomized, stratified, open-label controlled trial (ClinicalTrials.gov, number NCT01963013). Ninety-six critically illpatients requiring indwelling urinary catheter were assigned with either a non-return catheter valve or the standard urine bag. Symptoms and signs of CAUTI before and after enrollment for all patients were recorded. If CAUTI was suspected, urine for microbiological testing was collected The primary outcome was the incidence density rate of symptomatic CAUTI and bacteriurial presence. RESULTS: The 96 patients were randomized into two groups. Baseline patient characteristics were similar in both groups except for the sex distribution. The incidence rate ratio was 0.71 for symptomatic CAUTI in the non-return catheter valve group (95% CI 0.25-1.98, p-value = 0.51). The crude incidence rate ratio of bacteriuria in the non-return valve group was 0.66 (95% CI 0.3-1.46, p-value = 0.31). The sex-adjusted incidence rate ratio of bacteriuria in the non-return catheter valve group was 0.64 (95% CI 0.29-1.41, p-value = 0.27). CONCLUSION: Using a non-return catheter valve might not prevent CA UTI among critically ill patients.

Linezolid in the treatment of disseminated nontuberculous mycobacterial infection in anti-interferon-gamma autoantibody-positive patients.

Disseminated nontuberculous mycobacterial (NTM) infection is the most common feature in patients positive for anti-interferon-gamma autoantibody (IFN-gamma Ab). The condition is a form of anticytokine autoantibody syndrome. It is difficult to treat because of multiple drug resistance in mycobacteria. Linezolid is active against NTM in vitro; however clinical experience using this drug against NTM is limited. We report our experience using linezolid as part of an antimycobacterial regimen for treatment of 16 refractory cases of disseminated NTM at Srinagarind University Hospital, Khon Kaen, between September 2008 and December 2012. Complete resolution of signs and symptoms was seen in eight patients (50%) on linezolid therapy. Partial or no improvement was seen in a further four (25%) and three (19%) cases, respectively. Five (31%) patients developed an adverse reaction to linezolid; three of whom received 600 mg of linezolid twice daily. The study demonstrated the modest efficacy of linezolid for treating patients with a protracted course of disseminated-NTM; however, adverse effects were significant, especially for those on the high-dosage regimen.

Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results.

BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer with no antiretroviral activity in vitro. METHODS: An international, randomized, double-blind, double-dummy, active-controlled trial was conducted to evaluate the efficacy and safety of COBI versus ritonavir (RTV) as a pharmacoenhancer of atazanavir (ATV) in combination with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in treatment-naive patients. The primary end point was a human immunodeficiency virus type 1 (HIV-1) RNA load of <50 copies/mL at week 48 by the Food and Drug Administration snapshot algorithm; the noninferiority margin was 12%. RESULTS: A total of 692 patients were randomly assigned to a treatment arm and received study drug (344 in the COBI group vs 348 in the RTV group). At week 48, virologic success was achieved in 85% of COBI recipients and 87% of RTV recipients (difference, -2.2% [95% confidence interval, -7.4% to 3.0%]); among patients with a baseline HIV-1 RNA load of >100 000 copies/mL, rates were similar (86% vs 86%). Similar percentages of patients in both groups had serious adverse events (10% of COBI recipients vs 7% of RTV recipients) and adverse events leading to discontinuation of treatment with the study drug (7% vs 7%). Median increases in the serum creatinine level were 0.13 and 0.09 mg/dL, respectively, for COBI and RTV recipients. CONCLUSIONS: COBI was noninferior to RTV in combination with ATV plus FTC/TDF at week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the 2 regimens were comparable. Once-daily COBI is a safe and effective pharmacoenhancer of the protease inhibitor ATV.

Individualised, short-course antibiotic treatment versus usual long-course treatment for ventilator-associated pneumonia (REGARD-VAP): a multicentre, individually randomised, open-label, non-inferiority trial.

BACKGROUND: Ventilator-associated pneumonia (VAP) is associated with increased mortality, prolonged hospitalisation, excessive antibiotic use and, consequently, increased antimicrobial resistance. In this phase 4, randomised trial, we aimed to establish whether a pragmatic, individualised, short-course antibiotic treatment strategy for VAP was non-inferior to usual care. METHODS: We did an individually randomised, open-label, hierarchical non-inferiority-superiority trial in 39 intensive care units in six hospitals in Nepal, Singapore, and Thailand. We enrolled adults (age ≥18 years) who met the US Centers for Disease Control and Prevention National Healthcare Safety Network criteria for VAP, had been mechanically ventilated for 48 h or longer, and were administered culture-directed antibiotics. In culture-negative cases, empirical antibiotic choices were made depending on local hospital antibiograms reported by the respective microbiology laboratories or prevailing local guidelines. Participants were assessed until fever resolution for 48 h and haemodynamic stability, then randomly assigned (1:1) to individualised short-course treatment (≤7 days and as short as 3-5 days) or usual care (≥8 days, with precise durations determined by the primary clinicians) via permuted blocks of variable sizes (8, 10, and 12), stratified by study site. Independent assessors for recurrent pneumonia and participants were masked to treatment allocation, but clinicians were not. The primary outcome was a 60-day composite endpoint of death or pneumonia recurrence. The non-inferiority margin was prespecified at 12% and had to be met by analyses based on both intention-to-treat (all study participants who were randomised) and per-protocol populations (all randomised study participants who fulfilled the eligibility criteria, met fitness criteria for antibiotic discontinuation, and who received antibiotics for the duration specified by their allocation group). This study is registered with ClinicalTrials.gov, number NCT03382548. FINDINGS: Between May 25, 2018, and Dec 16, 2022, 461 patients were enrolled and randomly assigned to the short-course treatment group (n=232) or the usual care group (n=229). Median age was 64 years (IQR 51-74) and 181 (39%) participants were female. 460 were included in the intention-to-treat analysis after excluding one withdrawal (231 in the short-course group and 229 in the usual care group); 435 participants received the allocated treatment and fulfilled eligibility criteria, and were included in the per-protocol population. Median antibiotic treatment duration for the index episodes of VAP was 6 days (IQR 5-7) in the short-course group and 14 days (10-21) in the usual care group. 95 (41%) of 231 participants in the short-course group met the primary outcome, compared with 100 (44%) of 229 in the usual care group (risk difference -3% [one-sided 95% CI -∞ to 5%]). Results were similar in the per-protocol population. Non-inferiority of short-course antibiotic treatment was met in the analyses, although superiority compared with usual care was not established. In the per-protocol population, antibiotic side-effects occurred in 86 (38%) of 224 in the usual care group and 17 (8%) of 211 in the short-course group (risk difference -31% [95% CI -37 to -25%; p<0·0001]). INTERPRETATION: In this study of adults with VAP, individualised shortened antibiotic duration guided by clinical response was non-inferior to longer treatment durations in terms of 60-day mortality and pneumonia recurrence, and associated with substantially reduced antibiotic use and side-effects. Individualised, short-course antibiotic treatment for VAP could help to reduce the burden of side-effects and the risk of antibiotic resistance in high-resource and resource-limited settings. FUNDING: UK Medical Research Council; Singapore National Medical Research Council. TRANSLATIONS: For the Thai and Nepali translations of the abstract see Supplementary Materials section.

Lack of Association of TLR1 and TLR5 Coding Variants with Mortality in a Large Multicenter Cohort of Melioidosis Patients.

Melioidosis, infection caused by Burkholderia pseudomallei, is characterized by robust innate immune responses. We have previously reported associations of TLR1 single nucleotide missense variant rs76600635 with mortality and of TLR5 nonsense variant rs5744168 with both bacteremia and mortality in single-center studies of patients with melioidosis in northeastern Thailand. The objective of this study was to externally validate the associations of rs76600635 and rs5744168 with bacteremia and mortality in a large multicenter cohort of melioidosis patients. We genotyped rs76600635 and rs5744168 in 1,338 melioidosis patients enrolled in a prospective parent cohort study conducted at nine hospitals in northeastern Thailand. The genotype frequencies of rs76600635 did not differ by bacteremia status (P = 0.27) or 28-day mortality (P = 0.84). The genotype frequencies of rs5744168 did not differ by either bacteremia status (P = 0.46) or 28-day mortality (P = 0.10). Assuming a dominant genetic model, there was no association of the rs76600635 variant with bacteremia (adjusted odds ratio [OR], 0.75; 95% CI, 0.54-1.04, P = 0.08) or 28-day mortality (adjusted OR, 0.96; 95% CI, 0.71-1.28, P = 0.77). There was no association of the rs5744168 variant with bacteremia (adjusted OR, 1.24; 95% CI, 0.76-2.03, P = 0.39) or 28-day mortality (adjusted OR, 1.22; 95% CI, 0.83-1.79, P = 0.21). There was also no association of either variant with 1-year mortality. We conclude that in a large multicenter cohort of patients hospitalized with melioidosis in northeastern Thailand, neither TLR1 missense variant rs76600635 nor TLR5 nonsense variant rs5744168 is associated with bacteremia or mortality.

Statin Use and Reduced Risk of Pneumonia in Patients with Melioidosis: A Lung-Specific Statin Association.

Rationale: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) use is associated with a lower risk of incident pneumonia and, less robustly, with nonpulmonary infections. Whether statin use is associated with a lower risk of pneumonia than other clinical presentations of infection with the same pathogen is unknown. Objectives: To assess whether preadmission statin use is associated with a lower risk of pneumonia than nonpneumonia presentations among patients hospitalized with Burkholderia pseudomallei infection (melioidosis). Methods: We performed a secondary analysis of a prospective multicenter cohort study of patients hospitalized with culture-confirmed B. pseudomallei infection (melioidosis). We used Poisson regression with robust standard errors to test for an association between statin use and pneumonia. We then performed several sensitivity analyses that addressed healthy user effect and indication bias. Results: Of 1,372 patients with melioidosis enrolled in the parent cohort, 1,121 were analyzed. Nine hundred eighty (87%) of 1,121 were statin nonusers, and 141 (13%) of 1,121 were statin users. Forty-six (33%) of 141 statin users presented with pneumonia compared with 432 (44%) of 980 statin nonusers. Statin use was associated with a lower risk of pneumonia in unadjusted analysis (relative risk, 0.74; 95% confidence interval, 0.58-0.95; P = 0.02) and, after adjustment for demographic variables, comorbidities, environmental exposures, and symptom duration (relative risk, 0.73; 95% confidence interval, 0.57-0.94; P = 0.02). The results of sensitivity analyses, including active comparator analysis and inverse probability of treatment weighting, were consistent with the primary analysis. Conclusions: In hospitalized patients with melioidosis, preadmission statin use was associated with a lower risk of pneumonia than other clinical presentations of melioidosis, suggesting a lung-specific protective effect of statins.

Virological outcomes and metabolic effects after switching from ritonavir-boosted protease inhibitors to a dolutegravir-based regimen in virologically suppressed patients living with HIV.

BACKGROUND: A ritonavir-boosted protease inhibitor (PI)-based antiretroviral therapy (ART) regimen can cause abnormal lipid levels and increased incidence of cardiovascular disease. Switching to a dolutegravir (DTG)-based regimen has been shown to improve blood lipid levels, but data in the Thai population are limited. METHOD: A prospective cohort study was conducted at Srinagarind Hospital between April 28, 2021, and April 30, 2022. Patients were eligible if they (1) were over 18 years of age, 2) had received a ritonavir-boosted PI-based regimen for at least three months, and 3) had documented plasma HIV RNA levels below 50 copies/mL within six months before the enrollment. All eligible patients included in the study switched from a ritonavir-boosted PI-based ART regimen to a DTG-based regimen. The primary outcome was changes in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 24. RESULTS: Forty-six eligible patients were enrolled, 71.7% of whom were male, with a mean age of 49.4 years. Mean body weight was 62.7 kg and body mass index (BMI) was 22.86 kg/m2. The majority of patients had been on a regimen of boosted atazanavir (ATV/r; 60.9%), followed by boosted lopinavir (LPV/r; 37.0%). Six patients were withdrawn from the study. At week 24 after switching to DTG, LDL-C was significantly lower than at baseline, with a difference of -15.1 mg/dL (95% confidence interval [CI; -23.3 to -6.8]; p-value < 0.001), as were total cholesterol and triglycerides, with differences of -22.1 mg/dL (95% CI [-33.3 to -10.8]; p-value <0.001) and -67.7 mg/dL, (95% CI [-88.3 to -47.0]; p-value 0.001), respectively. There were no significant changes in body weight (0.51 kg; 95% CI [-0.37 to 1.38]; p-value 0.251) or BMI (0.17 kg/m2; 95% CI [-0.14 to 0.48]; p-value 0.284) from baseline to week 24. In addition, 39 of 40 patients (97.5%) maintained virological suppression (HIV RNA <50 copies/mL), with only one patient (2.5%) developing virological failure. Three grade 3 adverse events were observed. CONCLUSION: Switching from a boosted PI-based ART regimen to a DTG-based regimen in people living with HIV/AIDS who had attained prior virological suppression resulted in a significant reduction in total cholesterol, LDL-C, and triglyceride levels, but did not increase the patient's body weight at 24 weeks of follow-up. Furthermore, the DTG-based regimen was also highly effective in maintaining virological suppression. TRIAL REGISTRATION: Thai Clinical Trials Registry, TCTR20210625004.

Evaluating anti-GPL-core IgA as a diagnostic tool for non-tuberculous mycobacterial infections in Thai patients with high antibody background.

Diagnosis of non-tuberculous mycobacterial (NTM) infection is difficult due to low sensitivity and time-consuming laboratory tests. Current serological assays fail in tropical countries due to high antibody background. This study aimed to investigate an appropriate method for detecting anti-glycopeptidolipid (GPL)-core antibodies to diagnose NTM infection in Thailand. Heparinized plasma samples were collected from 20 patients with NTM-pulmonary disease (NTM-PD) and 22 patients with disseminated NTM (dNTM) for antibody detection by ELISA. The results were compared with those from patients with tuberculosis, other bacterial pulmonary infections and healthy controls. Among the different antibody isotypes, anti-GPL-core IgA exhibited the highest suitability. Therefore, anti-GPL-core IgA and its subclass IgA2 were further investigated. A significant increase in antibody levels was observed during the active infection stage, whereas NTM-PD with culture conversion at the 6-month follow-up showed reduced IgA levels. The diagnostic cut-off for IgA and IgA2 was newly defined as 1.4 and 1.0 U/ml, respectively. Using our IgA cut-off, the sensitivity and specificity for diagnosing NTM-PD were 77.3% and 81.4%, respectively. The new IgA cut-off demonstrated significantly improved specificity compared to the manufacturer's cut-off. Thus, serological detection of anti-GPL-core IgA, with a cut-off of 1.4 U/ml, can be a valuable tool for supporting NTM diagnosis in Thailand.