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.

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.

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.

Prevalence and risk factors of depression in patients with chronic obstructive airway disease: a tertiary care hospital, outpatient setting.

BACKGROUND: Chronic obstructive airway disease (COPD) has been found to be associated with depression. An overlap of COPD and depression may cause poor quality of life and an increase in mortality. A meta-analysis found that the prevalence and risk factors of depression in patients with COPD have high heterogeneity and are limited in tertiary care hospital outpatient settings. This study thus aimed to evaluate the prevalence and risk -factors of depression in patients with COPD using personal data in a tertiary care hospital outpatient setting. METHODS: This cross-sectional study included adult patients who were diagnosed with COPD according to the GOLD guidelines, had stable functional status within the past 4 weeks with the same treatment regimen, and had no history of other serious medical or surgical illness. A diagnosis of depression was made according to a score of 11 or higher on the hospital anxiety and depression scale (HADS). The prevalence and predictors of depression were then computed. RESULTS: The study enrolled and evaluated 150 patients with COPD, out of which 6 (4%) had depression. While the predictive model for depression comprised two factors, only severity of COPD was independently associated with depression. The adjusted odds ratio of severity of COPD was 5.20 (95% confidence interval of 1.75, 15.42;  p = 0.003). CONCLUSION: The prevalence of depression in patients with COPD in a tertiary care outpatient setting was low, at 4%. According to the study's comprehensive assessment, severity of COPD was the only factor associated with depression in patients with COPD.

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.

Appropriateness of obtaining blood cultures in patients with community acquired pneumonia.

Community acquired pneumonia (CAP) is a common disease and blood cultures are frequently performed to identify a causative agent, but doing this results in an economic burden. We evaluated the appropriateness of performing blood cultures in clinical practice and determined predictors for positive blood cultures in CAP patients. We reviewed patients diagnosed with CAP at Khon Kaen Hospital, Thailand between January 1 and December 31, 2009. Clinical features, and results of blood and sputum cultures were studied. Clinical factors predictive for positive blood cultures were evaluated by multiple logistic analysis. During the study period 1,160 patients were diagnosed with pneumonia; of those, 261 patients (22.5%) met the criteria for CAP. All patients were performed blood and sputum cultures. Blood cultures were positive in 24 patients (9.2%); 15 patients had severe pneumonia. On multivariate analysis, neutrophils comprising more than 80% of the white blood cell count in peripheral blood was the only significant predictor for a positive blood culture. The adjusted odds ratio was 3.713 (95% confidence interval was 1.333-10.340). In our study population blood cultures are only appropriate among CAP patients with a neutrophil count greater than 80%.

Characteristics and One Year Outcomes of Melioidosis Patients in Northeastern Thailand: A Prospective, Multicenter Cohort Study.

Background: Melioidosis is a neglected tropical infection caused by the environmental saprophyte Burkholderia pseudomallei. Methods: We conducted a prospective, observational study at nine hospitals in northeastern Thailand, a hyperendemic melioidosis zone, to define current characteristics of melioidosis patients and quantify outcomes over one year. Findings: 2574 individuals hospitalised with culture-confirmed melioidosis were screened and 1352 patients were analysed. The median age was 55 years, 975 (72%) were male, and 951 (70%) had diabetes. 565 (42%) patients presented with lung infection, 1042 (77%) were bacteremic, 442 (33%) received vasopressors/inotropes and 547 (40%) received mechanical ventilation. 1307 (97%) received an intravenous antibiotic against B. pseudomallei. 335/1345 (25%) patients died within one month and 448/1322 (34%) of patients died within one year. Most patients had risk factors for melioidosis, but patients without identified risk factors did not have a reduced risk of death. Of patients discharged alive, most received oral trimethoprim-sulfamethoxazole, which was associated with decreased risk of post-discharge death; 235/970 (24%) were readmitted, and 874/1015 (86%) survived to one year. Recurrent infection was detected in 17/994 patients (2%). Patients with risk factors other than diabetes had increased risk of death and increased risk of hospital readmission. Interpretation: In northeastern Thailand patients with melioidosis experience high rates of bacteremia, organ failure and death. Most patients discharged alive survive one year although all-cause readmission is common. Recurrent disease is rare. Strategies that emphasize prevention, rapid diagnosis and intensification of early clinical management are likely to have greatest impact in this and other resource-restricted regions. Funding: US NIH/NIAID U01AI115520.

Oxygen saturation is associated with recurrent primary spontaneous pneumothorax treated by intercostal chest drainage.

BACKGROUND: Primary spontaneous pneumothorax (PSP) is a condition that may lead to acute chest pain or dyspnea on exertion. Treatment with an intercostal chest drainage (ICD) is warranted. There is limited data on risk factors of recurrent PSP in patients treated with the ICD alone. This study aimed to evaluate risk factors of recurrent PSP in patients with PSP and treated with the ICD. METHODS: This was a retrospective study and enrolled patients diagnosed as PSP and treated with an ICD. Eligible patients were divided into two groups by evidence of recurrent PSP. Baseline characteristics, physical signs, laboratory results, and duration of ICD treatment were studied and recorded from medical charts. Factors associated with recurrent PSP were computed by using multivariate logistic regression analysis. RESULTS: There were 80 patients met the study criteria. Of those, 21 patients (26.3%) had recurrent PSP. Of those, 21 patients (26.3%) had recurrent PSP. There were eight factors in the final model for recurrent PSP. Only oxygen saturation at the time of diagnosis was independently associated with recurrent PSP. The adjusted odds ratio (95% confident interval) was 0.57 (0.34, 0.96). A cut point of 96% of oxygen saturation gave sensitivity of recurrent PSP of 80.95%. CONCLUSION: The prevalence of recurrent PSP was 26.3% in patients with PSP and treated with the ICD. Initial oxygen saturation may be an indicator for recurrent PSP.

Factors Associated with Duration of Intercostal Chest Drainage in Patients with Primary Spontaneous Pneumothorax and the Role of Pulmonary Rehabilitation.

PURPOSE: Primary spontaneous pneumothorax (PSP) is an urgent/emergency condition. Treatment with intercostal chest drainage (ICD) is necessary, particularly in symptomatic patients or those with tension. A previous study found that systematic breathing exercise significantly reduced ICD duration when compared with controls. This study aimed to evaluate if pulmonary rehabilitation can reduce the duration of ICD treatment in patients with PSP. PATIENTS AND METHODS: This was a retrospective study of patients diagnosed with PSP treated with ICD. Duration of ICD treatment was recorded from patients' medical charts. Factors associated with ICD duration were calculated using linear regression analysis. RESULTS: There were 66 patients who met the study criteria, with average (SD) age and body mass index of 31.68 (13.53) years and 20.94 (2.72) kg/m2. The majority of the patients were male (72.73%), and average (SD) duration of ICD treatment was 9.90 (7.83) days. Three factors remained in the final model: body mass index, systolic blood pressure, and recurrent PSP. Two factors were independently associated with longer ICD duration: systolic blood pressure and recurrent PSP, with adjusted coefficients of 0.21 (p value 0.041) and 7.69 (p value 0.039), respectively. Pulmonary rehabilitation was not included in the final model. CONCLUSION: Patients with a history of recurrent PSP or high systolic blood pressure at presentation may require longer ICD duration. Pulmonary rehabilitation was not associated with the duration of ICD treatment.

The best criteria to diagnose metabolic syndrome in hypertensive Thai patients.

The metabolic syndrome (MS) is commonly found in clinical practice. There are many criteria to diagnose MS. The authors did a cross-sectional study to study the difference among the WHO criteria, the National Cholesterol Educational Program (NCEP) Adult Treatment Panel (ATP III), and the International Diabetes Foundation (IDF) in hypertensive patients. Between July and September 2005, 100 patients (62 women) treated at the hypertension clinic, Srinagarind Hospital were included. The WHO, NCEP A TP III and IDF criteria gave the diagnosis of MS in 37, 33, 60 cases, respectively. The IDF criteria had the significantly highest yield among those three criteria (p < 0.0001). Body mass index (BMI) was the only significant correlated with the diagnosis of MS by the IDF criteria (p-value = 0.04). It also had moderately positive correlated with waist circumference, WC (p < 0.0001, Pearson Correlation 0.58). At the cut point of BMI 23 kg/m2, we suggested the appropriate WC cut-point for Thai hypertensive men and women was 82.5 cm (32.5") and 79.5 cm (31.3"), respectively.

What clinical factors are associated with mortality in septicemic melioidosis? A report from an endemic area.

INTRODUCTION: Melioidosis, caused by Burkholderia pseudomallei, has high mortality, particularly in its septicemic form. Data on the factors associated with mortality from melioidosis are still limited. METHODOLOGY: All patients (≥ 15 years of age) who were positive for melioidosis by blood culture in the year 2009 were enrolled. The study was conducted at Khon Kaen Hospital, Thailand. Patients were divided into two groups: surviving and deceased. Multivariate logistic regression was used to identify factors associated with death by three models: clinical, laboratory, and combined. RESULTS: There were 97 patients who had blood cultures positive for melioidosis. The mortality rate was 54.17% (52 patients). The clinical presentation model found one significant factor associated with mortality from septicemic melioidosis: pulmonary presentation. Two factors were statistically significant for death as determined by the laboratory model: white blood cell count (WBC) and blood urea nitrogen (BUN) value. For the combined model, three significant factors were associated with death: pulmonary presentation, WBC, and BUN. The adjusted odds ratios (95% confidence interval) of the three factors were 10.739 (3.300-34.953), 0.930 (0.877-0.985), and 1.057 (1.028-1.087), respectively. CONCLUSIONS: Three clinical factors associated with mortality in septicemic melioidosis were pulmonary presentation, white blood cell count, and blood urea nitrogen level. Physicians should be aware of high mortality if septicemic melioidosis patients have these clinical features. Aggressive treatment may be needed.

Breathing exercise using a new breathing device increases airway secretion clearance in mechanically ventilated patients.

OBJECTIVES: To evaluate the efficacy and safety of a new device (BreatheMAX) that humidifies and oscillates inspired air to increase secretion clearance in mechanically ventilated patients. BACKGROUND: Poor secretion clearance is a serious problem for intubated patients leading to lung complications and delayed weaning. METHODS: Double blinded crossover; fifteen patients, median age 60 years, range 16-75. Interventions consisted of spontaneous deep breathing with (treatment) and without (sham) humidification and oscillation of inspired air. Airway secretions were aspirated for 3 h before and after each intervention and wet weight and viscosity determined. RESULTS: The sham intervention caused no change in secretion clearance (95% CI: -1.8, 1.8 g) but after treatment secretions increased by 4.0 g (95% CI: 1.3, 6.7; p < 0.05). Viscosity decreased 30% after treatment and was unchanged after sham. Changes in cardiopulmonary function were not clinically significant and the patients reported only mild perceptions of breathlessness. CONCLUSIONS: Breathing exercise with a device that includes vibration and humidification of inspired air is effective for increasing secretion clearance with patients dependent on mechanical ventilation and was without any adverse effects.

Increasing incidence of human melioidosis in Northeast Thailand.

Melioidosis is a serious community-acquired infectious disease caused by the Gram-negative environmental bacterium Burkholderia pseudomallei. A prospective cohort study identified 2,243 patients admitted to Sappasithiprasong Hospital in northeast Thailand with culture-confirmed melioidosis between 1997 and 2006. These data were used to calculate an average incidence rate for the province of 12.7 cases of melioidosis per 100,000 people per year. Incidence increased incrementally from 8.0 (95% confidence interval [CI] = 7.2-10.0) in 2000 to 21.3 (95% CI = 19.2-23.6) in 2006 (P < 0.001; chi(2) test for trend). Male sex, age >/= 45 years, and either known or undiagnosed diabetes were independent risk factors for melioidosis. The average mortality rate from melioidosis over the study period was 42.6%. The minimum estimated population mortality rate from melioidosis in 2006 was 8.63 per 100,000 people (95% CI = 7.33-10.11), the third most common cause of death from infectious diseases in northeast Thailand after human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and tuberculosis.