High burden of antimicrobial drug resistance in Asia.

The rapid development of antimicrobial resistance among micro-organisms is a serious public health concern. Moreover, the dissemination of antibiotic-resistant bacteria makes this issue a global problem, and Asia is no exception. For example, since New Delhi metallo-ß-lactamase (NDM)-producing Enterobacteriaceae were identified in India, further spread of NDM has become a worldwide threat. However, the epidemiology of antibiotic-resistant bacteria in Asia may be different to other regions, and clinical condition may be worse than in western countries. Antibiotic-resistant bacteria, including community-acquired and hospital-acquired meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant enterococci, macrolide- and penicillin-resistant Streptococcus pneumoniae, extend-spectrum ß-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa and Acinetobacter spp., are becoming prevalent in many countries in Asia. Moreover, the prevalence of each antibiotic-resistant bacterium in each country is not identical. This review provides useful information regarding the critical condition of antibiotic resistance in Asia and emphasises the importance of continuous surveillance of resistance data.

The role of interferon-gamma in the increased tuberculosis risk in type 2 diabetes mellitus.

As patients with diabetes mellitus are at increased risk of developing tuberculosis, we hypothesized that this susceptibility to mycobacterial infection is due to a defective Th1-cytokine response. To explore this hypothesis, we examined four groups of subjects in Indonesia: 23 patients with tuberculosis, 34 patients with tuberculosis and diabetes, 32 patients with diabetes only and 36 healthy controls. Ex-vivo production of interferon (IFN)gamma, tumour necrosis factor-alpha and interleukin (IL)-1beta, 6, 10, -12 and -4 was measured following stimulation with Mycobacterium tuberculosis, Escherichia coli lipopolysaccharide and phytohaemagglutinin. Patients with active tuberculosis were found to have lower IFNgamma levels and a higher production of other pro-inflammatory cytokines and IL-4, both in the presence and absence of diabetes. Diabetes patients without tuberculosis, however, showed strongly reduced non-specific IFNgamma production, which is essential for inhibition of the initial growth of M. tuberculosis. Our data suggest that a defective non-specific immune response in diabetes may contribute to an increased susceptibility to develop tuberculosis.

Responsive treatment of pleural effusion due to probable tuberculosis infection.

Early diagnosis of Mycobacterium tuberculosis disease is crucial for initiating treatment and interrupting disease transmission. In keeping with the pathophysiology of disease, bacteriological evidence in extra-pulmonary tuberculosis proves to be difficult. Clinical judgment and radiographic findings are important to establish diagnosis and to evaluate treatment response. A case of 27 year-old-male with shortness of breath and associated TB symptoms is reported. The tuberculin test was highly positive and chest X-ray showed massive right-lung pleural effusion. Pleural analysis showed exudates with high mononuclear cells (98%), protein level of 5.0 g/dL, glucose level of 87 mg/dL, and high LDH level (1240 IU/L). The acid-fast bacilli (AFB) tests were negative for pleural fluid and sputum. Cultures of fluid and sputum were also negative. After being treated adequately with non-specific treatment, which showed no improvement and having undergone pleural puncture for his treatment and diagnosis, the patient started to have antituberculosis treatment. His condition was improved significantly as shown by a serial of chest X-ray follow-up.

Plasma granulysin levels and cellular interferon-gamma production correlate with curative host responses in tuberculosis, while plasma interferon-gamma levels correlate with tuberculosis disease activity in adults.

Granulysin is a recently identified cytolytic protein which is expressed by human cytotoxic T-lymphocytes and natural killer (NK)-cells, and has broad antimicrobial and tumoricidal activity. Circulating granulysin levels are associated with T- and NK-cell activity, and may thus reflect protection-associated cellular immune responses. In a case-control study in Indonesia, a highly tuberculosis (TB)-endemic country, we therefore determined plasma granulysin levels in adults with active pulmonary TB before, during, and after TB treatment, both in mild/moderate-TB and advanced-TB patients, and compared these to healthy neighbourhood controls. Adults with active pulmonary TB had significantly lower plasma granulysin levels compared to controls. After 2 months of anti-TB therapy, levels in TB patients had significantly increased, reaching values similar to those in controls. Plasma granulysin levels further increased after completion of TB therapy, being significantly higher than those in controls. Plasma granulysin levels correlated inversely with TB disease activity but not with TB disease severity. In contrast, plasma interferon-gamma (IFN-gamma) levels were significantly higher in active TB cases than in controls, normalised during treatment and correlated with both TB disease activity and TB disease severity. At the cellular level, granulysin and IFN-gamma expression both correlated inversely with disease activity. Interestingly, granulysin was predominantly expressed by IFN-gamma negative T-cells, suggesting that the cellular sources of IFN-gamma and granulysin in TB are partly non-overlapping. The observation that plasma granulysin levels and cellular IFN-gamma production correlate with curative host responses in pulmonary tuberculosis points to a potentially important role of granulysin, next to IFN-gamma, in host defence against M. tuberculosis.

Elevated lavels of soluble tumour necrosis factor receptor 1, thrombomodulin and soluble endothelial cell adhesion molecules in patients with dengue haemorrhagic fever.

The pathological mechanism of dengue haemorrhagic fever (DHF) is still poorly understood. Previous studies have suggested that immune responses contribute to an increase in capillary permeability. We examined the levels of cytokines and activated endothelial substances in serum samples collected from DHF patients in Indonesia. We measured the levels of soluble TNF-R1, MCP-1, GM-CSF, IL-17, TNF-α, soluble thrombomodulin, soluble E-selectin, soluble ICAM-1 and soluble VCAM-1. The levels of activated endothelial substances such as sE-selectin, sICAM-1 and sVCAM-1 were higher in DHF patients than in healthy controls. High levels of soluble activated endothelial substances suggest that endothelial cells are highly activated. When compared with patients with other febrile illness (OFI) or healthy controls, the levels of sTNF-R1 were higher in DHF patients. A similar trend was observed in the level of thrombomodulin. MCP-1, GM-CSF and IL-17 were not detected in serum samples from any patients and healthy controls. TNF-α was detected in 5(9%) of 53 patients. The results suggest that endothelial cells are highly activated in DHF patients and TNF-α is one of the factors which contributes to the activation.

Open study on efficacy and safety of levofloxacin in treatment of uncomplicated typhoid fever.

The main objective of this study was to determine the clinical efficacy and safety of levofloxacin in an open setting for typhoid fever cases. Patients with clinical signs and symptoms of typhoid fever without previous antimicrobial treatment admitted to affiliated hospitals of the Faculty of Medicine, University Indonesia were included in this study. Adults, 18 years or above, were screened for any serious underlying conditions, pregnancy or possible complications of typhoid fever before final enrollment. Fifty-three subjects were screened, 48 were enrolled. The final diagnosis of enteric fever was made by positive blood culture, polymerase chain reaction or serology, was obtained in 31 cases, in whom one had a concomitant sinus infection and had to be excluded. Thirty patients (11 males, 19 females) aged between 18-58 years (mean 31.7 years) with a history of fever between 1 and 10 days (mean 6.1 days) showed excellent clinical response, becoming afebrile at an average of 2.43 days (range 1-5 days). Adverse effects noted were nausea in 4 patients, vomiting in one and meteorism in another one, which were all difficult to distinguish from the enteric infection. A pruritic rash occurring in two patients may be related to levofloxacin, and insomnia in another patient may be related. Microbiological clearance was obtained both immediately after treatment and at one month. No carrier states were detected in the cases positive for Salmonella typhi or paratyphi. None of the treated typhoid fever cases experienced a clinical relapse. In this open study of levofloxacin 500 mg/day for one week in treatment of uncomplicated typhoid fever, a 100% clinical efficacy was obtained in 30 patients with minimal adverse reactions warranting more intensive studies for this new indication of an old but well known disease in the developing world.

Diabetes mellitus is strongly associated with tuberculosis in Indonesia.

SETTING: Diabetes mellitus is a known risk factor for tuberculosis (TB), but no studies have been reported from South-East Asia, which has a high burden of TB and a rapidly growing prevalence of diabetes. OBJECTIVE: To examine if and to what extent diabetes is associated with an increased risk of TB in an urban setting in Indonesia. DESIGN: Case-control study comparing the prevalence of diabetes mellitus (fasting blood glucose level >126 mg/dl) among newly diagnosed pulmonary TB patients and matched neighbourhood controls. RESULTS: Patients and control subjects had a similar age (median 30 years) and sex distribution (52% male), but malnutrition was more common among TB patients (median body mass index 17.7 vs. 21.5 kg/m2). HIV infection was uncommon (1.5% of patients). Diabetes mellitus was present in 60 of 454 TB patients (13.2%) and 18 of 556 (3.2%) control subjects (OR 4.7; 95%CI 2.7-8.1). Adjustment for possible confounding factors did not reduce the risk estimates. Following anti-tuberculosis treatment, hyperglycaemia reverted in a minority (3.7%) of TB patients. CONCLUSION: Diabetes mellitus is strongly associated with TB in young and non-obese subjects in an urban setting in Indonesia. This may have implications for TB control and patient care in this region.

Better patient instruction for sputum sampling can improve microscopic tuberculosis diagnosis.

To examine the effect of patient instruction for provision of sputum samples, we performed a randomised controlled trial involving 174 patients with suspected tuberculosis (TB) in an urban TB clinic in Indonesia. TB was diagnosed in 50.6% of patients who received additional counselling by paramedics compared with 35.5% of patients in the control group following routine diagnostic procedure, corresponding to a 15.1% higher detection rate (95%CI 2.9-27.4). Significant differences were also found for sputum volume, consistency, positivity rate and density of acid-fast bacilli. Simple interventions such as these may increase TB case detection in Indonesia and elsewhere.

Bioavailability of rifampicin in Indonesian subjects: a comparison of different local drug manufacturers.

To examine the bioavailability of rifampicin formulations produced in Indonesia, we conducted a single-dose, double-blind, cross-over bioavailability study. Antituberculosis drugs from three Indonesian manufacturers and one international manufacturer were compared in 12 healthy Indonesian subjects. Out of three local manufacturers, two showed equal bioavailability compared to the reference standard, and one showed slightly lower bioavailability (ratio 0.86; 90% confidence interval 0.80-0.91) and substandard rifampicin content of drug preparations. Plasma rifampicin concentrations in this study were more than three-fold higher than concentrations recently found in tuberculosis patients in Indonesia, which suggests that unknown (disease-related) determinants may reduce the bioavailability of rifampicin formulations.

The correlation between coagulation test and albumin with antithrombin III in Dengue hemorrhagic fever.

AIM: To analyse the correlation between coagulation tests (PT APTT fibrinogen, D-dimer) and albumin with AT-II in DHF as well to find the formula to calculate AT-III with the parameter of coagulation tests and albumin. METHODS: A descriptive-correlative cross sectional study was conducted to 49 patients with DHF consisted of DHF I(17), DHF (19), DHF III (6) and DHF IV (7). The diagnosis of DHF is based on WHO criteria 1997. The laboratory examinations were coagulation tests (PT, APT, fibrinogen and D-dimer), antithrombin III and albumin, performed when the fever subside and the platelets reached the lowest count(4(th) - 6(th) day). RESULTS: A significant correlation was found between PT and AT-III (r= -0.631; p=0.000), between D-dimer and AT-III (r= -0.337; p=0.021) and between albumin and AT-III (r= 0.291; p-0.045). In multiple linier regression analysis(backward), AT-III can be calculated with the formula, accuracy 68.3%. CONCLUSIONS: PT and D-dimer were correlated negatively with AT-III, however albumin was correlated positively with AT-III. PT, D-dimer and AT-III were correlated with the grading severity of the DHF. In this study, AT-III can be calculated with the formula, accuracy 68.3%.

Social aspects of patients with pulmonary tuberculosis in Indonesia.

Tuberculosis (TB) patients have not only medical but also social problems related to their illness, which may influence their motivation for the completion of treatment. This study investigated the social aspects of patients with TB in an urban area of Jakarta, Indonesia. Most TB patients had poor nutritional status and lived in crowded environments. They faced joblessness and negative attitudes from their neighbors and relatives. A few of the patients were afraid that they would not find a partner; others said that their diseases impaired their marriages. We found that patients with a subnormal body mass index restricted their social contact with their family more than patients with a normal body mass index. In general, patients were supported by their families, both financially and socially. Our findings suggest that priority should be given to developing programs aimed at strengthening the family support of TB patients.

Low plasma concentrations of rifampicin in tuberculosis patients in Indonesia.

SETTING: Although rifampicin is a key drug in tuberculosis treatment, little is known about its quality and bioavailability in countries endemic for tuberculosis. High drug levels may lead to increased toxicity, while low drug levels may predispose to treatment failure and relapse. OBJECTIVE: To investigate possible variations in the bioavailability of plasma rifampicin in tuberculosis patients in Indonesia. DESIGN: Plasma concentrations of rifampicin and the rifampicin content of drug formulations in use were measured among 62 non-selected tuberculosis patients in Jakarta, Indonesia. RESULTS: Plasma concentrations of rifampin were generally low: 70% of patients had 2-hour plasma concentrations (Cmax) below 4 mg/L. No toxic plasma concentrations of rifampicin (>20 mg/L) were found. The strongest predictive factor for the magnitude of rifampicin concentrations was the drug manufacturer. The rifampicin content of the different drug preparations used was normal (90.5-103.6% of the reference standard). No association was found between low plasma rifampicin concentrations and delayed sputum conversion or treatment failure. CONCLUSION: The unexpectedly low plasma concentrations of rifampicin in this setting are most likely due to reduced bioavailability of local drug preparations, as the rifampicin content of the drug preparations was found to be normal. The clinical significance of these findings remains to be determined.

Mycobacterium tuberculosis Beijing genotype strains associated with febrile response to treatment.

DNA fingerprinting has demonstrated predominance of the Beijing genotype among Mycobacterium tuberculosis strains isolated in Southeast Asia. We prospectively examined the occurrence of Beijing genotype strains in tuberculosis patients in Indonesia. Early in treatment, patients infected with Beijing genotype strains more often had fever unrelated to disease severity, toxicity, or drug resistance, indicating that Beijing genotype strains may have specific pathogenic properties.

Poor micronutrient status of active pulmonary tuberculosis patients in Indonesia.

Malnutrition is observed frequently in patients with pulmonary tuberculosis (TB), but their nutritional status, especially of micronutrients, is still poorly documented. The objective of this study was to investigate the nutritional status of patients with active TB compared with that of healthy controls in Jakarta, Indonesia. In a case-control study, 41 out-patients aged 15-55 y with untreated active pulmonary TB were compared with 41 healthy controls selected from neighbors of the patients and matched for age and sex. Cases had clinical and radiographic abnormalities consistent with pulmonary TB and at least two sputum specimens showing acid-fast bacilli. Anthropometric and micronutrient status data were collected. Compared with the controls, TB patients had significantly lower body mass index, skinfold thicknesses (triceps, biceps, subscapular, suprailiac), mid-upper arm circumference, proportion of fat, and concentrations of serum albumin, blood hemoglobin, plasma retinol and plasma zinc, whereas plasma zinc protoporphyrin concentration, as a measure of free erythrocyte protoporphyrin concentration, was greater. When patients and controls were subdivided on the basis of nutritional status, concentrations of serum albumin, blood hemoglobin, and zinc and retinol in plasma were lower in malnourished TB patients than in well-nourished healthy controls, well-nourished TB patients and malnourished healthy controls. In conclusion, the nutritional status of patients with active pulmonary TB was poor compared with healthy subjects, i.e., significantly more patients were anemic and more had low plasma concentrations of retinol and zinc. Low concentrations of hemoglobin, and of retinol and zinc in plasma were more pronounced in malnourished TB patients.

Increased production of interleukin 4 by CD4+ and CD8+ T cells from patients with tuberculosis is related to the presence of pulmonary cavities.

In tuberculosis, cellular immunity is considered to be responsible for the eradication of infection but also for damage of host tissues. In animal models, the balance between Th1-type cytokines, especially interferon (IFN)-gamma, and Th2-type cytokines, primarily interleukin (IL)-4, seems crucial for these effects. Reports on Th1-type and Th2-type cytokines in human tuberculosis are conflicting, and little is known about their role in tissue damage. Flow-cytometric assessment of cytokine responses was performed in human immunodeficiency virus (HIV)-seronegative patients with active tuberculosis and in healthy controls. Patients and controls showed no significant difference in expression of IFN-gamma. However, patients showed a striking increase in production of IL-4 in CD4+ as well as CD8+ T cells. Most remarkably, the expression of IL-4 was especially elevated in patients with cavitary tuberculosis. The Th2-type response with increased production of IL-4 in patients with tuberculosis may antagonize host defense and lead to tissue necrosis.