Decreased mortality seen in rifampicin/multidrug-resistant tuberculous meningitis treated with linezolid in Shenzhen, China.

BACKGROUND: The morbidity of rifampicin/multidrug-resistant tuberculous meningitis (RR/MDR-TBM) has shown an increasing trend globally. Its mortality rate is significantly higher than that of non-rifampicin/multidrug-resistant tuberculous meningitis (NRR/MDR-TBM). This article aimed to explore risk factors related to RR/MDR-TBM, and compare therapeutic effects of linezolid (LZD)- and non-linezolid-containing regimen for RR/MDR-TB patients in Shenzhen city. Furthermore, we aimed to find a better therapy for pathogen-negative TBM with RR/MDR-TBM related risk factors. METHODS: We conducted a retrospective study enrolling 137 hospitalized cases with confirmed TBM from June 2014 to March 2020. All patients were divided into RR/MDR-TBM group (12 cases) and NRR/MDR-TBM group (125 cases) based on GeneXpert MTB/RIF and (or) phenotypic drug susceptibility test results using cerebral spinal fluid (CSF). The risk factors related to RR/MDR-TBM were investigated through comparing clinical and examination features between the two groups. The mortality rate of RR/MDR-TBM patients treated with different regimens was analyzed to compare their respective therapeutic effects. A difference of P < 0.05 was considered statistically significant. RESULTS: Most patients (111/137, 81%) were from southern or southwestern China, and a large proportion (72/137, 52.55%) belonged to migrant workers. 12 cases were RR/MDR-TBM (12/137, 8.8%) while 125 cases were NRR/MDR-TBM (125/137, 91.2%). The proportion of patients having prior TB treatment history in the RR/MDR-TBM group was significantly higher than that of the NRR/MDR-TBM group (6/12 vs. 12/125, 50% vs. 10.5%, P < 0.01). No significant difference was observed on other clinical and examination features between the two groups. Mortality was significantly lower in RR/MDR-TBM patients on linezolid-containing treatment regimen than those who were not (0/7 versus 3/5, 0% versus 60%, P = 0.045). CONCLUSIONS: The main related risk factor of RR/MDR-TBM is the history of anti-tuberculosis treatment. Linezolid-containing regimen appears to lower mortality rate of RR/MDR-TBM significantly in our study. We think Linezolid should be evaluated prospectively in the treatment of RR/MDR-TBM.

Whole-body physiology-based pharmacokinetics of caspofungin for general patients, intensive care unit patients and hepatic insufficiency patients.

Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.

The association of ADORA2A and ADORA2B polymorphisms with the risk and severity of chronic heart failure: a case-control study of a northern Chinese population.

The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF. This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls. Four common single-nucleotide polymorphisms (SNPs) of ADORA2A (rs2236625, rs2236624, rs4822489, and rs5751876) and one SNP of ADORA2B (rs7208480) were genotyped and an association between SNPs and clinical outcomes was evaluated. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors (p = 0.040, OR = 1.912, 95% CI = 1.029-3.550). However, the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility. The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese. However, further studies performed in larger populations and aimed at better defining the role of this gene are required.

[Expression of Mycobacterium tuberculosis early secretory antigenic target-6 protein and its application in detection of Mycobacterium tuberculosis antigen-specific interferon-gamma response].

OBJECTIVE: To obtain the purified early secretory antigenic target-6 (ESAT-6) protein and to evaluate its application in detection of Mycobacterium tuberculosis antigen-specific interferon-gamma (IFN-gamma) response. METHODS: ESAT-6 protein was expressed by genetic engineering. The antigen specificity and reactivity of ESAT-6 were evaluated by Western blot. Using ESAT-6 as the antigen, the antigen-specific IFN-gamma response in patients with tuberculosis, healthy medical workers, and village residents was detected by the Elispot method. The results were also compared with those obtained by a commercial kit (QuantiFERON-TB-GOLD, QFT-G). RESULTS: ESAT-6 protein was successfully expressed and purified, and the antigen specificity of ESAT-6 was confirmed by its recognition by the antigen-specific antibody (anti-ESAT-6). The specificity and sensitivity of the Elispot assay using ESAT-6 as the antigen in detecting the IFN-gamma response was comparable with those of the commercial kit (QFT-G). The positive rates of the Elispot assay for patients with tuberculosis, healthy medical workers and villagers were 36/49 (73.5%), 11/62 (17.7%), and 17/194 (8.8%), respectively, while the rates of the OFT-G method for patients with tuberculosis and healthy medical workers were 38/49 (77.6%) and 14/58 (24.1%), respectively. The sensitivity (73.5%, 77.6%; chi2 = 0.381, P > 0.05) and specificity (82.3%, 75.9%; chi2 = 0.406, P > 0.05) of these two methods did not differ significantly. CONCLUSIONS: Recombinant ESAT-6 protein was expressed and purified. Elispot using recombinant ESAT-6 protein as antigen showed high sensitivity and specificity for detection of Mycobacterium tuberculosis antigen-specific IFN-gamma response. The purified ESAT-6 can be used for diagnosis of Mycobacterium tuberculosis infection.

Indicators for prediction of Mycobacterium tuberculosis positivity detected with bronchoalveolar lavage fluid.

BACKGROUND: The diagnosis of active pulmonary tuberculosis (TB) remains a challenge in clinic, especially for sputum negative pulmonary TB. Bronchoalveolar lavage fluid (BALF) has higher sensitivity than sputum for detection of Mycobacterium tuberculosis (Mtb). However, bronchoscopy is invasive and costly, and not suitable for all patients. In order to make TB patients get more benefit from BALF for diagnosis, we explore which indicator might be used to optimize the choice of bronchoscopy. METHODS: A total of 1539 sputum-smear-negative pulmonary TB suspects who underwent bronchoscopy were recruited for evaluation. The sensitivity, specificity and accuracy of Mtb detection in sputum and BALF were compared. Odds ratios and 95% confidence intervals were used to assess variables that associated with positive acid-fast bacilli (AFB) smear, Mtb culture and nucleic acid amplification test (NAAT) of BALF in sputum-negative and non-sputum-producing pulmonary TB suspects. RESULTS: BALF has significantly higher sensitivity (63.4%) than sputum (43.5%) for Mtb detection by culture and NAAT. 19.7% (122/620) sputum-negative and 40.0% (163/408) non-sputum-producing suspects had positive bacteriological results in BALF. Among sputum-negative and non-sputum-producing pulmonary TB suspects, the positivity of Mtb detection in BALF is associated with a younger age, the presence of pulmonary cavities and a positive result of interferon-gamma release assay (IGRA). Sputum-negative patients under 35 years old with positive IGRA and pulmonary cavity had 84.8% positivity of Mtb in BALF. CONCLUSIONS: Our study indicated that combination of age, the presence of pulmonary cavity, and the result of IGRA is useful to predict the positivity of Mtb detection in BALF among sputum-negative and non-sputum producing pulmonary TB suspects. Those who are under 35 years old, positive for the presence of pulmonary cavity and IGRA, should undergo bronchoscopy to collect BAFL for Mtb tests, as they have the highest possibility to get bacteriologically confirmation of TB.

[Detection of cryptosporidium infection among AIDS patients in Guangdong and Yunnan].

OBJECTIVE: To investigate the infection of Cryptosporidium and its epidemiological characteristics in AIDS patients of Southern China. METHODS: Stool samples colleted from AIDS confirmed patients. The samples were detected for oocyst of Cryptosporidium by acid fast bacteria stain and indirect fluorescent antibody stain respectively, CD4 count was detected by Flow Cytometry. RESULTS: 212 samples of fresh stool obtained from the AIDS patients who live in Guangdong and Yunnan province. The total infection rate of Cryptosporidium in AIDS patients was 4.25% (9/212), the infectious rate of oocyst in the group of 50- 59-years-old was significantly higher than those in 30-39 (P < 0.01); the infectious rate of oocyst in patients with antiretroviral therapy (ART) was also significantly lower (P = 0.0000); we found the patients coinfected with Cryptosporidium with CD4 count all below 100 cells/microl. However, there were no any difference between the infectious rate to the patient's gender, areas and stool shape. CONCLUSION: AIDS patients infected by Cryptosporidium are not rare in southern China, and the infectious rate was lower than western country. Patients received ART could decrease the infectious rate of Cryptosporidium, Cryptosporidium always happen in patient whose CD4 count was very low (< 100 cells/microl).

[Study of the clinical and laboratory features of hand-foot-mouth disease].

OBJECTIVE: To study the clinical and laboratory features of the mild and severe hand-foot-mouth diseases (HFMD) in Shenzhen in 2008. METHODS: 145 cases were observed in East-Lake Hospital and Shenzhen Children's Hospital. Of the 145 cases, 124 mild cases and 21 severe cases were involved.All the clinical data and laboratory findings were collected and summarized. After collection of the acute and convalescent consecutive stools and peripheral bloods from the patients with HFMDI, EV71 genes were amplified from these samples by RT-PCR. Enterovirus 71 were cultured and isolated using Vero cell line and R&D cell line. RESULTS: The WBC counts and blood glucose levels of the severe cases were significantly elevated, but the ages of the severe ones significantly decreased compared with those of the mild cases (P < 0.05). EV71 genes could be detected by RT-PCR with 35% positive rate in mild cases and 67% in severe cases. The EV71 gene detection rate of the severe cases was significantly increased in contrast to that of the mild ones. The EV71 were isolated and cultured from the stools of 9 patients, one specimens from the dead's stool. Two severe cases died of neurogenic pulmonary edema and brain-stem encephalitis. CONCLUSIONS: EV71 mainly contributes to HFMD and is responsible for death of some severe cases. High fever, less rash, elevated white blood cell counts and blood glucose concentrations as well as age less than 4 years old should be used for prediction of severe cases.