The traditional Chinese medicine compound preparation known as Jinbei Oral Liquid (JBOL) consists of 12 herbs, including Astragalus membranaceus (Fisch.) Bge, Codonopsis pilosula (Franch.) Nannf, et al. Having been used for over 30 years in the treatment of pulmonary diseases, JBOL was evaluated in this study in order to assess its effect on idiopathic pulmonary fibrosis as well as its safety (ChiCTR2000035351, Chictr.org.cn.09/08/2020). A double-blind, multicenter, randomized, proof-of-concept trial was conducted to assess the efficacy of oral JBOL 40 ml and Corbrin Capsules 1 g compared to a placebo and Corbrin Capsules in patients with idiopathic pulmonary fibrosis (IPF). Over a 26-week period, patients received the active treatment or placebo three times daily, in a 1:1 ratio. This clinical study uses a randomized method, with a cycle of every 4 patients. TCM doctors at or above the deputy director level of the research center conduct TCM dialectics on IPF patients. To assess efficacy, over the duration of the trial, we measured serial changes in a composite indicator encompassing time to first acute exacerbation of IPF (first hospitalization or death due to respiratory cause), total lung capacity (TLC) (mL), predicted forced vital capacity (FVC%), forced vital capacity (FVC) (mL), predicted diffusing capacity of the lungs for carbon monoxide (predicted DLco%), 6-minute walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ) total score, and arterial oxygen partial pressure (PaO2) from baseline to week 26 versus placebo. A total of 103 patients were screened, and 72 received the study medication. Of these, 68 patients were included in the analysis set, with 34 receiving JBOL and 34 receiving a placebo. After 26 weeks, a statistically significant reduction in total lung capacity (TLC) was observed for the JBOL group, with a change of 136 mL compared to -523 mL for the placebo group (difference 659 mL, 95% CI -1215 to -104 mL, p = 0.02). The study found that the change in FVC% predicted was − 1.48% and − 3.58% for the JBOL and placebo groups, respectively (difference of 2.10%, 95% CI -7.13 to 2.93, p = 0.41). Additionally the differences between the two groups in changes in FVC (mL), DLCO % predicted, PaO2 (mmHg) measures were − 67 mL (95% CI -238 to 104), -7.74% (95% CI -17.26 to 1.79), and − 3.57 mmHg (95% CI -10.02 to 2.87), respectively. Treatment with JBOL compared to placebo resulted in sequential changes in acute exacerbation, with no significant difference in SGRQ scores. It was not found that there was a statistically significant difference between the JBOL and placebo groups in TEAE reporting and serious TEAE reporting. Compared to the placebo group, there was a statistically significant reduction (p < 0.021) in TLC (mL) after 26 weeks for JBOL. The rates of FVC % predicted, FVC, DLCO % predicted, and PaO2 in the group treatment with JBOL were numerically lower than those in the placebo treatment group, although these differences did not reach statistical significance. JBOL exhibited comparable safety to placebo. This study has preliminarily shown the efficacy and safety of JBOL for IPF, but this is an exploratory clinical trial, more patient-involved studies should be needed in the near future. Trial registration: Chictr.org.cn ChiCTR2000035351; the trial was prospective clinical studies registered on August 9, 2020.

Background: Drug-resistant tuberculosis (DR-TB), diabetes and exposure to air pollution are thought to be important threat to human health, but no studies have explored the effects of ambient air pollutants on DR-TB when adjusting diabetes status so far. Methods: We performed a study among 3759 newly diagnosed TB cases with drug-susceptibility testing results, diabetes status, and individual air pollution data in Shandong from 2015 to 2019. Generalized linear mixed models (GLMM) including three models (Model 1: without covariates, Model 2: adjusted by diabetes status only, Model 3: with all covariates) were applied. Results: Of 3759 TB patients enrolled, 716 (19.05%) were DR-TB, and 333 (8.86%) had diabetes. High exposure to O-3 was associated with an increased risk of RFP-resistance (Model 2 or 3: odds ratio (OR) = 1.008, 95% confidence intervals (CI): 1.002-1.014), ethambutol-resistance (Model 3: OR = 1.015, 95%CI: 1.004-1.027) and any rifampicin+streptomycin resistance (Model 1,2,3: OR = 1.01, 95%CI: 1.002-1.018) at 90 days. In contrast, NO2 was associated with a reduced risk of DR-TB (Model 3: OR = 0.99, 95%CI: 0.981-0.999) and multidrug-resistant TB (MDR-TB) (Model 3: OR = 0.977, 95%CI: 0.96-0.994) at 360 days. Additionally, SO2 (Model 1, 2, 3: OR = 0.987, 95%CI: 0.977-0.998) showed a protective effect on MDR-TB at 90 days. PM2.5 (90 days, Model 2: OR = 0.991, 95%CI: 0.983-0.999), PM10 (360 days, Model 2: OR = 0.992, 95%CI: 0.985-0.999) had protective effects on any RFP+SM resistance. Conclusions: O-3 contributed to an elevated risk of TB resistance but PM2.5, PM10, SO2, NO2 showed an inverse effect. Air pollutants may affect the development of drug resistance among TB cases by adjusting the status of diabetes.

The incidence of resistant Candida isolates, especially Candida albicans, has increased continuously. To overcome the resistance, research on antifungal agent sensitizers has attracted considerable attention. Omeprazole and lansoprazole were found to inhibit the growth of sensitive C. albicans and hyphae formation in a high dose, respectively. This study aimed to determine the interactions of common clinically proton pump inhibitors (PPIs) and fluconazole both in vitro and in vivo and to further explore the possible mechanisms. In vitro, the tested PPIs all acted synergistically with fluconazole against both resistant C. albicans planktonic cells and biofilms preformed for ≤12 h with the minimum inhibitory concentration of fluconazole decreased from >512 μg/mL to 1–4 μg/mL. In vivo, PPIs plus fluconazole prolonged the survival rate of infected Galleria mellonella larvae by two-fold compared with that for the fluconazole monotherapy group and significantly reduced the tissue damage of infected larvae. Mechanism studies showed that PPIs significantly suppressed efflux pump activity, which is the common resistance mechanism of C. albicans, and significantly inhibited the virulence factors: phospholipase activity and morphology switching. These findings will provide new insights into antifungal agent discovery and potential approaches for the treatment of candidiasis caused by resistant C. albicans.

Background: Although the association between diabetes mellitus (DM) and tuberculosis (TB) has been welldocumented for centuries, evidence of the link between diabetes and drug resistance among previously treated TB patients remains limited and inconsistent. Methods: An observational study was performed that involved 1791 retreated TB-no DM patients (refers to TB cases without diabetes) and 93 retreated TB-DM patients (refers to TB cases with diabetes) in Shandong, China from 2004 to 2017. Baseline data including demographic and clinical characteristics, drug susceptibility test (DST) results, and diabetes status were collected. Categorical baseline characteristics were compared by Fisher's exact or Pearson Chi-square test. Univariable analysis and multivariable logistic models were used to estimate the association between diabetes and different drug resistance profiles. Results: Retreated TB-DM patients have a higher rate of drug resistance than TB-no DM patients (34.41% vs 25.00%, P < 0.01). Diabetes co-morbidity was significantly associated with any drug-resistant tuberculosis (DR-TB, odds ratio (OR):1.56, 95% confidence interval (CI): 1.01-2.43), multidrug resistant tuberculosis (MDR-TB, OR: 2.48, 95%CI:1.39-4.41; adjusted OR (aOR):2.94, 95%CI:1.57-5.48), isoniazid-related resistance (OR:1.71, 95%CI:1.04-2.81), rifampin-related resistance (OR:2.56, 0.54, 95%CI: 1.54-4.26; aOR:2.69, 95%CI:1.524-4.74), isoniazid + rifampin resistance (OR: 3.55, 95%CI:1.33-9.44; aOR:4.13, 95%CI:1.46-11.66), any resistance to isoniazid + streptomycin (OR:2.34, 95%CI:1.41-3.89; aOR:2.22, 95%CI:1.26-3.94), and any resistance to rifampin + isoniazid (OR:2.48, 95%CI:1.39-4.41; aOR:2.94, 95%CI: 1.57-5.48), compared with pan susceptible TB cases, P < 0.05. Conclusions: The risk of acquired drug resistance increased significantly among retreated TB-DM patients compared with retreated TB-no DM patients, underlining the necessity of more interventions during the clinical management of TB-DM cases.

Fungal infections remain a challenge to clinicians due to the limited available antifungals. With the increasing use of antifungals in clinical practice, drug resistance has been emerging continuously, especially to fluconazole (FLC). Thus, a search for new antifungals and approaches to overcome antifungal resistance is needed. However, the development of new antifungals is usually costly and time consuming; discovering the antifungal activity of non-antifungal agents is one way to address these problems. Interestingly, some researchers have demonstrated that several classes of immunosuppressants (calcineurin inhibitors, glucocorticoids, etc) also displayed potent antifungal activity when used alone or in combination with antifungals, especially with FLC. Some of them could increase FLC's susceptibility against resistant Candida albicans significantly reversing fungal resistance to FLC. This article reviews the antifungal activities of immunosuppressants used alone or in combination with antifungals and their potential antifungal mechanisms that have been discovered so far. Although immunosuppressive agents have been identified as risk factors for fungal infection, we believe these findings are very important for overcoming drug resistance and developing new antifungals.

The incidence of resistant Candida isolates has increased continuously in recent decades, especially Candida albicans. To overcome this resistance, research on antifungal sensitizers has attracted considerable attention. Linezolid was found to inhibit the growth of Pythium insidiosum and synergize with amphotericin B against Cryptococcus neoformans. The objective of this study was to determine the interactions of linezolid and azoles against C. albicans in vitro and in vivo. In vitro, linezolid combined with azoles induced synergistic effects not only against some susceptible C. albicans isolates, but also against all tested resistant C. albicans isolates. For all resistant isolates, exposure to the combination of linezolid with azoles induced a significant decrease in the minimum inhibitory concentrations (MIC) of azoles, from >512 to 0.5–1 μg/mL for fluconazole, from >16 to 0.25–1 μg/mL for itraconazole, and from >16 to 0.03–0.25 μg/mL for voriconazole. Additionally, linezolid synergized with fluconazole against biofilms that were preformed for ≤ 12 h from both susceptible and resistant C. albicans, and the sessile MIC of fluconazole decreased from >1024 to 1–4 μg/mL. In vivo, linezolid plus azoles prolonged the survival rate of infected Galleria mellonella larvae twofold compared with the azole monotherapy group, significantly decreased the fungal burden of the infected larvae, and reduced the damage of resistant C. albicans to the larval tissue. These findings will contribute to antifungal agent discovery and new approaches for the treatment of candidiasis caused by C. albicans.

Pseudomonas aeruginosa is related to nosocomial infections, and it tends to become resistant during or after antimicrobial treatment. The ability to develop carbapenems resistance makes it difficult to treat. P. aeruginosa infections are often associated with high mortality, morbidity and treatment costs. A group of Chinese experts drafted a consensus for treatment of extensively drug-resistant Gram-negative bacilli (XDR-GNB) including extensively drug-resistant P. aeruginosa (XDR-PA). In this study, we studied the antibacterial activities of different antibiotic combinations against six carbapenems-resistant P. aeruginosa (CRPA) strains in vitro, and the results indicated that the combination of ceftazidime with cefoperazone-sulbatam was the best combination with excellent synergistic rate (100%). Besides, some combinations exhibited better effects than using antibiotics alone, reducing the MICs of both drugs significantly, such as ceftazidime/piperacillin-tazobactam and ceftazidime/aztreonam etc. However, there are also some combinations that showed no additional or synergistic effects, suggesting that not all combinations recommended by the guideline have the same effect against resistant P. aeruginosa. Our study screened out some effective combinations against six CRPA strains which might help to prevent the spread of antibiotic resistance through improving antibiotic effectiveness. Significance and Impact of the Study This study measured the synergistic interactions between various antibiotics in vitro recommended by Chinese consensus statement against carbapenems-resistant Pseudomonas aeruginosa. The results of this study provide valuable evidence that some combinations may be a promising option for clinical treatment.

鲍曼不动杆菌(Acinetobacter baumannii,AB)是不动杆菌属中最常见的一种非发酵革兰氏阴性球杆菌,广泛分布于水、土壤及医院环境中,是人类皮肤、呼吸道、胃肠道和生殖道的正常菌群.作为条件致病菌,可引起医院获得性肺炎、社区获得性肺炎、血流感染、泌尿系统感染、脑膜炎等[J].近年来,由于广谱抗生素的广泛应用,再加上AB对一些常用抗生素的先天耐药性,使得AB的耐药性不断增加,多重耐药(MDR)、泛耐药菌株(XDR,指仅对1～2类潜在有抗不动杆菌活性的药物敏感的菌株)日趋增多,甚至出现全耐药(PDR)菌株[2].

Objective To study clinical distribution and drug resistance tendency ofpseudomonas aeruginosa in Shandong Qianfoshan Hospital from 2005 to 2014.Methods Susceptibility rate were determined by KirbyBauer methods.The data were collected by software WHONET 5.6 and analysed by software R2.12.1 with the application of Cox-Staurt trend test.Results 9 041 strains ofpseudomonas aeruginosa were isolated and the isolating rate was 21.05％,both rank first among other pathogen strains.The isolating strains ofpseudomonas aeruginosa were in an increasing trend,while the isolating rate had no variation trend.The drug resistance rate of pseudomonas aeruginosa to ceftiaxone was 63.74％,being the highest,to ceftazidime was 41.63％,being the lowest.The drug resistant strains ofpseudomonas aeruginosa to ceftazidime and aztreonam were in decreasing trends.The drug resistance rates of pseudomonas aeruginosa to piperacilin,piperacillin/tazobactam,amikacin,gentamicin and levofloxacin were in decreasing trends.There were no variation trends for the drug resistant strains or the drug resistance rates ofpse udomonas aeruginosa to other antibiotics.3 290 strains of multiple resistant pseudomonas aeruginosa were isolated,which account for 36.39％ of all isolated strains ofpseudomonas aeruginosa.Multiple resistant pseudomonas aeruginosa strains were in an increasing trend,but its percentage ofpseudomonas aeruginosa had no variation trend.Conclusion Pseudomonas aeruginosastill is mainly pathgeon in nosocomial infection.However,in recent ten years the drug resistant rate of pseudomonas aeruginosa shows relatively stable trend.

In recent decades, the incidence of invasive fungal infections has increased notably. Candida albicans (C. albicans), a common opportunistic fungal pathogen that dwells on human mucosal surfaces, can cause fungal infections, especially in immunocompromised and high-risk surgical patients. In addition, the wide use of antifungal agents has likely contributed to resistance of C. albicans to traditional antifungal drugs, increasing the difficulty of treatment. Thus, it is urgent to identify novel antifungal drugs to cope with C. albicans infections. Heat shock proteins (Hsps) exist in most organisms and are expressed in response to thermal stress. In C. albicans, Hsps control basic physiological activities or virulence via interaction with a variety of diverse regulators of cellular signaling pathways. Moreover, it has been demonstrated that Hsps confer drug resistance to C. albicans. Many studies have shown that disrupting the normal functions of C. albicans Hsps inhibits fungal growth or reverses the tolerance of C. albicans to traditional antifungal drugs. Here, we review known functions of the diverse Hsp family, Hsp-associated intracellular signaling pathways and potential antifungal targets based on these pathways in C. albicans. We hope this review will aid in revealing potential new roles of C. albicans Hsps in addition to canonical heat stress adaptions and provide more insight into identifying potential novel antifungal targets.

In this study, we found that ambroxol hydrochloride (128 μg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 μg/mL) against resistant planktonic Candida albicans (C. albicans) cells. This combination also exhibited synergistic effects against resistant C. albicans biofilms in different stages (4, 8, and 12 h) according to the microdilution method. In vitro data were further confirmed by the success of this combination in treating Galleria mellonella infected by resistant C. albicans. With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant C. albicans, increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the in vitro and in vivo antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant C. albicans. The results show the potential role for this drug combination as a therapeutic alternative to treat resistant C. albicans and provide insights into the development of antifungal targets and new antifungal agents.

Candida spp. are the primary opportunistic pathogens of nosocomial fungal infections, causing both superficial and life-threatening systemic infections. Combination therapy for fungal infections has attracted considerable attention, especially for those caused by drug-resistant fungi. Gentamicin (GM), an aminoglycoside antibiotic, has weak antifungal activity against Fusarium spp. The aim of this study was to investigate the interactions of GM with azoles against Candida spp. and the underlying mechanisms. In a chequerboard assay, GM was found not only to work synergistically with azoles against planktonic cells of drug-resistant Candida albicans with a fractional inhibitory concentration index (FICI) of 0.13-0.14, but also synergised with fluconazole (FLC) against C. albicans biofilms pre-formed in <12 h. Synergism of GM with FLC was also confirmed in vivo in a Galleria mellonella infection model. In addition, mechanism studies showed that GM not only suppressed the efflux pump of resistant C. albicans in a dose-dependent manner but also inhibited extracellular phospholipase activity of resistant C. albicans when combined with FLC. These findings suggest that GM enhances the efficacy of azoles against resistant C. albicans via efflux inhibition and decreased activity of extracellular phospholipase. (c) 2017 Published by Elsevier B.V.

Candida albicans is the most commonly isolated Candida spp. in the clinic and its resistance to fluconazole (FLC) has been emerging rapidly. Combination therapy may be a potentially effective approach to combat drug resistance. In this study, the combination antifungal effects of dexamethasone (DXM) and FLC against resistant C. albicans in vitro were assayed using minimum inhibitory concentrations (MICs), sessile MICs and time–kill curves. The in vivo efficacy of this drug combination was evaluated using a Galleria mellonella model by determining survival rate, fungal burden and histological damage. In addition, the impact of DXM on efflux pump activity was investigated using a rhodamine 6G assay. Expression of CDR1, CDR2 and MDR1 was determined by real-time quantitative PCR, and extracellular phospholipase activity was detected by the egg yolk agar method to reveal the potential synergistic mechanism. The results showed that DXM potentiates the antifungal effect of FLC against resistant C. albicans strains both in vitro and in vivo, and the synergistic mechanism is related to inhibiting the efflux of drugs and reducing the virulence of C. albicans.

MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. Here, we identified that miR-599 is up-regulated in non-small cell lung cancer (NSCLC) patients. It promoted NSCLC cell proliferation by negatively regulating SATB2. In NSCLC cell lines, CCK-8 proliferation assay indicated that the cell proliferation is promoted by miR-599 mimics. Transwell assay showed that miR-599 mimics promoted the invasion and migration of NSCLC cells. Luciferase assays confirmed that miR-599 directly binds to the 3'untranslated region of SATB2, and western blotting showed that miR-599 suppresses the expression of SATB2 at the protein level. This study indicates that miR-599 promotes proliferation and invasion of NSCLC cell lines via SATB2. The miR-599 may represent a potential therapeutic target for NSCLC treatment.

Objectives: Treatment of azole-resistant Candida albicans infections continues to pose significant challenges. With limited options of licensed agents, drug combinations may be a practical treatment alternative. In our previous studies, the combinations minocycline/fluconazole (MINO/FLC) and doxycycline/fluconazole (DOXY/FLC) shown synergistic effects in vitro. It is necessary to explore their appropriate dosage, potential toxicity and in vivo efficacy. Methods: The Galleria mellonella infection model was employed to study the in vivo efficacy of MINO/FLC and DOXY/FLC by survival analysis, quantification of C. albicans fungal burden and histological studies. Results: The survival rates of G. mellonella larvae infected with lethal doses of resistant C. albicans CA10 increased significantly when treated with the drug combinations compared with FLC treatment alone, and the fungal burden was reduced by almost four-fold. The histopathological study showed that fewer infected areas in larvae were observed and the destructive degree was less when larvae were exposed to the drug combinations. Conclusions: These findings suggest that combination of a tetracycline antibiotic (MINO or DOXY) with FLC has antifungal activity against azole-resistant C. albicans in vivo. This is in agreement with several previous in vitro studies and provides preliminary in vivo evidence that such a combination might be useful therapeutically. (C) 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Candida is an important opportunistic fungal pathogen, especially in biofilm associated infections. The formation of a Candida biofilm can decrease Candida sensitivity to antifungal drugs and cause drug resistance. Although many effective antifungal drugs are available, their applications are limited due to their high toxicity and cost. Seeking new antifungal agents that are effective against biofilm-associated infection is an urgent need. Many research efforts are underway, and some progress has been made in this field. It has been shown that the arachidonic acid cascade plays an important role in fungal morphogenesis and pathogenicity. Notably, prostaglandin E2 (PGE2) can promote the formation of a Candida biofilm. Recently, the inhibition of PGE2 has received much attention. Studies have shown that cyclooxygenase (COX) inhibitors, such as aspirin, ibuprofen, and indomethacin, combined with fluconazole can significantly reduce Candida adhesion and biofilm development and increase fluconazole susceptibility; the MIC of fluconazole can be decrease from 64 to 2 μg/ml when used in combination with ibuprofen. In addition, in vivo studies have also confirmed the antifungal activities of these inhibitors. In this article, we mainly review the relationship between PGE2 and Candida biofilm, summarize the antifungal activities of COX inhibitors and analyze the possible antifungal activity of microsomal prostaglandin E synthase-1 (MPGES-1) inhibitors; additionally, other factors that influence PGE2 production are also discussed. Hopefully this review can disclose potential antifungal targets based on the arachidonic acid cascade and provide a prevailing strategy to alleviate Candida albicans biofilm formation.

Candida albicans is an important opportunistic pathogen, causing both superficial mucosal infections and life-threatening systemic diseases in the clinic. The emergence of drug resistance in Candida albicans has become a noteworthy phenomenon due to the extensive use of antifungal agents and the development of biofilms. This study showed that budesonide potentiates the antifungal effect of fluconazole against fluconazole-resistant Candida albicans strains both in vitro and in vivo. In addition, our results demonstrated, for the first time, that the combination of fluconazole and budesonide can reverse the resistance of Candida albicans by inhibiting the function of drug transporters, reducing the formation of biofilms, promoting apoptosis and inhibiting the activity of extracellular phospholipases. This is the first study implicating the effects and mechanisms of budesonide against Candida albicans alone or in combination with fluconazole, which may ultimately lead to the identification of new potential antifungal targets.

目的 探讨盐酸小檗碱、黄芩苷与6种抗菌药物(头孢他啶、哌拉西林-他唑巴坦、亚胺培南西司他丁钠、氨曲南、左氧氟沙星、加替沙星)对多重耐药鲍曼不动杆菌的联合抑菌作用.方法 根据临床药敏结果选取7株鲍曼不动杆菌多重耐药菌株作为实验对象.用微量稀释法测定盐酸小檗碱、黄芩苷分别与6种抗菌药物的联合抑菌效应.结果 盐酸小檗碱与亚胺培南西司他丁钠、氨曲南联用表现为协同作用.黄芩苷与氨曲南表现为协同作用.结论 盐酸小檗碱、黄芩苷与某些抗菌药物联用后对多重耐药鲍曼不动杆菌的抗菌活性有协同作用,可能对多重耐药鲍曼不动杆菌的治疗有所帮助.