Meta‑analysis of influencing factors associating with treatment outcome of multidrug resistant tuberculosis

Objective:To systematically review the influencing factors of the treatment outcome of multidrug-resistant pulmonary tuberculosis and provide reference for the prevention and treatment of multidrug-resistant pulmonary tuberculosis.Method:Case control studies on the factors influencing the treatment outcome of multidrug-resistant pulmonary tuberculosis in Chinese databases(CNKI,VIP,Wanfang,Sinomed)and English databases(Pubmed,Web of science,Medline,Embase,Scopus)were searched and collected by computer.The search period was from the establishment of the database to January 2023.After screening and quality evaluation,RevMan5.4 was used for meta-analysis.Result:Totally 18 articles were ultimately included,with a sample size of 7328 people.The results showed that retreatment,complications,adverse reactions,and gender were related to the treatment outcome of multidrug-resistant pulmonary tuberculosis.The OR values and 95%CI of each factor were 0.22(0.17-0.29),0.38(0.32-0.46),0.27(0.17-0.44),and 0.43(0.33-0.56),respectively.Conclusion:Complications,retreatment,adverse reactions,and male gender are effective risk factors for the treatment outcome of multidrug-resistant pulmonary tuberculosis.In clinical practice,more targeted measures are needed for different types of patients.Due to the limitations of the number of studies,the above conclusions require more research to support them.

Synergistic Effect of Combined Antibiotics against Some Selected Multidrug Resistant Human Pathogenic Bacteria Isolated from Poultry Droppings in Akure, Nigeria

Antibiotic resistant bacteria pass between humans, between animals and between humans and animals in both directions, the use of antibiotics in poultry has contributed to multiple antibiotic resistant in pathogenic bacteria and use of two antibiotics might prevent the emergence of resistance to either. In this study, synergistic effect of combined antibiotics against multidrug resistant human pathogenic bacterial isolates from poultry droppings in Akure, Nigeria was examined. Collection of samples, isolation and identification of bacteria were carried out using standard microbiological method, antibiotic sensitivity test was performed by disc diffusion method and zone of inhibition was used to interpret the sensitivity test as resistant, susceptible or intermediate while combined effects of two antibiotics were investigated by macrobroth dilution and checkerboard assay methods while the synergetic effects of combined antibiotics were calculated using Fractional Inhibitory Concentration (FIC) and percentage synergistic interaction was calculated. All the ten (10) species of bacterial isolates were multidrug resistant and are less resistant to ofloxacin. The highest percentage synergistic interactions observed were Ofloxacin + Amoxicillin (90%), Ciprofloxacin + Amoxicillin (90%), Tetracycline + Amoxicillin (70%), Tetracycline + Augmentin (80%), Cotrimoxazol + Amoxicillin (50%), Cotrimoxazol + Augmentin (70%), Chloramphenicol + Amoxicillin (70%) and Chloramphenicol + Augmentin (80%). Poultry droppings is a potential source of human pathogenic bacteria, high frequency of multiple antibiotic resistance bacteria observed in this study is of great treat to man as this may cause the treatment of infection caused by these bacteria to be difficult. Combination of beta-lactam antibiotic with fluoroqunolones, tetracycline, Chloramphenicol and Cotrimoxazole was synergetic and this will reduce dose related toxicity and prevent resistance to single antibiotic.

Establishment of a human hepatoma multidrug resistant cell line in vitro

AIM:To establish a multidrug-resistant hepatoma cell line(SK-Hep-1),and to investigate its biological characteristics.METHODS:A highly invasive SK-Hep-1 cell line of human hepatocellular carcinoma,also known as malignant hepatoma was incubated with a high concentration of cisplatin(CDDP) to establish a CDDP-resistant cell subline(SK-Hep-1/CDDP).The 50% inhibitory dose(IC50) values and the resistance indexes [(IC50 SK-Hep-1/CDDP)/(IC50 SK-Hep-1)] for other chemotherapeutic agents and the growth curve of cells were all evaluated using cell counting kit-8 assays.The distribution of the cell cycles were detected by flow cytometry.Expression of acquired multidrug resistance P-glycoprotein(MDR1,ABCB1) and multidrug resistance-associated protein 1(MRP1,ABCC1) was compared with that in parent cells by Western blotting and immunofluorescence combined with laser scanning confocal microscopy.RESULTS:The SK-Hep-1/CDDP cells(IC50 = 70.61 ± 1.06 μg/mL) was 13.76 times more resistant to CDDP than the SK-Hep-1 cells(IC50 = 5.13 ± 0.09 μg/mL),and CDDP-resistant cells also demonstrated cross-resistance to many anti-tumor agents such as doxorubicin,5-fluorouracil and vincristine.Similar morphologies were determined in both SK-Hep-1 and SK-Hep-1/CDDP groups.The cell cycle distribution of the SK-Hep-1/CDDP cell line exhibited a significantly increased percentage of cells in S(42.2% ± 2.65% vs 27.91% ± 2.16%,P < 0.01) and G2/M(20.67% ± 5.69% vs 12.14% ± 3.36%,P < 0.01) phases in comparison with SK-Hep-1 cells,while the percentage of cells in the G0/G1 phase decreased(37.5% ± 5.05% vs 59.83% ± 3.28%,P < 0.01).The levels of MDR1 and MRP1 were overexpressed in the SK-Hep-1/CDDP cells exhibiting the MDR phenotype.CONCLUSION:Multiple drug resistance of multiple drugs in the human hepatoma cell line SK-Hep-1/CDDP was closely related to the overexpression of MDR1 and MRP1.

Down-regulation of extracellular signal-regulated kinase 1/2 activity in P-glycoprotein-mediated multidrug resistant hepatocellular carcinoma cells

AIM： To study the expression and phosphorylation of extracellular signal-regulated kinase （ERK） i and ERK2 in multidrug resistant （MDR） hepatocellular carcinoma （HCC） cells.METHODS： MDR HCC cell lines, HepG2/adriamycin （ADM） and SMMC7721/ADM, were developed by exposing parental cells to stepwise increasing concentrations of ADM. MTT assay was used to determine drug sensitivity. Flow cytometry was employed to analyze cell cycle distribution and measure cell P-glycoprotein （P-gp） and multidrug resistant protein 1 （MRP1） expression levels. ERK1 and ERK2 mRNA expression lev-ls were measured by quantitative real-time PCR （QRTPCR）. Expression and phosphorylation of ERK1 and ERK2 were analyzed by Western blot.RESULTS： MTT assay showed that HepG2/ADM andSMMC7721/ADM were resistant not only to ADM, but also to multiple anticancer drugs. The P-gp expression was over 10-fold higher in HepG2/ADM cells than in HepG2 cells （8.92% ±0.22% vs 0.88% ± 0.05%, P 〈 0.001） and over 4-fold higher in SMMC7721/ADM cells than in SMMC7721 cells （7.37% ± 0.26% vs 1.74% ± 0.25%, P 〈 0.001）. However, the MRP1 expression was not significantly higher in HepG2/ADM and SMMC7721/ADM cells than in parental cells. In addition, the percentage of MDR HepG2/ADM and SMMC7721/ADM cells was significantly decreased in the G0/G1 phase and increased in the the S phase or G2/M phase. QRT-PCR analysis demonstrated that the ERK1 and ERK2 mRNA expression increased apparently in HepG2/ADM cells and decreased significantly in SMMC7721/ADM cells. Compared with the expression of parental cells, ERK1 and ERK2 protein expressions were markedly decreased in SMMC7721/ADM cells. However, ERK2 protein expression was markedly increased while ERK1 protein expression had no significant change in HepG2/ADM cells. Phosphorylation of ERK1 and ERK2 was markedly decreased in both HepG2/ADM and SMMC7721/ADM MDR cells.CONCLUSION： ERK1 and ERK2 activities are downregulated in P-gp-mediated MDR HCC cells. ERK1 or ERK2 might be a potential drug target for circumventing MDR HCC cells,

Development and characterization of multidrug resistant human hepatocarcinoma cell line in nude mice

AIM： To establish a multidrug resistant （MDR） cell subline from the human hepatocardnoma cell line （HepG2） in nude mice. METHODS： HepG2 cell cultures were incubated with increasing concentrations of adriamycin （ADM） to develop an ADM-resistant cell subline （HepG2/ADM） with crossresistance to other chemotherapeutic agents. Twenty male athymic BALB/c-nu/nu mice were randomized into HepG2/nude and HepG2/ADM/nude groups （10 in each group）. A cell suspension （either HepG2 or HepG2/ADM） was injected subcutaneously into mice in each group. Tumor growth was recorded, and animals were sacrificed 4-5 wk after cell implantation. Tumors were prepared for histology, and viable tumor was dispersed into a single-cell suspension. The IC50 values for a number of chemotherapeutic agents were determined by 2, 3-bis （2-methoxy-4-nitro-5-sulfophenyl）-2H-tetrazolium-5-carboxanilide inner salt （MTT） assay. Rhodamine-123 retention/efflux and the level of resistance-associated proteins were determined by flow cytometry. The mRNA expression of mdr1, mrp and Irp genes was detected using reverse transcriptase polymerase chain reaction （RT-PCR） in HepG2/nude and HepG2/ADM/nude groups. RESULTS： The appearances of HepG2/nude cells were slightly different from those of HepG2/ADM/nude cells. Similar tumor growth curves were determined in both groups. A cross-resistance to ADM, vincristine, cisplatin and 5-fluorouracil was seen in HepG2/ADM/nude group. The levels of P-glycoprotein and multidrug resistanceassociated proteins were significantly increased. The mRNA expression levels of mdrl, mrp and/rp were higher in HepG2/ADM/nude cells. CONCLUSION： ADM-resistant HepG2 subline in nude mice has a cross resistance to chemotherapeutic drugs. It may be used as an in vivo model to investigate the mechanisms of MDR, and explore the targeted approaches to overcoming MDR.

Folic acid-conjugated liposomal vincristine for multidrug resistant cancer therapy

We encapsulated vincristine into folic acid-conjugated PEGylated liposomes to improve the anti-tumor efficacy on multidrug resistant cancers.It was observed that the drug delivery system we constructed exhibited maximum cytotoxicity on KBv200 cells(multidrug resistant variant)compared with any other formulations.The semi-quantitative analysis of region of interest revealed that there was a great increase in area under curve(AUC)of a near-infrared fluorescein in solid tumors due to folic acid-mediated accumulation.Folic acid-conjugated PEGylated liposomes showed a significant tumor growth inhibiting effect in vitro and in vivo.TUNEL assay revealed that folic acid-conjugated PEGylated liposomes could induce cell apoptosis much more greatly than others.This study demonstrated that it had potential application prospective for the treatment of multidrug resistant cancer.

GENE EXPRESSION PROFILING IN MULTIDRUG RESISTANT KB CELLS USING cDNA MICROARRAYS

Objective: A single mechanistic pathway cannot explain the genesis of drug resistance in cancer. Drug resistance in cancer is a major obstacle to successful chemotherapy. KB cells provide a useful starting point for selection of the multidrug resistant (MDR) cell lines. Methods: We used cDNA microarrays containing 12,720 sequences of known genes, expressed sequence tags and unknown clones to monitor gene expression profiles in MDR KB cells. Results: Preliminary data analysis showed that 18 genes were up-regulated and 18 genes were down-regulated by comparison of expression patterns between KB 3-1 and MDR KB-V1 cells. Furthermore, the highly over-expressed CGA, CLU genes in MDR KB-V1 cell were verified with conventional Northern blot analysis. These genes contain information predictive of drug resistance of cancer cells. Conclusion: Our study demonstrates that genome-wide gene expression profiling by using cDNA microarray technique is a valuable approach in obtaining molecular mechanism of drug resistance in cancer cells.

Risk factors and antibiotic resistance of pneumonia caused by multidrug resistant Acinetobacter baumannii in pediatric intensive care unit

With beta-lactam drugs and immunosuppressants widely used, the infection caused by Acinetobacter baumannfi （Ab） has become more and more serious with multidrug resistant Acinetobacter baumannfi （MDRAb） emerging and worsening rapidly. Compared with other patients, the incidence and multidrug resistance of MDRAb are higher in children in pediatric intensive care unit （PICU） because of immune deficiency, severe basic diseases, prolonged hospitalization and invasive operations. Hence it is significant to study the epidemiology and changes of antibacterial susceptibility in order to reduce the incidence of MDRAb in children. A total 115 patients with MDRAb pneumonia and 45 patients with negative MDRAb （NMDRAb） pneumonia who had been treated from January 2009 to August 2011 were studied retrospectively at the PICU of Wuhan Children＇s Hospital. Clinical data were analyzed with univariate and multivariate Logistic regression. In 176 clinical strains of Acinetobacter baumannfi isolated, there were 128 strains of MDRAb, accounting for 72.73%. Drug susceptibility tests showed that the resistance rates of 13-1actam antibiotics were more than 70% except for cefoperazone sulbactam. The rates to carbapenems were higher than 90%. They were significantly higher than those of NMDRAb. Amikacin, levofloxacin, ciprofloxacin and minocycline had the lowest drug-resistance rates （〈20%）. Multivariate Logistic regression revealed that ICU stay, the time of mechanical ventilation, anemia, hypoproteinemia and the use of carbapenems were independent risk factors for MDRAb pneumonia. MDRAb is an important opportunistic pathogen to pneumonia in PICU, and its drug-resistance is severe. It increases significantly the mortality of patients. It is important to take the effective prevention measures for controlling it.

Ventilator-associated pneumonia in patients with cancer: Impact of multidrug resistant bacteria

BACKGROUND Patients with cancer have several risk factors for developing respiratory failure requiring mechanical ventilation(MV).The emergence of multidrug resistant bacteria(MDRB)has become a public health problem,creating a new burden on medical care in hospitals,particularly for patients admitted to the intensive care unit(ICU).AIM To describe risk factors for ventilator-acquired pneumonia(VAP)in patients with cancer and to evaluate the impact of MDRB.METHODS A retrospective study was performed from January 2016 to December 2018 at a cancer referral center in Mexico City,which included all patients who were admitted to the ICU and required MV≥48 h.They were classified as those who developed VAP versus those who did not;pathogens isolated,including MDRB.Clinical evolution at 60-d was assessed.Descriptive analysis was carried out;comparison was performed between VAP vs non-VAP and MDRB vs non-MDRB.RESULTS Two hundred sixty-three patients were included in the study;mean age was 51.9 years;52.1%were male;68.4%had solid tumors.There were 32 episodes of VAP with a rate of 12.2%;11.5 episodes/1000 ventilation-days.The most frequent bacteria isolated were the following:Klebsiella spp.[n=9,four were Extended-Spectrum Beta-Lactamase(ESBL)producers,one was Carbapenem-resistant(CR)];Escherichia coli(n=5,one was ESBL),and Pseudomonas aeruginosa(n=8,two were CR).One Methicillin-susceptible Staphylococcus aureus was identified.In multivariate analysis,the sole risk factor associated for VAP was length of ICU stay(OR=1.1;95%CI:1.03-1.17;P=0.003).Sixty-day mortality was 53%in VAP and 43%without VAP(P=0.342).There was not higher mortality in those patients with MDRB.CONCLUSION This study highlights the high percentage of Gram-negative bacteria,which allows the initiation of empiric antibiotic coverage for these pathogens.In this retrospective,single center,observational study,MDRB VAP was not directly linked to increased mortality at 60 days.

Antibacterial Activity of Exogenous Glutathione and Its Synergism on Antibiotics in Methicillin-Associated Multidrug Resistant Clinical Isolates of Staphylococcus aureus

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most problematic human pathogens. Antibiotic treatment of MRSA often associated with resistance to multiple classes of antibiotics is extremely challenging and urgently demands action to treat MRSA. Glutathione (GSH) is a biogenic thiol-compound that maintains an optimal intracellular redox-potential required for various normal cellular processes. Antibacterial activity of exogenous GSH has been reported in some bacterial pathogens but is largely unknown in MRSA. Aim: This study aimed to understand antibacterial activity of GSH, its role in antibiotic susceptibility, and a potential antibacterial mechanism in clinical isolates of S. aureus. Materials and Methods: Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), checkerboard, time-killing, and bacterial killing assays were performed for 14 clinical isolates of S. aureus including 10 MRSA and two type strains (ATCC 700699 and 35556). Results: MIC and MBC levels for the clinical and type strains were 15 - 20 mM and 25 - 40 mM of GSH, respectively. Subinhibitory concentrations of GSH synergistically enhanced susceptibility of all tested-antibiotics, resulting in sensitizing all-tested S. aureus. Bacterial-killing produced by GSH-mediated acidity was significantly higher than that by hydrochloric acid-mediated acidity. Conclusion: Overall results concluded that GSH exhibited antibacterial activity on S. aureus regardless of antibiotic susceptibility and synergistically enhanced antibiotic susceptibility. Additionally, GSH-mediated acidity was one of the antibacterial mechanisms. These findings suggest that GSH may be a potential antimicrobial agent or adjuvant for the conventional anti-MRSA regimens.

Mycosynthesis,characterization and antibacterial properties of AgNPs against multidrug resistant(MDR)bacterial pathogens of female infertility cases

Recently,biosynthesis of silver nanoparticles using bacteria,fungus and plants has emerged as a simple and viable alternative to more complex physical and chemical synthetic procedures.The present investigation explains rapid and extracellular synthesis of silver nanoparticles using fungus Fusarium oxysporum NGD and characterization of the synthesized silver nanoparticles using UV-Vis spectroscopy,scanning electron microscopy,energy dispersive spectroscopy and X-ray diffraction analysis.The size range of the synthesized silver nanoparticles was around 16.3e70 nm.The FTIR studies showed major peaks of proteins involved in the synthesis of silver nanoparticles.Further,antibacterial effect of the silver nanoparticles against multidrug resistant pathogens Enterobacter sp.ANT 02[HM803168],Pseudomonas aeruginosa ANT 04[HM803170],Klebsiella pneumoniae ANT 03[HM803169]and Escherichia coli ANT 01[HM803167]was tested using turbidometric assay at 10,20,30,40 mg AgNPs/ml alone and in combination with ampicillin using agar well diffusion assay.All the resistant bacteria were found to be susceptible to the antibiotic in the presence of the silver nanoparticles.

Prevalence of Multidrug Resistant <i>Mycobacterium tuberculosis</i>among Tuberculosis Patients Admitted to Adama Hospital Medical College, Adama, Ethiopia: A Retrospective Study

Multidrug resistant tuberculosis (MDR-TB) is an emerging challenge for TB control programs globally. Ethiopia ranks 7th among the world’s 22 high TB burden countries. According to report of WHO (2017), TB is one of the leading infectious causes of death in Ethiopia claiming the life of more than 30 thousand people annually. The surge of MDR-TB has been compounding the problem further. Facility-based MDR-TB researches have not been generated in equal pace with community-based ones. The aim of this study was to assess the prevalence of MDR-TB using clinical records of MDR-TB patients in Adama Hospital Medical College (AHMC) from 2014 to 2018. All clinical data of MDR-TB from 2014-2018 was collected from AHMC TB department. Socio-demographic and risk factor data were collected from patients using semi-structured questionnaire. Data were analyzed using Microsoft excel and SPSS version 20. Out of a total 2332 TB suspected cases admitted to AHMC from 2014 to 2018, 175 (7.5%) were confirmed MDR-TB cases or confirmed Rifampicin resistant cases. In particular, 97 (4.2%) presented presumptive MDR-TB alone and 78 (3.3%) showed confirmed Rifampicin resistance alone. Comparison among age groups showed the highest prevalence for 24 - 44 years with 1.8% and 1.5% confirmed MDR-TB and Rifampicin resistance. The overall prevalence of MDR-TB was moderate indicating for possible rise of the problem due to course of time. Further study combining both community and health facility based is recommended to highlight the need to make useful strategies for testing, surveillance and effective clinical management of MDR-TB cases.

Biotyping of Multidrug Resistant <i>Campylobacter jejuni</i>from Poultry and Humans in Northern Region of Ghana

Thermophilic Campylobacters are zoonotic bacteria which are universally famous for causing enteritis in humans. They are normally found as commensals in the digestive tract of food animals with poultry being a major reservoir of the pathogenic species. This study highlighted the presence of Campylobacter in poultry (commercial and domestic) and humans (patients and asymptomatic individuals) and characterized strains by biotyping and susceptibility test in the Northern region of Ghana where animal husbandry is commonly practiced but zoonotic studies are limited. A total of 1087 specimens from stools of humans and cloacal swabs of poultry were screened from 25th October, 2017 to 7th May, 2019. Samples were cultured on modified charcoal-cefoperazone-deoxycholate agar and isolates identified using standard microbiological procedures and Lior Biotyping, while the antibiogram of isolates was determined by the Kirby-Bauer disk diffusion method. The frequency of Campylobacter was 43.1% and 12.9% respectively in poultry and humans. Campylobacter jejuni were recovered from 84% of commercial birds and 64% of domestic birds and in humans significantly fewer strains were observed in patients than asymptomatic individuals (p < 0.05). Biotype distribution revealed C. jejuni biotype I prevalence in domestic birds, patients and asymptomatic individuals whereas Bioytype II was largely found in commercial poultry. All isolated strains of Campylobacter were resistant to tetracycline and 69.4% of Campylobacter jejuni strains were resistant to erythromycin. Imipenem and the aminoglycosides were relatively effective as resistance of 10% and below 20% were respectively obtained. None of the endorsed treatment drugs (erythromycin, ciprofloxacin, and tetracycline) can be admitted in this region due to common resistance found among strains against these agents.

High Prevalence of Multidrug Resistant <i>Klebsiella</i>Species Isolated from the Yaounde University Teaching Hospital, Cameroon

Background and Purpose: Klebsiella species are amongst the most common causes of a variety of community-acquired and hospital-acquired infections (HAI), characterized by high morbidity and mortality rates. Most infections caused by Klebsiella species are usually treated using antibiotics. The aim of this study was to determine the antimicrobial resistance profile of Klebsiella species isolated from in-patients and out-patients at the Yaounde University Teaching Hospital. The data generated will go a long way to improve on the choice of an adequate empiric antibiotic treatment for infections caused by Klebsiella species. Methodology: A cross-sectional descriptive study was carried out over a period of 6 months, spanning from February 2019 to July 2019 with a sample size of 37 isolates, obtained from 6 different clinical specimens. Identification of isolates was done using API 20E identification system (Biomerieux SA, Lyon, France). Susceptibility to antibiotics was tested as described by Kirby-Bauer in 1956. Inhibition diameters were interpreted according to recommendations from the European Committee on Antimicrobial Susceptibility Testing (EUCAST, 2019). Results and Conclusion: Among the 37 Klebsiella isolates identified, Klebsiella pneumoniae was the most prevalent species isolated with a percentage of 54.1%, followed by Klebsiella rhinoscleromatis 18.9%, Klebsiella ozaenae 16.2% and Klebsiella oxytoca, 10.8%. The resistance pattern of Klebsiella to amoxicillin, amoxicillin/clavulanate, tircacillin, tircacillin + clavulanic acid, piperacillin, piperacillin + tazobactam, cefalotin, cefuroxim, ceftazidime, cefotaxime, ceftriaxone, cefepime, imipenem, meropenem, aztreonam, amikacin, gentamicin, tobramycin, trimethoprim/ sulfamethoxazole, nalidixic acid, pipemidic acid, norfloxacin, ciprofloxacin, levofloxacin, ofloxacin, and moxifoxacin was as follows;100%, 86.5%, 97.3%, 83.6%, 86.5%, 16.2%, 86.5%, 83.8%, 78.4%, 32.4%, 78.4%, 76.7%, 2.7%, 2.7%, 76.7%, 13.5%, 75.7%, 73.0%, 91.9%, 51.4%, 48.6%, 64.9%, 48.6%, 48.6%, 73.0% and 62.2% respectively. Multidrug resistance was observed in 94.6% of the Klebsiella isolates. Conclusion: This study shows that the level of multidrug resistance is high. The isolates expressed good sensitivity to carbapenems, piperacillin + tazobactam, amikacin and high resistance to all other antimicrobials tested. Therefore, antimicrobial susceptibility testing prior to prescriptions should be encouraged and sensitization of the population about consequences of inappropriate antibiotic treatment and auto medication should be enforced as a means to curb antimicrobial resistance.

Efficacy and Safety of Combined Bedaquiline and Delamanid Use among Patients with Multidrug-Resistant Tuberculosis in Beijing,China

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQcontaining regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients.Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM.Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups.Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Diarrheal Diseases: A Review on Gastroenteritis Bacteria Global Burden and Alternative Control of Multidrug-Resistant Strains

Diarrheal diseases represent a significant and pervasive health challenge for humanity. The aetiology of diarrheal diseases is typically associated with the presence of enteropathogens, including viruses, bacteria and parasites. The implementation of preventive measures, including the maintenance of good food hygiene, effective water sanitation, and the development of rotavirus vaccines, has resulted in a notable reduction in the prevalence of the disease. However, the emergence of bacterial multidrug resistance due to the past or present inappropriate use of antibiotics has rendered bacterial infections a significant challenge. The objective of this review is threefold: firstly, to provide an overview of diarrheal diseases associated with bacteria;secondly, to offer a concise analysis of bacterial multidrug resistance on a global scale;and thirdly, to present the potential of filamentous fungi as an alternative solution to the challenge posed by multidrug-resistant strains. Campylobacter spp. is the most dangerous bacteria, followed by Shigella spp. and Vibrio cholerae in all age groups combined. However, Shigella spp. was the deadliest in children under five years of age and, together with E. coli, are the most antibiotic-resistant bacteria. With their highly developed secondary metabolism, fungi are a reservoir of natural bioactive compounds.

Apatinib reduces liver cancer cell multidrug resistance by modulating NF-κB signaling pathway

Objectives:This investigation aimed to elucidate the inhibitory impact of apatinib on the multidrug resistance of liver cancer both in vivo and in vitro.Methods:To establish a Hep3B/5-Fu resistant cell line,5-Fu concentrations were gradually increased in the culture media.Hep3B/5-Fu cells drug resistance and its alleviation by apatinib were confirmed via flow cytometry and Cell Counting Kit 8(CCK8)test.Further,Nuclear factor kappa B(NF-κB)siRNA was transfected into Hep3B/5-Fu cells to assess alterations in the expression of multidrug resistance(MDR)-related genes and proteins.Nude mice were injected with Hep3B/5-Fu cells to establish subcutaneous xenograft tumors and then categorized into 8 treatment groups.The treatments included oxaliplatin,5-Fu,and apatinib.In the tumor tissues,the expression of MDRrelated genes was elucidated via qRT-PCR,immunohistochemistry,and Western blot analyses.Results:The apatinibtreated mice indicated slower tumor growth with smaller size compared to the control group.Both the in vivo and in vitro investigations revealed that the apatinib-treated groups had reduced expression of MDR genes GST-pi,LRP,MDR1,and p-p65.Conclusions:Apatinib effectively suppresses MDR in human hepatic cancer cells by modulating the expression of genes related to MDR,potentially by suppressing the NF-κB signaling pathway.

Identification of FDA-Approved Drugs as Modulators of Multidrug Resistance Protein 2 (MRP2/ABCC2) Expression Levels in MRP2-Overexpressing Cells: Preliminary Data

Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.

Silver nitrate restores susceptibility of clinical multidrug resistant gram-negative and gram-positive bacteria to amikacin in vitro

Silver nitrate could inhibit the clinical multidrug resistant isolates at high concentrations（with minimal inhibitory concentrations（MICs） from 32 μM to 64 μM）. The activities of amikacin in the presence of sub-lethal silver nitrate（15 μM） were tested for the combinational effects against multidrug resistant clinical isolates in vitro. Silver nitrate restored the susceptibility of drug-resistant Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus to amikacin. It lowered the MICs of amikacin from 〉128 μg/mL to（2–16） μg/mL and 32 μg/mL, respectively, and lowered the MICs of amikacin on extended spectrum β-lactamase-producing Pseudomonas aeruginosa and Escherichia coli from（16–32） μg/mL and 16 μg/mL to（〈1–4） μg/mL and 〈1 μg/mL, respectively.

Using ^(99m)Tc-MIBI to Evaluate the Effects of Chemosensitizer on P-glycoprotein in Multidrug-resistant Carcinoma Cells

To establish a method to evaluate the effects of chemosensitizer onP-glycoprotein using ^(99m)Tc-MIBI, and observe the changes of ^(99m)Tc-MIBI uptake kinetics andP-glycoprotein levels after using verapamil in MDR human breast cells MCF-7/Adr. Methods: MDR breastcarcinoma cells, MCF-7/Adr, were incubated and different protocols were performed. Protocol Ⅰ: achemosensitizer, verapamil (10 μmol/L), was added into cell culture medium, while in control group,the same volume of DMEM was given. Cells were harvested after 2 h incubation with ^(99m)Tc-MIBI.Protocol Ⅱ: Verapamil (10 μmol/L) was added into cell culture medium and incubated for 20 min, 40min, 60 min, 80 min, 8 h, 24 h, 48 h and 72 h respectively. Cells were harvested after 2 hincubation with ^(99m)Tc-MIBI. The radioactivity of the cells was measured and P-glycoproteinexpression levels were determined with immunohistochemical stain. Results: Protocol Ⅰ: After 2hincubation with verapamil the cellular uptake of ^(99m)Tc-MIBI was remarkably higher than controlgroup (t=2.33, P 【 0.05), but there was no difference in P-glycoprotein expression levels betweentwo groups (P 】 0.05). Protocol Ⅱ: In verapamil group, ^(99m)Tc-MIBI uptake was increased withincubation time prolonging (F=58.2, P 【 0.05). When verapamil incubation time surpassed 8 h the^(99m)Tc-MIBI uptake negatively correlated to the P-glycoprotein expression levels (r=-0.73, P 【0.01). However, when incubation time was less than 80 min, there was no correlation between^(99m)Tc-MIBI accumulation and P-glycoprotein levels (r=0.16, P 】 0.05). Conclusion: ^(99m)Tc-MIBImay be used to evaluate the qualitative as well as quantitative change of P-glycoprotein expressionlevels induced by the chemosensitizer, verapamil.