Multidrug Therapy Research Articles

Inhibitory effect of natural compounds on Dihydropteroate synthase of Mycobacterium leprae: Molecular dynamic study

Leprosy is a chronic infectious disease caused by a bacillus, Mycobacterium leprae. According to official data from 139 countries in the 6 WHO Regions, there were 127558 new leprosy cases worldwide in 2020. Leprosy mainly affects the skin, the peripheral nerves, mucosa of the upper respiratory tract, and the eyes. If this disease is left untreated, can harm the skin, nerves, limbs, eyes, and skin permanently. The disease is curable with multidrug therapy. Over a period of time Mycobacterium leprae has become resistant to these drugs. Therefore, new therapeutic molecules are warranted. This study was aimed to carry out the in-silico analysis to determine the inhibitory effect of natural compounds on Dihydropteroate synthase (DHPS) of Mycobacterium leprae. The DHPS is a key enzyme in the folate biosynthesis pathway in M. leprae and acts as a competitive inhibitor of PABA. The 3D structure of DHPS protein was modeled using homology modeling and was validated. Molecular docking and simulation along with other in-silico methods were employed to determine the inhibitory effect of ligand molecules towards DHPS target protein. Results revealed ZINC03830554 molecule as a potential inhibitor of DHPS. Binding experiments and bioassays utilizing this strong inhibitor molecule against purified DHPS protein are necessary to validate these early findings.Communicated by Ramaswamy H. Sarma

Epidemiological and Clinical Features of Leprosy Reactions and Associated Risk Factors in Malagasy People from 2012 to 2021

<i>Introduction</i>: Leprosy is a transmissible infectious disease while cutaneous and neurological manifestations vary according to the patient's immunity. It is a chronic disease with acute immunological complication called leprosy reactions. Leprosy remains endemic in Madagascar. The objective of this study is to characterize the epidemiological and clinical profile of leprosy and leprosy reactions and to determine the risk factors for leprosy reactions. <i>Methods</i>: This was a retrospective, case-control study over a period of 10 years from January 2012 to December 2021 conducted among leprosy patients of the University Hospital Joseph Raseta Befelatanana. Univariate and multivariate logistic regression was used to determine the risk factors for leprosy reactions. <i>Results:</i> Of the 161 patients selected, 53 patients had a leprosy reaction. There were 91 males and 70 females with a mean age of 35.8 years (±15,47). The borderline lepromatous type was the most common clinical form. The prevalence of lepromatous reaction was 33%. Type 1 and type 2 reactions were found in 41.50% and 45.28% of cases respectively. The average time to develop leprosy reactions after the initiation of multidrug therapy was 5.80 months (±3.91). From multivariate analysis, the risk factors identified were: male gender [OR=2.64 (95% CI: 1.80-9.57), p=0.02], positive BI [OR=3.53 (95% CI: 2.41-48.98), p=0.02], MB treatment regimen [OR=8.87 (95% CI: 1.23-3.57), p=0.008)], and poor adherence to treatment [OR=1.97 (95% CI: 1.34-12.95), p=0.0354]. <i>Conclusion: </i>The knowledge of these risk factors allows for early diagnosis and treatment of leprosy reactions to prevent the morbidities due to leprae disease such as amputations and disabilities that are a source of stigma.

DAPSONE-INDUCED TOXIC MACULOPATHY IN LEPROSY PATIENT

Introduction: Dapsone has been widely used as a part of multidrug therapy for leprosy patients. Ocular side effects are rare. Ocular toxicity manifestations include retinal necrosis, optic atrophy, macular infarction, bilateral exudative retinal detachment, and choroidal detachment. We reported a rare case of dapsone-induced toxic maculopathy in a leprosy patient. Case Report: A 32-year-old male complained of blurred vision and a gray spot in central vision in the left eye (LE) for one month prior to admission. He had been treated with multidrug therapy (MDT) for leprosy for seven months. The MDT consists of dapsone, clofazimine, and rifampicin. The best-corrected visual acuity (BCVA) of the right eye (RE) and the LE were 6/6 and 6/12, respectively. A funduscopy of the LE showed decreased macular reflex. A color vision defect following the tritan axis was found in the LE. The Humphrey visual field (HVF) test of the LE revealed a central scotoma. Macular optical coherence tomography (OCT) showed intraretinal hyperreflectivity and subretinal fluid. Dapsone was then stopped in collaboration with a dermatologist. Two months after the discontinuation of Dapsone, the BCVA of the LE improved to 6/7.5, then 6/6 three months later. Color vision, macular OCT, and HVF tests revealed improvements. Multifocal ERG of both eyes (BE) also showed improvement in N1 and P1 wave amplitude in both eyes on 9-month follow-up after dapsone discontinuation. Discussion: Instead of direct drug toxicity, the mechanism of ocular side effects is thought to be ischemia caused by two distinct mechanisms. Macular ischemia is caused by acute, severe peripheral hypoxia and the physical effect of red cell fragmentation due to the hemolytic process. After discontinuation of dapsone, this case showed improvement in visual function and macular structure. Conclusion: Toxic maculopathy may be present in leprosy patients receiving dapsone treatment, although it is uncommon. Regular follow-up and evaluation of visual function and macular involvement are essential. Early detection of dapsone-induced toxic maculopathy and prompt discontinuation of dapsone may result in an improvement of visual functions.

Leprosy Reactions: Clinical Pharmacologist Perspective with Repurposed Medications.

The elimination of leprosy has been possible with the available anti-leprotic drugs. However, the lepra reactions usually occur months or years after multi-drug therapy completion, and continue to be a formidable challenge mainly owing to its role in causing nerve damage and disability. Corticosteroids are commonly used but they lead to systemic complications, and hence require dose reduction and adjunct therapy with a different target. Various drugs with different targets have been identified and are in practice to treat lepra reactions. The newer targets can include genetic and tissue targets in the skin and nerve. Thalidomide treatment reducing pentraxin-3, toll-like receptor antagonists, minocycline, apremilast, immunomodulators, and tenidap can be helpful in lepra reaction. Other modalities to manage lepra reactions include plasma exchange, intravenous immunoglobulins, and immunotherapy. Most of these treatments are based only on the pathological process of the reaction and tend to be incomplete leading to recurrence. Newer multimodal approaches are required based on various biomarkers (genetic, tissue, serological), which can be monitored to prevent the recurrence of reactions. Hence, there is a need for newer targets and drugs to be identified for the management of lepra reactions.

Seventy years of evidence on the efficacy and safety of drugs for treating leprosy: a network meta-analysis

The World Health Organization (WHO) recommends multidrug therapy (MDT) with rifampicin, dapsone, and clofazimine for treating leprosy, which is based on very low-quality evidence. Here, we performed a network meta-analysis (NMA) to produce quantitative evidence to strengthen current WHO recommendations. All studies were obtained from Embase and PubMed from the date of establishment to October 9, 2021. Data were synthesized with frequentist random-effects network meta-analyses. Outcomes were assessed using odds ratios (ORs), 95% confidence intervals (95% CIs), and P score. Sixty controlled clinical trials and 9256 patients were included. MDT was effective (range of OR: 1.06-1255584.25) for treating leprosy and multibacillary leprosy. Six treatments (Range of OR: 1.199-4.50) were more effective than MDT. Clofazimine (P score=0.9141) and dapsone+rifampicin (P score=0.8785) were effective for treating type 2 leprosy reaction. There were no significant differences in the safety of any of the tested drug regimens. The WHO MDT is effective for treating leprosy and multibacillary leprosy, but it may not be effective enough. Pefloxacin and ofloxacin may be good adjunct drugs for increasing MDT efficacy. Clofazimine and dapsone+rifampicin can be used in the treatment of a type 2 leprosy reaction. Single-drug regimens are not efficient enough to treat leprosy, multibacillary leprosy, or a type 2 leprosy reaction. All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Synergistic Combination of the Total Steroidal Saponins from the Berries of Black Nightshade and Adriamycin to Overcome Leukemia Multidrug Resistance.

The berries of black nightshade (Solanum nigrum L.) are consumed as a favorite fruit in some regions and have been reported to possess a range of biological activities. Previous studies have found that the steroidal saponins from the berries of S. nigrum (SN) showed potential antileukemic activity, although the underlying mechanism remains to be revealed. This study investigated the effects and mechanisms of SN in combination with adriamycin to reverse leukemia multidrug resistance in vivo and in vitro. The results indicated that the combination of SN and adriamycin displayed enhanced suppression ability both in vitro and in vivo by the modulation of drug efflux proteins. Further study revealed that SN and adriamycin co-treatment induced cell apoptosis in K562/ADR cells through caspase pathways and autophagy through the PI3K/Akt/mTOR and MAPK signaling pathway. This study provides a new prospect of the berries of black nightshade in multidrug resistance therapy of cancer.

Evidence of Insulin-Sensitizing and Mimetic Activity of the Sesquiterpene Quinone Avarone, a Protein Tyrosine Phosphatase 1B and Aldose Reductase Dual Targeting Agent from the Marine Sponge Dysidea avara.

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First-line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrug therapies to ensure that non-responding patients maintain target glycemia levels. The use of multitarget drugs instead of mono- or multidrug therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets; for this purpose, exploration of the chemical space of natural products represents a powerful tool. Our study demonstrates that avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, is capable of inhibiting in vitro PTP1B, the main negative regulator of the insulin receptor, while it improves insulin sensitivity, and mitochondria activity in C2C12 cells. We observe that when avarone is administered alone, it acts as an insulin-mimetic agent. In addition, we show that avarone acts as a tight binding inhibitor of aldose reductase (AKR1B1), the enzyme involved in the development of diabetic complications. Overall, avarone could be proposed as a novel natural hit to be developed as a multitarget drug for diabetes and its pathological complications.

Analysis of socioeconomic condition and bacillary index with respect to the development of Hansen's disease.

Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae or Mycobacterium lepromatosis and mainly affects the skin and peripheral nerves. Although treatable, its early intervention can significantly reduce the occurrence of disability. India accounts for more than half of new cases globally. This study was undertaken to better understand the clinical traits of newly diagnosed cases in a tertiary facility of Western Uttar Pradesh, and a few from Madhya Pradesh and Uttarakhand. The observational prospective study was carried out on all the newly diagnosed leprosy cases who visited the Outpatient Department of ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, during October 2019-December 2022. After obtaining answers to a prestructured questionnaire with their consent, participants were enrolled in the study and underwent clinical examination and a slit-skin smear test. A total of 56 cases were investigated, and among them, 20 (35.7%) and 36 (64.3%) women and men, respectively, had positive contact with persons affected by leprosy either within family, friends, or neighbors. It is observed that due to the delayed detection of leprosy cases, paucibacillary (PB) patients converted into multibacillary (MB) patients, and the number of MB cases is much higher compared to PB cases. Leprosy instances continue to spread frequently from sick to healthy people indicating continued transmission of leprosy in society. Multidrug therapy in the management of leprosy cases is effective; however, early diagnosis of PB cases is still a challenge and needs to be addressed on priority.

Phase Ib study of dabrafenib, trametinib, irinotecan and cetuximab in BRAF V600E-mutated metastatic colorectal cancer.

156 Background: The low efficacy of single-agent BRAF inhibitor in metastatic colorectal cancer (mCRC) is usually due to EGFR feedback upregulation caused by BRAF blockade. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. Here, we reported the preliminary results of quadruple therapy with dabrafenib, a selective BRAF inhibitor, trametinib, a selective MEK inhibitor, irinotecan and cetuximab in patients with BRAF V600E-mutated mCRC. Methods: This was an ongoing phase Ib study, patients with mCRC who relapse or refractory to standard treatments were enrolled. Patients were treated with dabrafenib (150mg/150mg doses orally twice daily), trametinib (2mg orally once daily), irinotecan (80mg/m2 weekly) and cetuximab (400mg/m2 in first dose and 250mg/m2 weekly). Treatment was continued until disease progression, development of unacceptable toxicity, or drawal of consent. The primary end-point was disease control rate (DCR), and the secondary end-points included progression-free survival (PFS) and duration of disease remission (DOR). This trial is registered with Chinese ClinicalTrials.gov, number ChiCTR2200063316. Results: From July 2018 to January 2021, 10 patients were enrolled. The median age was 53.5 (age 25-65), nine with colon cancer and one with rectal cancer. The most common adverse events (AEs) (50% or more) were fatigue, fever, rash, vomit, leukopenia, anemia, ALT elevation, and AST elevation. Four patients suffered rash which was the most common severe AE (SAE). Two patients presented with grade 3/4 anemia. Only one patient suffered grade 3/4 AEs with nausea and vomit. The DCR was 90% (9/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months (range 1.8-32.4 months). The median DOR was 5.2 months (range 0-27.7 months). Conclusions: Dabrafenib, trametinib, irinotecan and cetuximab has tolerable toxicity and promising antitumor activity in BRAF V600E-mutated mCRC. This regimen warrants a further phase II clinical trial. Clinical trial information: ChiCTR2200063316 . [Table: see text]

The application of digital health as a nursing solution for leprosy patients during the COVID-19 pandemic: a systematic review

To analyse the effect of using digital health technology on leprosy control programmes. The systematic review comprised search on PubMed, Scopus, ScienceDirect, SAGE and ProQuest databases for interventional studies published in English language from 2013 to 2021 which used digital health technology for leprosy contact tracing, active leprosy detection, monitoring of multi-drug therapy and treatment management during the corona virus disease-2019 pandemic A standard risk of bias tool was used to evaluate bias in the studies, and the Joanna Briggs Institute protocol was used to assess the quality of the studies analysed. Of the 205 studies initially identified, 15(7.3%) were analysed in detail. Quasi-experimental studies had a low risk of bias compared to the rest. The e-leprosy framework was being used along with applications based on smartphones and artificial intelligence Digital health technology was found to be practical, accessible and effective in leprosy control programmes. Studies reported favourable findings regarding the use of digital health technology in services related to leprosy patients.

An unusual case of tenosynovitis in Hansen's disease.

Tenosynovitis is an infrequent presentation of Hansen's disease. It may occur during the natural course of disease or treatment as part of type 1 reaction or rarely may be the presenting complaint. We report a case of tenosynovitis of bilateral wrist joints who after being ineffectively treated by an orthopedician as well as rheumatologist for several months and was finally diagnosed as a case of Hansen's disease (borderline lepromatous) in type 1 reaction with excellent response to multidrug therapy and tapering doses of systemic steroids.

Refractory diffuse coronary artery spasm post aortic valve replacement

Postoperative coronary artery spasm occurs rarely after valve replacement surgery. We report the case of a 64-year-old man with normal coronary arteries who underwent aortic valve replacement. Nineteen hours postoperatively, his blood pressure plummeted with an elevated ST-segment. Coronary angiography demonstrated a 3-vessel diffuse coronary artery spasm, and direct intracoronary infusion therapy was performed with isosorbide nitrate, nicorandil and sodium nitroprusside hydrate within 1 h of onset. Nonetheless, there was no improvement, and the patient was resistant to treatment. The patient died due to prolonged low cardiac function and pneumonia complications. Prompt intracoronary vasodilator infusion is considered effective. However, this case was refractory to multi-drug intracoronary infusion therapy and was not salvageable.

A Rapid Screening Assay for Clarithromycin-Resistant Mycobacterium avium Complex Using Melting Curve Analysis with Nonfluorescent Labeled Probes.

Mycobacterium avium complex (MAC) thrives in various environments and mainly causes lung disease in humans. Because macrolide antibiotics such as clarithromycin or azithromycin are key drugs for MAC lung disease, the emergence of macrolide-resistant strains prevents the treatment of MAC. More than 95% of macrolide-resistant MAC strains are reported to have a point mutation in 23S rRNA domain V. This study successfully developed a melting curve assay using nonfluorescent labeled probes to detect the MAC mutation at positions 2058 to 2059 of the 23S rRNA gene (AA genotype, clarithromycin susceptible; TA, GA, AG, CA, AC, and AT genotypes, clarithromycin resistant). In the AA-specific probe assay, the melting peak of the DNA fragment of the AA genotype was higher than that of DNA fragments of other genotypes. Melting temperature (Tm) values of the AA genotype and the other genotypes were about 80°C and 77°C, respectively. DNA fragments of each genotype were identified correctly in six other genotype-specific probes (TA, GA, AG, CA, AC, and AT) assays. Using genomic DNA from six genotype strains of M. avium and four genotype strains of M. intracellulare, we confirmed that all genomic DNAs could be correctly identified as individual genotypes according to the highest Tm values among the same probe assays. These results indicate that this melting curve-based assay is able to determine MAC genotypes at positions 2058 to 2059 of the 23S rRNA gene. This simple method could contribute to the rapid detection of clarithromycin-resistant MAC strains and help to provide accurate drug therapy for MAC lung disease. IMPORTANCE Since macrolide antibiotics such as clarithromycin or azithromycin are key drugs in multidrug therapy for Mycobacterium avium complex (MAC) lung diseases, the rapid detection of macrolide-resistant MAC strains has important implications for the treatment of MAC. Previous studies have reported a correlation between drug susceptibility testing and the mutation of macrolide resistance genes. In this study, we developed a novel melting curve-based assay using nonfluorescent labeled probes to identify both clarithromycin-resistant M. avium and M. intracellulare with mutations in the 23S rRNA gene, which is the clarithromycin or azithromycin resistance gene. This assay contributed to not only the detection of MAC mutations but also the determination of all genotypes at positions 2058 to 2059 of the 23S rRNA gene. Furthermore, because nonfluorescent labeled probes are used, this assay is more easily and more immediately available than other methods.

Tools to develop antibiotic combinations that target drug tolerance in Mycobacterium tuberculosis.

Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are urgently needed. The adaptation of Mycobacterium tuberculosis to various lesion microenvironments in infection induces various states of slow replication and non-replication and subsequent antibiotic tolerance. This non-heritable tolerance to treatment necessitates lengthy combination therapy. Therefore, it is critical to develop combination therapies that specifically target the different types of drug-tolerant cells in infection. As new tools to study drug combinations earlier in the drug development pipeline are being actively developed, we must consider how to best model the drug-tolerant cells to use these tools to design the best antibiotic combinations that target those cells and shorten tuberculosis therapy. In this review, we discuss the factors underlying types of drug tolerance, how combination therapy targets these populations of bacteria, and how drug tolerance is currently modeled for the development of tuberculosis multidrug therapy. We highlight areas for future studies to develop new tools that better model drug tolerance in tuberculosis infection specifically for combination therapy testing to bring the best drug regimens forward to the clinic.

Evaluation of Dental and Periodontal Health Status in Leprosy Patients during Three Different Stages of Drug Regimen: A Cross-sectional Study

Introduction: The prevalence of oral lesions in leprosy patients and the risk of developing them with the disease are considerably high. Multidrug Therapy (MDT) can effectively treat leprosy, but its effectiveness is heavily dependent on early detection, when chronic disability might be avoided. Poor oral hygiene combined with weakened immunity increases the risk of developing oral lesions in leprosy patients and impacts their overall health. Aim: To evaluate the oral, dental and periodontal findings in patients during three different stages of drug regimen. Materials and Methods: A cross-sectional study was conducted on 150 known leprosy patients from four leprosy facilities in the Vidarbha area, Maharashtra, India. Comprehensive oral examination was performed from July 2022 to September 2022, including the Decayed, Missing, Filled Teeth (DMFT) index, assessment of Non-Carious Cervical Lesions (NCCLs), Plaque Index (PI), Papillary bleeding Index (PBI) and complete periodontal examination by measuring Probing Pocket Depth (PPD) and Clinical Attachment Loss (CAL). Descriptive statistics were done utilising SPSS version 23. The Analysis of Variance (ANOVA) test was used to check the mean difference between the three groups. The statistical significance established was p&lt;0.05. Results: The evaluation revealed the prevalence of decayed teeth as 103 out of 150 (68%), that of a missing tooth was 93 out of 150 (62%). NCCLs were found in 80 out of 150 with the prevalence of abrasion as seen in 51 (63.7%) patients and 38 patients (47.5%) for abfraction, and 18 out of 80 patients (22.5%) for erosion. Comparing the PI and PBI between the groups, significantly higher scores were observed in patients who had not undergone treatment (p-value &lt;0.01). CAL was found to be statistically significant with higher scores in patients who had completed their treatment (p-value &lt;0.001). Conclusion: The findings of the present study indicate that the NCCLS and the DMFT scores were higher in the untreated group. However, there was increased attachment loss in treated patients, which can be supplemented to the drug therapy prescribed for leprosy

Predictors of adverse safety events and unscheduled care among an outpatient parenteral antimicrobial therapy (OPAT) patient cohort.

Select circumstances require outpatient parenteral antimicrobial therapy (OPAT). The potency of OPAT agents presents an increased risk of adverse events and unscheduled medical care. We analyzed these outcomes among OPAT recipients as part of the implementation of a collaborative OPAT program. Adult patients discharged home from an academic hospital with OPAT between January 2019 and June 2021 were included in this retrospective cohort; participants discharged between June 2020 and June 2021 were part of the collaborative OPAT program. Patients with cystic fibrosis were excluded. Data on patient characteristics and outcomes were collected from electronic medical records by two reviewers. Multivariable analysis was conducted to identify predictors of vascular access device (VAD) complications, adverse drug events (ADEs), and OPAT-related emergency department (ED) visits and rehospitalizations. Among 265 patients included in the cohort, 57 (21.5%) patients experienced a VAD complication; obesity [odds ratio (OR): 3.32; 95% confidence interval (CI): 1.38-8.73; p = 0.01) and multi-drug therapy (OR: 2.56; 95% CI: 1.21-5.39; p = 0.01) were associated with an increased odds of VAD complication. Eighty-two (30.9%) participants experienced an ADE; 30 (11.3%) experienced a severe/serious ADE. Lipo/glycopeptide receipt, (OR: 5.28; 95% CI: 1.89-15.43; p < 0.01) and Black/African American race (OR: 4.85; 95% (CI): 1.56-15.45; p < 0.01) were associated with an increased odds of severe/serious ADE. Inclusion in the OPAT collaborative was associated with a decreased odds of severe/serious ADE (OR: 0.26; 95% CI: 0.08-0.77; p = 0.01). Fifty-eight (21.9%) patients experienced an OPAT-related ED visit and 53 (20.0%) experienced an OPAT-related rehospitalization. VAD complication (OR: 2.37; 95% (CI): 1.15-4.86, p = 0.02) and ADEs (OR: 2.19; CI: 1.13-4.22; p = 0.02) were associated with OPAT-related ED visits. ADE was associated with 90-day OPAT-related rehospitalization (OR: 3.21; (CI): 1.59-6.58; p < 0.01). Adverse safety events and OPAT-related unscheduled care occurred often in our cohort. A structured OPAT program that includes ID pharmacist antibiotic reconciliation may reduce rates of ADEs.

Sustaining and augmenting the pace of ongoing prevention and control activities to attain the goal of leprosy-free world

Leprosy is a chronic infectious disease, predominantly affecting the skin and peripheral nerves, and is completely curable with multidrug therapy. Considering the global estimates, there is no doubt that disease-related control activities have significantly improved in endemic nations due to the campaigns at different levels and the integration of the disease-specific activities with the general health services, as a result of which diagnostic and therapeutic aspects of the disease have improved. A number of global strategies have been launched by the World Health Organization to support all nations to strengthen their routine prevention and control activities. In conclusion, leprosy is a major public health concern in endemic nations and there is an immense need to improve the detection rates and ensure the expansion of the treatment. In addition, there is a great need to empower the affected people, to eventually improve their integration into society.

Different Efflux Pump Systems in Acinetobacter baumannii and Their Role in Multidrug Resistance.

Several infections, such as pneumonia, urinary tract infections (UTIs), as well as bloodstream, skin, and soft tissue infections, are caused by Acinetobacter baumannii, a nosocomial pathogen and Gram-negative coccobacillus. Due to its resistance to a variety of medications, multidrug therapy, and occasionally pan therapies, this bacterium is a huge public health concern. Drug resistance is a big worry not only in A. baumannii, but it is also a major challenge in many other diseases. Antibiotic resistance, biofilm development, and genetic alterations are all linked to variables like the efflux pump. Efflux pumps are transport proteins involved in the extrusion of hazardous substrates from within cells into the external environment (including nearly all types of therapeutically relevant antibiotics). Both Gram-positive and Gram-negative bacteria, as well as eukaryotic organisms, contain these proteins. Efflux pumps may be specialized for a single substrate or can transport a variety of structurally dissimilar molecules (including antibiotics of many classes); these pumps have been linked to multiple drug resistance (MDR). There are five primary families of efflux transporters in the prokaryotic kingdom: MF (major facilitator), MATE (multidrug and toxic efflux), RND (resistance-nodulation-division), SMR (small multidrug resistance), and ABC (ATP-binding cassette). The efflux pumps and their types as well as the mechanisms of an efflux pump involved in multidrug resistance in bacteria have been discussed here. The main focus is on the variety of efflux pumps commonly found in A. baumannii, along with their mechanism by which they make this bacteria drug resistant. The efflux-pump-inhibitor-based strategies that are significant in targeting efflux pumps in A. baumannii have also been discussed. The connection of biofilm and bacteriophage with the efflux pump can prove as an efficient strategy for targeting efflux-pump-based resistance in A. baumannii.

A Cross-Sectional Study to Evaluate the Alteration of Cytokine Expression and Activation of Inflammatory Pathway in Response to NOD1 and NOD2 Signal in Leprosy.

Leprae bacilli are identified as foreign by pattern recognition receptors (PRRs) present in the microbes but absent in the host. The Nucleotide oligomerization domain (NOD)-like receptor (NLR) family comprises the nucleotide-binding oligomerisation domain (NOD1 and NOD2) proteins, which are two well-known PRRs. The objectives of this study were to study the expression of cytoplasmic NOD1 and NOD2 in the pathogenesis of leprosy and the serum level of expressed cytokines and to measure the messenger Ribonucleic Acid (mRNA) expression. Clinically suspected Hansen's patients were analysed for 4 years. Newly diagnosed leprosy patients were considered leprosy disease control (LDC). The cases with active or new lesions and an increase in Bacteriological index (BI) by at least 2 + after 12 months of completion of Multidrug therapy (MDT) were considered leprosy disease relapse (LDR) cases. Age- and sex-matched healthy individuals served as our control group (healthy control (HC)). enzyme-linked immunosorbent assay (ELISA) was performed to measure the concentration of five human cytokines in serum, including three pro-inflammatory cytokines (Tumor necrosis factor (TNF)-α, Interferon gamma (IFN-γ) and IL-6), one anti-inflammatory cytokine (IL-10) and one chemokine (IL-8). Quantitative expression of receptor genes (NOD1 and NOD2) and cytokine genes (TNF-α, IFN-γ, IL-6, IL-10 and IL-8) was evaluated by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR). We studied NOD1 and NOD2 expression in the tissues through fluorescence immunohistochemistry. Differential NLR intracellular expression on peripheral blood monocytes (PBMs) and their response to stimulation with specific ligands (lipopolysaccharide (LPS) and muramyl dipeptide (MDP)) were studied. A significant difference in the expression of the NOD1 gene was observed in unstimulated monocytes of the LDC and LDR cases when compared to HC. The NOD2 transcript level was significantly higher in stimulated monocytes from LDC and LDR patients than in similarly stimulated cells from HC. The LDC patients had a significantly higher level of pro-inflammatory cytokines as compared to the HC. In conclusion, this study has demonstrated the expression of both cytokines and chemokines in response to NLR activation in the skin of leprosy patients.

Relapse After Drug Withdrawal in Patients with Epilepsy After Two Years of Seizure-Free: A Cohort Study.

Antiepileptic drugs are the first choice of treatment for patients with epilepsy. However, the withdrawal of antiepileptic drugs after seizure-free remains a significant focus for the majority of patients with epilepsy and their families. In this study, we evaluated the risk factors associated with relapse after drug withdrawal in patients with seizure free for 2 years. We aimed to guide patients in seizure-free to assess the risk of drug withdrawal. Through screening, 452 patients with epilepsy were included in the study.Patients were followed up for at least 2 years or more. Analyzed their clinical data by applying the χ2-test, Kaplan-Meier survival analysis and multivariate Cox regression analysis. 423 patients completed follow-up, of which 304 cases recurred (71.9%).Related recurrence factors include age of onset, type of seizure, number of AEDs, seizure-free time before withdrawal, and electroencephalogram (EEG) results before drug withdrawal (P<0.05). The results of correlation analysis showed that age of onset, seizure frequency, seizure type, number of AEDs, the period from AEDs treatment to a seizure-free status, EEG results before drug withdrawal, and pre-medication course, were all significantly related to the recurrence of seizures after drug reduction and withdrawal (P<0.05). We identified a range of independent risk factors, including onset age, seizure frequency, Multiple AEDs and the period from AEDs treatment to a seizure-free status. The overall recurrence rate of epilepsy in our patient cohort was high, and the peak recurrence period was within one-year of drug withdrawal. Patients with partial seizures, a short seizure-free time before withdrawal, severe EEG abnormalities before drug reduction, and a long course of the disease, are prone to relapse. Patients with an older age at onset and a high frequency of attack, those taking multi-drug combination therapy, and those that take a long time to gain control, should be managed carefully to AEDs withdrawal.