Beyond Psychotropic: Potential Repurposing of Fluoxetine toward Cancer Therapy.

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood-brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer.

Hypoxia modulates P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) drug transporters in brain endothelial cells of the developing human blood-brain barrier.

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) multidrug resistance (MDR) transporters are localized at the luminal surface of the blood-brain barrier (BBB). They confer fetal brain protection against harmful compounds that may be circulating in the peripheral blood. The fetus develops in low oxygen levels; however, some obstetric pathologies such as pre-eclampsia, placenta accreta/previa may result in even greater fetal hypoxic states. We investigated how hypoxia impacts MDR transporters in human fetal brain endothelial cells (hfBECs) derived from early and mid-stages of pregnancy. Hypoxia decreased BCRP protein and activity in hfBECs derived in early pregnancy. In contrast, in hfBECs derived in mid-pregnancy there was an increase in P-gp and BCRP activity following hypoxia. Results suggest a hypoxia-induced reduction in fetal brain protection in early pregnancy, but a potential increase in transporter-mediated protection at the BBB during mid-gestation. This would modify accumulation of various key physiological and pharmacological substrates of P-gp and BCRP in the developing fetal brain and potentially contribute to the pathogenesis of neurodevelopmental disorders commonly associated with in utero hypoxia.

Recent trends and challenges to overcome Pseudomonas aeruginosa infections.

INTRODUCTION: Pseudomonas aeruginosa (PA) is a Gram-negative bacterium that can cause a wide range of severe infections in immunocompromised patients. The most difficult challenge is due to its ability to rapidly develop multi drug-resistance. New strategies are urgently required to improve the outcome of patients with PA infections. The present patent review highlights the new molecules acting on different targets involved in the antibiotic resistance. AREA COVERED: This review offers an insight into new potential PA treatment disclosed in patent literature. From a broad search of documents claiming new PA inhibitors, we selected and summarized molecules that showed in vitro and in vivo activity against PA spp. in the period 2020 and 2023. We collected the search results basing on the targets explored. EXPERT OPINION: This review examined the main patented compounds published in the last three years, with regard to the structural novelty and the identification of innovative targets. The main areas of antibiotic resistance have been explored. The compounds are structurally unrelated to earlier antibiotics, characterized by a medium-high molecular weight and the presence of heterocycle rings. Peptides and antibodies have also been reported as potential alternatives to chemical treatment, hereby expanding the therapeutic possibilities in this field.

Membrane-Fusing Vehicles for Re-Sensitizing Transporter-Mediated Multiple-Drug Resistance in Cancer.

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane. CsA-loaded MFVs successfully reversed MDR for all three investigated efflux transporters at significantly lower concentrations compared with CsA in solution. Results showed a 15-fold decrease in the IC50 value for ABCB1, a 7-fold decrease for ABCC1 and an 11-fold decrease for ABCG2. We observed binding site specificity for ABCB1 and ABCG2 transporters. Lower concentrations of empty MFVs along with CsA contribute to the inhibition of Hoechst 33342 efflux. However, higher concentrations of CsA along with the high amount of MFVs activated transport via the H-binding site. This supports the conclusion that MFVs can be useful beyond their role as delivery systems and also help to elucidate differences between these transporters and their binding sites.

Phenylspirodrimane with Moderate Reversal Effect of Multidrug Resistance Isolated from the Deep-Sea Fungus Stachybotrys sp. 3A00409.

Two new phenylspirodrimanes, stachybotrins K and L (1 and 2), together with eight known analogues (3-10), were isolated from deep-sea-derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Absolute configurations of new compounds were determined through a comparison of their circular dichroism (CD) spectra with other reported compounds. The possible reversal effects of all compounds were assayed in the resistant cancer cell lines. Stachybotrysin B (8) can reverse multidrug resistance (MDR) in ABCB1-overexpression cells (KBv200, Hela/VCR) at the non-cytotoxic concentration. Doxorubicin accumulation assay and molecular-docking analysis reveal that the mechanism of its reversal MDR effect may be related to the increase in the intracellular concentration of substrate anticancer drugs.

Molecular mechanisms of tigecycline-resistance among Enterobacterales.

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin.

Advances in traditional herbal formulation based nano-vaccine for cancer immunotherapy: Unraveling the enigma of complex tumor environment and multidrug resistance.

Cancer is attributed to uncontrolled cell growth and is among the leading causes of death with no known effective treatment while complex tumor microenvironment (TME) and multidrug resistance (MDR) are major challenges for developing an effective therapeutic strategy. Advancement in cancer immunotherapy has been limited by the over-activation of the host immune response that ultimately affects healthy tissues or organs and leads to a feeble response of the patient's immune system against tumor cells. Besides, traditional herbal medicines (THM) have been well-known for their essential role in the treatment of cancer and are considered relatively safe due to their compatibility with the human body. Yet, poor solubility, low bio-availability, and lack of understanding about their pathophysiological mechanism halt their clinical application. Moreover, considering the complex TME and drug resistance, the most precarious and least discussed concerns for developing THM-based nano-vaccination, are identification of specific biomarkers for drug inhibitory protein and targeted delivery of bioactive ingredients of THM on the specific sites in tumor cells. The concept of THM-based nano-vaccination indicates immunomodulation of TME by THM-based bioactive adjuvants, exerting immunomodulatory effects, via targeted inhibition of key proteins involved in the metastasis of cancer. However, this concept is at its nascent stage and very few preclinical studies provided the evidence to support clinical translation. Therefore, we attempted to capsulize previously reported studies highlighting the role of THM-based nano-medicine in reducing the risk of MDR and combating complex tumor environments to provide a reference for future study design by discussing the challenges and opportunities for developing an effective and safe therapeutic strategy against cancer.

The role of ABCC10/MRP7 in anti-cancer drug resistance and beyond.

Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 ß-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.

Advances in Engineered Nano-Biosensors for Bacteria Diagnosis and Multidrug Resistance Inhibition.

Bacterial infections continue to pose a significant global health challenge, with the emergence of multidrug-resistant (MDR) bacteria and biofilms further complicating treatment options. The rise of pan-resistant bacteria, coupled with the slow development of new antibiotics, highlights the urgent need for new therapeutic strategies. Nanotechnology-based biosensors offer fast, specific, sensitive, and selective methods for detecting and treating bacteria; hence, it is a promising approach for the diagnosis and treatment of MDR bacteria. Through mechanisms, such as destructive bacterial cell membranes, suppression of efflux pumps, and generation of reactive oxygen species, nanotechnology effectively combats bacterial resistance and biofilms. Nano-biosensors and related technology have demonstrated their importance in bacteria diagnosis and treatment, providing innovative ideas for MDR inhibition. This review focuses on multiple nanotechnology approaches in targeting MDR bacteria and eliminating antimicrobial biofilms, highlighting nano-biosensors via photodynamics-based biosensors, eletrochemistry biosensors, acoustic-dynamics sensors, and so on. Furthermore, the major challenges, opportunities of multi-physical-field biometrics-based biosensors, and relevant nanotechnology in MDR bacterial theranostics are also discussed. Overall, this review provides insights and scientific references to harness the comprehensive and diverse capabilities of nano-biosensors for precise bacteria theranostics and MDR inhibition.

Bacterial Diversity and Antibiotic Resistance Patterns of Community-Acquired Urinary Tract Infections in Mega Size Clinical Samples of Egyptian Patients: A Cross-Sectional Study.

BACKGROUND:  Community-acquired urinary tract infection (UTI) is one of the most common infectious diseases nowadays. Alarming increased levels of antimicrobial resistance are developing globally which limit treatment options and may lead to life-threatening problems. AIM: Our study aimed to collect surveillance data on non-hospitalized Egyptian UTI cases and to develop strategies against multidrug-resistant pathogens (MDR). According to our knowledge, this is the first study to screen this high number (15,252 urine samples) in a short period (three months), providing valuable data on resistance profiles in non-hospitalized Egyptian UTI patients. METHODS: A total of 15,252 urine samples were collected from different patients. Positive cultures were identified using a semi-quantitative method. Kirby-Bauer's disc diffusion method was used for antibiotic susceptibility testing, the double disc diffusion method was used for extended-spectrum beta-lactamases-producing strains, and the Chi-square test was used for statistical data processing. RESULTS: The results showed 61% positive cultures, females accounted for 67.5%. Infants and elderly patients showed the highest positive cultures (74.4% and 69.2%, respectively). Despite Escherichia coli being the most common uropathogen (47.19%), Klebsiella species(24.42%) were the most MDR and extended-spectrum ß-lactamase (ESBL)-producing organisms. E. coli and Klebsiella spp. displayed increased resistance to cephalosporins (75% and 81%, respectively). In contrast, both organisms displayed high sensitivity to carbapenems. Unlike Klebsiella spp., E. coli was highly sensitive (92%) to first-line treatment (nitrofurantoin) for UTI. Moreover, trimethoprim/sulfamethoxazole showed higher sensitivity rates compared to other nations. CONCLUSION:  Despite Escherichia coli being the most often identified bacteria in our isolates Klebsiella spp. displayed higher resistance to the majority of tested antibiotics. Fortunately, trimethoprim/sulfamethoxazole significantly increased sensitivity, especially against E. coli. However, both species showed high rates of cephalosporin resistance. Moreover, It is important to promote Egypt's national action plan for antimicrobial resistance in collaboration with the World Health Organization, especially in the community to minimize the chance of bacterial resistance in the Egyptian community.

Harnessing function of EMT in cancer drug resistance: a metastasis regulator determines chemotherapy response.

Epithelial-mesenchymal transition (EMT) is a complicated molecular process that governs cellular shape and function changes throughout tissue development and embryogenesis. In addition, EMT contributes to the development and spread of tumors. Expanding and degrading the surrounding microenvironment, cells undergoing EMT move away from the main location. On the basis of the expression of fibroblast-specific protein-1 (FSP1), fibroblast growth factor (FGF), collagen, and smooth muscle actin (-SMA), the mesenchymal phenotype exhibited in fibroblasts is crucial for promoting EMT. While EMT is not entirely reliant on its regulators like ZEB1/2, Twist, and Snail proteins, investigation of upstream signaling (like EGF, TGF-ß, Wnt) is required to get a more thorough understanding of tumor EMT. Throughout numerous cancers, connections between tumor epithelial and fibroblast cells that influence tumor growth have been found. The significance of cellular crosstalk stems from the fact that these events affect therapeutic response and disease prognosis. This study examines how classical EMT signals emanating from various cancer cells interfere to tumor metastasis, treatment resistance, and tumor recurrence.

Antibiotic Resistances of Clostridioides difficile.

The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are a matter of concern for public health. Antibiotic resistance plays an important role in driving C. difficile epidemiology. Emergence of new types is often associated with the emergence of new resistances, and most of the epidemic C. difficile clinical isolates is currently resistant to multiple antibiotics. In particular, it is to worth to note the recent identification of strains with reduced susceptibility to the first-line antibiotics for CDI treatment and/or for relapsing infections. Antibiotic resistance in C. difficile has a multifactorial nature. Acquisition of genetic elements and alterations of the antibiotic target sites, as well as other factors, such as variations in the metabolic pathways or biofilm production, contribute to the survival of this pathogen in the presence of antibiotics. Different transfer mechanisms facilitate the spread of mobile elements among C. difficile strains and between C. difficile and other species. Furthermore, data indicate that both genetic elements and alterations in the antibiotic targets can be maintained in C. difficile regardless of the burden imposed on fitness, and therefore resistances may persist in C. difficile population in absence of antibiotic selective pressure.

Efflux-mediated Multidrug Resistance in Critical Gram-negative Bacteria and Natural Efflux Pump Inhibitors.

Multidrug Resistance mechanisms in microorganisms confer the slackness of the existing drugs, leading to added difficulty in treating infections. As a consequence, efficient novel drugs and innovative therapies to treat MDR infections are necessarily required. One of the primary contributors to the emergence of multidrug resistance in gram-negative bacteria has been identified as the efflux pumps. These transporter efflux pumps reduce the intracellular concentration of antibiotics and aid bacterial survival in suboptimal low antibiotic concentration environments that may cause treatment failure. The reversal of this resistance via inhibition of the efflux mechanism is a promising method for increasing the effectiveness of antibiotics against multidrug-resistant pathogens. Such EPI, in combination with antibiotics, can make it easier to reintroduce traditional antibiotics into clinical practice. This review mostly examines efflux-mediated multidrug resistance in critical gram-negative bacterial pathogens and EPI of plant origin that have been reported over previous decades.

Jugiones A-D: Antibacterial Xanthone-Anthraquinone Heterodimers from Australian Soil-Derived Penicillium shearii CMB-STF067.

The Australian roadside soil-derived fungus Penicillium shearii CMB-STF067 was prioritized for chemical investigation based on an SDA cultivation extract exhibiting both antibacterial properties and natural products with unprecedented molecular formulae (GNPS). Subsequent miniaturized 24-well plate cultivation profiling (MATRIX) identified red rice as optimal for the production of the target chemistry, with scaled-up cultivation, extraction and fractionation yielding four new xanthone-anthraquinone heterodimers, jugiones A-D (1-4), whose structures were assigned by detailed spectroscopic analysis and biosynthetic considerations. Of note, where 1-2 and 4 were active against the Gram-positive bacteria vancomycin-resistant Enterococcus faecalis (IC50 2.6-3.9 µM) and multiple-drug-resistant clinical isolates of Staphylococcus aureus (IC50 1.8-6.4 µM), and inactive against the Gram-negative bacteria Escherichia coli (IC50 > 30 µM), the closely related analog 3 exhibited no antibacterial properties (IC50 > 30 µM). Furthermore, where 1 was cytotoxic to human carcinoma (IC50 9.0-9.8 µM) and fungal (IC50 4.1 µM) cells, 2 and 4 displayed no such cytotoxicity (IC50 > 30 µM), revealing an informative structure activity relationship (SAR). We also extended the SAR study to other known compounds of this heterodimer class, which showed that the modification of ring G can reduce or eliminate the cytotoxicity while retaining the antibacterial activity.

Multifunctional nanoparticles inhibit tumor and tumor-associated macrophages for triple-negative breast cancer therapy.

HYPOTHESIS: Tumor-associated macrophages (TAM) are the mainstay of immunosuppressive cells in the tumor microenvironment, and elimination of M2-type macrophages (M2-TAM) is considered as a potential immunotherapy. However, the interaction of breast cancer cells with macrophages hinders the effectiveness of immunotherapy. In order to improve the efficacy of triple-negative breast cancer (TNBC) therapy, strategies that simultaneously target the elimination of M2-TAM and breast cancer cells may be able to achieve a better therapy. EXPERIMENTS: LyP-SA/AgNP@Dox multifunctional nanoparticles were synthesized by electrostatic adsorption. They were characterized by particle size, potential and spectroscopy. And the efficacy of multifunctional nanoparticles was evaluated in 4 T1 cell lines and M2 macrophages, including their cell uptake intracellular reactive oxygen species (ROS) production and the therapeutic effect. Furthermore, based on the orthotopic xenotransplantation model of triple negative breast cancer, the biological distribution, fluorescence imaging, biosafety evaluation and combined efficacy evaluation of the nanoplatform were performed. FINDINGS: We have successfully prepared LyP-SA/AgNP@Dox and characterized. Administering the nanosystem to 4 T1 tumor cells or M2 macrophages in culture induced accumulation of reactive oxygen species, destruction of mitochondria and apoptosis, and inhibited replication and transcription. Animal experiments demonstrated the nanoparticle had favorable targeting and antitumor activity. Our nanosystem may be useful for simultaneously inhibiting tumor and tumor-associated macrophages in breast cancer and, potentially, other malignancies.

From farm to fork: Spread of a multidrug resistant Salmonella Infantis clone encoding blaCTX-M-1 on pESI-like plasmids in Central Italy.

Salmonella enterica subsp. enterica serovar Infantis (S. Infantis) is one of the "top five Salmonella serovars" of clinical significance in the European Union (EU). Antimicrobial resistant and extended spectrum ß-lactamase (ESBL) AmpC-producing S. Infantis have been described in food production systems and human clinical samples in Italy. Recently, an increase of MDR S. Infantis carrying blaCTX-M genes involved in 3rd generation cephalosporin resistance was noticed in the EU, including Italy, mainly due to the spread of S. Infantis harboring a pESI-like plasmid. The aim of this study was to investigate the occurrence of the S. Infantis pESI-like plasmid among antibiotic resistant S. Infantis strains isolated at different points of the food chain, and to provide a phylogenetic analysis to gain further insight on their transmission pathways from 'farm to fork'. MDR S. Infantis strains (n. 35) isolated from 2016 to 2021 at different stages of the food chain (animals, food, food-related environments, and humans) were investigated with in depth molecular characterization using real-time PCR, S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and whole genome sequencing (WGS). Our study reported the occurrence of S. Infantis strains harboring pESI-like plasmids, carrying blaCTX-M-1 genes, in Central Italy, at different sampling points along the food chain. Results confirmed the presence of a plasmid with a molecular size around 224-310 kb, thus consistent with the pESI-like, in 97 % of the 35 samples investigated. Two variants of S. Infantis pESI-like IncFIB(K)_1_Kpn3 were detected, one associated with the European clone carrying blaCTX-M-1 (21 isolates) and the other associated with U.S. isolates carrying blaCTX-M-65 (2 isolates, pESI-like U.S. variant). The majority was resistant to 3rd generation cephalosporins but none of the strains tested positive for the carbapenemase encoding genes. A total of 118 virulence genes were identified in isolates harboring the pESI-like plasmid. cgMLST and SNP-based analysis revealed the presence of one main cluster, composed by strains isolated from the environment, animals, food and humans. The results of this investigation underline the importance of phylogenetic studies to monitor and understand pathogen and AMR spread in a One Health approach.

Boolean model of the gene regulatory network of Pseudomonas aeruginosa CCBH4851.

Introduction: Pseudomonas aeruginosa infections are one of the leading causes of death in immunocompromised patients with cystic fibrosis, diabetes, and lung diseases such as pneumonia and bronchiectasis. Furthermore, P. aeruginosa is one of the main multidrug-resistant bacteria responsible for nosocomial infections worldwide, including the multidrug-resistant CCBH4851 strain isolated in Brazil. Methods: One way to analyze their dynamic cellular behavior is through computational modeling of the gene regulatory network, which represents interactions between regulatory genes and their targets. For this purpose, Boolean models are important predictive tools to analyze these interactions. They are one of the most commonly used methods for studying complex dynamic behavior in biological systems. Results and discussion: Therefore, this research consists of building a Boolean model of the gene regulatory network of P. aeruginosa CCBH4851 using data from RNA-seq experiments. Next, the basins of attraction are estimated, as these regions and the transitions between them can help identify the attractors, representing long-term behavior in the Boolean model. The essential genes of the basins were associated with the phenotypes of the bacteria for two conditions: biofilm formation and polymyxin B treatment. Overall, the Boolean model and the analysis method proposed in this work can identify promising control actions and indicate potential therapeutic targets, which can help pinpoint new drugs and intervention strategies.

Evaluation of Antibiotic Resistance Mechanisms in Gram-Negative Bacteria.

Multidrug-resistant Gram-negative bacterial infections are exponentially increasing, posing one of the most urgent global healthcare and economic threats. Due to the lack of new therapies, the World Health Organization classified these bacterial species as priority pathogens in 2017, known as ESKAPE pathogens. This classification emphasizes the need for urgent research and development of novel targeted therapies. The majority of these priority pathogens are Gram-negative species, which possess a structurally dynamic cell envelope enabling them to resist multiple antibiotics, thereby leading to increased mortality rates. Despite 6 years having passed since the WHO classification, the progress in generating new treatment ideas has not been sufficient, and antimicrobial resistance continues to escalate, acting as a global ticking time bomb. Numerous efforts and strategies have been employed to combat the rising levels of antibiotic resistance by targeting specific resistance mechanisms. These mechanisms include antibiotic inactivating/modifying enzymes, outer membrane porin remodelling, enhanced efflux pump action, and alteration of antibiotic target sites. Some strategies have demonstrated clinical promise, such as the utilization of beta-lactamase inhibitors as antibiotic adjuvants, as well as recent advancements in machine-based learning employing artificial intelligence to facilitate the production of novel narrow-spectrum antibiotics. However, further research into an enhanced understanding of the precise mechanisms by which antibiotic resistance occurs, specifically tailored to each bacterial species, could pave the way for exploring narrow-spectrum targeted therapies. This review aims to introduce the key features of Gram-negative bacteria and their current treatment approaches, summarizing the major antibiotic resistance mechanisms with a focus on Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Additionally, potential directions for alternative therapies will be discussed, along with their relative modes of action, providing a future perspective and insight into the discipline of antimicrobial resistance.

Clinical presentations and microbiological analysis of cerebrospinal fluid samples in cases of suspected bacterial meningitis patients attending a 1600 bedded teaching hospital from 2019 to 2022: A retrospective study.

Background: Meningitis can be attributed to bacterial, fungal, or viral agents. In this study, we demonstrate the common bacterial agents causing meningitis along with their antibiotics susceptibility pattern in patients of all age groups. Material and Methods: This retrospective, observational study was carried out in the Department of Microbiology with cerebrospinal fluid (CSF) samples collected from November 2019 to May 2022. We collected 1986 nonrepeat CSF samples from clinically suspected patients of bacterial meningitis, and clinical information about the patients was extracted from the hospital information system. Results: Out of the 1986 CSF samples included in our study, 150 (7.55%) were found to be positive on bacterial culture. Most of our patients were in the age group of 0-20 years. Common clinical manifestations observed in our patients were: high-grade fever, 87 patients (58%); severe headache, 126 patients (84%); neck rigidity, 47 patients (31.3%); altered mental status, 76 patients (50.7%) and photophobia, 83 patients (55.3%). The most commonly isolated bacteria was Acinetobacter species (30%). The mean length of hospitalization (37.76 ± 25.30), the mean total cell count, high levels of protein (mg/dl) and low levels of glucose (mg/dl) of CSF were statistically significant in meningitis caused by multidrug-resistant bacteria. Conclusion: We recognized the spectrum of pathogens causing meningitis at our center along with the antibiotic resistance pattern to guide and facilitate early treatment by primary health care professionals and family medicine practitioners.

Pediatric multi-drug-resistant tuberculosis in Germany - diagnostic and therapeutic challenges of an "orphan disease".

Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). CONCLUSIONS: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. TRIAL REGISTRATION: Deutsches Register Klinischer Studien ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817 ), DRKS00023817, 2020-09-08. WHAT IS KNOWN: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). •Choice of treatment regimen and monitoring of side effects. WHAT IS NEW: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.