Burden and Management of Multi-Drug Resistant Organism Infections in Solid Organ Transplant Recipients Across the World: A Narrative Review.

Solid organ transplant (SOT) recipients are particularly susceptible to infections caused by multidrug-resistant organisms (MDRO) and are often the first to be affected by an emerging resistant pathogen. Unfortunately, their prevalence and impact on morbidity and mortality according to the type of graft is not systematically reported from high-as well as from low and middle-income countries (HIC and LMIC). Thus, epidemiology on MDRO in SOT recipients could be subjected to reporting bias. In addition, screening practices and diagnostic resources may vary between countries, as well as the availability of new drugs. In this review, we aimed to depict the burden of main Gram-negative MDRO in SOT patients across HIC and LMIC and to provide an overview of current diagnostic and therapeutic resources.

Development and validation of a novel prediction model for Carbapenem-resistant organism infection in a large-scale hospitalized patients.

Carbapenem-resistant organism (CRO) are defined as gram-negative bacteria. The lack of safe and effective antibiotics has led to an increase in incidence rate. The purpose of this study is to establish and determine a risk nomogram to predict CRO infection in hospitalized patients. Hospitalized patients' information were collected from the electronic medical record system of hospital between January 2019 and December 2022. Based on the inclusion and exclusion criteria, we identified 131390 inpatients who met the criteria for this study. For the training cohort, the area under the curves (AUC) for predicting the CRO infection was 0.935. For the validation cohort, the AUC for predicting the CRO infection was 0.937. We have developed the first novel nomogram to predict CRO infection in hospitalized patients, which is reliable and high-performance. The nomogram performs well among hospitalized patients and has good predictive ability.

A systematic review of the pharmacokinetics and pharmacodynamics of novel beta-lactams and beta-lactam with beta-lactamase inhibitor combinations for the treatment of pneumonia caused by carbapenem-resistant Gram-negative bacteria.

BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia. OBJECTIVES: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam. METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/ pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed, and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens. RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies. CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.

Optimizing Treatment for Carbapenem-Resistant Acinetobacter baumannii Complex Infections: A Review of Current Evidence.

Carbapenem-resistant Acinetobacter baumannii complex (CRAB) poses a significant global health challenge owing to its resistance to multiple antibiotics and limited treatment options. Polymyxin-based therapies have been widely used to treat CRAB infections; however, they are associated with high mortality rates and common adverse events such as nephrotoxicity. Recent developments include numerous observational studies and randomized clinical trials investigating antibiotic combinations, repurposing existing antibiotics, and the development of novel agents. Consequently, recommendations for treating CRAB are undergoing significant changes. The importance of colistin is decreasing, and the role of sulbactam, which exhibits direct antibacterial activity against A. baumannii complex, is being reassessed. High-dose ampicillin-sulbactam-based combination therapies, as well as combinations of sulbactam and durlobactam, which prevent the hydrolysis of sulbactam and binds to penicillin-binding protein 2, have shown promising results. This review introduces recent advancements in CRAB infection treatment based on clinical trial data, highlighting the need for optimized treatment protocols and comprehensive clinical trials to combat the evolving threat of CRAB effectively.

Incidence, identification and antibiotic resistance of Salmonella spp. in the well waters of Tadla Plain, Morocco.

Concerns about challenges with water availability in the Tadla Plain region of Morocco have grown as a result of groundwater contamination brought on by human activity, climate change, and insufficient groundwater management. The objective of the study is to measure the number of resistant bacteria in the groundwater of Beni Moussa and Beni Aamir, as well as to evaluate the level of water pollution in this area. 200 samples were therefore gathered from 43 wells over the course of four seasonal campaigns in 2017 and 2018. Additionally, the samples were examined to determine whether Salmonella species were present and if they were resistant to the 16 antibiotics that were tested. Salmonella spp. have been identified in 31 isolated strains in total, accounting for 18.02% of all isolated strains. Data on antibiotic resistance show that 58.1% of Salmonella spp. strains are multidrug-resistant (MDR); 38.7% of Salmonella strains are tolerant to at least six antibiotics, 19.4% to at least nine antibiotics, 9.7% to four to seven antibiotics, 6.5% to at least eleven antibiotics, and the remaining 3.2% to up to twelve antibiotics. A considerable level of resistance to cefepime (61.29%), imipenem (54.84%), ceftazidime (45.16%), ofloxacin (70.97%), and ertapenem (74.19%) was found in the data. Consequently, it is important to monitor and regulate the growth of MDR in order to prevent the groundwater's quality from declining.

Apramycin has high in vitro activity against Mycobacterium tuberculosis.

Introduction. Aminoglycoside antibiotics such as amikacin and kanamycin are important components in the treatment of Mycobacterium tuberculosis (Mtb) infection. However, more and more clinical strains are found to be aminoglycoside antibiotic-resistant. Apramycin is another kind of aminoglycoside antibiotic that is commonly used to treat infections in animals.Hypothesis. Apramycin may have in vitro activity against Mtb.Aim. This study aims to evaluate the efficacy of apramycin against Mtb in vitro and determine its epidemiological cut-off (ECOFF) value.Methodology. One hundred Mtb isolates, including 17 pansusceptible and 83 drug-resistant tuberculosis (DR-TB) strains, were analysed for apramycin resistance using the MIC assay.Results. Apramycin exhibited significant inhibitory activity against Mtb clinical isolates, with an MIC50 of 0.5 µg ml-1 and an MIC90 of 1 µg ml-1. We determined the tentative ECOFF value as 1 µg ml-1 for apramycin. The resistant rates of multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains were 12.12 % (4/33), 20.69 % (6/29) and 66.67 % (14/21), respectively. The rrs gene A1401G is associated with apramycin resistance, as well as the cross-resistance between apramycin and other aminoglycosides.Conclusion. Apramycin shows high in vitro activity against the Mtb clinical isolates, especially the MDR-TB clinical isolates. This encouraging discovery calls for more research on the functions of apramycin in vivo and as a possible antibiotic for the treatment of drug-resistant TB.

Risk factors for colonisation by Multidrug-Resistant bacteria in critical care units.

INTRODUCTION: Antimicrobial resistance is a major public health challenge recognised by the WHO as an urgent global healthcare concern. Patients in Intensive Care Units (ICUs) are particularly prone to colonisation and/or infection by multidrug-resistant organisms (MDROs). OBJECTIVES: Delineate the epidemiological characteristics and risk factors for MDROs colonisation in mixed ICUs and Resuscitation Units by focusing on initial and nosocomial colonisation. MATERIAL AND METHODS: A descriptive observational study with analytical elements. It uses the Zero-Resistance register from the Preventive Medicine Service of the Albacete General University Hospital (Spain) from April 2016 to December 2021. It identifies the risk factors for MDROs colonisation. RESULTS: Of 7,541 cases, 61.0 % with initial colonisation had risk factors for MDROs versus 34.0 % not colonised upon hospitalisation (p < 0.001). Significant risk factors for initial colonisation included hospitalisation for ≥ 5 days within the last 3 months, prior MDROs colonisation/infection and institutionalization. No significant risk factor differences were found for nosocomial colonisation. An association between longer ICU stays and nosocomial colonisation (p < 0.001) was noted. CONCLUSIONS: Significant risk factors for initial MDROs colonisation were hospitalisation for ≥ 5 days in the last 3 months, prior MDROs colonisation/infection and institutionalisation. Longer ICU stays increased the nosocomial colonisation risk. IMPLICATIONS FOR CLINICAL PRACTICE: This study underscores the importance to early identify and manage patients at risk for MDROs colonisation in ICUs. By recognising factors (i.e. previous hospitalisations, existing colonisation or infection, impact of prolonged ICU stay), healthcare providers can implement targeted strategies to mitigate the spread of MDROs; e.g. enhanced surveillance, stringent infection control measures and judicious antibiotics use. Our findings highlight the need for a comprehensive approach to manage antimicrobial resistance in critical care settings to ultimately improve patient outcomes and reduce MDROs burden in hospitals.

Bacterial Infections in Acute-on-chronic Liver Failure: Epidemiology, Diagnosis, Pathogenesis, and Management.

Acute-on-chronic liver failure (ACLF) is a distinct condition characterized by the abrupt exacerbation of pre-existing chronic liver disease, often leading to multi-organ failures and significant short-term mortalities. Bacterial infection is one of the most frequent triggers for ACLF and a common complication following its onset. The impact of bacterial infections on the clinical course and outcome of ACLF underscores their critical role in the pathogenesis of systemic inflammation and organ failures. In addition, the evolving epidemiology and increasing prevalence of multidrug-resistant bacteria in cirrhosis and ACLF highlight the importance of appropriate empirical antibiotic use, as well as accurate and prompt microbiological diagnosis. This review provided an update on recent advances in the epidemiology, diagnosis, pathogenesis, and management of bacterial infections in ACLF.

Pathogenomics analysis of high-risk clone ST147 multidrug-resistant Klebsiella pneumoniae isolated from a patient in Egypt.

BACKGROUND: The emergence of multi-drug-resistant Klebsiella pneumoniae (MDR-KP) represents a serious clinical health concern. Antibiotic resistance and virulence interactions play a significant role in the pathogenesis of K. pneumoniae infections. Therefore, tracking the clinical resistome and virulome through monitoring antibiotic resistance genes (ARG) and virulence factors in the bacterial genome using computational analysis tools is critical for predicting the next epidemic. METHODS: In the current study, one hundred extended spectrum ß-lactamase (ESBL)-producing clinical isolates were collected from Mansoura University Hospital, Egypt, in a six-month period from January to June 2022. One isolate was selected due to the high resistance phenotype, and the genetic features of MDR-KP recovered from hospitalized patient were investigated. Otherwise, the susceptibility to 25 antimicrobials was determined using the DL Antimicrobial Susceptibility Testing (AST) system. Whole genome sequencing (WGS) using Illumina NovaSeq 6000 was employed to provide genomic insights into K. pneumoniae WSF99 clinical isolate. RESULTS: The isolate K. pneumoniae WSF99 was phenotypically resistant to the antibiotics under investigation via antibiotic susceptibility testing. WGS analysis revealed that WSF99 total genome length was 5.7 Mb with an estimated 5,718 protein-coding genes and a G + C content of 56.98 mol%. Additionally, the allelic profile of the WSF99 isolate was allocated to the high-risk clone ST147. Furthermore, diverse antibiotic resistance genes were determined in the genome that explain the high-level resistance phenotypes. Several ß-lactamase genes, including blaCTX-M-15, blaTEM-1, blaTEM-12, blaSHV-11, blaSHV-67, and blaOXA-9, were detected in the WSF99 isolate. Moreover, a single carbapenemase gene, blaNDM-5, was predicted in the genome, positioned within a mobile cassette. In addition, other resistance genes were predicted in the genome including, aac(6')-Ib, aph(3')-VI, sul1, sul2, fosA, aadA, arr-2, qnrS1, tetA and tetC. Four plasmid replicons CoIRNAI, IncFIB(K), IncFIB(pQil), and IncR were predicted in the genome. The draft genome analysis revealed the occurrence of genetic mobile elements positioned around the ARGs, suggesting the ease of dissemination via horizontal gene transfer. CONCLUSIONS: This study reports a comprehensive pathogenomic analysis of MDR-KP isolated from a hospitalized patient. These findings could be relevant for future studies investigating the diversity of antimicrobial resistance and virulence in Egypt.

The Prevalence of Multidrug-Resistant Escherichia coli in Chennai and Whole Genome Sequence Analysis of Carbapenem-Resistant Escherichia coli ST410.

The current study evaluates antibiotic susceptibility and Extended Spectrum ß-Lactamase (ESBL) production of 557 Escherichia coli isolates obtained from clean catch midstream urine samples using VITEK 2 compact automated microbial identification system. Different classes of drugs were used to determine the Minimum inhibitory concentration (MIC). In our study, 50.45% of isolates were ESBL producers. There is a higher incidence of UTI in females (77.4%) than in males (22.6%). The isolates reveal a high percentage of resistance to antibiotics like nalidixic acid (89.59%), ampicillin (75.76%), ticarcillin (73.43%), cefalotin (67.68%), cefixime (65.17%), ciprofloxacin (58.35%) and ceftriaxone (56.37%). An increased susceptibility pattern was observed for the isolates against drug classes like fosfomycin (98.03%) and nitrofurantoin (91.02%). Among the isolates, 395 (70.91%) were classified as Multidrug-resistant organisms based on the resistance pattern observed against three or more classes of antibiotics. One of the isolates resistant to fluoroquinolones, penicillins, penicillins along with ß-lactamase inhibitor, aminoglycosides, third-generation cephalosporins and carbapenems was subjected to Whole genome sequencing (WGS). WGS data revealed the isolate to be a high-risk clone ST410, which contains antimicrobial-resistance genes (blaTEM-1B, blaCTX-M-15, blaNDM-5, aac(3)-IId, armA, gyrA(p.S83L), gyrA(p.D87N)) conferring resistance to ß-lactam, cephalosporins, carbapenem, aminoglycoside and fluoroquinolone class of antibiotics. The core genome MLST was carried out using BacWGSTdb to assess the global phylogenetic relationship of the genome sequence. Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-023-01125-1.

Real-life use of delamanid: results from the European post-authorisation safety study.

BACKGROUND: A post-authorisation safety study (PASS) on delamanid (DLM) was conducted as part of a post-approval commitment to the European Medicines Agency. The aim of this study was to evaluate the use of DLM in a real-life setting, its safety, and treatment outcomes in patients with multidrug-resistant TB (MDR-TB). METHODS: This was a prospective, multicentric, non-interventional study conducted in the European Union. MDR-TB Regimen selection and patient monitoring were conducted in accordance with existing medical practices. Data on the use of DLM, related adverse events, and treatment outcomes were collected for up to 30 months after the first DLM dose. Descriptive summary statistics were used for continuous and categorical variables. RESULTS: Out of 86 patients, one had extrapulmonary TB. Two-thirds of the patients were treated with DLM for more than 24 weeks. The most frequent adverse drug reaction to DLM was QT interval prolongation. Resistance to DLM was detected in one patient during treatment. The treatment success rate was 77%. CONCLUSION: No new safety concerns were revealed, including in patients treated with DLM for more than 24 weeks. QT interval prolongations were well managed and did not lead to any clinically significant cardiac effects. The treatment outcomes were in line with the WHO target for Europe.

CONTEXTE: Une étude de sécurité post-autorisation (PASS) sur le délamanide (DLM) a été menée dans le cadre d'un engagement post-approbation auprès de l'Agence européenne des médicaments. L'objectif de cette étude était d'évaluer l'utilisation du DLM dans un contexte réel, son innocuité et les résultats du traitement chez les patients atteints de TB multirésistante (MDR-TB). MÉTHODES: Il s'agissait d'une étude prospective, multicentrique et non interventionnelle menée dans l'Union européenne. La sélection du schéma thérapeutique de la MDR-TB et le suivi des patients ont été effectués conformément aux pratiques médicales existantes. Les données sur l'utilisation du DLM, les effets indésirables connexes et les résultats du traitement ont été recueillies jusqu'à 30 mois après la première dose de DLM. Des statistiques sommaires descriptives ont été utilisées pour les variables continues et catégorielles. RÉSULTATS: Sur 86 patients, un avait une TB extrapulmonaire. Les deux tiers des patients ont été traités avec du DLM pendant plus de 24 semaines. L'effet indésirable le plus fréquent du DLM était l'allongement de l'intervalle QT. Une résistance au DLM a été détectée chez un patient pendant le traitement. Le taux de réussite du traitement était de 77%. CONCLUSION: Aucun nouveau problème de sécurité n'a été révélé, y compris chez les patients traités par le DLM pendant plus de 24 semaines. Les allongements de l'intervalle QT ont été bien gérés et n'ont pas entraîné d'effets cardiaques cliniquement significatifs. Les résultats du traitement étaient conformes à l'objectif de l'OMS pour l'Europe.

Xpert MTB/XDR implementation in South Africa: cost outcomes of centralised vs. decentralised approaches.

INTRODUCTION: In South Africa, Xpert® MTB/RIF Ultra (Ultra) is the recommended diagnostic assay for TB with line-probe assays for first- (LPAfl) and second-line drugs (LPAsl) providing additional drug susceptibility testing (DST) for samples that were rifampicin-resistant (RR-TB). To guide implementation of the recently launched Xpert® MTB/XDR (MTB/XDR) assay, a cost-outcomes analysis was conducted comparing total costs for genotypic DST (gDST) for persons diagnosed with RR-TB considering three strategies: replacing LPAfl/LPAsl (centralised level) with MTB/XDR vs. Ultra reflex testing (decentralised level). Further, DST was performed using residual specimen following RR-TB diagnosis. METHODS: The total cost of gDST was determined for three strategies, considering loss to follow-up (LTFU), unsuccessful test rates, and specimen volume. RESULTS: For 2019, 9,415 persons were diagnosed with RR-TB. A 35% LTFU rate between RR-TB diagnosis and LPAfl/LPAsl-DST was estimated. Unsuccessful test rates of 37% and 23.3% were reported for LPAfl and LPAsl, respectively. The estimated total costs were $191,472 for the conventional strategy, $122,352 for the centralised strategy, and $126,838 for the decentralised strategy. However, it was found that sufficient residual volume for reflex MTB/XDR testing is a limiting factor at the decentralised level. CONCLUSION: Centralising the implementation of XDR testing, as compared to LPAfl/LPAsl, leads to significant cost savings.

INTRODUCTION: En Afrique du Sud, Xpert® MTB/RIF Ultra (Ultra) est le test de diagnostic recommandé pour la TB avec des tests par sonde de ligne pour les médicaments de première (LPAfl) et de deuxième ligne (LPAsl) fournissant des tests de sensibilité aux médicaments (DST) supplémentaires pour les échantillons résistants à la rifampicine (RR-TB). Afin d'orienter la mise en œuvre du test Xpert® MTB/XDR (MTB/XDR) récemment lancé, une analyse coûts-résultats a été réalisée en comparant les coûts totaux de la DST génotypique (gDST) pour les personnes diagnostiquées avec une RR-TB en tenant compte de trois stratégies : remplacer le LPAfl/LPAsl (niveau centralisé) par le MTB/XDR par rapport au test Ultra reflex (niveau décentralisé). De plus, l'heure d'été a été réalisée à l'aide d'un échantillon résiduel après le diagnostic de RR-TB. MÉTHODES: Le coût total de la gDST a été déterminé pour trois stratégies, en tenant compte de la perte de suivi (LTFU), des taux d'échec des tests et du volume d'échantillons. RÉSULTATS: En 2019, 9 415 personnes ont reçu un diagnostic de RR-TB. Un taux de LTFU de 35% entre le diagnostic de RR-TB et le diagnostic de LPAfl/LPAsl-DST a été estimé. Des taux d'échec de 37% et de 23,3% ont été signalés pour LPAfl et LPAsl, respectivement. Les coûts totaux estimés étaient de 191 472 dollars pour la stratégie conventionnelle, de 122 352 dollars pour la stratégie centralisée et de 126 838 dollars pour la stratégie décentralisée. Cependant, il a été constaté qu'un volume résiduel suffisant pour les tests réflexes MTB/XDR est un facteur limitant au niveau décentralisé. CONCLUSION: La centralisation de la mise en œuvre des tests XDR, par rapport à LPAfl/LPAsl, permet de réaliser d'importantes économies.

New generation fluoroquinolone sitafloxacin could potentially overcome the majority levofloxacin and moxifloxacin resistance in multidrug-resistant Mycobacterium tuberculosis.

Introduction. Pre-existing fluoroquinolones (FQs) resistance is a major threat in treating multidrug-resistant (MDR) tuberculosis. Sitafloxacin (Sfx) is a new broad-spectrum FQ.Hypothesis. Sfx is more active against drug-resistant Mycobacterium tuberculosis (Mtb) isolates.Aim. To determine whether there is cross-resistance between Sfx and ofloxacin (Ofx), levofloxacin (Lfx) and moxifloxacin (Mfx) in MDR Mtb.Methods. A total of 106 clinical Mtb isolates, including 23 pan-susceptible and 83 MDR strains, were analysed for Sfx, Lfx and Mfx resistance using MIC assay. The isolates were also subjected to whole-genome sequencing to analyse drug-resistant genes.Results. Sfx exhibited the most robust inhibition activity against Mtb clinical isolates, with a MIC50 of 0.0313 µg ml-1 and MIC90 of 0.125 µg ml-1, which was lower than that of Mfx (MIC50 = 0.0625 µg ml-1, MIC90 = 1 µg ml-1) and Lfx (MIC50 = 0.125 µg ml-1, MIC90 = 2 µg ml-1). We determined the tentative epidemiological cut-off values as 0.5 µg ml-1 for Sfx. Also, 8.43% (7/83), 43.37% (36/83), 42.17% (35/83) and 51.81% (43/83) MDR strains were resistant to Sfx, Mfx, Lfx and Ofx, respectively. Cross-resistance between Ofx, Lfx and Mfx was 80.43% (37/46). Only 15.22% (7/46) of the pre-existing FQs resistance isolates were resistant to Sfx. Among the 30 isolates with mutations in gyrA or gyrB, 5 (16.67%) were Sfx resistant. The combination of Sfx and rifampicin could exert partial synergistic effects, and no antagonism between Sfx and six clinically important anti-Mtb antibiotics was evident.Conclusion. Sfx exhibited superior activity against MDR isolates comparing to Lfx and Mfx, and could potentially overcome the majority pre-existing FQs resistance in Mtb strains.

Revolutionizing Antibacterial Strategies: Lipid Nanoparticles as Game-Changers in Combatting Multi-Drug-Resistant Infections.

To overcome the limits of traditional antibiotic medications, novel approaches are needed to combat the growing global epidemic of Multidrug-resistant (MDR) infections. As drug-resistant bacteria develop, the importance of innovative antimicrobial methods is underscored by antibiotic abuse and misuse. The global threat of MDR microorganisms is increasing, which calls for a coordinated global response. Lipid Nanoparticles (LNPs) possess several characteristics that make them attractive choices for managing multidrug resistant (MDR) infections, as well as potential delivery systems for antimicrobial agents. Thus, LNPs improve drug solubility, stability, and targeted delivery, thereby mitigating the drawbacks of conventional antibiotic therapy. Several characteristics of LNPs, which stop MDR bacteria from developing resistance mechanisms, serve as guidelines for precision medicine. It presents a powerful approach for combating the growing concern of MDR bacteria by increasing Anti-Microbial Peptides (AMPs) bioavailability and targeting distribution to bacterial cells. LNPs have the potential to redefine antibacterial treatments for MDR illnesses in the context of this study. Further, it discusses LNP use in larger applications, such as fighting Anti-Microbial Resistance (AMR) and MDR. A complete understanding of the unique features, many uses, and importance of collaborative efforts to overcome the global challenge of antibiotic resistance are also conveyed in the study.

Antibiotic adjuvants against multidrug-resistant Gram-negative bacteria: important component of future antimicrobial therapy.

The swift emergence and propagation of multidrug-resistant (MDR) bacterial pathogens constitute a tremendous global health crisis. Among these pathogens, the challenge of antibiotic resistance in Gram-negative bacteria is particularly pressing due to their distinctive structure, such as highly impermeable outer membrane, overexpressed efflux pumps, and mutations. Several strategies have been documented to combat MDR Gram-negative bacteria, including the structural modification of existing antibiotics, the development of antimicrobial adjuvants, and research on novel targets that MDR bacteria are sensitive to. Drugs functioning as adjuvants to mitigate resistance to existing antibiotics may play a pivotal role in future antibacterial therapy strategies. In this review, we provide a brief overview of potential antibacterial adjuvants against Gram-negative bacteria and their mechanisms of action, and discuss the application prospects and potential for bacterial resistance to these adjuvants, along with strategies to reduce this risk.

Clinical characteristics, risk factor analysis and peripheral blood cell changes for early warning of multidrug-resistant bacteria (MDR) infection in elderly patients.

OBJECTIVE: To explore peripheral blood indicators that may serve as early indicators for multidrug-resistant bacteria (MDR) infections in this demographic, with the goal of providing reference suggestions for the clinical prevention of MDR infections in elderly inpatients. METHODS: Clinical data of patients were divided into the MDR-infected group (n = 488) and the MDR-uninfected group (n = 233) according to the results of drug sensitivity experiments, risk factors for MDR infection, and peripheral blood indicators related to MDR infections were analyzed using univariate and multivariate logistic regression in conjunction with the construction of a Chi-squared automatic interaction detector (CHAID) decision tree model, considering statistical significance at p < .05. RESULTS: Of 721 patients, 488 multidrug-resistant strains were identified. Among them, with Staphylococcus spp. the most prevalent in 148 strains. The most frequent detection of MDR occurred in puncture fluid samples (167 cases). Univariate and multivariate regression analyses revealed that prolonged hospitalization, use of antibiotics preadmission, duration of antibiotics, invasive procedures or recent surgery, and coexisting lung disease were independent risk factors for contracting MDR. Subsequent analysis comparing the aforementioned influences with peripheral blood cells revealed associations between the number of antibiotic treatment days and increased neutrophil-to-lymphocyte ratio (NLR), platelet count-to-lymphocyte ratio (PLR), neutrophils, decreased lymphocytes, and increased eosinophils; preadmission antibiotic use correlated with increased PLR, NLR, neutrophils, and decreased lymphocytes; and invasive manipulation or surgery correlated with increased PLR and NLR. CONCLUSIONS: Elevated NLR, PLR, neutrophils, lowered lymphocytes, and eosinophils may serve as early indicators of MDR infections in elderly hospitalized patients.

maxPIE: An innovative high throughput approach to enhance pathogen inactivation practices.

Effective pathogen inactivation is highly desired in public health but limited by existing methods each capable of assessing pathogen inactivation effectiveness (PIE) only in a specific condition. We therefore developed a novel method maxPIE designed to identify maximal PIEs across inactivation conditions by leveraging the power of massive array technologies. maxPIE implements a three-step algorithm to quickly identify maximal PIEs of inactivation treatments: (1) dilute pathogens into different initial titers each stored in an array well, (2) submit one sorted array to one treatment, (3) scan the treated array to find the maximum. maxPIE outperformed the conventional methods in (a) inactivating S. aureus using ultraviolet light of different wavelengths with different durations; (b) antibiotic treatment of S. aureus, E. coli, and multidrug-resistant E. coli; (c) inactivating S. aureus in plasma using ultraviolet light in different wavelengths with and without riboflavin. maxPIE was easy to understand and interpret and was robust in situations where conventional PIE methods would suffer. Hence, maxPIE can serve as an innovative and high throughput approach that can be widely used to enhance pathogen inactivation practices.

Incidence of drug-resistant pathogens in community-acquired pneumonia at a safety net hospital.

The 2019 Infectious Diseases Society of America guideline for the management of community-acquired pneumonia (CAP) emphasizes the need for clinician to understand local epidemiological data to guide selection of appropriate treatment. Currently, the local distribution of causative pathogens and their associated resistance patterns in CAP is unknown. A retrospective observational study was performed of patients admitted to an 870-bed safety net hospital between March 2016 and March 2021 who received a diagnosis of CAP or healthcare-associated pneumonia within the first 48 hours of admission. The primary outcome was the incidence of CAP caused by methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa (PsA) as determined by comparing the number of satisfactory sputum cultures or blood cultures with these drug-resistant organisms to the total number of reviewed patients. Secondary outcomes studied included risk factors associated with CAP caused by drug-resistant organisms, utilization of broad-spectrum antibiotics, appropriate antibiotic de-escalation within 72 hours, and treatment duration. In this 220-patient cohort, MRSA or PsA was isolated from three sputum cultures and no blood cultures. The local incidence of drug-resistant pathogens among the analyzed sample of CAP patients was 1.4% (n = 3/220). The overall incidence of CAP caused by MRSA or PsA among admitted patients is low at our safety-net county hospital. Future research is needed to identify local risk factors associated with the development of CAP caused by drug-resistant pathogens.IMPORTANCEThis study investigates the incidence of drug-resistant pathogens including methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa among community-acquired pneumonia (CAP) patients at a safety net hospital. Understanding local bacteria resistance patterns when treating CAP is essential and supported by evidence-based guidelines. Our findings empower other clinicians to investigate resistance patterns at their own institutions and identify methods to improve antibiotic use. This has the potential to reduce the unnecessary use of broad-spectrum antibiotic agents and combat the development of antibiotic resistance.

Reactive Oxygen Species (ROS)-Mediated Antibacterial Oxidative Therapies: Available Methods to Generate ROS and a Novel Option Proposal.

The increasing emergence of multidrug-resistant (MDR) pathogens causes difficult-to-treat infections with long-term hospitalizations and a high incidence of death, thus representing a global public health problem. To manage MDR bacteria bugs, new antimicrobial strategies are necessary, and their introduction in practice is a daily challenge for scientists in the field. An extensively studied approach to treating MDR infections consists of inducing high levels of reactive oxygen species (ROS) by several methods. Although further clinical investigations are mandatory on the possible toxic effects of ROS on mammalian cells, clinical evaluations are extremely promising, and their topical use to treat infected wounds and ulcers, also in presence of biofilm, is already clinically approved. Biochar (BC) is a carbonaceous material obtained by pyrolysis of different vegetable and animal biomass feedstocks at 200-1000 °C in the limited presence of O2. Recently, it has been demonstrated that BC's capability of removing organic and inorganic xenobiotics is mainly due to the presence of persistent free radicals (PFRs), which can activate oxygen, H2O2, or persulfate in the presence or absence of transition metals by electron transfer, thus generating ROS, which in turn degrade pollutants by advanced oxidation processes (AOPs). In this context, the antibacterial effects of BC-containing PFRs have been demonstrated by some authors against Escherichia coli and Staphylococcus aureus, thus giving birth to our idea of the possible use of BC-derived PFRs as a novel method capable of inducing ROS generation for antimicrobial oxidative therapy. Here, the general aspects concerning ROS physiological and pathological production and regulation and the mechanism by which they could exert antimicrobial effects have been reviewed. The methods currently adopted to induce ROS production for antimicrobial oxidative therapy have been discussed. Finally, for the first time, BC-related PFRs have been proposed as a new source of ROS for antimicrobial therapy via AOPs.