Multidrug-resistant Pseudomonas Aeruginosa Research Articles

Hyaluronidase-Responsive Bactericidal Cryogel for Promoting Healing of Infected Wounds: Inflammatory Attenuation, ROS Scavenging, and Immune Regulation.

Wounds infected with multidrug-resistant (MDR) bacteria are increasingly threatening public health and challenging clinical treatments because of intensive bacterial colonization, excessive inflammatory responses, and superabundant oxidative stress. To overcome this malignant burden and promote wound healing, a multifunctional cryogel (HA/TA2/KR2) composed of hyaluronic acid (HA), tannic acid (TA), and KR-12 peptides is designed. The cryogel exhibited excellent shape-memory properties, strong absorption performance, and hemostatic capacity. In vitro experiments demonstrated that KR-12 in the cryogel can be responsively released by stimulation with hyaluronidase produced by bacteria, reaching robust antibacterial activity against Escherichia coli (E. coli), MDR Pseudomonas aeruginosa (MDR-PA), and methicillin-resistant Staphylococcus aureus (MRSA)by disrupting bacterial cell membranes. Furthermore, the synergetic effect of KR-12 and TA can efficiently scavenge ROS and decrease expression of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α & interleukin (IL)-6), as well as modulate the macrophage phenotype toward the M2 type. In vivo animal tests indicated that the cryogel can effectively destroy bacteria in the wound and promote healing process via accelerating angiogenesis and re-epithelialization. Proteomic analysis revealed the underlying mechanism by which the cryogel mainly reshaped the infected wound microenvironment by inhibiting the Nuclear factor kappa B (NF-κB) signaling pathway and activating the Janus kinase-Signal transducer and activator of transcription (JAK-STAT6) signaling pathway. Therefore, the HA/TA2/KR2 cryogel is a promising dressing candidate for MDR bacteria-infected wound healing.

Multi-comparted microgels delivering human derived probiotics and deferoxamine for multidrug-resistant infection and healing

Infection and vascular dysfunction are two major reasons for delayed wound healing, especially in the scenario of multidrug-resistant bacterial has been a challenge for antibiotics usage. Probiotics are effective in fighting pathogens, while avoiding the destruction of skin microbiome. However, the viability of probiotics is a major obstacle in clinical application. As a non-protein proangiogenic drug, deferoxamine (DFO) has significant advantages over traditional growth factors in terms of cost, storage and transportation conditions, and stability. However, there is still a problem of short half-life that requires reliable drug delivery carriers to maximize its effect. Here, we developed multiple-chambered microgels using electrospray and microfluidics. Lactobacillus fermentum (LF) and DFO, respectively, for the management of multidrug-resistant Pseudomonas aeruginosa (MPA) and promotion of wound healing. We first tested five probiotics isolated from healthy people and found LF inhibiting the growth of MPA by lowering local pH and antimicrobial substances. The multi-chambered microgels effectively inhibited MPA by delivering probiotics, they can also protect probiotics from antibiotics. DFO promoted the angiogenesis of human umbilical venous endothelial cells. The microgel system had good biocompatibility and hemocompatibility. In a MPA infected wound, the microgel system effectively alleviated wound infection by 87.44%, improved angiogenesis by 29.32% and accelerated wound healing. This work suggests that multi-compartmented microgels loaded with probiotics and deferoxamine have great potential in wounds with multidrug-resistant bacteria.

Amine Basicity of Quinoline ATP Synthase Inhibitors Drives Antibacterial Activity against Pseudomonas aeruginosa.

Pseudomonas aeruginosa (PA), a Gram-negative pathogen, is a common cause of nosocomial infections, especially in immunocompromised and cystic fibrosis patients. PA is intrinsically resistant to many currently prescribed antibiotics due to its tightly packed, anionic lipopolysaccharide outer membrane, efflux pumps, and ability to form biofilms. PA can acquire additional resistance through mutation and horizontal gene transfer. PA ATP synthase is an attractive target for antibiotic development because it is essential for cell survival even under fermentation conditions. Previously, we developed two lead quinoline compounds that were capable of selectively inhibiting PA ATP synthase and acting as antibacterial agents against multidrug-resistant PA. Herein we conduct a structure-activity relationship analysis of the lead compounds through the synthesis and evaluation of 18 quinoline derivatives. These compounds function as new antibacterial agents while providing insight into the balance of physical properties needed to promote cellular entry while maintaining PA ATP synthase inhibition.

Is Short-Course Antibiotic Therapy Suitable for Pseudomonas Aeruginosa Bloodstream Infections in Onco-Hematology Patients with Febrile Neutropenia? Results of a Multi-Institutional Analysis

Background. Several studies have suggested that short-course antibiotic therapy does not increase infection recurrence or mortality in immunocompetent patients. While similar studies in patients with hematological malignancies were rare. Methods. This cohort included onco-hematology patients with Pseudomonas aeruginosa (PA) bloodstream infections (BSI). These patients had undergone chemotherapy or hematopoietic stem cell transplantation (HSCT) and experienced febrile neutropenia. Inverse probability of treatment weighting was used to balance the confounding factors. Results. 434 patients met eligibility criteria (short-course, 7-11 days, n=229; prolonged therapy, 12-21 days, n=205). In the weighted cohort, after multivariate analysis, the recurrent PA infection at any site or mortality within 30 days of completing therapy occurred in 8 (3.9%) patients in the short-course group and in 10 (4.9%) in the prolonged-course group ( p = 0.926), the recurrent infection within 90 days occurred in 20 (9.8%) patients in the short-course group and in 13 (6.3%) patients in the prolonged-course group ( p =0.276), and the recurrent fever within 7 days occurred in 17 (8.3%) patients in the short-course group and in 15 (7.4%) in the prolonged-course group ( p = 0.980). While multidrug-resistant PA, relapsed/refractory hematological malignancies and perianal mucositis were the key determinants of infection recurrence/mortality other than the short course of antibiotic treatment (p<0.05 for all). On average, patients who received short-course antibiotic therapy spent 3.3 fewer days in the hospital ( p<0.001). Conclusions. We found that onco-hematology patients with PA BSI who received approximately 8 days of antibiotics had similar clinical outcomes to those who received a prolonged-course therapy, with the potential added benefit of earlier hospital discharge.

In vitro, molecular docking and in silico/ADMET study of cuminaldehyde against Candida, MDR bacteria and human colorectal and cervical carcinoma

Many people have recently been diagnosed with cancer and other multi-resistant infections. These illnesses are now considered among the leading causes of mortality worldwide. In addition, infectious organisms such as microbes and viruses are responsible for around 2 million new cancer cases. Cuminaldehyde (CUM), the main bioactive component of Cuminum cyminum, also called 4-isopropylbenzaldehyde, is the most prevalent in C. cyminum seeds. Extensive research has been conducted on natural compounds in general; however, the investigation of CUM, a unique component of cumin oil, is still in its preliminary phases. Therefore, this study aimed to screen CUM for possible anticancer (colon cancer HCT-116 and cervical cancer HeLa cells), antibacterial, and antifungal activities. The number of DAPI-stained cells was lower in the CUM treatment group compared to the control group. The results showed that the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for Gram-negative bacteria, i.e., Escherichia coli ATCC 25922, multidrug-resistant Pseudomonas aeruginosa (MDR-PA), and multidrug-resistant Acinetobacter baumannii (MDR-A. baumannii), were 6.25/12.5, 12.5/25, and 6.25/12.5 mM, respectively, while the MICs for Gram-positive bacteria Staphylococcus aureus ATCC 25923, and methicillin-resistant S. aureus (MRSA) were 25/50 and 6.25/12.5 mM, respectively. However, MIC and minimum fungicidal concentration (MFC) values against Candida albicans ATCC 14053 were 6.25 and 12.5 mM, respectively. In addition, the anticancer and antibacterial efficacy of CUM has also been analyzed by an in silico molecular docking study, which demonstrated noteworthy binding energy with the sterol 14-alpha demethylase (-5.53 kcal/mol), followed by cyclin-dependent kinase 2 (-5.35 kcal/mol), poly-beta-1,6-N-acetyl-d-glucosamine synthase (-4.90 kcal/mol), GDP-mannose dehydrogenase (-4.35 kcal/mol), and intact bacterial peptidoglycan (-2.65 kcal/mol). Our predicted results need to be further validated through in vitro and in vivo studies before they can be applied to the development of therapeutic compound against cancer and infectious diseases, two of humanity's gravest health issues.

Экспериментальное лечение эндофтальмита, вызванного синегнойной инфекцией с множественной лекарственной устойчивостью, с помощью конъюгатов на основе наночастиц

Relevance. Pseudomonas aeruginosa (PA) is an extremely dangerous microorganism whose elimination from the host organism is very difficult due to the presence of multidrug resistance (MDR) factors in PA. The outcome of endophthalmitis (EP) mediated by PA in 50% of cases will be evisceration of the eyeball, and more than 95% of patients receive visual acuity – hand movements near the face and below. In this regard, studies of quantum dots (QDs), which have shown high anti-infective activity in laboratory conditions, are of particular relevance. Purpose. Evaluation of the effectiveness of the treatment of EP caused by PA with MDR using QDs-based conjugates in the experiment. Material and methods. The object of the study was laboratory rabbits of the Chinchilla breed (n=27), male, aged from 3 to 3.5 months. As an EP inducer, all laboratory animals underwent intravitreal injection (IVI) of a multidrug-resistant PA strain in a volume of 0.05 ml in the right eye. QDs of the Ag (10%):InP/ZnS MPA type were taken as the basis for the creation of conjugates with antibiotics (AB). After the manifestation of EP, the animals underwent intravitreal injections (IVI) of dosage forms in accordance with the distribution into the following subgroups, 3 rabbits in each. Subgroups No. 1–3 – IVI 2.25 mg/0.1 ml Ceftazidime. Subgroups No. 4–6 – IVI 0.1 ml of QDs solution at concentrations of 10%, 0.1%, 0.01%, respectively. Subgroups No. 7–9 – IVI solution of QDs 0.05 ml (at concentrations of 10%, 0.1%, 0.01%, respectively) in combination with 2.25 mg/0.05 ml of Ceftazidime (conjugates). Efficacy was evaluated based on clinical parameters: the dynamics of hypopyon resorption, the presence of inflammatory cells in the anterior chamber, the dynamics of regression of pathological suspension in the vitreal cavity, the dynamics of pathological neovascularization of the iris, the dynamics of the cornea. Results. Rabbits from subgroups No. 1–3 (1st group) were characterized by the least dynamics in relation to the regression of symptoms during the 7-day observation period. Rabbits from subgroups No. 4–6 (2nd group) were characterized by moderate positive dynamics in relation to the regression of symptoms. Rabbits from subgroups No. 7–9 (3rd group) were characterized by the best positive dynamics in relation to the regression of symptoms. Conclusion. It was possible to prove the effectiveness of the treatment of experimental antibiotic-resistant EP caused by a strain of PA with MDR by means of QDs Ag(10%):InP/ZnS MPA at concentrations of 10%, 0.1% and 0.01%, especially in combination with 2.25 mg/0.05 ml of Ceftazidime in as a conjugate. Based on the results obtained, it can be assumed that active research and the use of QDs as conjugates with modern ABs can solve the overall problem of combating MDR strains. Key words: Pseudomonas Aeruginosa, quantum dots, endophthalmitis, multidrug resistance, antibiotic resistance, conjugates

Determination of Multidrug Resistance and Extended Drug Resistance Pattern of Pseudomonas aeruginosa in Clinical Isolates of Tertiary Care Hospital Lahore

Background: 
 Pseudomonas aeruginosa (PA) is a major public health community-acquired threat around the globe due to the growing rate of antimicrobial resistance. It is one of the most common trending causes of nosocomial infections. 
 Objective: 
 The current study aimed to check the rate of multidrug-resistant (MDR) and extended drug-resistant (XDR) PA and to analyze the invitro activity of different antimicrobial agents against clinically isolated bacterial samples. Molecular Detection and amplification of L lipoprotein (OprL gene) were also done to determine the frequency and species of different strains of Pseudomonas aeruginosa (PA2192, C3719, PA01, PA14 and PACS2).
 Method:
 This cross-sectional study was conducted at at the Department of Pathology, King Edward Medical University/ Mayo Hospital Lahore. Total 140 patients were included in the study. Biochemical characterization, molecular identification, antimicrobial susceptibility profiling and DNA sequencing of the desired gene were done to confirm different strains' identification. 
 Results:
 MDR and XDR Pseudomonas aeruginosa infection are more common among males 81(57.5%) and high among the 31-45 age group, i.e., 55 (39.3%). After antibiotic susceptibility testing, 60% of strains were found to be MDR PA, while 40% were categorized as XDR PA. Doripenem showed the highest sensitivity, 93 (66.4%) among all carbapenems. Polymyxin B showed the highest activity against Pseudomonas aeruginosa multi and extensively drug-resistant strains, i.e., 108 (77.1%). 
 Conclusion:
 The present study suggests that doripenem can be the only active agent for combating infections, and the Carbapenem drug appears effective against highly resistant strains of Pseudomonas aeruginosa.

Multifunctional Properties of BMAP-18 and Its Aliphatic Analog against Drug-Resistant Bacteria.

BMAP-18, derived from the N-terminal region of bovine myeloid antimicrobial peptide BMAP-27, demonstrates potent antimicrobial activity without cytotoxicity. This study aimed to compare the antibacterial, antibiofilm, and anti-inflammatory properties of BMAP-18, rich in aromatic phenylalanine residues, with its aliphatic analog, BMAP-18-FL. Both aromatic BMAP-18 and aliphatic BMAP-18-FL exhibited equally potent antimicrobial activities against Gram-positive and Gram-negative bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Mechanistic investigations employing SYTOX green uptake, DNA binding, and FACScan analysis revealed that both peptides acted by inducing membrane permeabilization and subsequent intracellular targeting. Moreover, both BMAP-18 and BMAP-18-FL effectively prevented biofilm formation and eradicated existing biofilms of MRSA and MDRPA. Notably, BMAP-18-FL displayed a superior anti-inflammatory activity compared to BMAP-18, significantly reducing the expression levels of pro-inflammatory cytokines in lipopolysaccharide-stimulated macrophages. This study emphasizes the similarities and differences in the antimicrobial, antibiofilm, and anti-inflammatory properties between aromatic BMAP-18 and aliphatic BMAP-18-FL, providing valuable insights for the development of multifunctional antimicrobial peptides against drug-resistant bacteria.

Antibacterial Activities of Fungal Endophytes from Philippine Endemic Plant Dillenia philippinensis

Fungal endophytes represent a group of microorganisms that establish symbiotic associations with plants and hold significant ecological importance. Their ability to produce a diverse array of biologically active secondary metabolites has garnered considerable interest in the search for novel drug leads. In this study a total of 33 fungal endophytes were isolated from leaf specimens of the Philippine endemic tree Dillenia philippinensis (Rolfe). The morphological characterization of the fungal isolates revealed their taxonomic affiliation with the following eight genera: Alternaria sp., Aspergillus sp., Geotrichum sp., Guignardia sp., Nigrospora sp., Paecilomyces sp., Pestalotiopsis sp., and Phialophora sp. A representative set of 22 fungal endophyte isolates was selected from the pool of isolates and subjected to large-scale cultivation, followed by extraction of their bioactive metabolites through liquid-submerged fermentation. The resulting crude extracts were evaluated for their inhibitory potential against two Gram-positive bacteria, namely Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA); and two Gram-negative bacteria, namely Escherichia coli and Multi-drug resistant Pseudomonas aeruginosa (MRPA), using the disc diffusion assay. The results indicate that the crude extracts obtained from endophytic fungi colonizing D. philippinensis represent a promising source of bioactive metabolites that exhibit noteworthy inhibitory activity against S. aureus, E. coli, and MRSA, with an effective concentration of 10 mg/mL. This study demonstrates that the fungal endophytes associated with Dillenia philippinensis foliage represent a rich source of bioactive metabolites with significant inhibitory activity against Gram-positive and Gram-negative bacteria. These lead to exploring the potential of these fungal endophytes as a viable source of novel therapeutics.

Evaluation of deoxythymidine-based cationic amphiphiles as antimicrobial, antibiofilm, and anti-inflammatory agents

ObjectivesWe recently designed a series of cationic deoxythymidine-based amphiphiles that mimic the cationic amphipathic structure of antimicrobial peptides (AMPs). Among these amphiphiles, ADG-2e and ADL-3e displayed the highest selectivity against bacterial cells. In this study, ADG-2e and ADL-3e were evaluated for their potential as novel classes of antimicrobial, antibiofilm, and anti-inflammatory agents. MethodsMinimum inhibitory concentrations of ADG-2e and ADL-3e against bacteria were determined using the broth microdilution method. Proteolytic resistance against pepsin, trypsin, α-chymotrypsin, and proteinase K was determined by radial diffusion and HPLC analysis. Biofilm activity was investigated using the broth microdilution and confocal microscopy. The antimicrobial mechanism was investigated by membrane depolarization, cell membrane integrity analysis, scanning electron microscopy (SEM), genomic DNA influence and genomic DNA binding assay. Synergistic activity was evaluated using checkerboard method. Anti-inflammatory activity was investigated using ELISA and RT-PCR. ResultsADG-2e and ADL-3e showed good resistance to physiological salts and human serum, and a low incidence of drug resistance. Moreover, they exhibit proteolytic resistance against pepsin, trypsin, α-chymotrypsin, and proteinase K. ADG-2e and ADL-3e were found to kill bacteria by an intracellular target mechanism and bacterial cell membrane-disrupting mechanism, respectively. Furthermore, ADG-2e and ADL-3e showed effective synergistic effects when combined with several conventional antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Importantly, ADG-2e and ADL-3e not only suppressed MDRPA biofilm formation but also effectively eradicated mature MDRPA biofilms. Furthermore, ADG-2e and ADL-3e drastically decreased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gene expression and protein secretion in lipopolysaccharide (LPS)-stimulated macrophages, implying potent anti-inflammatory activity in LPS-induced inflammation. ConclusionOur findings suggest that ADG-2e and ADL-3e could be further developed as novel antimicrobial, antibiofilm, and anti-inflammatory agents to combat bacterial infections.

Assessment of mortality-related risk factors and effective antimicrobial regimens for treatment of bloodstream infections caused by carbapenem-resistant Pseudomonas aeruginosa in patients with hematological diseases.

Infections caused by carbapenem-resistant Pseudomonas aeruginosa (CRPA) are related to higher mortality. The objective of this study was to explore clinical outcomes of CRPA bacteremia, identify risk factors and also, compare the efficacy of traditional and novel antibiotic regimens. This retrospective study was conducted at a blood diseases hospital in China. The study included hematological patients who were diagnosed with CRPA bacteremia between January 2014 and August 2022. The primary endpoint was all-cause mortality at day 30. Secondary endpoints included 7-day and 30-day clinical cure. Multivariable Cox regression analysis was employed to identify mortality-related risk factors. 100 patients infected with CRPA bacteremia were included and 29 patients accepted allogenic-hematopoietic stem cell transplantation. 24 received ceftazidime-avibactam (CAZ-AVI)-based therapy and 76 received other traditional antibiotics. 30-day mortality was 21.0%. Multivariable cox regression analysis showed neutropenia >7 days after bloodstream infections (BSI) (P=0.030, HR: 4.068, 95%CI: 1.146~14.434), higher Pitt bacteremia score (P<0.001, HR:1.824, 95%CI: 1.322~2.517), higher Charlson comorbidity index (P=0.01, HR: 1.613, 95%CI: 1.124~2.315) and bacteremia due to multidrug-resistant Pseudomonas aeruginosa (MDR-PA) (P=0.024, HR:3.086, 95%CI: 1.163~8.197) were identified as independent risk factors of 30-day mortality. After controlling for confounders, an additional multivariable cox regression analysis revealed definitive regimens containing CAZ-AVI were associated with lower mortality in CRPA bacteremia (P=0.016, HR: 0.150, 95%CI: 0.032~0.702), as well as in MDR-PA bacteremia (P=0.019, HR: 0.119, 95%CI: 0.020~0.709). For patients with hematological diseases and CRPA bacteremia, 30-day mortality rate was 21.0% (21/100). Neutropenia >7 days after BSI, higher Pitt bacteremia score, higher Charlson comorbidity index and bacteremia due to MDR-PA increased 30-day mortality. CAZ-AVI-based regimens were effective alternatives for bacteremia due to CRPA or MDR-PA.

Activity of Delafloxacin and Comparator Fluoroquinolones against Multidrug-Resistant Pseudomonas aeruginosa in an In Vitro Cystic Fibrosis Sputum Model.

Delafloxacin (DLX) is a recently approved fluoroquinolone with broad activity against common cystic fibrosis (CF) pathogens, including multidrug-resistant Pseudomonas aeruginosa (MDR-Psa). Delafloxacin has been previously shown to have excellent lung and biofilm penetration and enhanced activity at lower pH environments, such as those that would be observed in the CF lung. We analyzed six Psa strains isolated from CF sputum and compared DLX to ciprofloxacin (CPX) and levofloxacin (LVX). Minimum inhibitory concentrations (MICs) were determined for DLX using standard culture media (pH 7.3) and artificial sputum media (ASM), a physiologic media recapitulating the CF lung microenvironment (pH 6.9). Delafloxacin activity was further compared to CPX and LVX in an in vitro CF sputum time-kill model at physiologically relevant drug concentrations (Cmax, Cmed, Cmin). Delafloxacin exhibited 2- to 4-fold MIC reductions in ASM, which corresponded with significant improvements in bacterial killing in the CF sputum time-kill model between DLX and LVX at Cmed (p = 0.033) and Cmin (p = 0.004). Compared to CPX, DLX demonstrated significantly greater killing at Cmin (p = 0.024). Overall, DLX demonstrated favorable in vitro activity compared to alternative fluoroquinolones against MDR-Psa. Delafloxacin may be considered as an option against MDR-Psa pulmonary infections in CF.

NIR-II Responsive Nanohybrids Incorporating Thermosensitive Hydrogel as Sprayable Dressing for Multidrug-Resistant-Bacteria Infected Wound Management.

Developing an effective dressing against bacterial infection and synchronously addressing wound complications, such as bleeding, long-term inflammation, and reinfection, are highly desirable in clinical practice. In this work, a second near-infrared (NIR-II) responsive nanohybrid consisting of imipenem encapsulated liposome with gold-shell and lipopolysaccharide (LPS)-targeting aptamer, namely ILGA, is constructed for bacteria elimination. Benefiting from the delicate structure, ILGA exhibits strong affinity and a reliable photothermal/antibiotic therapeutic effect toward multidrug-resistant Pseudomonas aeruginosa (MDR-PA). Furthermore, by incorporating ILGA with a thermosensitive hydrogel poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA), a sprayable dressing ILGA@Gel was prepared, which enables a quick on-demand gelation (10 s) for wound hemostasis and offers excellent photothermal/antibiotic efficacy to sterilize the infected wound. Additionally, ILGA@Gel provides satisfactory wound-healing environments by reeducating wound-associated macrophages for inflammation alleviation and forming a gel layer to block exogenous bacterial reinfection. This biomimetic hydrogel reveals excellent bacteria eradication and wound recovery effectiveness, demonstrating its promising potential for managing complicated infected wounds.

Neutropenic Sepsis and Challenges to Combat

Neutropenic sepsis (NS) is a common and predictable complication of bone marrow disorders and cytotoxic chemotherapy. After intensive chemotherapy, the incidence of NS is about 70–100% during the neutropenic phase. Patients with neutropenia are vulnerable to invasive infections, which can be rapidly overwhelming, causing septic shock and death. The epidemiology of sepsis in industrialized countries is mainly influenced by the age of the population and the increasing prevalence of comorbidities, such as chronic organ dysfunctions, non-cancer-related immunosuppressive diseases, or cancer itself. Patients with cancer are at more than 10 times higher risk for sepsis than the general population, with some variability according to the cancer types. There is frequent frustration among physicians caring for patients with neutropenic sepsis. Infections are a frequent complication in leukopenic patients, affecting an estimated 24% of patients after chemotherapy for hematologic diseases or solid organ tumors. Bloodstream infections (BSIs) are the most frequent infection in febrile neutropenic, onco-hematological patients, with incidence rates spanning from 10% to 38%. Septic shock is the most severe clinical presentation form of such infections. This is becoming a cause for growing concern due to several factors. Rates of Gram-negative bacilli (GNB) in oncohematological patients are progressively increasing. It is shown that ~50% of bacteremia in cancer patients was caused by GNB, among which almost 14% were MDR GNB. This could impact a greater percentage of patients presenting with septic shock. The widespread emergence and dissemination of multidrug-resistant Gram-negative bacilli, which are a common cause of infection and sepsis in patients with cancer, is of great concern. Several investigators have reported high rates of bacteremia due to extended-spectrum â-lactamase (ESBL)-producing Enterobacterales, MDR Pseudomonas aeruginosa (MDR-PA), and carbapenem-resistant Enterobacterales. Additionally, empirical antibiotic therapy is challenging in the era of emerging multidrug-resistant (MDR) GNB. Indeed, inappropriate empirical antibiotic therapy (IEAT) has been associated with increased mortality in patients with febrile neutropenia and BSI. Neutropenic sepsis is a medical emergency in which broad-spectrum antibiotics must be given without delay. Delaying treatment in neutropenic sepsis may increase the risk of death. â-Lactam/â-lactamase inhibitors (BL/ BLIs) and carbapenems are often considered for the treatment of sepsis when the main suspected pathogens are Gram-negative bacteria, because of their broad spectrum of coverage. Ceftazidime avibactam is a new molecule available against these bugs. It is a novel combination of ceftazidime (thirdgeneration cephalosporin) and avibactam (novel, nonâ- lactam â-lactamase inhibitor) which covers ESBL isolates like E Coli &amp; K. Pneumoniae, MDR Pseudomonas aeruginosa, and CRE. Ceftazidime and avibactam are now playing a crucial role in combating MDR gram-negative infections in sepsis patients. Many international guidelines recommend using early ceftazidime and avibactam in sepsis patients to achieve better outcomes and reduce volatility. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 197-198

The impact of multi-drug resistant Pseudomonas aeruginosa infections on acute pancreatitis patients

IntroductionAcute pancreatitis (AP) accounts for a high proportion of digestive diseases worldwide and has a high risk of infection. Pseudomonas aeruginosa, a common pathogen of hospital infections, has been observed to increase the resistance rate to several antibiotics, causing difficulties in treatments. Our study aims to investigate the impact of the multi-drug resistant Pseudomonas aeruginosa (MDR-PA) infections on AP patients.MethodsAt two Chinese tertiary referral centers for AP patients infected with MDR-PA, a retrospective case-control study with a 1:2 case-control ratio was performed. Comparisons were preformed between with/without MDR-PA infections and different drug-resistance of MDR-PA infections patients, respectively. Independent risk factors of overall mortality were assessed via univariate and multivariate binary logistic regression analyses, and the distribution and antibiotic resistant rates of strains were described.ResultsMortality in AP patients with MDR-PA infections was significantly higher than in those without MDR-PA infections (7 (30.4%) vs. 4 (8.7%), P = 0.048). The rate of prophylactic use of carbapenem for 3 days (0 vs. 50%, P = 0.019) and the incidence rate of multiple organ failure (MOF) (0 vs. 57.1%, P = 0.018) were remarkably higher in the carbapenem-resistant Pseudomonas aeruginosa group compared with the carbapenem-sensitive Pseudomonas aeruginosa group. In the multivariate analysis, the severe categories of AP (OR = 13.624, 95% CIs = 1.567–118.491, P = 0.018) and MDR-PA infections (OR = 4.788, 95% CIs = 1.107–20.709, P = 0.036) were independent risk factors for mortality. The resistance rates of MDR-PA strains were low for amikacin (7.4%), tobramycin (3.7%), and gentamicin (18.5%). The resistance rates of MDR-PA strains to imipenem and meropenem were up to, 51.9% and 55.6%, respectively.ConclusionIn AP patients, severe categories of AP and MDR-PA infections were both independent risk factors for mortality. Inappropriate use of carbapenem antibiotics and MOF were related to carbapenem-resistant Pseudomonas aeruginosa infections. Amikacin, tobramycin, and gentamicin are recommended for the treatment of AP patients with MDR-PA infections.

Biochemical Characteristics and Antibiograms of Methicillin-Resistant Staphylococcus aureus and Multi-Drug Resistant Pseudomonas aeruginosa Isolated from Skin Wounds of Patients in a Tertiary-Level Hospital in Enugu, Nigeria

Infections by antibiotic-resistant pathogens are known to be the most challenging factor that can impair wound healing. Early detection and effective diagnosis contribute to appropriate therapeutic interventions, which significantly lead to successful treatment outcomes in non-healing wounds. The aim of this study was to identify and evaluate resistance patterns as well as characteristics of Methicillin Resistant Staphylococcus aureus (MRSA) and Multi-drug Resistant Pseudomonas aeruginosa (MDR-PA) isolated from skin wounds of patients in the National Orthopaedic Hospital, Enugu, Nigeria. Cultural and biochemical characterizations of the isolates were, therefore, carried out. Results of the biochemical tests confirmed the presence of Staphylococcus aureus and Pseudomonas aeruginosa isolates. Antibiotic disk diffusion method was adopted for antimicrobial susceptibility tests (ASTs) on the isolates. Based on inhibition zone diameters obtained, various degrees of resistance (50 ‒ 100 %) as well as susceptibility (40 ‒ 70 %) of the organisms were recorded against the test antibiotics. This showed that there was high prevalence of MRSA and MDR-PA strains among the wound pathogens in that part of the country. From the findings, it could be inferred that the occurrence of multi-drug resistant pathogens would contribute significantly to poor clinical responses to wound treatments with antibiotics.

Luteolin, a promising quorum quencher mitigates virulence factors production in Pseudomonas aeruginosa - In vitro and In vivoapproach

Pseudomonas aeruginosa (PA) is an opportunistic pathogen that causes healthcare-associated infection and high mortality in immunocompromised patients. It produces several virulence factors through quorum sensing (QS) mechanisms that is essential for subverting host immune system. Even front-line antibiotics are unable to control PA pathogenicity due to the emergence of antibiotic resistance. Luteolin is a naturally derived compound that has proven to be the effective drug to annihilate pathogens through quorum quenching mechanism. In this study, the protective effect of luteolin against the PA-mediated inflammation was demonstrated using zebrafish model. Luteolin protects zebrafish from PA infection and increases their survival rate. It was found that PA-mediated ROS, lipid peroxidation, and apoptosis were also significantly reduced in luteolin-treated zebrafish larvae. Open field test (OFT) reveals that luteolin rescued PA-infected zebrafish from retarded swimming behavior. Furthermore, luteolin increases SOD and CAT levels and decreases LDH and NO levels in PA-infected zebrafish compare to control group. Histological and gene expression analysis reveals that luteolin protects PA-infected zebrafish by decreasing gut inflammation and altering the expression of inflammatory (TNF-α, IL-1β, IL-6) and antioxidant markers (iNOS, SOD, CAT). Thus, luteolin was found to have dual effect in protecting PA-infected zebrafish by decreasing virulence factors production in PA and stimulating host immune system. This is the first study demonstrating the protective effect of luteolin using animal model. Hence, luteolin could be used as a future therapeutic drug to control multi-drug resistant PA.

In Vivo Activity of Hydrogen-Peroxide Generating Electrochemical Bandage Against Murine Wound Infections.

Biofilms formed by antibiotic-resistant bacteria in wound beds present unique challenges in terms of treating wound infections. In this work, the in vivo activity of a novel electrochemical bandage (e-bandage) composed of carbon fabric and controlled by a wearable potentiostat, designed to continuously deliver low amounts of hydrogen peroxide (H2O2) was evaluated against methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Pseudomonas aeruginosa (MDR-PA) and mixed-species (MRSA and MDR-PA) wound infections. Wounds created on Swiss Webster mice were infected with the above-named bacteria and biofilms allowed to establish on wound beds for 3 days. e-Bandages, which electrochemically reduce dissolved oxygen to H2O2 when polarized at -0.6 VAg/AgCl, were placed atop the infected wound bed and polarized continuously for 48 hours. Polarized e-bandage treatment resulted in significant reductions (p <0.001) of both mono-species and mixed-species wound infections. After e-bandage treatment, electron microscopy showed degradation of bacterial cells, and histopathology showed no obvious alteration to the inflammatory host response. Blood biochemistries showed no abnormalities. Taken all together, results of this work suggest that the described H2O2-producing e-bandage can effectively reduce in vivo MRSA, MDR-PA and mixed-species wound biofilms, and should be further developed as a potential antibiotic-free strategy for treatment of wound infections.

Selective Photothermal Therapy Based on Lipopolysaccharide Aptamer Functionalized MoS2 Nanosheet-Coated Gold Nanorods for Multidrug-Resistant Pseudomonas aeruginosa Infection.

Chronic wounds infected by multidrug-resistant gram-negative bacteria have evolved resistance to traditional antibiotic therapy, posing a threat to global public health in recent years. Herein, a selective therapeutic nanorod (MoS2 -AuNRs-apt) based on molybdenum disulfide (MoS2 ) nanosheets coated gold nanorods (AuNRs) targeting lipopolysaccharide (LPS) is presented. AuNRs have excellent photothermal conversion efficiency in 808nm laser-guided photothermal therapy (PTT), and the MoS2 nanosheets coating significantly enhances the biocompatibility of AuNRs. Furthermore, the conjugation of the nanorods with aptamer permits active targeting of LPS on the surface of gram-negative bacteria and a specific anti-inflammatory ability in the multidrug-resistant Pseudomonas aeruginosa (MRPA)-infected wound murine model. It is concluded that the antimicrobial effect of these nanorods is considerably more significant than non-targeted PTT. Moreover, they can precisely overcome MRPA bacteria by physical damage and effectively reduce excess M1 inflammatory macrophages to accelerate the healing of infected wounds. Overall, this molecular therapeutic strategy displays great potential as a prospective antimicrobial treatment for MRPA infections.

Prevalence and molecular analysis of antibiotic resistance of Pseudomonas aeruginosa isolated from clinical and environmental specimens in Basra, Iraq.

The steady increase in the spread of multidrug-resistant Pseudomonas aeruginosa (MDR) has become a major threat to the global health systems, including Iraq. This study aimed to investigate the prevalence and the molecular basis of antibiotic resistance in Pseudomonas aeruginosa isolated from clinical and environmental samples. Pseudomonas aeruginosa strains were identified by standard microbiological procedures followed by PCR confirmation. Antibiotic susceptibility testing, for 16 antimicrobials, was conducted according to the Clinical and Laboratory Standard Institute (CLSI) standardized by disk diffusion and VITEK 2 methods. Detection of beta-lactamases (ESBLs, AmpC and carbapenemase) activities and related encoding genes was performed by using phenotypic methods and PCR technique respectively. A total of 81 clinical specimens and 14 environmental samples were positive for P. aeruginosa. Antimicrobial susceptibility test showed high rates of resistance to antipseudomonal cephalosporines (74.74 to 98.95%), aztreonam (82.11%), antipseudomonal carbapenems (68.4%), piperacillin/tazobactam (69.5%) ciprofloxacin (71.6%), and aminoglycosides (69%), with emergence of resistance to colistin (7.4%) among tested P. aeruginosa. Among the tested isolates, 69 (72.63%) strains were MDR, of which 63 (91.3%) strains were extremely drug resistance (XDR). Most of the isolated strains harbored one or more of ESBL genes (bla SHV-2a, bla CTX-M-28, bla VEB-2, bla OXA-677, bla PER) with predominant bla OXA-677, but none of the MBLs (GIM, SIM, SPM, IMP) and AmpC (FOX) genes were detected. The results highlighted a high prevalence rate of MDR and XDR and emergence of colistin resistance P. aeruginosa at Basra hospitals, Iraq.