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Background: The increasing drug resistance of Pseudomonas aeruginosa (PA) poses a serious challenge to the current treatment. Antibiograms of this pathogen often take 3-5 days, and treatment of Pseudomonas aeruginosa keratitis (PAK) is mainly based on preliminary physical examination, clinical experience, and medical guidelines. Pertinent clinical data on the causative agent and antibiotics for high efficacy are essential for early recognition and subsequent treatment., Purpose: To report the etiology, risk factors, treatment outcomes, antibiotic susceptibilities, and trends of PAK., Methods: This retrospective study included culture-proven PAK cases at the Ho Chi Minh City Eye Hospital Cornea Department between January 2018 and December 2022. Culture results showing coinfection were excluded from the study., Results: Among 154 eyes infected by PA (n = 154) of 154 patients, ocular trauma was the leading risk factor (53.2%); only 16 patients had contact lenses (10.4%). Among the 154 eyes, 102/154 required surgical intervention (66.2%); and 31/154 eyes required evisceration (20.1%). PA was sensitive to tobramycin (95.9%), ciprofloxacin (91.9%), levofloxacin (91.9%), ofloxacin (87.4%), and moxifloxacin (20.0%). The prevalence of multidrug resistance (MDR) was 31.8%, and extensive drug resistance (XDR) was 3.9%. Poor outcomes (need for surgical intervention or final visual acuity ≤ CF 3 m) included age > 50 years, ocular surface diseases, deep infiltrate, large infiltrate size ≥ 5 mm, and ring infiltrate (p < 0.05)., Conclusion: PAK, which is associated with increasing drug resistance, poses significant challenges in terms of treatment, with 66.2% of patients requiring surgical intervention. With the rapid progression of PAK, early treatment with broad-spectrum and effective antibiotics is necessary. However, future research should focus on new methods to enhance treatment effectiveness., Competing Interests: Declarations. Conflicts of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Bacterial infections of the lower airways are the main cause of mortality and morbidity in cystic fibrosis. The most frequently isolated pathogens are S. aureus and P. aeruginosa; bacterial co-infections are frequently observed. The aim of this review is to provide, in the current context, the indications regarding the best antibiotic strategy to adopt in subjects affected by CF infected with the most common pathogens. We selected relevant publications (guidelines, systematic reviews and clinical studies published so far on these topics) and we analysed the sampling methods used and antibiotic strategies adopted. Oropharyngeal sampling methods are considered less sensitive for pathogen detection than sputum. In non-expectorating people, induced sputum is considered equivalent to two-lobe bronchoalveolar lavage, which is considered invasive. Antibiotic treatment against the main pathogens can consist in eradication treatment in the early stages of infection, chronic suppressive therapy and treatment of the pulmonary exacerbations. This scheme is valid for P. aeruginosa but remains to be demonstrated for the other pathogens. For S. aureus, no evidence-based therapeutic strategies on how to treat the different stages of bacterial infection have been established with certainty. With regard to the treatment of the other classic pathogens (B. cepacia complex, A. xylosoxidans and S. maltophilia), no evidence-based indications exist and decision is left to the clinician. The recent introduction of highly effective modulators on the CFTR protein, in addition to the favourable effects described in regulatory trials, has led to a reduction in bacterial isolations; the real effect of which in clinical practice has still to be assessed on the basis of scientific data. CONCLUSIONS: The reliability of culture examination depends on sampling methods, and expectorated sputum continues to be the best method as it is simple and non-invasive. P. aeruginosa is the pathogen for which antibiotic strategies for the various stages of infection appear best established, and the efficacy of early eradication treatment and chronic suppressive therapy have been underlined in clinical trials and systematic reviews. The recent introduction of modulators into clinical practice, despite their widely described efficacy, has not yet led to suggestions for changes in antibiotic strategies against the pathogens most frequently isolated., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In recent years, naturally occurring darobactins have emerged as a promising compound class to combat infections caused by critical Gram-negative pathogens. In this study, we describe the in vivo evaluation of derivative D22, a non-natural biosynthetic darobactin analogue with significantly improved antibacterial activity. We found D22 to be active in vivo against key critical Gram-negative human pathogens, as demonstrated in murine models of Pseudomonas aeruginosa thigh infection, Escherichia coli peritonitis/sepsis, and urinary tract infection (UTI). Furthermore, we observed the restored survival of Acinetobacter baumannii -infected embryos in a zebrafish infection model. These in vivo proof-of-concept (PoC) in diverse models of infection against highly relevant pathogens, including drug-resistant isolates, highlight the versatility of darobactins in the treatment of bacterial infections and show superiority of D22 over the natural darobactin A. Together with a favorable safety profile, these findings pave the way for further optimization of the darobactin scaffold toward the development of a novel antibiotic.

Pseudomonas aeruginosa is a leading bacterial pathogen that causes persistent infections. One major reason that antibiotics fail to clear such infections is the presence of a dormant subpopulation called persister cells. To eradicate persister cells, it is important to change drug development from traditional strategies that focus on growth inhibition to the search for new leads that can kill dormant cells. In this study, we demonstrate that eravacycline can effectively accumulate in P. aeruginosa persister cells, leading to strong killing during wakeup, including persister cells in both planktonic cultures and biofilms of the wild-type strain and its mucoid mutant. The effects of eravacycline on persister control were further validated in vivo using a lung infection model in mice. Collectively, these results demonstrate the possibility to control persister cells of bacterial pathogens by targeting dormancy.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) are of major clinical concern. We analyzed 85 P . aeruginosa blood isolates non-susceptible to carbapenems collected during 2021-2023 from 15 medical centers in Israel. We aimed to determine the prevalence of high-risk clones, examine clonality, test antibiotic susceptibility, and assess the presence of acquired resistance genes, including carbapenemases. Whole-genome sequencing was performed using Illumina sequencing technology. Susceptibly was determined using the broth microdilution method. In the entire sample, 43.5% were high-risk clones. A main clade (27.1% of isolates) found in multiple hospitals comprised 19 isolates belonging to the high-risk ST654 clone and four closely related isolates. The isolates in this main clade harbored a broad set of resistance genes, including GES-type genes, and 91% had a mutated outer membrane protein (OprD). Isolates in the main clade were uniformly tobramycin (TOB) resistant and 83% were ceftolozane/tazobactam resistant. In the entire sample, we found high resistance to most antipseudomonal agents, including new beta-lactam/beta-lactamase inhibitor combinations. No uniform susceptibility to an antipseudomonal agent was found. Carbapenemases were carried by 9.4% of isolates (5.9% bla GES-5 and 3.5% bla NDM-1 ) and oprD was mutated in 67% of isolates. Thus, the epidemiology of CRPA is explained by a combination of clonal expansion of a dominant high-risk clade and sporadic occurrence of mutated strains. Our findings highlight the importance of susceptibility testing using a wide panel of antibiotics when CRPA is detected. Prevention measures tracking and controlling emerging high-risk clades and clones are crucial to limit the spread of CRPA., Competing Interests: Yehuda Carmeli has received grants and personal fees from Enlivex Therapeutics, MSD, Pfizer, Roche, Qpex Pharmaceuticals, and Spero Therapeutics. All other authors declare no conflict of interest.

Background: Unsaturated fatty acids targeting quorum sensing (QS) system have shown potential application in reducing bacterial virulence. We aim to investigate the effect of palmitoleic acid (PMA) on P. aeruginosa QS activation, and its impact on infection-induced lung injury., Methods: The influence of PMA on QS signaling molecule (3OC12-HSL and C4-HSL) concentrations, pyocyanin production, and QS gene transcription levels were examined in wildtype PAO1 culture. The roles of PMA in reducing infection-induced injury were assessed in human bronchial epithelial BEAS-2B cells and mouse lung infection models, respectively. PMA levels and QS signaling molecule concentrations were tested in the bronchoalveolar lavage fluid (BALF) of bronchiectasis patients with first-time detection of P. aeruginosa infection., Results: PMA administration dose-dependently suppressed the expression of QS signaling molecules, pyocyanin, and QS genes during the logarithmic stage of bacterial growth. In BEAS-2B cells, PMA-treated PAO1 filtrates significantly reduced cell apoptosis and expression of IL-8 and IL-6. In mouse lung infection models, prophylactically oral administration of PMA significantly downregulated the expression of P. aeruginosa QS signals and QS genes (lasR, rhlR, rhlI, lasB, rhlA, phzA1, phnA) in lungs, and relieved neutrophilic airway inflammation. Finally, PMA levels were negatively correlated with the concentrations of both 3OC12-HSL and C4-HSL in BALF of bronchiectasis patients, and positively correlated with their forced vital capacity (FVC) and forced expiratory volume in the first second (FEV 1.0 )., Conclusion: Our findings show that PMA inhibits P. aeruginosa QS activation and protects lungs from injury caused by bacterial virulence. Hence, PMA may serve as a potential anti-QS agent against P. aeruginosa infection and would help to alleviate lung injury in bronchiectasis patients., Competing Interests: Declarations. Ethics approval and consent to participate: The animal study was reviewed and approved by the Experimental Animal Care and Ethics Committee of the Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (IACUC: 2019-A011-01). All animal housing and experiments were conducted in strict accordance with the institutional guidelines for the care and use of laboratory animals. The studies involving human participants were reviewed and approved by the Ethics Committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (Approval No. 2020-50). The patients/participants provided their written informed consent to participate in this study. The study was performed in accordance with the 1964 declaration of HELSINKI and later amendments. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Bacterial persistence is a phenomenon whereby a subpopulation of bacteria survive high concentrations of an active antibiotic in the absence of phenotypic alterations. Persisters are associated with chronic and recurrent infections for pathogens including Pseudomonas aeruginosa. Understanding persister profiles of newer antibiotics such as cefiderocol and ceftolozane/tazobactam against P. aeruginosa is warranted as these agents generally target difficult-to-treat infections., Methods: Persister formation was assessed using in vitro assays against nine clinical P. aeruginosa isolates exposed to cefiderocol or ceftolozane/tazobactam. Quantitative persister assays were performed using a stationary phase of bacteria challenged with 10-fold MIC drug concentrations. Persisters were quantitated as the percent persisters at 24 h and the log ratio (LR) difference in AUC for cfu for each antibiotic alone compared with growth control. The tolerance disc test (TDtest) was used to qualitatively detect persisters., Results: Percent persisters at 24 h was lower with cefiderocol compared with ceftolozane/tazobactam for six of the nine tested isolates. Eight of the nine isolates had higher reduction in LR for cefiderocol groups, suggesting an overall higher and more rapid bacterial reduction in cefiderocol groups. For cefiderocol, five of the nine tested isolates lacked regrowth after replacement with glucose disc, suggesting no persistence via the TDtest. For ceftolozane/tazobactam, three isolates lacked persister formation., Conclusions: Cefiderocol resulted in less bacterial persistence relative to ceftolozane/tazobactam against nine clinical P. aeruginosa isolates. Cefiderocol's siderophore mechanism may be advantageous over ceftolozane/tazobactam through enhanced anti-persister effects. Clinical correlation of these findings is warranted as persisters can lead to antibiotic resistance and treatment failure., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Lack of uniformity in infection models complicates preclinical development. The COMBINE protocol has standardized the murine neutropenic pneumonia model. Herein we provide benchmark efficacy data of humanized exposures of tigecycline and levofloxacin in plasma and epithelial lining fluid (ELF) against a collection of Klebsiella pneumoniae and Pseudomonas aeruginosa., Methods: Following the COMBINE protocol, plasma and ELF human-simulated regimens (HSRs) of tigecycline 100 mg followed by 50 mg q12h and levofloxacin 750 mg once daily were developed and confirmed in the murine neutropenic pneumonia model. Tigecycline HSRs were tested against seven K. pneumoniae isolates. Levofloxacin HSRs were assessed against 10 K. pneumoniae and 9 P. aeruginosa. The change in cfu/lung over 24 h for each treatment was calculated. Each isolate was tested in duplicate against both the plasma and ELF HSRs on separate experiment days., Results: Tigecycline 1.8 and 3 mg/kg q12h achieved humanized exposures of serum and ELF, respectively. Levofloxacin 120 and 90 mg/kg q8h led to fAUC exposures in plasma and ELF similar to in humans. Both tigecycline regimens were ineffective across the MIC range. Levofloxacin regimens achieved multilog kill against susceptible isolates, and no appreciable cfu/lung reductions in isolates with an MIC of ≥32 mg/L. Differences in cfu/lung were evident between the levofloxacin plasma and ELF HSRs against isolates with MICs of 4 and 8 mg/L., Conclusions: Administering HSRs of tigecycline and levofloxacin based on both serum/plasma and ELF in the COMBINE pneumonia model resulted in cfu/lung values reasonably aligned with MIC. These data serve as translational benchmarks for future investigations with novel compounds., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: Bioengineered artificial skin substitutes (BASS) are an advanced therapy for treating extensively burned patients. Pseudomonas aeruginosa (P. aeruginosa) infections represent a major challenge in these patients as formation of biofilms impede wound healing and perpetuate a chronic inflammatory state. Here we assessed antibiotics (alone or in combination) with respect to cytotoxicity, as well as antimicrobial efficacy in P. aeruginosa biofilm formed on infection of BASS., Methods: Cell viability, structure and functionality were evaluated using microscopy and trans-epidermal water loss analyses, respectively. BASS were established and infected for 24 h to allow P. aeruginosa biofilm formation, after which two antimicrobial approaches, treatment and prevention, were tested. In the latter, antibiotics were added to BASS before infection. The antimicrobial effect was determined using real-time calorimetry., Results: In dose-response experiments, 1.25 mg/mL amikacin, 0.02 mg/mL ciprofloxacin, 0.051 mg/mL colistin, 1 mg/mL meropenem and colistin in combination with either amikacin, ciprofloxacin and meropenem did not affect BASS' viability, structure and functionality. All antibiotics, except colistin, showed effective antimicrobial activity at these non-cytotoxic concentrations. For concentrations below the highest non-cytotoxic ones, successive treatments resulted in higher bacterial metabolic rates. Only the combinations managed to eradicate the infection with repeated treatments. With respect to prevention of infection, all antibiotics at the highest non-cytotoxic concentrations and the combinations were effective. This preventive capacity was maintained for at least 5 days., Conclusion: The findings highlight the potential for developing BASS with antimicrobial properties that can prevent infections during wound healing in burn patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pseudomonas aeruginosa is an opportunistic pathogen designated as a high-priority pathogen because of its role in major healthcare-associated and nosocomial infections. Biofilm production by these bacteria is one of the adaptive resistance mechanisms to traditional antibiotics, making treatment challenging, especially for immunocompromised patients. P. aeruginosa also produces a variety of virulence factors, which aid in invasion, adhesion, persistence, and immune system protection. Recent advances in nanotechnology-based therapy, notably the application of bioinspired metal and metal-oxide nanomaterials, have been seen as a viable way to control P. aeruginosa biofilm and virulence. Because of its ease of growth and culture, synthesizing metal and metal-oxide nanomaterials using bacterial species has become one of the most environmentally benign green synthesis options. The application of bacterial-inspired nanomaterials is particularly successful for targeted control of P. aeruginosa infection due to interactions with cell membrane components and transport systems. This paper delves into and provides a complete overview of the application of bacterial-inspired metal and metal-oxide nanomaterials to treat P. aeruginosa infection by targeting biofilm and virulence characteristics. The review focused on synthesizing and applying gold, silver, copper, iron, magnetite, and zinc oxide nanomaterials to mitigate P. aeruginosa biofilm and virulence. The underlying mechanism of these metal and metal-oxide nanoparticles in relation to biofilm and virulence features has also been thoroughly discussed. The current review introduces novel approaches to treating and controlling drug-resistant P. aeruginosa using bacterial-inspired nanomaterials as a targeted therapeutic strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Multidrug-resistant P. aeruginosa (MDR-P. aeruginosa), associated with elevated morbidity, mortality, and readmission rates, presents a formidable challenge to eradication due to its robust resistance to antimicrobial agents and biofilm formation. Herein, self-assembling nanoparticles (NO-PE/PLL NPs) comprised of NO donor-conjugated γ-polyglutamic acid (GSNO-PGA), epsilon-poly-l-lysine (PLL) and colistin were fabricated. The negatively charged NO-PE/PLL NPs exhibited effective penetration through airway mucus, reaching the infection site where GSNO-PGA released NO in response to glutathione within biofilm. PLL worked synergistically with colistin (fractional inhibitory concentration index: 0.281), reducing the minimum inhibitory concentration (MIC) of colistin from 2 to 0.5 μg/mL. Benefiting from this synergistic antibacterial action and NO-mediated biofilm disruption, NO-PE/PLL NPs achieved a 99.99 % eradication rate against MDR-P. aeruginosa biofilms. Additionally, NO-PE/PLL NPs efficiently inhibited endotoxins-stimulated inflammation response. In a chronic pulmonary infection model, NO-PE/PLL NPs displayed the highest eradication efficiency (99.78 %) to infected mice, while having no adverse effects on their major organs or pulmonary functions. These results highlight NO-PE/PLL NPs as a promising therapeutic strategy for treating recalcitrant infections caused by MDR-P. aeruginosa biofilms., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to evaluate the efficacy of inhaled cationic antibiotics, including tobramycin (TOB) and colistin (CST), using an in vitro alginate bead model that simulates Pseudomonas aeruginosa lung biofilms., Methods: Bioluminescent P. aeruginosa were encapsulated within alginate beads and dispersed in either Mueller-Hinton broth (MHB) or artificial sputum medium (ASM). The impact of bead size and culture medium on TOB and CST efficacy was assessed by monitoring bioluminescence kinetics, followed by colony-forming unit (CFU/mL) measurements. Antibiotic efficacy was quantified using a Hill inhibitory model to analyze variations in CFU/mL in response to TOB and CST concentrations., Results: The TOB EC 50 was found to be 8-fold higher when P. aeruginosa was encapsulated in larger beads (1200 μm) compared to smaller beads (60 μm). TOB efficacy further decreased twofold when larger beads were dispersed in ASM. In contrast, CST demonstrated superior efficacy, being four times more potent than TOB, with corresponding EC 50 values of 20.5 ± 2.8 times MIC and 78.4 ± 10.2 times MIC, respectively. No change in MICs was observed for either antibiotic, even after exposing bacteria to 200 times the MIC., Conclusions: This P. aeruginosa biofilm model highlights how alginate and mucus modulated the efficacy of TOB and CST, and suggested the superior efficacy of CST in eradicating pulmonary biofilms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Children with cerebral palsy have increased respiratory morbidity and mortality. Infection with Pseudomonas aeruginosa (PA) is associated with poorer outcomes, yet there are no formal guidelines to inform treatment of respiratory infection in children with cerebral palsy. This review explores the existing literature regarding management of PA-infection in children with cerebral palsy, with the aim of synthesising clinical recommendations and identifying gaps in current understanding. Medline (Ovid), PubMed and Embase were searched using keywords. Full-text articles involving the paediatric population and antimicrobial therapy were included. There was no limit on date of publication. Four retrospective case series were identified. Respiratory microbiology, in samples collected from a range of sites along the respiratory tract, was reported in three studies. Patients who received PA-specific antibiotics clinically improved. Two studies suggest that the use of suppressive inhaled anti-pseudomonal therapy may improve respiratory morbidity in the chronic setting. There is minimal evidence to guide management of PA respiratory infection in children with cerebral palsy. Children with cerebral palsy are at risk of developing bronchiectasis, so in the absence of high-quality evidence, management should be informed by extrapolating from the non-cystic fibrosis bronchiectasis guidelines. Further research examining surveillance and management of PA-infection in this population is required given that early intervention may prevent irreversible lung damage., (© 2024 Wiley Periodicals LLC.)

In the context of growing antibiotic resistance in bacteria, the quorum-sensing (QS) system of Pseudomonas aeruginosa (P. aeruginosa) has become a target for new therapeutic strategies. QS is a crucial communication process and an essential pathogenic mechanism. This comprehensive review explores the critical role of QS in the pathogenesis of P. aeruginosa infections, including lung, burn, bloodstream, gastrointestinal, corneal, and urinary tract infections. In addition, this review delves into the complexity of the bacterial QS communication network and highlights the intricate mechanisms underlying these pathological processes. Notably, in addition to the four main QS systems, bacterial QS can interact with various external and internal signaling networks, such as host environments and nutrients in the external microbiome, as well as internal virulence regulation systems within bacteria. These elements can significantly influence the behavior and virulence of microbial communities. Therefore, this review reveals that inhibitors targeting singular QS pathways may inadvertently promote virulence in other pathways, leading to new trends in drug resistance. In response to evolving resistance challenges, this study proposes more cautious treatment strategies, including multitarget interventions and combination therapies, aimed at combating the escalating issue of resistance., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: We report results from the national CLEAR (Canadian Leadership on Antimicrobial Real-Life Usage) registry on the usage of ceftolozane/tazobactam in Canada from 2022 to 2024., Research Design and Methods: The authors reviewed the final data using the national ethics approved CLEAR study. Thereafter, the literature is surveyed regarding the usage of ceftolozane/tazobactam to treat patients with HABP and VABP via PubMed (up to May 2024)., Results: Ceftolozane/tazobactam was primarily used as directed therapy to treat HABP and VABP caused by Pseudomonas aeruginosa . It was primarily used alone, or in combination with another agent, to treat resistant and multidrug-resistant (MDR) P. aeruginosa infections. Despite primarily being used to treat severely ill patients in intensive care units, its use was associated with relatively high microbiological/clinical cure rates, along with an excellent safety profile. Several reports attest to the microbiological/clinical efficacy and safety of using ceftolozane/tazobactam to treat HABP and VABP., Conclusions: In Canada, ceftolozane/tazobactam is primarily used as directed therapy alone, or in combination, to treat MDR P. aeruginosa infections. Though mostly used to treat severely ill patients in the ICU, ceftolozane/tazobactam use in HABP and VABP is associated with relatively high microbiological/clinical cure rates and an excellent safety profile.

Purpose: This study aimed to investigate the effects of the combination of levofloxacin (LVFX) and cefmenoxime (CMX) on ocular isolates of Pseudomonas aeruginosa., Methods: Twenty-three strains of P. aeruginosa isolated from microbial keratitis cases in Australia were utilized in this study. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of each antibiotic alone were determined and the combined susceptibility of antibiotics was assessed through fractional inhibitory concentration index (FICI). Additionally, tolerance of a ciprofloxacin tolerant P. aeruginosa isolate to each antibiotic alone and combination were analyzed., Results: The median MIC and MBC values of CMX against P. aeruginosa were 16 µg/mL and 32 µg/mL, respectively. The median MIC and MBC values of LVFX were 0.5 µg/mL and 1 µg/mL, respectively, and all isolates were susceptible. In dual combination, the median of FICI of all strains was 0.63; seven strains showed synergistic effects (FICI≤0.5), and fifteen strains showed additive activities, while no strains exhibited antagonism. The isolate of P. aeruginosa that had previously exhibited tolerance to ciprofloxacin showed high tolerance to CMX alone and low tolerance to LVFX alone. This strain showed low tolerance to the combination of CMX and LVFX., Conclusion: The combination of LVFX with CMX may have beneficial interactions which increase antibacterial activity against P. aeruginosa isolates and may be a feasible option for addressing the issue of bacteria resistant to each antibiotic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Antibiotic resistance complicates infection treatments. Natural products, such as phenylethanoid glycosides, including forsythoside B (FB), are gaining attention in clinical use as alternative treatments, either alone or in combination with antibiotics., Purpose: To investigate the antibacterial effects and mechanisms of FB alone and in combination with antibiotics against Acinetobacter baumannii and Pseudomonas aeruginosa., Methods: To elucidate the underlying antibacterial mechanism of FB, we assessed intracellular ATP concentration, pH levels, membrane potential, and cell membrane integrity. We also observed bacterial morphology and conducted biofilms eradication assay. FB toxicity was evaluated using the cell counting kit-8 assay. The in vivo pharmacodynamics of FB was explored using a P. aeruginosa systemic infection mouse model. The study also examined the potential synergistic effects of FB with commonly used antibiotics by the checkerboard dilution method and time-kill assay., Results: The findings indicate that the mechanism of antibacterial activity of FB is through the disruption of bacterial cell membranes, thereby increasing cell membrane permeability, particularly in gram-negative bacteria. Synergistic effects of FB combined with meropenem were demonstrated against resistant strains. FB demonstrated low toxicity in both in vitro and in vivo models, supporting its safety and efficacy for use alone or as an antibiotic adjuvant., Conclusions: FB expands the antibacterial spectrum and enhances the effectiveness of existing antibiotics against resistant bacterial strains, making it a promising adjuvant for treating gram-negative bacterial infections. This study highlights the potential of FB in combating antibiotic resistance and suggests further research into its mechanisms and drug development applications. It provides a framework for studying the interaction between natural products and microorganisms, revealing new biological mechanisms., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Otitis externa (OE) is one of the most frequently diagnosed dermatological diseases in dogs, having a multifactorial aetiology. Among the bacterial agents associated with canine OE, Pseudomonas aeruginosa is of special concern owing to its frequent multidrug resistance profile and ability to form biofilms related to the infection's chronicity and recurrence., Objectives: The main objective of this study was to evaluate and compare the antibiofilm activity of two innovative antimicrobials-an otological gel containing a synthetic antimicrobial peptide and Lavandula angustifolia essential oil-with gentamicin (a conventional antibiotic) using biofilm-producing P. aeruginosa isolates obtained from dogs with OE., Materials and Methods: The biofilm eradication capacity of gentamicin, otological gel and lavender oil was determined against a collection of 12 P. aeruginosa biofilm-producers among 35 clinical isolates obtained from the ear canals of dogs with OE. Also, the antimicrobial activity of the otological gel against P. aeruginosa biofilms was assessed in an in vitro model of dog cerumen., Results: Lavender oil showed the best effectiveness after 30 min of contact, eradicating 58.3% (seven of 12) of the isolates, and gentamicin showed full eradication (12 of 12) after 24 h. The otological gel acted more slowly than the lavender oil; yet at 24 h, the antibiofilm capacity of both compounds was similar, with no significant difference between them. It also was found that triglycerides from synthetic cerumen earwax had antipseudomonal activity and, when combined with the otological gel, led to the full eradication of P. aeruginosa., Conclusions and Clinical Relevance: The results of this in vitro study indicate that lavender oil and the otological gel may be effective topical treatments for canine OE promoted by P. aeruginosa biofilm-producers, as alternatives to gentamicin., (© 2024 ESVD and ACVD.)

Antibiotic-resistant pathogens are a growing global issue, leading to untreatable infectious diseases in both humans and animals. Personalized bacteriophage (phage) therapy, the use of specific anti-bacterial viruses, is currently a leading approach to combat antibiotic-resistant infections. The implementation of phage therapy has primarily been focused on humans, almost neglecting the impact of such infections on the health and welfare of companion animals. Pets also have the potential to spread resistant infections to their owners or the veterinary staff through zoonotic transmission. Here, we showcase personalized phage-antibiotic treatment of a cat with a multidrug-resistant Pseudomonas aeruginosa implant-associated infection post-arthrodesis surgery. The treatment encompassed a tailored combination of an anti- P. aeruginosa phage and ceftazidime, precisely matched to the pathogen. The phage was topically applied to the surgical wound while the antibiotic was administered intramuscularly. After two treatment courses spanning 7 and 3 weeks, the surgical wound, which had previously remained open for five months, fully closed. To the best of our knowledge, this is the first case of personalized phage therapy application in felines, which provides further evidence of the effectiveness of this approach. The successful outcome paves the way for personalized phage-antibiotic treatments against persistent infections therapy in veterinary practice.

Objectives: Multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is a life-threatening infection with limited treatment options. This is the first meta-analysis of recently published data to compare the clinical outcomes of ceftazidime-avibactam (CAZ-AVI) with other antimicrobial agents in treating MDR-PA infections., Design: Systematic review and meta-analysis., Data Sources: PubMed, Embase and the Cochrane Library have been systematically reviewed, for publications in the English language, from database inception to July 2023., Eligibility Criteria for Selecting Studies: Studies comparing CAZ-AVI outcomes with other antimicrobial agents were included. In-hospital mortality & 30-day mortality were assessed as the main outcomes., Data Extraction and Synthesis: Literature screening, data extraction, and the quality evaluation of studies were conducted by two researchers independently, with disagreements resolved by another researcher. The Newcastle-Ottawa Scale was used to assess the bias risk for the included studies. Review Manager V.5.4 was employed for the meta-analysis., Results: The meta-analysis included four retrospective studies, enrolling 1934 patients. The CAZ-AVI group demonstrated significantly lower in-hospital mortality (risk ratio (RR) = 0.60, 95% CI:0.37-0.97, I2 = 74%, p = 0.04) in three studies with 1444 patients and lower 30-day mortality, in 438 patients from three studies (RR = 0.54, 95% CI:0.28-1.05, I2 = 67%, p = 0.07). No significant difference in clinical success, microbiological success, length of hospital, and ICU stay was observed., Conclusions: This meta-analysis demonstrated that CAZ-AVI treatment significantly lowered in-hospital mortality compared with other antimicrobial agents in MDR-PA infections. However, the analysis only included a few observational studies and high-quality, randomized controlled trials are needed to investigate further the scope of CAZ-AVI in MDR-PA  infections., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict on interest., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Colistin is an effective antibiotic utilized for the treatment of Gram-negative bacterial infections with coverage against a broad spectrum of bacteria. Despite the broad antibacterial coverage, this antibiotic can have serious complications such as acute kidney injury. Colistin also can have a toxic effect on the loop of Henle, causing tubulopathy, electrolyte imbalances, and the occurrence of Bartter-like syndrome (BLS) which is characterized by magnesium and calcium disturbances, polyuria, and metabolic alkalosis. We here report a 32-year-old male with a history of multiple trauma due to an accident that received colistin therapy for Pseudomonas isolation from wound culture on the 5th day of hospitalization. Polyuria, hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalcemia were developed on the first week of colistin administration. The patient received colistin until the 21st day of hospitalization. Serum calcium and magnesium levels became normal 1 day after stopping colistin, while urine volume and metabolic alkalosis resolved 6 days after colistin discontinuing. Therefore, it is crucial to adjust the dose of colistin to minimize its toxicity., Competing Interests: Declarations. Conflict of interest: None to declare. Ethics approval and consent to participate: Informed consent was obtained from the patient. This study is approved by the ethics committee of Abadan University of Medical Sciences (IR.ABADANUMS.REC.1402.090). Human and animal rights: There is no studies with human or animals performed by the authors., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Purpose of Review: To correlate the resistance mechanisms and the susceptibility to new antibiotics in Pseudomonas aeruginosa ., Recent Findings: Definition of antibiotic resistance in Pseudomonas aeruginosa is still debated. Carbapenem-resistant Pseudomonas aeruginosa (CRPA) and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA) are used but which of them better correlate with the risk of mortality remains debated. Mechanisms underlying resistance in Pseudomonas aeruginosa are complex and may be combined, resulting in unpredictable phenotype and cross-resistance. Thus, not all CRPA are alike and tailoring antibiotic therapy on resistance mechanisms is challenging., Summary: Current guidelines recommend the use of new antipseudomonal agents for CRPA or DTR-PA infections but they don't provide specific information on how tailoring antibiotic therapy on underlying resistance mechanisms. This review may be useful to understand which mechanisms are involved in CRPA and may have practical implications helping clinicians to select an appropriate antibiotic regimen. Several antibiotics are now available for Pseudomonas aeruginosa but their rational use is important to avoid development of future resistance. The knowledge of local epidemiology and most common resistance mechanisms may guide empirical therapy, but targeted antibiotic therapy should be re-evaluated as soon as susceptibility testing profile is available and selected according to Pseudomonas aeruginosa phenotype., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: This study aimed to assess the susceptibility of ocular isolates of Pseudomonas aeruginosa to two multi-purpose disinfectant solutions (MPDS) and to determine if there was a relationship with resistance to antibiotics., Methods: Twenty-three strains of P. aeruginosa isolated from microbial keratitis cases in Australia were utilized in this study. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of two commercially available MPDSs, Biotrue and cleadew MPS were determined. Additionally, the MIC of the strains to five antibiotics, ciprofloxacin, levofloxacin, gentamicin, ceftazidime, and imipenem, were analyzed., Results: All strains were susceptible to 100 % of each of the MPDS. However, when MPDSs were diluted, cleadew MPS had significantly lower median MIC (median = 12.5 vs 25; p = 0.00008) and MBC (median = 25 vs 50; p = 0.0027) compared to Biotrue. All tested strains were susceptible to levofloxacin and gentamicin. Susceptibility rates to ciprofloxacin, imipenem, and ceftazidime were 52.2 %, 30.4 %, and 91.3 %, respectively. There were no significant relations between MIC or MBC to either MPDS and resistance to the antibiotics (p≧0.23)., Conclusion: Both MPDSs were active against P. aeruginosa isolated from microbial keratitis in Australia. However, after dilution, cleadew MPS remained active against P. aeruginosa at lower concentrations. Certain strains of P. aeruginosa were resistant to imipenem, ceftazidime or ciprofloxacin. The lack of association of susceptibility to MPDS and antibiotics suggest that resistance to one did not predispose to resistance to the other., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bacteriophage (phage) therapy is a promising therapeutic modality for multidrug-resistant bacterial infections, but its application is mainly limited to personalized therapy due to the narrow host range of individual phages. While phage cocktails targeting all possible bacterial receptors could theoretically confer broad coverage, the extensive diversity of bacteria and the complexity of phage-phage interactions render this approach challenging. Here, using screening protocols for identifying "complementarity groups" of phages using non-redundant receptors, we generate effective, broad-range phage cocktails that prevent the emergence of bacterial resistance. We also discover characteristic interactions between phage complementarity groups and particular antibiotic classes, facilitating the prediction of phage-antibiotic as well as phage-phage interactions. Using this strategy, we create three phage-antibiotic cocktails, each demonstrating efficacy against ≥96% of 153 Pseudomonas aeruginosa clinical isolates, including biofilm cultures, and demonstrate comparable efficacy in an in vivo wound infection model. We similarly develop effective Staphylococcus aureus phage-antibiotic cocktails and demonstrate their utility of combined cocktails against polymicrobial (mixed P. aeruginosa/S. aureus) cultures, highlighting the broad applicability of this approach. These studies establish a blueprint for the development of effective, broad-spectrum phage-antibiotic cocktails, paving the way for off-the-shelf phage-based therapeutics to combat multidrug-resistant bacterial infections., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Pseudomonas aeruginosa is a significant opportunistic pathogen, and its complex mechanisms of antibiotic resistance pose a challenge to modern medicine. This literature review explores the advancements made from 1979 to 2024 in understanding the regulatory networks of antibiotic resistance genes in Pseudomonas aeruginosa, with a particular focus on the molecular underpinnings of these resistance mechanisms. The review highlights four main pathways involved in drug resistance: reducing outer membrane permeability, enhancing active efflux systems, producing antibiotic-inactivating enzymes, and forming biofilms. These pathways are intricately regulated by a combination of genetic regulation, transcriptional regulators, two-component signal transduction, DNA methylation, and small RNA molecules. Through an in-depth analysis and synthesis of existing literature, we identify key regulatory elements mexT, ampR, and argR as potential targets for novel antimicrobial strategies. A profound understanding of the core control nodes of drug resistance offers a new perspective for therapeutic intervention, suggesting that modulating these elements could potentially reverse resistance and restore bacterial susceptibility to antibiotics. The review looks forward to future research directions, proposing the use of gene editing and systems biology to further understand resistance mechanisms and to develop effective antimicrobial strategies against Pseudomonas aeruginosa. This review is expected to provide innovative solutions to the problem of drug resistance in infectious diseases., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Introduction: Given the increasing frequency of drug-resistant bacteria and the limited progress in developing new antibiotics, it is necessary to explore new methods of combating microbial infections. Nanoparticles, particularly silver nanoparticles (Ag-NPs), have shown exceptional antibacterial characteristics; however, elevated concentrations of Ag-NPs can produce noticeable levels of toxicity in mammalian cells., Aim: This study examined the potential synergistic effect of combining a low dosage of Ag-NPs and anti-pseudomonas drugs against Pseudomonas aeruginosa (ATCC strain) and eleven clinical isolates from cystic fibrosis patients., Methods: The Ag-NPs were chemically produced by utilizing a seed extract from Peganum Harmala and characterized via ultraviolet-visible spectroscopy and scanning electron microscopy. The broth microdilution technique was utilized to investigate the minimum inhibitory concentration (MIC) of Ag-NPs and eight antibiotics (Piperacillin, Ciprofloxacin, Levofloxacin, Meropenem, Amikacin, Ceftazidime, Gentamicin, Aztreonam). The fractional inhibitory concentration index (FICI) was determined via the checkerboard method to evaluate the synergistic effects of Ag-NPs and various antibiotics., Results: The biosynthesized Ag-NPs were uniformly spherical and measured around 15 nm in size. When combined with antibiotics, Ag-NP produced statistically significant reductions in the amount of antibiotics required to completely prevent P. aeruginosa growth for all strains. The findings revealed that the MIC of Ag-NPs was 15 ug/mL for all strains which decreased substantially when administered with antibiotics at a dose of 1.875-7.5 ug/mL. The majority of Ag-NP and antibiotic combinations exhibited a synergistic or partially synergistic impact. This was particularly noticeable in combinations containing Meropenem, Ciprofloxacin, and Aztreonam (in which the FIC index was less than or equal to 0.5)., Conclusion: The findings revealed that combining Ag-NPs with antibiotics was more effective than using Ag-NPs or antibiotics in isolation and that combinations of Ag-NPs and antimicrobial agents displayed synergistic activity against the majority of strains assessed., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Al-Momani et al.)

We present the case of a patient with cystic fibrosis on long-term oral linezolid treatment for Mycobacteria abscessus lung infection who developed severe linezolid-induced lactic acidosis (LILA) resulting in deranged clotting and pancytopenia. The lactic acidosis was resistant to treatment with intravenous fluid but resolved within 20 hours of initiating continuous veno-venous haemofiltration. An unintended consequence of haemofiltration was that vascular access interfered with effective chest physiotherapy, resulting in worsened lung consolidation requiring prolonged intravenous antibiotic therapy for coexisting Pseudomonas aeruginosa infection. Given the potential mortality and morbidity of LILA, monitoring lactate levels may be clinically important but the optimum timing of monitoring is currently unclear., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Pseudomonas aeruginosa associated with hospital-acquired infection is often resistant to various antibiotics and is associated with high mortality worldwide. The appropriate treatment of Pseudomonas aeruginosa resistant to carbapenems but susceptible to traditional antipseudomonal non-carbapenem β-lactam agents (Car-R/NonCar-S P. aeruginosa) remains unclear. This retrospective study evaluated risk factors for 14-day and 30-day mortality among treatment regimens against Car-R/NonCar-S P. aeruginosa. This study enrolled 180 patients with Car-R/NonCar-S P. aeruginosa infection at Phramongkutklao Hospital between January 2019 and December 2023. The 14-day and 30-day mortality rates were 18.3% and 28.9%, respectively. Bloodstream infection (OR 1.97, 95% CI 0.88-4.43), septic shock (OR 3.3, 95% CI 1.30-8.40), Acute Physiology and Chronic Health Evaluation (APACHE) II < 14 (OR 0.13, 95% CI 0.03-0.54), Sequential Organ Failure Assessment (SOFA) <7 (OR 0.25, 95% CI 0.11-0.56), and Pitt bacteremia score <4 (OR 0.16, 95% CI 0.05-0.47) were associated with 14-day mortality. There was a higher 14-day and 30-day mortality in patients treated with piperacillin/tazobactam or aminoglycosides but there was no significant difference among antipseudomonal antimicrobial agents in the treatment of Car-R/NonCar-S P. aeruginosa infection. We supported the use of traditional antipseudomonal β-lactam agents to treat Car-R/NonCar-S P. aeruginosa infections, however the use of piperacillin/tazobactam might be concerned in some cases and further investigations were needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Supreeyasakon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Histones possess significant antimicrobial potential, yet their activity against biofilms remains underexplored. Moreover, concerns regarding adverse effects limit their clinical implementation. We investigated the antibacterial efficacy of human recombinant histone H1 subtypes against Pseudomonas aeruginosa PAO1, both planktonic and in biofilms. After the in vitro tests, toxicity and efficacy were assessed in a P. aeruginosa PAO1 infection model using Galleria mellonella larvae. Histones were also evaluated in combination with ciprofloxacin (Cpx) and gentamicin (Gm). Our results demonstrate antimicrobial activity of all three histones against P. aeruginosa PAO1, with H1.0 and H1.4 showing efficacy at lower concentrations. The bactericidal effect was associated with a mechanism of membrane disruption. In vitro studies using static and dynamic models showed that H1.4 had antibiofilm potential by reducing cell biomass. Neither H1.0 nor H1.4 showed toxicity in G. mellonella larvae, and both increased larvae survival when infected with P. aeruginosa PAO1. Although in vitro synergism was observed between ciprofloxacin and H1.0, no improvement over the antibiotic alone was noted in vivo . Differences in antibacterial and antibiofilm activity were attributed to sequence and structural variations among histone subtypes. Moreover, the efficacy of H1.0 and H1.4 was influenced by the presence and strength of the extracellular matrix. These findings suggest histones hold promise for combating acute and chronic infections caused by pathogens such as P. aeruginosa .IMPORTANCEThe constant increase of multidrug-resistant bacteria is a critical global concern. The inefficacy of current therapies to treat bacterial infections is attributed to multiple mechanisms of resistance, including the capacity to form biofilms. Therefore, the identification of novel and safe therapeutic strategies is imperative. This study confirms the antimicrobial potential of three histone H1 subtypes against both Gram-negative and Gram-positive bacteria. Furthermore, histones H1.0 and H1.4 demonstrated in vivo efficacy without associated toxicity in an acute infection model of Pseudomonas aeruginosa PAO1 in Galleria mellonella larvae. The bactericidal effect of these proteins also resulted in biomass reduction of P. aeruginosa PAO1 biofilms. Given the clinical significance of this opportunistic pathogen, our research provides a comprehensive initial evaluation of the efficacy, toxicity, and mechanism of action of a potential new therapeutic approach against acute and chronic bacterial infections., Competing Interests: The authors declare no conflict of interest.

Introduction: Pseudomonas aeruginosa (P. aeruginosa) -induced pneumonia is marked by considerable infiltration of inflammatory cells and biofilm formation, which causes acute and transient lung inflammation and infection. Nevertheless, the discovery of alternative preventative and therapeutic methods is essential due to the high mortality rates in clinical settings and the resistance of P. aeruginosa infection to multiple medications., Purpose: In this research, we constructed amphiphilic Janus nanoparticles (JNPs, denoted as SSK1@PDA/CaP@CIP), loaded with hydrophobic SSK1, a β-galactosidase (β-gal)-activated prodrug for reducing macrophages, and hydrophilic ciprofloxacin (CIP), a classic antibiotic for treating infection. SSK1@PDA/CaP@CIP was designed to effectively attenuate inflammation, eradicate biofilms, and combat planktonic P. aeruginosa ., Results: As expected, SSK1@PDA/CaP@CIP was able to target the infection site and demonstrated outstanding efficacy in treating P. aeruginosa strain PAO1-induced pneumonia by regulating macrophage infiltration to reduce inflammation and removing planktonic bacteria and biofilms to control infection. Additionally, the primary organs did not exhibit any discernible pathological changes following treatment with SSK1@PDA/CaP@CIP, which indicates superior biocompatibility throughout the treatment course., Discussion: In conclusion, our investigation introduced a promising approach to the treatment of pneumonia associated with PAO1., Competing Interests: This research was conducted without any financial or inappropriate influence from other professional or personal interests., (© 2024 Chen et al.)

Objectives: To investigate the clinical characteristics of carbapenem-resistant Pseudomonas aeruginosa (CRPA) infection in children and the risk factors for such infection., Methods: A retrospective analysis was conducted among 60 children with CRPA infection (CRPA group) who were hospitalized in Shenzhen Children's Hospital, China Medical University, from January 2018 to September 2023, and 82 children with carbapenem-sensitive Pseudomonas aeruginosa infection during the same period were randomly selected as the control group. A multivariate logistic regression analysis was used to investigate the risk factors for CRPA infection., Results: Among the 60 children with CRPA infection, 31 (52%) were admitted to the intensive care unit (ICU), and the lower respiratory tract was the main detection site in 32 children (53%). The univariate analysis showed that sex, history of invasive treatment within 1 year, antibiotic use before admission, presence of underlying condition, ICU admission, invasive procedure after admission, antibiotic use for >14 days, and the type of antibiotics used of ≥3 were associated with CRPA infection ( P <0.05). The multivariate logistic regression analysis showed that the history of invasive treatment within 1 year ( OR =3.228, P <0.05), antibiotic use before admission ( OR =4.052, P <0.05), antibiotic use for >14 days ( OR =4.961, P <0.05), and the type of antibiotics used of ≥3 ( OR =3.687, P <0.05) were independent risk factors for CRPA infection in children., Conclusions: CRPA infection in children may be associated with a history of invasive treatment within the past year, antibiotic use before admission, duration of antibiotic use after admission, and the diversity of antibiotic types used.

This study aimed to elucidate the resistance trends of P. aeruginosa isolates from 2005 to 2023 in Zhejiang Province, emphasizing the impact of Coronavirus disease 2019 (COVID-19) on antimicrobial resistance patterns and clinical management. We retrospectively analyzed 7326 P. aeruginosa isolates collected from diverse clinical sources in a tertiary hospital in Zhejiang Province from 2005 to 2023. Identification and antibiotic susceptibility testing of each isolate were performed using the VITEK-32 automated system and the disk diffusion method, following Clinical and Laboratory Standards Institute guidelines. We assessed resistance patterns for key antibiotic classes relevant to P. aeruginosa treatment, including carbapenems, β-lactams, aminoglycosides, and quinolones. Statistical analyses, including trend evaluations and resistance determinant assessments, were conducted in R software (version 4.2.2), with visualizations generated through ggplot2 to illustrate resistance trends over time. This study focused on key anti-pseudomonal agents including carbapenems (imipenem and meropenem), β-lactams (piperacillin), and quinolones (ciprofloxacin and levofloxacin). We observed a progressive increase in resistance to imipenem from 6.8% in 2005 to 48.2% in 2023 and meropenem from 25.4% to 44.2% over the same period. Conversely, resistance rates to aminoglycosides declined, with gentamicin resistance dropping from 22.0% in 2005 to 5.0% in 2019. Cephalosporins exhibited variable trends, with cefepime resistance peaking at 40.4% in 2013 before declining to 12.1% in 2023. The findings indicated a progressive increase in resistance rates for these antibiotics, with notable peaks coinciding with changes in clinical practices and the COVID-19 pandemic. The analysis demonstrated that shifts in prescription habits, particularly during the COVID-19 pandemic, influenced resistance patterns, underscoring the need for context-specific antimicrobial stewardship strategies. This study identifies significant, evolving resistance patterns in P. aeruginosa over a 19-year period, with marked increases in resistance to critical antibiotics, including carbapenems (imipenem, meropenem), quinolones (levofloxacin, ciprofloxacin), and certain β-lactams (piperacillin). These findings underscore an urgent need for dynamic, tailored infection control measures, emphasizing the importance of robust antibiotic stewardship programs, localized treatment guidelines, and proactive monitoring of resistance trends. Implementing these strategies is essential to effectively counter the challenges posed by multi-drug resistant P. aeruginosa, improve patient outcomes, and sustain the efficacy of vital antibiotic therapies., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Therapeutic deep eutectic solvents (THEDES) are a type of deep eutectics that can be used as active pharmaceutical ingredients (APIs) by enhancing the drug bioavailability, by increasing the solubility of APIs in aqueous solutions or by increasing their permeability through biological barriers. In this study, we demonstrate the utility of designer THEDES, based on Quillaja Saponin (SAP), a triterpene natural product to unravel the antimicrobial potential of such THEDES. THEDES were prepared by gently mixing and heating five different α- hydroxy acids- malic, citric, tartaric, glycolic, lactic acids and SAP with water as a third component in the THEDES. The antimicrobial assays were performed with the as-prepared SAP-THEDES and among the panel of bacterial strains, saponin-malic acid THEDES [SMA-THEDES] displayed potent activity in disassembling PA biofilms, demonstrating that the SMA-THEDES can serve as therapeutic antibacterial biomaterials. To further optimize, a Box-Behnken- response surface methodology (RSM) experimental design was done and at the optimum conditions of SAP (1.014 m.mol), Malic acid (1.003 m.mol), Water (0.117 m.mol), SMA-THEDES exhibited maximum MIC of P. aeruginosa with the minimum absorbance at 590 nm of 0.105. The effectiveness of SMA-THEDES as antibiofilm agents on P. aeruginosa with the mechanism studies have been explored. The colony count from the in vivo infection zebrafish model in the treatment group showed a decline of > 2 fold for SMA-THEDES. Toxicity studies did not reveal any abnormality in liver and brain enzyme levels. Liver morphology images show no severe cytological alterations when treated with SMA-THEDES and were almost similar to the normal liver., Competing Interests: Declarations Competing interests The authors declare no competing interests. Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

The release of virulence factors and biofilm formation by Pseudomonas aeruginosa are pivotal drivers of its severe pathogenicity and antibiotic resistance. Based on our prior findings, cyclic di-GMP (c-di-GMP) G-quadruplex inducers are promising biofilm inhibitors and that quorum sensing systems are central regulators of virulence, we aimed to design and synthesize c-di-GMP G-quadruplex inducer-quorum sensing inhibitor hybrids. These hybrids were envisioned as bifunctional agents with both antibiofilm and antivirulence capabilities. Hybrids A7 and A11 , characterized by their quinoline and 3-indole rings, emerged as potent inhibitors. They achieve this dual action by inducing c-di-GMP G-quadruplex formation and disrupting the las and pqs signaling system. Additionally, hybrids A7 and A11 attenuated virulence factors and inhibited the motility phenotypes of P. aeruginosa . Furthermore, when tested in in vivo Caenorhabditis elegans infection models, these hybrids, in combination with antibiotics such as tetracycline, improved survival rates, all while maintaining a favorable biosafety profile.

Pseudomonas aeruginosa bloodstream infections (PA BSIs) in adults, especially those complicated by sepsis, are associated with high rates of morbidity and mortality. Early identification of risk factors for both mortality and sepsis-induced coagulopathy (SIC) is critical to optimizing patient management and improving outcomes. We conducted a retrospective analysis of 118 adult patients diagnosed with PA BSIs at the Affiliated Hospital of Xuzhou Medical University from January 2022 to February 2024. Univariate analysis was employed to identify significant clinical factors, followed by multivariate stepwise logistic regression to determine independent predictors of mortality and SIC. Based on these findings, nomogram models were constructed and evaluated using the area under the receiver operating characteristic curve (AUC), Bootstrap resampling, and calibration plots to assess model performance. Empiric sensitive antibiotic therapy (ESAT) (OR = 0.039, P < 0.001), coronary artery disease (CAD) (OR = 10.315, P = 0.010), and invasive mechanical ventilation (OR = 3.926, P = 0.020) emerged as significant predictors of mortality. In contrast, elevated C-reactive protein (CRP) (OR = 1.011, P = 0.003), procalcitonin (PCT) (OR = 1.030, P = 0.005), and lower hemoglobin levels (OR = 0.963, P = 0.004) were independently associated with SIC. The AUC of mortality prediction model is 0.908, while the SIC prediction model yielded an AUC of 0.817. The predictive models developed in this study demonstrate early identification of mortality rates and SIC risk in PA BSI patients, which may have the potential to guide timely therapeutic interventions and improve clinical outcomes in this high-risk population., Competing Interests: Declarations Competing interest The authors declare no competing interests. Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publish Not applicable.Ethical approval.Our study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethical Committee for medical research at the Affiliated Hospital of Xuzhou Medical University (No. XYFY2024-KL405)., (© 2024. The Author(s).)

Pseudomonas aeruginosa is a major nosocomial pathogen that persists in healthcare settings despite rigorous disinfection protocols due to intrinsic mechanisms conferring resistance. We sought to systematically assess cationic biocide efficacy against this pathogen using a panel of multidrug-resistant P. aeruginosa clinical isolates. Our studies revealed widespread resistance to commercial cationic disinfectants that are the current standard of care, raising concerns about their efficacy. To address this shortcoming, we highlight a new class of quaternary phosphonium compounds that are highly effective against all members of the panel. To understand the difference in efficacy, mechanism of action studies were carried out, which identified a discrete inner-membrane selective target. Resistance selection studies implicated the SmvRA efflux system (a transcriptionally regulated, inner membrane-associated efflux system) as a major determinant of resistance. This system is also implicated in resistance to two commercial bolaamphiphile antiseptics, octenidine and chlorhexidine, which was further validated herein. In sum, this work highlights, for the first time, a discrete inner-membrane specific mechanism for the bolaamphiphile class of disinfectants that contrasts with the prevailing model of indiscriminate membrane interactions of commercial amphiphiles paving the way for future innovations in disinfectant research.

The mechanisms underlying ceftazidime/avibactam resistance development in four ceftazidime/avibactam susceptible/resistant pairs of GES-5-producing ST235 Pseudomonas aeruginosa clinical isolates were investigated. In three of the cases, ceftazidime/avibactam resistance was driven by a single mutation leading to GES-27 (P162Q), GES-29 (P162A), or the novel GES-60 (N136S), as confirmed through cloning experiments. Moreover, these mutations were associated with increased cefiderocol MICs but reduced carbapenem, particularly imipenem/relebactam, resistance. Understanding the complexity of resistance mechanisms to the growing repertoire of antipseudomonal β-lactams is crucial to guide optimized treatments and antimicrobial stewardship measures., Competing Interests: The authors declare no conflict of interest.

Diffuse panbronchiolitis (DPB) is a rare, idiopathic inflammatory disease primarily diagnosed in East Asian populations. DPB is characterized by diffuse pulmonary lesions, inflammation of the respiratory bronchioles, and bacterial infections of the airway. Historically, sputum cultures reveal Pseudomonas aeruginosa in 22% of DPB patients, increasing to 60% after 4 years from disease onset. Although DPB patients have a known susceptibility to respiratory P. aeruginosa infections, as is observed in other chronic lung diseases such as cystic fibrosis (CF), the characterization of DPB P. aeruginosa strains is limited. In this study, we characterized 24 strains obtained from a cohort of DPB patients for traits previously associated with virulence, including growth, motility, antibiotic susceptibility, lipopolysaccharide structure, and genomic diversity. Our cohort of DPB P. aeruginosa strains exhibits considerable genomic variability when compared with isolates from people with cystic fibrosis chronically colonized with P. aeruginosa and acute P. aeruginosa infection isolates. Similar to CF, DPB P. aeruginosa strains produce a diverse array of modified lipid A structures. Antibiotic susceptibility testing revealed increased resistance to erythromycin, a representative agent of the macrolide antibiotics used to manage DPB patients. Differences in the O-antigen type among P. aeruginosa strains collected from these different backgrounds were also observed. Ultimately, the characterization of DPB P. aeruginosa strains highlights several unique qualities of P. aeruginosa strains collected from chronically diseased airways, underscoring the challenges in treating DPB, CF, and other obstructive respiratory disease patients with P. aeruginosa infections., Importance: Diffuse panbronchiolitis (DPB), a chronic lung disease characterized by persistent P. aeruginosa infection, serves as an informative comparator to more common chronic lung diseases, such as cystic fibrosis (CF). This study aimed to better address the interplay between P. aeruginosa and chronically compromised airway environments through the examination of DPB P. aeruginosa strains, as existing literature regarding DPB is limited to case reports, case series, and clinical treatment guidelines. The evaluation of these features in the context of DPB, in tandem with prevailing knowledge of P. aeruginosa strains collected from more common chronic lung diseases (e.g., CF), can aid in the development of more effective strategies to combat respiratory P. aeruginosa infections in patients with chronic lung diseases., Competing Interests: The authors declare no conflict of interest.

Background: Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear., Methods: We used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung., Results: We found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection., Conclusions: The data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model., (© 2024. The Author(s).)

Background: Ceftolozane/tazobactam and ceftazidime/avibactam are commonly used in patients with MDR-Pseudomonas aeruginosa (PSA) pneumonia (PNA). This study compared outcomes between non-COVID-19 hospitalized patients with MDR-PSA PNA who received ceftolozane/tazobactam or ceftazidime/avibactam., Methods: The study included non-COVID-19 adult hospitalized patients with MDR-PSA PNA in the PINC AI Healthcare Database (2016-22) who received ceftolozane/tazobactam or ceftazidime/avibactam within 3 days of index culture for ≥2 days. Outcomes were mortality, recurrent MDR-PSA PNA, discharge destination, post-index culture day length of stay (LOS) and costs (in US dollars, USD), and hospital readmission., Results: The final sample included 197 patients (117 ceftolozane/tazobactam, 80 ceftazidime/avibactam). No significant differences were observed in mortality and post-index culture LOS and costs between groups. In the multivariable analyses, patients who received ceftolozane/tazobactam versus ceftazidime/avibactam had lower recurrent MDR-PSA PNA (7.9% versus 18.0%, P = 0.03) and 60 day PNA-related readmissions (11.1% versus 28.5%, P = 0.03) and were more likely to be discharged home (25.8% versus 9.8%, P = 0.03). Compared with ceftazidime/avibactam patients, ceftolozane/tazobactam patients had lower adjusted median total antibiotic costs (5052 USD versus 8099 USD, P = 0.003) and lower adjusted median comparator (ceftolozane/tazobactam or ceftazidime/avibactam) antibiotic costs (3938 USD versus 6441 USD, P = 0.005). In the desirability of outcome ranking (DOOR) analysis, a ceftolozane/tazobactam-treated patient was more likely to have a more favourable outcome than a ceftazidime/avibactam-treated patient [DOOR probability: 59.6% (95% CI: 52.5%-66.8%)]., Conclusions: Early treatment with ceftolozane/tazobactam may offer some clinical and cost benefits over ceftazidime/avibactam in patients with MDR-PSA PNA. Further large-scale studies are necessary to comprehensively understand the outcomes associated with these treatments for MDR-PSA PNA., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: To determine the association of adequate empirical combination therapy (AECT) with 30-day all-cause mortality in patients with septic shock due to Pseudomonas aeruginosa bloodstream infections (BSI)., Methods: This multicentre, retrospective cohort study analysed data from 14 public hospitals in Italy, including all consecutive adult patients admitted during 2021-2022 with septic shock due to P. aeruginosa BSI. We compared the outcomes of patients receiving AECT to those on adequate empirical monotherapy (AEMT) using Cox regression analyses., Results: Of the 98 patients who received adequate empirical antibiotic treatment for septic shock due to P. aeruginosa BSI, 24 underwent AECT and 74 were given AEMT. AECT was associated with a lower 30-day all-cause mortality (25%, six out of 24) compared to AEMT (56.8%, 42 out of 74; P = 0.007). Multivariate Cox regression analysis indicated AECT as the only factor significantly associated with improved survival (aHR 0.30; 95% CI 0.12-0.71; P = 0.006). By contrast, the use of monotherapy or combination therapy in the definitive regimen did not influence mortality (aHR 0.73; 95% CI 0.25-2.14; P = 0.568)., Conclusions: AECT may be associated with reduced mortality compared to monotherapy in septic shock patients due to P. aeruginosa BSI. However, the administration of definitive adequate monotherapy or combination therapy yields similar outcomes, suggesting that once susceptibility is documented, switching to a single active in vitro drug is safe and feasible. Further studies are recommended to validate these findings., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Candida albicans can form polymicrobial biofilms with other microorganisms, such as Pseudomonas aeruginosa, at infection sites., Objectives: As biofilms are highly resistant to antibiotics there is a need for new antibiofilm agents that have unique targets and modes of action., Methods: In this study the antibiofilm effects of two quorum-sensing molecules (QSMs), farnesol and tyrosol, were investigated alone and in combination with antibiotics (aztreonam, colistin, tobramycin) and antifungals (fluconazole, amphotericin B, caspofungin), against single- and dual-species biofilms of C. albicans and P. aeruginosa in in vitro and in vivo systems., Results: It was observed that QSMs alone, especially farnesol, showed at least a 1-log reduction against preformed single- and dual-species biofilms of C. albicans and P. aeruginosa. Combination of QSMs with colistin or fluconazole was found to be effective against both single- and dual-species biofilms in vitro. Increased survival was observed in C. elegans when treated with colistin or fluconazole in combination with QSMs, compared with no treatment. Additionally, the QSMs and colistin and farnesol combinations effectively inhibited biofilm formation by C. albicans and P. aeruginosa on bronchial epithelial cells, and reduced IL-1β expression in lung bronchial epithelial cells., Conclusions: There is a need for effective treatments for bacterial-fungal biofilm infections and, to our knowledge, there have been no studies of QSMs and antimicrobial combinations against dual-species biofilms involving C. albicans and P. aeruginosa. Hence these findings will make a significant contribution to the literature., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The global increase in carbapenem resistance poses a significant public health threat due to the potential emergence of multidrug-resistant pathogens and limited treatment options. To learn more about this issue and offer potential solutions, we conducted a study of carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections in a secondary care hospital setting. The study utilized the carbapenem inactivation method (CIM), a leading phenotypic analysis, to determine carbapenemase activity in 63 CRPA isolates. Additionally, polymerase chain reaction (PCR) analysis was conducted to test for the presence of carbapenemase genes associated with the production or expression of various carbapenemase enzymes, including bla KPC , bla NDM , bla VIM , bla OXA-48 , bla IMP , and bla GES . Arbitrary primed PCR (AP-PCR) was performed to assess the clonal relationship between different isolates. The isolates were also classified as either health care-associated infections or community-acquired infections, and their clonal relationship and gene positivity were evaluated. A total of 63 CRPA samples underwent evaluation, with 14 isolates determined to be carbapenemase producers via CIM tests. PCR assays revealed that 14 isolates carried carbapenemase genes, with 9 carrying bla NDM , 2 carrying bla GES , 2 carrying bla VIM , and 1 carrying bla IMP . CRPA exhibited a 22% prevalence of carbapenemase genes, of which 64% were attributed to the NDM gene responsible for multidrug resistance. AP-PCR revealed high clonal diversity among the isolates. Molecular epidemiological evaluation also showed no dominant outbreak strain among PA isolates. This study presents significant data on the prevalence and distribution of carbapenemase-producing CRPA strains isolated from secondary health care facilities. Typically, the literature focuses on resistance rates in tertiary care public hospitals. These findings may aid in understanding resistance and its mechanisms, as well as in developing effective treatment strategies and infection control measures.

An 8-year-old spayed female Maltese dog was referred with a 4-month history of multifocal pruritic erosive or ulcerative lesions on the head, ventral neck, chest, and abdomen; and chronic otitis externa. Biopsy revealed cytotoxic dermatitis and apoptotic keratinocytes with occasional lymphocytic satellitosis. Bacterial culture and antimicrobial susceptibility tests revealed multidrug-resistant Pseudomonas aeruginosa infection of the skin and ears. The skin lesions regressed after treatment of P. aeruginosa infection with ciprofloxacin. Based on the skin lesions, histological characteristics, and response to therapy, the dog was presumed to have erythema multiforme induced by P. aeruginosa infection. This case report emphasizes that P. aeruginosa infection could be a trigger of erythema multiforme in dogs. Key clinical message: Erythema multiforme caused by infection is rare and poorly characterized in the veterinary literature. This case report describes the clinical characteristics of, diagnostic approach to, and treatment of erythema multiforme caused by Pseudomonas aeruginosa ., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Antibiotic resistance is one of the most important concerns in global health today. A growing number of infections are becoming harder to treat with conventional drugs and fewer new antibiotics are being developed. In this context, strategies based on blocking or attenuating virulence pathways that do not focus on eradication of bacteria are potential therapeutic approaches that should reduce the selective pressure exerted on the pathogen. This virulence depletion can be achieved by inhibiting the conserved quorum sensing (QS) system, a mechanism that enables bacteria to communicate with one another in a density-dependent manner. QS regulates gene expression, leading to the activation of important processes such as virulence and biofilm formation. This review highlights the approaches reported so far for disrupting different steps of the QS system of the multiresistant pathogen Pseudomonas aeruginosa. The authors describe different types of molecules (including enzymes, natural and synthetic small molecules, and antibodies) already identified as P. aeruginosa quorum quenchers (QQs) or QS inhibitors (QSIs), grouped according to the QS circuit that they block (Las, Rhl, Pqs and some examples from the controversial pathway Iqs). The discovery of new QQs and QSIs is expected to help reduce antibiotic doses, or at least to provide options that act as adjuvants to enhance the effect of antibiotic treatment. Moreover, this article outlines the advantages and possible drawbacks of each strategy and provides perspectives on the potential developments in this field in the future., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Systemic inflammation and hemodynamic or microvascular alterations are a hallmark of sepsis and play a role in organs hypoperfusion and dysfunction. Pimobendan, an inodilator agent, could be an interesting option for inotropic support and microcirculation preservation during shock. The objectives of this study were to evaluate effect of pimobendan on cytokine and nitric oxide (NO) release and investigate whether changes of macro and microcirculation parameters are associated with the release of cytokines and NO in pigs sepsis model. After circulatory failure, induced by intravenous inoculation of live Pseudomonas aeruginosa, eight animals were treated with pimobendan and eight with placebo. Pimobendan did not affect cytokines secretion (TNF-α, IL-6 and IL-10), but decreased time-dependently NO release. Data of macro and microcirculation parameters, NO and TNF- α recorded at the time of circulatory failure (T hypotension ) and the time maximum of production cytokines was used for analyses. A positive correlation was observed between TNF-α and cardiac index (r = 0.55, p = 0.03) and a negative with systemic vascular resistance (r = -0.52, p = 0.04). Positive correlations were seen both between IL-10, 30 min after resuscitation (T 30min ), and systolic arterial pressure (r = 0.57, p = 0.03) and cardiac index (r = 0.67, p = 0.01), and also between IL-6, taken 2 h after resuscitation and systolic arterial pressure (r = 0.53, p = 0.04). Negative correlations were found between IL-10 and lactate, measured resuscitation time (r = -0.58, p = 0.03). Regarding microcirculation parameters, we observed a positive correlation between IL-6 and IL-10 with the microvascular flow index (r = 0.52, p = 0.05; r = 0.84, p = 0.0003) and a negative correlation with the heterogeneity index with TNF-α and IL-10 (r = -0.51, p = 0.05; r = -0.74, p = 0.003) respectively. NO derivatives showed a positive correlation with temperature gradient (r = 0.54, p = 0.04). Pimobendan did not show anti-inflammatory effects in cytokines release. Our results also, suggest changes of macro- and microcirculation are associated mainly with low levels of IL-10 in sepsis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest related to this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is an urgent need to develop sensitive, non-invasive biomarkers that can track airway inflammatory activity for patients with cystic fibrosis (CF). Urinary glutathione sulfonamide (GSA) levels correlate well with GSA levels in BAL samples and other markers of neutrophilic inflammation, suggesting that this biomarker may be suitable for tracking disease activity in this population. We recruited 102 children (median 11.5 years-old) and 64 adults (median 32.5 years-old) who were admitted to hospital for management of an acute pulmonary exacerbation and/or eradication of infectious agents such as Pseudomonas aeruginosa or Staphylococcus aureus. Our aim was to explore how urinary GSA levels changed across admission timepoints. Urine samples were collected at admission and discharge, and GSA measured by liquid chromatography with mass spectrometry. Paired admission-discharge results were compared using Wilcoxon signed-rank test. Paired admission-discharge samples were available for 53 children and 60 adults. A statistically significant difference was observed between admission-discharge for children and adults. Spearman's correlation analysis identified a correlation between urinary GSA levels and sex and S. aureus infection for children only. Our preliminary findings suggest that urinary GSA is responsive to the resolution of an acute pulmonary exacerbation and therefore warrants further studies in this population., Competing Interests: Declaration of competing interest T.L. Blake holds a Children's Hospital Foundation ECR Fellowship for salary support and an Australian CFA Research Trust Innovation Grant for unrelated research. P.D. Sly holds NHMRC Investigator and Clinical Trials & Cohort Study grants. Authors C.E. Wainwright and S.C. Bell have received institutional payments for chairing and speaking at educational events (Vertex Pharmaceuticals). C.E. Wainwright also declares participating in steering committee and advisory board sessions for Vertex Pharmaceuticals. N. Dickerhof holds a Sir Charles Hercus Research Fellowship from the Health Research Council of New Zealand. Remaining authors I. Andersen, D.W. Reid B.R. Smith and A.J. Kettle declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Antimicrobial resistance has been an increasingly serious threat to global public health. The contribution of non-antibiotic pharmaceuticals to the development of antibiotic resistance has been overlooked. Our study found that the anti-inflammatory drug phenylbutazone could protect P. aeruginosa against antibiotic mediated killing by binding to the efflux pump regulator MexR. In this study, antibiotic activity against P. aeruginosa alone or in combination with phenylbutazone was evaluated in vitro and in vivo. Resazurin accumulation assay, transcriptomic sequencing, and PISA assay were conducted to explore the underlying mechanism for the reduced antibiotic susceptibility caused by phenylbutazone. Then EMSA, ITC, molecular dynamic simulations, and amino acid substitutions were used to investigate the interactions between phenylbutazone and MexR. We found that phenylbutazone could reduce the susceptibility of P. aeruginosa to multiple antibiotics, including parts of β-lactams, fluoroquinolones, tetracyclines, and macrolides. Phenylbutazone could directly bind to MexR, then promote MexR dissociating from the mexA-mexR intergenic region and de-repress the expression of MexAB-OprM efflux pump. The overexpressed MexAB-OprM pump resulted in the reduced antibiotic susceptibility. And the His41 and Arg21 residues of MexR were involved in the phenylbutazone-MexR interaction. We hope this study would imply the potential risk of antibiotic resistance caused by non-antibiotic pharmaceuticals., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

An 86-year-old woman with residual left hemiplegia from a prior stroke, residing in a nursing facility, presented with swelling of the right side of her neck. Tuberculous lymphadenitis was diagnosed through polymerase chain reaction analysis and sputum culture, leading to treatment with isoniazid, rifampicin, and ethambutol. After 2 months, an abscess and ulcer formed; analysis of the bacterial flora of the ulcer revealed a Pseudomonas infection. Treatment with a topical iodine-containing ointment eradicated the Pseudomonas and led to increased diversity with the emergence of species from the Eukaryota and Archaea kingdoms. Subsequently, a loss of diversity occurred, ultimately resulting in a dominance of Escherichia-Shigella. We suggest that the bacterial flora of early ulcers may be dominated by multidrug-resistant Pseudomonas. Escherichia-Shigella may emerge during the ulcer healing process. We, therefore, strongly encourage recognition of the fact that individuals with tuberculosis are immunocompromised and emphasize the critical importance of early intervention in such infections., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Objective: To characterize factors that influence the decision to treat suspected pediatric bacterial tracheostomy-associated respiratory infections (bTRAINs; e.g., pneumonia, tracheitis)., Methods: We conducted a multicenter, prospective cohort study of children with pre-existing tracheostomy hospitalized at six children's hospitals for a suspected bTRAIN (receipt of respiratory culture plus ≥1 doses of an antibiotic within 48 h). The primary predictor was respiratory culture growth categorized as Pseudomonas aeruginosa, P. aeruginosa + ≥1 other bacterium, other bacteria alone, or normal flora/no growth. Our primary outcome was bTRAIN treatment with a complete course of antibiotics as documented by the discharge team. We used logistic regression with generalized estimating equations to identify the association between our primary predictor and outcome and to identify demographic, clinical, and diagnostic testing factors associated with treatment., Results: Of the 440 admissions among 289 patients meeting inclusion criteria, 307 (69.8%) had positive respiratory culture growth. Overall, 237 (53.9%) of admissions resulted in bTRAIN treatment. Relative to a negative culture, a culture positive for P. aeruginosa plus ≥1 other organism (adjusted odds ratio [aOR] 2.3; 95% confidence interval [CI] 1.02-5.0)] or ≥1 other organism alone (aOR: 2.8; 95% CI: 1.4-5.6)] was associated with treatment. Several clinical and diagnostic testing (respiratory Gram-stain and chest radiograph) findings were also associated with treatment. Positive respiratory viral testing was associated with reduced odds of treatment (aOR: 0.5; 95% CI: 0.2-0.9)., Conclusions: Positive respiratory cultures as well as clinical indicators of acute illness and nonculture test results were associated with bTRAIN treatment. Clinicians may be more comfortable withholding antibiotics when a virus is identified during testing., (© 2024 Wiley Periodicals LLC.)