Search Results (31)

Background: Aspiration pneumonia is increasingly recognized as a fatal pulmonary disease among older people. Although antipseudomonal antibiotics are commonly used in clinical practice, their efficacy in this population remains uncertain. Methods: Nationwide data collected from patients aged ≥65 years who were hospitalized due to aspiration pneumonia from January 2018 to December 2018 were analyzed. The in-hospital mortality between patients who received antipseudomonal antibiotics within 3 days of hospital admission and those who did not were compared. A logistic regression analysis was performed to assess the effect of antipseudomonal antibiotics on in-hospital mortality after adjusting for potential prognostic confounders. Results: This study included 46,980 patients, and 13,340 (28.4%) patients received antipseudomonal antibiotics. In total, 7011 (14.9%) patients died during hospitalization. Advanced age, male sex, a lower body mass index, decreased Barthel Index, impaired consciousness, interstitial pneumonia, malignancy, renal failure, and use of immunosuppressive agents were significantly associated with increased in-hospital mortality. After adjusting for the confounders, the use of antipseudomonal antibiotics was found to be associated with an elevated in-hospital mortality (odds ratio: 1.33; 95% confidence interval: 1.26–1.41; p < 0.001). Conclusions: In this nationwide data analysis of older patients with aspiration pneumonia, early antipseudomonal antibiotic administration did not improve prognosis. Therefore, the routine use of antipseudomonal antibiotics should be avoided in older patients with aspiration pneumonia. Full article

Background/Objectives: Pseudomonas aeruginosa (Psa) can circumvent antimicrobial chemotherapy, an ability enhanced by cigarette smoking (CS). This study probed potential benefits of combinations of anti-pseudomonal agents, and potential augmentation by a macrolide, in the absence or presence of cigarette smoke condensate (CSC). Methods: Two susceptible (WT: wild-type and DS: drug-sensitive) and one multidrug-resistant (MDR) strains of Psa were treated with amikacin, cefepime, and ciprofloxacin, individually and in combination, and with and without clarithromycin, followed by the measurement of planktonic growth and biofilm formation by spectrophotometry. Antibiotic interactions were determined using the fractional inhibitory concentration index (FICI) method. Effects on preformed biofilm density were measured following the addition of antibiotics: all procedures were performed in the absence and presence of CSC. Results: The minimal inhibitory concentrations (MICs) of the three agents ranged from 0.125 mg/L to 1 mg/L (WT and DS strains) and 16 mg/L to 64 mg/L (MDR strain), with all resistant to clarithromycin (125 mg/L). MIC values closely correlated with the antibiotic concentrations required to inhibit biofilm formation. FICI revealed synergism between most combinations, with augmentation by clarithromycin. Amikacin had the greatest effect on biofilm density, which was potentiated by combination with the other antibiotics, particularly clarithromycin. Exposure to CSC had variable, albeit modest, effects on bacterial growth and biofilm formation, but low concentrations increased biofilm mass and attenuated synergistic antimicrobial interactions and effects on biofilm density. Conclusions: Amikacin, cefepime, and ciprofloxacin, especially with clarithromycin, exhibit synergistic anti-pseudomonal activity and decrease preformed biofilm density. CSC attenuated these effects, illustrating the pro-infective potential of CS. Full article

Background/Objectives: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is an important pathogen associated with high mortality and treatment failure rates. We aimed to assess the susceptibility of CRPA to antipseudomonal agents, identify its resistance mechanisms, and evaluate clinical outcomes in a sample of CRPA isolates. Methods: This was an in vitro study of a clinical isolate of CRPA from hospitalized patients with CRPA infection and a retrospective observational study of these patients, who were diagnosed between 14 February 2021 and 10 August 2023 at Songklanagarind Hospital in Songkhla, Thailand. In vitro experiments were conducted to determine the minimum inhibitory concentrations (MICs) of the antipseudomonal agents using the broth microdilution method. Resistance mechanisms were assessed using the modified carbapenem inactivation method, combined disk tests, and quantitative real-time reverse transcription polymerase chain reaction. Results: A total of 140 CRPA isolates were analyzed. Both traditional and novel β-lactams had high MICs. The most common resistance mechanism was the upregulation of the MexAB-OprM efflux pump (81.3%), followed by the downregulation of the OprD porin (48.9%) and metallo-β-lactamase (MBL) production (45.0%), and the overexpression of bla_AmpC (41.0%). The 30-day all-cause mortality rate was 30.5%. The risk factors associated with 30-day mortality included a Charlson Comorbidity Index of ≥5 (OR: 3.43; 95% CI: 1.07–10.99; p = 0.03), sepsis (OR: 10.62; 95% CI: 1.26–89.44; p = 0.03), and septic shock (OR: 4.39; 95% CI: 1.67–11.55; p < 0.01). In contrast, receiving active documented therapy was significantly associated with reduced mortality (OR: 0.17; 95% CI: 0.04–0.74; p = 0.01). Conclusions: This study revealed higher MIC values of all β-lactams for CRPA, while colistin and amikacin remained effective. The resistance mechanisms included MexAB-OprM overexpression, OprD downregulation, MBL production, and bla_AmpC overexpression, with a higher prevalence of MBL than in other regions of Thailand. High 30-day mortality was associated with comorbidities, sepsis, and septic shock, but active therapy reduced mortality. Full article

Background/Objectives: Although chronic infection by Pseudomonas aeruginosa among patients with bronchiectasis is associated with poor prognosis, the impact of antibiotics with P. aeruginosa coverage in patients with bronchiectasis who experienced bacterial pneumonia or exacerbation of bronchiectasis has not been fully investigated. Methods: This study targeted patients with bronchiectasis who were admitted to hospitals because of bacterial pneumonia or exacerbation of bronchiectasis between April 2018 and March 2020 using a national inpatient database in Japan. The association of antipseudomonal antibiotic treatment with in-hospital mortality was assessed after propensity score matching to adjust the patients’ backgrounds. Results: In total, 4943 patients with bacterial pneumonia and 1914 patients with exacerbation of bronchiectasis were included in this study. The in-hospital mortality rate did not differ between patients who did and did not receive antipseudomonal agents among patients with bacterial pneumonia (9.0% [185/2045] vs. 7.4% [151/2045]; p = 0.053) and those with exacerbation of bronchiectasis (5.2% [42/803] vs. 4.1% [33/803] group; p = 0.287). Conclusions: The use of antibiotics covering P. aeruginosa does not apparently improve prognosis in patients with bacterial pneumonia or exacerbation of bronchiectasis. A prospective study focusing on the impact of antibiotics covering P. aeruginosa among patients with bronchiectasis in whom P. aeruginosa is isolated is required. Full article

Background: Empirical antibacterial therapy for febrile neutropenia reduces mortality due to Gram-negative blood stream infections (BSIs). Pediatric guidelines recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem and to add a second anti-Gram-negative agent in selected situations. We evaluated the changes in the proportions of resistance of beta-lactam monotherapies vs. their combination with amikacin, and the possible impact on ICU admission or death. Results: 797 BSIs due to Gram-negative bacteria in 685 patients were included. Combination therapies with amikacin had a lower percentage of isolates resistant to one or to both drugs compared with the respective monotherapy. The highest OR for ICU admission was observed when both drugs of the combination of meropenem–amikacin were resistant. Mortality was significantly associated with relapse or the progression of the underlying malignancy, and resistance to both drugs of the combinations of cefepime–amikacin or meropenem–amikacin. Methods: This study was based on data collected for a large multinational study, in which the susceptibility of Gram-negative bloodstream isolates was categorized following either EUCAST or CLSI according to local laboratory standards. An escalation antibiogram was generated for each selected drug. For resistant bacteria, the conditional susceptibility probability on resistance was calculated. Conclusions: In pediatric cancer patients with Gram-negative BSIs, the proportion of the resistant organism correlates with ICU admission or death, which may be reduced by combination therapy. In patients with suspected or confirmed Gram-negative BSIs that are not-improving or deteriorating under monotherapy, escalation to meropenem may represent the best option. Amikacin should be preferred when combination therapy is considered with ciprofloxacin as an alternative in the case of impaired renal function. Full article

Inhibitors of the serine protease furin have been widely studied as antimicrobial agents due to their ability to block the cleavage and activation of certain viral surface proteins and bacterial toxins. In this study, the antipseudomonal effects and safety profiles of the furin inhibitors MI-1851 and MI-2415 were assessed. Fluorescence quenching studies suggested no relevant binding of the compounds to human serum albumin and α₁-acid glycoprotein. Both inhibitors demonstrated significant antipseudomonal activity in Madin–Darby canine kidney cells, especially compound MI-1851 at very low concentrations (0.5 µM). Using non-tumorigenic porcine IPEC-J2 cells, neither of the two furin inhibitors induced cytotoxicity (CCK-8 assay) or altered significantly the intracellular (Amplex Red assay) or extracellular (DCFH-DA assay) redox status even at a concentration of 100 µM. The same assays with MI-2415 conducted on primary human hepatocytes also resulted in no changes in cell viability and oxidative stress at up to 100 µM. Microsomal and hepatocyte-based CYP3A4 activity assays showed that both inhibitors exhibited a concentration-dependent inhibition of the isoenzyme at high concentrations. In conclusion, this study indicates a good safety profile of the furin inhibitors MI-1851 and MI-2415, suggesting their applicability as antimicrobials for further in vivo investigations, despite some inhibitory effects on CYP3A4. Full article

Antibiotic resistance is a critical public health issue. Among the multi-drug resistant microorganisms in question, Pseudomonas aeruginosa has been designated by the WHO as a priority threat. Its virulence is orchestrated through quorum sensing (QS). This sophisticated communication network relies on the release and perception of autoinducers acting as population density indicators. Therefore, the interest of a quorum silencing pharmacological approach has unfolded to quench bacterial pathogenicity without impairing growth. In this article, we reported the development of a family of indazole–quinolone hybrids as anti-virulence agents. These new biaromatic compounds were designed as potential specific QS quenchers against P. aeruginosa. Our transdisciplinary research methodology included their synthesis using palladocatalyzed cross-coupling reactions, as well as their in silico physicochemical and in vitro biological evaluation. The hit 7-chloro-2-indazolyl-4-quinolone Ie shows a promising anti-biofilm and anti-pyocyanin efficiency (35% inhibition at 25 µM and 35% inhibition at 100 µM, respectively) without an anti-pseudomonal bacteriostatic effect. It also demonstrated a moderate eukaryotic cytotoxicity. Its anti-QS properties have been investigated using metabolomic and molecular modelling studies. Full article

Co-infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) and Pseudomonas aeruginosa (CRPA) is associated with poor outcomes and historically relied on combination therapy with toxic agents for management. However, several novel β-lactam/β-lactamase inhibitor combination agents have been developed, offering potential monotherapy options. Here, we compare the in vitro activity of ceftazidime-avibactam (CZA), imipenem-relebactam (IRL), and meropenem-vaborbactam (MVB) against both CRKP and CRPA clinical isolates. Minimum inhibitory concentrations (MICs) for each agent were determined using broth microdilution. Carbapenemase gene detection was performed for representative isolates of varying carbapenem resistance phenotypes. IRL demonstrated excellent activity against CRKP and CRPA with susceptibility rates at 95.8% and 91.7%, respectively. While CZA and MVB showed comparable susceptibility to IRL against CRKP (93.8%), susceptibility of CRPA to CZA was modest at 79.2%, whereas most CRPA strains were resistant to MVB. Of the 35 CRKP isolates tested, 91.4% (32/35) carried a bla_KPC gene. Only 1 of 37 (2.7%) CRPA isolates tested carried a bla_VIM gene, which conferred phenotypic resistance to all three agents. None of the CRKP strains were cross-resistant to all three agents. Source of infection and co-infection did not significantly influence antimicrobial activity for IRL and CZA; none of the CRPA isolates from co-infected patients were susceptible to MVB. Our results suggest that novel β-lactam agents with antipseudomonal activity and stability against carbapenemases, such as IRL and CZA, offer potential monotherapy options for the treatment of co-infection involving both CRKP and CRPA, but not MVB. Full article

Both Mucorales and Gram-negative rods (GNRs) commonly infect patients with hematological malignancies (HM); however, their co-occurrence is understudied. Therefore, we retrospectively reviewed the records of 63 patients with HM and proven or probable sinopulmonary mucormycosis at MD Anderson Cancer Center (Houston, Texas) from 2000–2020. Seventeen out of sixty-three reviewed patients (27.0%) had sinopulmonary co-occurrence of GNRs (most commonly Pseudomonas aeruginosa and Stenotrophomonas maltophilia) within 30 days of a positive Mucorales culture or histology demonstrating Mucorales species. Eight of seventeen co-isolations of Mucorales and GNRs were found in same-day samples. All 15 patients with GNR co-occurrence and reported antimicrobial data had received anti-Pseudomonal agents within 14 days prior to diagnosis of mucormycosis and 5/15 (33.3%) had received anti-Stenotrophomonal agents. Demographic and clinical characteristics of patients with and without GNR co-occurrence were comparable. Forty-two-day all-cause mortality was high (34.9%) and comparable in patients with (41.2%) and without (32.6%) GNR detection (p = 0.53). In summary, over a quarter of heavily immunosuppressed patients with sinopulmonary mucormycosis harbored GNRs in their respiratory tract. Although no impact on survival outcomes was seen in a background of high mortality in our relatively underpowered study, pathogenesis studies are needed to understand the mutualistic interplay of GNR and Mucorales and their influence on host responses. Full article

Outpatient parenteral antimicrobial therapy (OPAT) is a useful treatment strategy against Pseudomonas aeruginosa and other multidrug-resistant bacteria. However, it is hindered by the lack of stability data for the administration of antibiotics under OPAT conditions. Our objective was to investigate the stability of nine antipseudomonal and broad-spectrum beta lactam antibiotics (aztreonam, cefepime, cefiderocol, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, meropenem/vaborbactam, and piperacillin/tazobactam) to allow the spread of OPAT programs. All the antibiotics were diluted in 500 mL 0.9% sodium chloride and stored at 4, 25, 32, and 37 °C for 72 h in two different devices (infusion bags and elastomeric pumps). The solutions were considered stable if the color, clearness, and pH remained unchanged and if the percentage of intact drug was ≥90%. All the antimicrobials remained stable 72 h under refrigerated conditions and at least 30 h at 25 °C. At 32 °C, all the antibiotics except for meropenem and meropenem/vaborbactam remained stable for 24 h or more. At 37 °C, only aztreonam, piperacillin/tazobactam, cefepime, cefiderocol, and ceftolozane/tazobactam were stable for at least 24 h. The stability results were the same in the two devices tested. All the antibiotics studied are actual alternatives for the treatment of antipseudomonal or multidrug-resistant infections in OPAT programs, although the temperature of the devices is crucial to ensure antibiotic stability. Full article

Hospital-acquired infections caused by P. aeruginosa contribute to global distress because of the elevated rates of microbial antibiotic resistance. Aminoglycosides are antipseudomonal agents that are effectively and frequently utilized to eradicate this infection. This current study is a retrospective study investigating plasmid-mediated aminoglycoside resistance by focusing on the prevalence of the genes encoding aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methylase among P. aeruginosa clinical isolates from Taif, Saudi Arabia. A hundred clinical isolates of P. aeruginosa were collected. The isolates were identified from February 2021 to February 2022. Antibiotic susceptibility testing and MICs were determined using (DD) and (BM-MIC) testing, respectively. AMEs and 16S rRNA methylase variants in bacterial isolates were amplified via PCR for genetic detection. A relatively high multiple antibiotic resistance rate corresponding to 10–32% was reported. Eighteen percent of P. aeruginosa isolates were gentamicin–amikacin–tobramycin resistant according to the MIC levels. The aminoglycoside-resistant strains were additionally identified via GyrA gene sequencing. The phylogenic relatedness dendrogram of the sequenced GyrA genes was performed using a neighbor-joining method via MEGAX software version 10.2.6. The most prevalent AME encoding gene was aac(6′)-Ib, observed in 94.4% of resistant isolates, while a resistance gene cocktail of [aac(6′)-Ib and ant(3″)-I] was a highly frequent combination (27.8%). This study updated the knowledge about aminoglycoside resistance mechanisms in P. aeruginosa, which constitutes an urgent need, especially after the COVID-19 crisis, which was associated with increased antimicrobial use and resistance rates. Full article

Low molecular weight alginate oligosaccharides have been shown to exhibit anti-microbial activity against a range of multi-drug resistant bacteria, including Pseudomonas aeruginosa. Previous studies suggested that the disruption of calcium (Ca²⁺)–DNA binding within bacterial biofilms and dysregulation of quorum sensing (QS) were key factors in these observed effects. To further investigate the contribution of Ca²⁺ binding, G-block (OligoG) and M-block alginate oligosaccharides (OligoM) with comparable average size DPn 19 but contrasting Ca²⁺ binding properties were prepared. Fourier-transform infrared spectroscopy demonstrated prolonged binding of alginate oligosaccharides to the pseudomonal cell membrane even after hydrodynamic shear treatment. Molecular dynamics simulations and isothermal titration calorimetry revealed that OligoG exhibited stronger interactions with bacterial LPS than OligoM, although this difference was not mirrored by differential reductions in bacterial growth. While confocal laser scanning microscopy showed that both agents demonstrated similar dose-dependent reductions in biofilm formation, OligoG exhibited a stronger QS inhibitory effect and increased potentiation of the antibiotic azithromycin in minimum inhibitory concentration and biofilm assays. This study demonstrates that the anti-microbial effects of alginate oligosaccharides are not purely influenced by Ca²⁺-dependent processes but also by electrostatic interactions that are common to both G-block and M-block structures. Full article

Pseudomonas aeruginosa (P. aeruginosa) poses a grave clinical challenge due to its multidrug resistance (MDR) phenotype, leading to severe and life-threatening infections. This bacterium exhibits both intrinsic resistance to various antipseudomonal agents and acquired resistance against nearly all available antibiotics, contributing to its MDR phenotype. Multiple mechanisms, including enzyme production, loss of outer membrane proteins, target mutations, and multidrug efflux systems, contribute to its antimicrobial resistance. The clinical importance of addressing MDR in P. aeruginosa is paramount, and one pivotal determinant is the resistance-nodulation-division (RND) family of drug/proton antiporters, notably the Mex efflux pumps. These pumps function as crucial defenders, reinforcing the emergence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) strains, which underscores the urgency of the situation. Overcoming this challenge necessitates the exploration and development of potent efflux pump inhibitors (EPIs) to restore the efficacy of existing antipseudomonal drugs. By effectively countering or bypassing efflux activities, EPIs hold tremendous potential for restoring the antibacterial activity against P. aeruginosa and other Gram-negative pathogens. This review focuses on concurrent MDR, highlighting the clinical significance of efflux pumps, particularly the Mex efflux pumps, in driving MDR. It explores promising EPIs and delves into the structural characteristics of the MexB subunit and its substrate binding sites. Full article

The corneal epithelium is a layer in the anterior part of eye that contributes to light refraction onto the retina and to the ocular immune defense. Although an intact corneal epithelium is an excellent barrier against microbial pathogens and injuries, corneal abrasions can lead to devastating eye infections. Among them, Pseudomonas aeruginosa-associated keratitis often results in severe deterioration of the corneal tissue and even blindness. Hence, the discovery of new drugs able not only to eradicate ocular infections, which are often resistant to antibiotics, but also to elicit corneal wound repair is highly demanded. Recently, we demonstrated the potent antipseudomonal activity of two peptides, Esc(1-21) and its diastereomer Esc(1-21)-1c. In this study, by means of a mouse model of P. aeruginosa keratitis and an in vivo corneal debridement wound, we discovered the efficacy of these peptides, particularly Esc(1-21)-1c, to cure keratitis and to promote corneal wound healing. This latter property was also supported by in vitro cell scratch and ELISA assays. Overall, the current study highlights Esc peptides as novel ophthalmic agents for treating corneal infection and injury, being able to display a dual function, antimicrobial and wound healing, rarely identified in a single peptide at the same micromolar concentration range. Full article

As a follow-up to previous studies, the effects of Thymus vulgaris essential oil on selected virulence factors (growth, sessile cell survival, swimming, swarming, and exopolysaccharide production) were evaluated in phytopathogenic Pseudomonas syringae strains isolated from soybean fields in Argentina; reference strains Pseudomonas savastanoi pv. glycinea B076 and Pseudomonas aeruginosa PAO1. P. syringae are responsible for bacterial blight, a disease that affects crops worldwide. Plant bacterioses are usually treated with antibiotics and copper compounds, which may contribute to the development of resistance in pathogens and damage the environment. For these reasons, eco-friendly alternatives are necessary. Although aromatic plants are a natural source of antimicrobial substances, the effects of these substances on phytopathogenic bacteria remain largely unexplored. Subinhibitory concentrations of the oil significantly reduced the slope and rate of bacterial growth. In addition, biofilm and exopolysaccharide (EPS) production were inhibited, with swimming and swarming motility patterns being affected at all of the oil concentrations tested. Therefore, TEO could potentially be a highly efficient antipseudomonal agent for treating plant infections caused by P. syringae. Full article