Antimicrobial efficacy of aloe-emodin mediated photodynamic therapy against antibiotic-resistant Pseudomonas aeruginosa in vitro.

Multidrug-resistant Pseudomonas aeruginosa is a common pathogen that causes topical infections following burn injuries. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach for treating antibiotic-resistant bacterial infections. The objective of this study was to evaluate the aPDT efficacy of aloe-emodin (AE), which is a photosensitizer extracted from traditional Chinese herbs, on antibiotic-sensitive and antibiotic-resistant P. aeruginosa in vitro. In this study, we confirmed the effectiveness of AE-mediated aPDT against both standard and MDR P. aeruginosa, explored the effects of irradiation time and AE concentration on bacterial survival in AE-mediated aPDT, and observed the structural damage of P. aeruginosa by using transmission electron microscope. Our results showed that neither AE nor light irradiation alone caused cytotoxic effects on P. aeruginosa. However, AE-mediated aPDT effectively inactivated both antibiotic-sensitive and antibiotic-resistant P. aeruginosa. The transmission electron microscope investigation showed that aPDT mediated by AE primarily caused damage to the cytoplasm and cell membrane. Our findings suggest that AE is a photosensitizer in the aPDT of MDR P. aeruginosa-caused topical infections following burn injuries. Future investigations will concentrate on the safety and efficacy of AE-mediated aPDT in animal models and clinical trials.

Ceftazidime-avibactam in the treatment of bacteremia due to carbapenem-resistant gram-negative bacteria in hematological patients: Experience in a single center.

INTRODUCTION: Limited experience exists with ceftazidime-avibactam (CAZ-AVI) in treating bacteremia caused by carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) in hematological patients. METHODS: We performed a single-center, retrospective, observational study including patients who received CAZ-AVI for bacteremia due to CRE or CRPA between 2018 and 2022. The primary outcome was 30-day survival. We conducted a multivariable analysis to identify predictors of survival. RESULTS: 56 patients were included and 57 (41 CRE and 16 CRPA) strains were isolated. 35 strains produced carbapenemase, including 25 metallo-beta-lactamase (MBL) and 10 serine-beta-lactamase. 48 patients (85.7 %) received combination therapy. All patients with MBL-CRE bacteremia (n = 24) received combination therapy with aztreonam (AZT). The susceptibility rates to CAZ-AVI were only 26.8 % (11/41) in CRE and 80.0 % (8/10) in CRPA. The 30-day survival rates were 85.0 % (34/40) in the CRE group and 81.3 % (13/16) in the CRPA group. In patients with MBL-CRE bacteremia, the 30-day survival was as high as 91.7 % (22/24) due to combination with AZT. Ceftazidime did not influence the activity of aztreonam-avibactam against MBL-CRE in-vitro. Multivariable cox analysis revealed neutropenia >14 days (P = 0.002, HR: 34.483, 95%CI: 3.846-333.333) and a higher Pitt bacteremia score (P = 0.005, HR: 2.074, 95%CI: 1.253-3.436) were risk factors for 30-day survival. CONCLUSIONS: CAZ-AVI is highly effective in treating bacteremia due to CRPA and serine-beta-lactamase CRE. The combination of avibactam with AZT is highly effective in treating bacteremia due to AZT-resistant MBL producers.

Update of clinical application in ceftazidime-avibactam for multidrug-resistant Gram-negative bacteria infections.

PURPOSE: Multidrug-resistant Gram-negative bacteria (MDR-GNB) have become a major global public health threat. Ceftazidime-avibactam (CAZ-AVI) is a newer combination of ß-lactam/ß-lactamase inhibitor, with activity against carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA). The aim of this review is to describe the recent real-world experience of CAZ-AVI for the infections due to MDR-GNB. METHODS: We searched PubMed, Embase and Google Scholar for clinical application in CAZ-AVI for MDR-GNB infections. Reference lists were reviewed and synthesized for narrative review. RESULTS: MDRGNB infections are associated with higher mortality significantly comparing to drug-susceptible bacterial infections. Fortunately, CAZ-AVI shows significant benefits for infections due to KPC or OXA-48 CRE, comparing to colistin, carbapenem, aminoglycoside and other older agents, even in those with immunocompromised status. The efficacy of CAZ-AVI varies in different infection sites due to CRE, which is lower in pneumonia. Early use is associated with improved clinical outcomes. Noteworthy, when adopted as salvage therapy, CAZ-AVI is still superior to other GNB active antibiotics. CAZ-AVI plus aztreonam is recommended as the first line of MBL-CRE infections. However, for infections caused by KPC- and OXA-48-producing isolates, further investigations are needed to demonstrate the benefit of combination therapy. Besides CRE, CAZ-AVI is also active to MDR-PA. However, the development of resistance in CRE and MDR-PA against CAZ-AVI is alarming, and more investigations and studies are needed to prevent, diagnose, and treat infections due to CAZ-AVI-resistant pathogens. CONCLUSIONS: CAZ-AVI appears to be a valuable therapeutic option in MDR-GNB infections. Using CAZ-AVI appropriately to improve efficacy and decrease the emergence of resistance is important.

Part I Antimicrobial resistance: Bacterial pathogens of dermatologic significance and implications of rising resistance.

Although the COVID-19 pandemic has been the defining global health crisis of our time, public health officials have been sounding the alarm of another ominous threat for years: an impending antimicrobial resistance crisis. In dermatology, antibiotics are often used for prolonged courses in the treatment of skin and soft tissue infections and common inflammatory skin conditions, increasing the risk of microbiome alteration and antibiotic-related adverse effects, all while exerting consequential selective pressures on both pathogenic and bystander bacteria. In this review, we hope to raise awareness of the crisis of antimicrobial resistance and review resistance concerns related to dermatology-relevant bacterial pathogens.

Successful treatment of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa after allogeneic hematopoietic stem cell transplantation with colistin and amikacin inhalation therapy.

Pseudomonas aeruginosa is a Gram-negative bacillus that often causes severe infections during immunosuppression in patients with hematologic malignancies. P. aeruginosa can easily acquire drug resistance, and often develops into multidrug-resistant P. aeruginosa (MDRP). Although many antibiotics are used in combination to treat MDRP infections, colistin and amikacin are less likely to be transferred to the lungs, and inhalation therapy may be used. Herein, we report a Case of pneumonia caused by MDRP after allogeneic hematopoietic stem cell transplantation (HSCT) treated with inhaled colistin and amikacin. This 61-year-old female patient was diagnosed with myelodysplastic syndromes and underwent allogeneic HSCT from an 8/8 HLA-matched unrelated donor after reduced-intensity conditioning. On the day of the stem cell infusion, the patient's sputum culture was found to be positive for MDRP. The patient subsequently developed bacteremia, pneumonia, and lung abscess caused by MDRP, and we administered multidrug antibiotic therapy including colistin and amikacin inhalation therapy. The patient's blood cultures were subsequently turned negative, and the lung abscess disappeared. To our knowledge, this is the first case of MDRP pneumonia after HSCT in which colistin and amikacin inhalation therapy was effective.

Reducing the urine collection rate could prevent hospital-acquired horizontal transmission of multidrug-resistant Pseudomonasaeruginosa.

INTRODUCTION: Multidrug-resistant Pseudomonas aeruginosa (MDRP) is a waterborne pathogen that occasionally causes hospital-acquired infection in immunocompromised or critically ill patients. Urine is frequently collected to evaluate renal function or to perform hormonal examinations, but the procedure involves risk due to the possibility of healthcare workers with contaminated hands. Our objective was to evaluate the association between the urine collection and hospital-acquired horizontal transmission of MDRP. METHODS: We monitored the urine collection rate from 2011 to 2017, as part of ongoing efforts to reduce the need to collect urine. The urine collection rate and the frequency of isolation of MDRP, Methicillin resistant S. aureus (MRSA) and extended spectrum ß-lactamases (ESBL)-producing E. coli were analyzed during the same period. PFGE and MLST were also performed to analyze the identity of 5 MDRP strains detected on the same ward in 2014-2015. RESULTS: The urine collection rate was dramatically decreased from 4.8% in 2011 to less than 0.5% in 2017, because the isolation rate of MDRP was significantly positively associated (RR = 1.72, 95%CI:1.03-2.85) with the urine collection rate. Isolations of MRSA and ESBL-producing E. coli showed no significant. Molecular typing showed the PFGE patterns of 3 of 5 MDRP strains were closely related as did MLST (ST17), and the remaining 2 MDRP strains had different PFGE and MLST patterns (ST14, ST655). Our data implicated the urine collection as one of the causes of hospital-acquired MDRP infections. CONCLUSIONS: We concluded that a reducing the urine collection rate could contribute to preventing hospital-acquired horizontal transmission of MDRP.

Efficacy of Vaporized Hydrogen Peroxide Combined with Silver Ions against Multidrug-Resistant Gram-Negative and Gram-Positive Clinical Isolates.

Antimicrobial resistance (AMR) is a serious public health problem that results in high morbidity and mortality rates. In particular, multidrug-resistant (MDR) strains circulating in hospital settings pose a major threat as they are associated with serious nosocomial infections. Therefore, regular cleaning and disinfection procedures, usually using chemical disinfectants, must be implemented in these facilities. Hydrogen peroxide (HP)-based disinfectants have proven high microbicidal activity and several comparative advantages over conventional disinfectants. We assessed the in vitro biocidal activity of an 8% HP solution combined with 30 mg/L silver ions (HP + Ag) against MDR clinical isolates of Klebsiella pneumoniae (MDRKp) and Pseudomonas aeruginosa (MDRPa), and methicillin-resistant Staphylococcus aureus (MRSA). Accordingly, the in vitro antibacterial activity was determined using the macrodilution method, and the efficacy was determined for 30 min in terms of (1) activity on bacteria in suspension and (2) activity on surfaces using vaporized HP + Ag on a 20 cm2 stainless steel surface. A strong bactericidal effect of HP + Ag was observed against MDRKp, MDRPa, and MRSA strains, with minimum inhibitory concentrations and minimum bactericidal concentrations between 362.5 and 5800 mg/L. A strong effect was observed during the 30 min of HP + Ag exposure to the resistant clinical isolates, with over 4-Log10 reduction in CFUs. Regarding the efficacy of the disinfectant on surfaces, bacterial load reductions of >99% were observed. These results suggest that HP + Ag is potentially useful as an effective disinfectant for decontaminating surfaces in hospital settings suspected of contamination with MDR bacteria.

A Heme-Acquisition Protein Reconstructed with a Cobalt 5-Oxaporphyrinium Cation and Its Growth-Inhibition Activity Toward Multidrug-Resistant Pseudomonas aeruginosa.

Using artificial hemes for the reconstruction of natural heme proteins represents a fascinating approach to enhance the bioactivity of the latter. We report the synthesis of various metal 5-oxaporphyrinium cations as cofactors, and a cobalt 5-oxaporphyrinium cation was successfully incorporated into the heme-acquisition protein (HasA) secreted by Pseudomonas aeruginosa. We hypothesize that the oxaporphyrinium cation strongly binds to the HasA-specific outer membrane receptor (HasR) due to its cationic charge, which prevents the subsequent acquisition of heme. In fact, the reconstructed HasA inhibited the growth of Pseudomonas aeruginosa and even of multidrug-resistant P. aeruginosa.

Real-World Experience with Ceftolozane-Tazobactam for Multidrug-Resistant Gram-Negative Bacterial Infections.

Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.

Antibacterial Activity of a Cationic Antimicrobial Peptide against Multidrug-Resistant Gram-Negative Clinical Isolates and Their Potential Molecular Targets.

Antimicrobial resistance reduces the efficacy of antibiotics. Infections caused by multidrug-resistant (MDR), Gram-negative bacterial strains, such as Klebsiella pneumoniae (MDRKp) and Pseudomonas aeruginosa (MDRPa), are a serious threat to global health. However, cationic antimicrobial peptides (CAMPs) are promising as an alternative therapeutic strategy against MDR strains. In this study, the inhibitory activity of a cationic peptide, derived from cecropin D-like (ΔM2), against MDRKp and MDRPa clinical isolates, and its interaction with membrane models and bacterial genomic DNA were evaluated. In vitro antibacterial activity was determined using the broth microdilution test, whereas interactions with lipids and DNA were studied by differential scanning calorimetry and electronic absorption, respectively. A strong bactericidal effect of ΔM2 against MDR strains, with minimal inhibitory concentration (MIC) and minimal bactericidal concentrations (MBC) between 4 and 16 µg/mL, was observed. The peptide had a pronounced effect on the thermotropic behavior of the 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG) membrane models that mimic bacterial membranes. Finally, the interaction between the peptide and genomic DNA (gDNA) showed a hyperchromic effect, which indicates that ΔM2 can denature bacterial DNA strands via the grooves.

Cationic antimicrobial peptides: alternatives and/or adjuvants to antibiotics active against methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa.

BACKGROUND: Methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa are becoming difficult to treat with antibiotics whereas Cationic Antimicrobial Peptides (CAMPs) represent promising alternatives. The effects of four CAMPs (LL-37: human cathelicidin, CAMA: cecropin(1-7)-melittin A(2-9) amide, magainin-II and nisin) were investigated against clinical and laboratory S. aureus (n = 10) and P. aeruginosa (n = 11) isolates either susceptible or resistant to antibiotics. Minimal Inhibitory Concentrations (MICs), Minimal Bactericidal Concentrations (MBCs), and bacterial survival rates (2 h post-treatment) were determined by microbroth dilution. The antipseudomonal effects of the antibiotics colistin or imipenem combined to LL-37 or CAMA were also studied. The toxicity of CAMPs used alone and in combination with antibiotics was evaluated on two human lung epithelial cell lines by determining the quantity of released cytoplasmic lactate dehydrogenase (LDH). Attempts to induce bacterial resistance to gentamicin, LL-37 or CAMA were also performed. RESULTS: The results revealed the rapid antibacterial effect of LL-37 and CAMA against both antibiotic susceptible and resistant strains with almost a total reduction in bacterial count 2 h post-treatment. Magainin-II and nisin were less active against tested strains. When antibiotics were combined with LL-37 or CAMA, MICs of colistin decreased up to eight-fold and MICs of imipenem decreased up to four-fold. Cytotoxicity assays revealed non-significant LDH-release suggesting no cell damage in all experiments. Induction of bacterial resistance to LL-37 was transient, tardive and much lower than that to gentamicin and induction of resistance to CAMA was not observed. CONCLUSION: This study showed the potent and rapid antibacterial activity of CAMPs on both laboratory and clinical isolates of S. aureus and P. aeruginosa either susceptible or resistant to antibiotics. Most importantly, CAMPs synergized the efficacy of antibiotics, had non toxic effects on human cells and were associated with transient and low levels of induced resistance.

Successful adjunctive use of bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient.

INTRODUCTION: We describe the use of bacteriophage therapy in a 26-year-old cystic fibrosis (CF) patient awaiting lung transplantation. HOSPITAL COURSE: The patient developed multidrug resistant (MDR) Pseudomonas aeruginosa pneumonia, persistent respiratory failure, and colistin-induced renal failure. We describe the use of intravenous bacteriophage therapy (BT) along with systemic antibiotics in this patient, lack of adverse events, and clinical resolution of infection with this approach. She did not have recurrence of pseudomonal pneumonia and CF exacerbation within 100 days following the end of BT and underwent successful bilateral lung transplantation 9 months later. CONCLUSION: Given the concern for MDR P. aeruginosa infections in CF patients, BT may offer a viable anti-infective adjunct to traditional antibiotic therapy.

Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria.

BACKGROUND: Avian ß-defensins (AvBD) are cationic antimicrobial peptides (CAMP) with broad-spectrum antimicrobial activity, chemotactic property, and low host cytotoxicity. However, their bactericidal activity is greatly compromised under physiological salt concentrations which limits the use of these peptides as therapeutic agents. The length and the complex structure involving three conserved disulfide bridges are additional drawbacks associated with high production cost. In the present study, short linear CAMPs (11 to 25 a.a. residues) were developed based on the key functional components of AvBDs with additional modifications. Their biological functions were characterized. RESULTS: CAMP-t1 contained the CCR2 binding domain (N-terminal loop and adjacent α-helix) of AvBD-12 whereas CAMP-t2 comprised the key a.a. residues responsible for the concentrated positive surface charge and hydrophobicity of AvBD-6. Both CAMP-t1 and CAMP-t2 demonstrated strong antimicrobial activity against Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus pseudintermedius. However, CAMP-t1 failed to show chemotactic activity and CAMP-t2, although superior in killing Staphylococcus spp., remained sensitive to salts. Using an integrated design approach, CAMP-t2 was further modified to yield CAMP-A and CAMP-B which possessed the following characteristics: α-helical structure with positively and negatively charged residues aligned on the opposite side of the helix, lack of protease cutting sites, C-terminal poly-Trp tail, N-terminal acetylation, and C-terminal amidation. Both CAMP-A and CAMP-B demonstrated strong antimicrobial activity against multidrug-resistant P. aeruginosa and methicillin-resistant S. pseudintermedius (MRSP) strains. These peptides were resistant to major proteases and fully active at physiological concentrations of NaCl and CaCl2. The peptides were minimally cytotoxic to avian and murine cells and their therapeutic index was moderate (≥ 4.5). CONCLUSIONS: An integrated design approach can be used to develop short and potent antimicrobial peptides, such as CAMP-A and CAMP-B. The advantageous characteristics, including structural simplicity, resistance to salts and proteases, potent antimicrobial activity, rapid membrane attacking mode, and moderate therapeutic index, suggest that CAMP-A and CAMP-B are excellent candidates for development as therapeutic agents against multidrug-resistant P. aeruginosa and methicillin-resistant staphylococci.

Control of Multidrug-Resistant Pseudomonas aeruginosa in Allogeneic Hematopoietic Stem Cell Transplant Recipients by a Novel Bundle Including Remodeling of Sanitary and Water Supply Systems.

Background: Infections by multidrug-resistant Pseudomonas aeruginosa (MDRPa) are an important cause of morbidity and mortality in patients after allogeneic hematopoietic stem cell transplantation (HSCT). Humid environments can serve as a reservoir and source of infection by this pathogen. To minimize the risk of infection from these reservoirs, we performed extensive remodeling of sanitation and water installations as the focus of our hygiene bundle. Methods: During the reconstruction of our transplantation unit (April 2011-April 2014) we implemented several technical modifications to reduce environmental contamination by and subsequent spreading of MDRPa, including a newly designed shower drain, disinfecting siphons underneath the sinks, and rimless toilets. During a 3-year study period (2012-2014), we tracked the number of patients affected by MDRPa (colonized and/or infected) and the outcome of infected patients, and monitored the environmental occurrence of this pathogen. We further performed whole-genome sequencing of nosocomial MDRPa strains to evaluate genotypic relationships between isolates. Results: Whereas 31 (9.2%; 18 colonized, 13 infected) patients were affected in 2012 and 2013, the number decreased to 3 in 2014 (17%; 3 colonized, 0 infected). Lethality by MDRPa similarly decreased from 3.6% to 0%. Environmental detection of MDRPa decreased in toilets from 18.9% in 2012-2013 to 6.1% in the following year and from 8.1% to 3.0%, respectively, in shower outlets. Whole-genome sequencing showed close relationships between environmental and patient-derived isolates. Conclusions: Hospital construction measures aimed at controlling environmental contamination by and spread of MDRPa are effective at minimizing the risk of highly lethal MDRPa infections.

Multidrug-resistant organisms in allogeneic hematopoietic cell transplantation.

OBJECTIVE: Multidrug-resistant organisms (MDRO) are a challenge in allogeneic hematopoietic cell transplantation (HCT). However, in the literature there is no comprehensive analysis on MDRO in HCT. In this retrospective, single-center analysis, we appraised prevalence and clinical impact of MDRO in 98 consecutive allogeneic HCT patients. METHOD: Prior to the conditioning (baseline) and whenever clinically indicated patients underwent a full screening for MDRO (stool and urine cultures, swabs from several body regions). RESULTS: It turned out that 26 patients were colonized by 33 MDRO, either at baseline (n=16) or at any other time until day 100 post-transplantation. Of these 26 patients, eight developed an infection with MDRO, four of them by 4MRGN Pseudomonas aeruginosa, and three of them died MDRO-related. However, there was no significant difference between MDRO-colonized and non-colonized patients regarding overall survival (OS) and non-relapse-mortality (NRM). There was only a trend toward a higher NRM in patients already colonized by MDRO at baseline. This was due to the high NRM in multidrug-resistant P. aeruginosa-colonized patients. CONCLUSION: In summary, colonization with MDRO other than P. aeruginosa had no negative impact on NRM and OS. Patients colonized by multidrug-resistant P. aeruginosa had a dismal outcome. HCT of these patients should be considered with care. Screening for MDRO in the pretransplant work-up is suggested.

Successful treatment of multidrug-resistant Pseudomonas aeruginosa breakthrough bacteremia with ceftolozane/tazobactam.

INTRODUCTION: Ceftolozane/tazobactam is a novel antibiotic approved for the treatment of complicated intra-abdominal and complicated urinary tract infections. CASE DESCRIPTION: We describe the use of off-label ceftolozane/tazobactam in the management of a multidrug-resistant Pseudomonas aeruginosa bacteremia that was already being treated with colistin and amikacin, the only active antibiotics according to the antibiogram.

Colistin loading dose enhanced antimicrobial activity for in vivo mouse thigh infection model with Pseudomonas aeruginosa with highly antimicrobial resistant.

This is the first report to test the loading dosage of colistin against Pseudomonas aeruginosa, including MDRP. Using in vivo murine thigh infection model, in the loading dosage regimen (Day 1:50 mg/kg q12 h, Day 2-3: 25 mg/kg q12 h) group, 5 to 6 log10 CFU/ml reduction compared with control were observed for both strains of P. aeruginosa with colistin MIC 0.5 and 1 µg/mL at 72 h. But, similar reduction was observed for the strains with colistin MIC 0.5 µg/mL only in normal dosage regimen (Day 1-3: 25 mg/kg q12 h) group. For P. aeruginosa with colistin MIC 1 µg/mL, colistin loading dosage regimens showed greater antimicrobial activity than that of without loading dosage group (p < 0.05). These data suggest that the colistin loading regimen would be one of the useful options for P. aeruginosa with antimicrobial resistance infection treatment.

Mechanism of Qiguiyin Decoction Sensitizing Levofloxacin Against Multidrug-Resistant Pseudomonas aeruginosa Infection Based on PK-PD and Antibody Chip Technology.

Background: Qiguiyin decoction (QGYD) is a traditional Chinese medicine (TCM) and its combined application with levofloxacin (LVFX) has been confirmed effective in the clinical treatment of multidrug-resistant Pseudomonas aeruginosa (MDR PA) infection. This study investigated the therapeutic effect and possible mechanism of QGYD in sensitizing LVFX against MDR PA infection. Materials and Methods: Pulmonary infections were induced in rats by MDR PA. The changes in pharmacokinetics-pharmacodynamics (PK-PD) parameters of LVFX after combined with QGYD were investigated in MDR PA-induced rats. Subsequently, the correlation between PK and PD was analyzed and PK-PD models were established to elucidate the relationship between QGYD-induced alterations in LVFX metabolism and its sensitization to LVFX. Antibody chip technology was used to detect the levels of inflammatory factors, suggesting the relationship between the beneficial effect of immune regulation and the sensitization of QGYD. Results: QGYD significantly enhanced the therapeutic efficacy of LVFX against MDR PA infection. The combination of QGYD changed the PK parameters of LVFX such as Tmax, t1/2, MRT, Vd/F, CL/F and PD parameters such as MIC, AUC0-24h/MIC. Predicted results from PK-PD models demonstrated that the antibacterial effect of LVFX was significantly enhanced with the combination of QGYD, consistent with experimental findings. Antibody chip results revealed that the combination of QGYD made IL-1 ß, IL-6, TNF- α, IL-10, and MCP-1 levels more akin to those of the blank group. Conclusion: These findings indicated that QGYD could change the PK-PD behaviors of LVFX and help the body restore immune balance faster. This implied that a potential drug interaction might occur between QGYD and LVFX, leading to improved clinical efficacy when combined.

The Guardian of Vision: Intelligent Bacteriophage-Based Eyedrops for Clinical Multidrug-Resistant Ocular Surface Infections.

Clinical multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is the leading cause of refractory bacterial keratitis (BK). However, the reported BK treatment methods lack biosecurity and bioavailability, which usually causes irreversible visual impairment and even blindness. Herein, for BK caused by clinically isolated MDR-PA infection, armed phages are modularized with the type I photosensitizer (PS) ACR-DMT, and an intelligent phage eyedrop is developed for combined phagotherapy and photodynamic therapy (PDT). These eyedrops maximize the advantages of bacteriophages and ACR-DMT, enabling more robust and specific targeting killing of MDR-PA under low oxygen-dependence, penetrating and disrupting biofilms, and efficiently preventing biofilm reformation. Altering the biofilm and immune microenvironments alleviates inflammation noninvasively, promotes corneal healing without scar formation, protects ocular tissues, restores visual function, and prevents long-term discomfort and pain. This strategy exhibits strong scalability, enables at-home treatment of ocular surface infections with great patient compliance and a favorable prognosis, and has significant potential for clinical application.

Baicalin ameliorates multidrug-resistant Pseudomonas aeruginosa induced pulmonary inflammation in rat via arginine biosynthesis.

Multidrug-resistance (MDR) Pseudomonas aeruginosa (P. aeruginosa) is a lethal gram-negative pathogen causing hospital-acquired and ventilator-associated pneumonia, which is difficult to treat. Our previous studies confirmed that baicalin, an essential bioactive component in Scutellaria baicalensis Georgi, exhibited anti-inflammatory effects in an acute pneumonia rat model induced by MDR P. aeruginosa. However, this effect of baicalin in constrast its low bioavailability, and its mechanism of action is still unknown. Thus, this study investigated whether the therapeutic effects of baicalin against MDR P. aeruginosa acute pneumonia are owing to the regulation of gut microbiota and their metabolites using pyrosequencing of the 16S rRNA genes in rat feces and metabolomics. As a result, baicalin attenuated the inflammation by acting directly on neutrophils and regulated the production of the inflammatory cytokines TNF-α, IL-1ß, IL-6, and IL-10. The mechanisms were through down-regulation of TLR4 and inhibition of NF-κB. Furthermore, pyrosequencing of the 16S rRNA genes in rat feces revealed that baicalin regulated the composition of gut microbial communities. At the genus level, baicalin efficiently increased the abundance of Ligilactobacillus, Lactobacillus and Bacteroides, but decreased the abundance of Muribaculaceae and Alistipes. Further, arginine biosynthesis was analyzed as the core pathway regulated by baicalin via combination with predicting gut microbiota function and targeted metabolomics. In conclusion, this study has demonstrated that baicalin relieved inflammatory injury in acute pneumonia rat induced by MDR P. aeruginosa via arginine biosynthesis associated with gut microbiota. Baicalin could be a promising and effective adjunctive therapy for lung inflammation caused by MDR P. aeruginosa infection.