The Potentiation Activity of Azithromycin in Combination with Colistin or Levofloxacin Against Pseudomonas aeruginosa Biofilm Infection.

Objective: Pseudomonas aeruginosa (PA) often displays drug resistance and biofilm-mediated adaptability. Here, we aimed to evaluate the antibiofilm efficacy of azithromycin-based combination regimens. Methods: Minimum inhibitory concentrations (MICs), minimal biofilm eradication concentrations (MBECs), and MBEC-combination of azithromycin, colistin, amikacin, and levofloxacin to bioluminescent strain PAO1 and carbapenem-resistant PAO1 (CRPAO1) were assessed. An animal biofilm infection model was established and detected using a live animal bio-photonic imaging system. Results: In vitro, PAO1 and CRPAO1 were susceptible to colistin, amikacin, and levofloxacin, while they were unsusceptible to azithromycin. The combinations based on azithromycin have no synergistic effect on biofilm in vitro. In vivo, azithromycin plus colistin or levofloxacin could shorten the PAO1 biofilm eradication time, which totally eradicates the biofilm in all mice on the 8th or 6th day, while monotherapy only eradicate biofilm in 70% or 80% mice on the 8th day. For CRPAO1 biofilm, only azithromycin-colistin combination and colistin monotherapy eradicated the bacteria in 60% and 40% of mice at the 6th day. Conclusion: Azithromycin-based combinations containing levofloxacin or colistin had no synergistic effect in vitro, and they are promising for clinical applications due to the good synergistic activity against PAO1 biofilms in vivo.

An overview of gram-negative bacteria with difficult-to-treat resistance: definition, prevalence, and treatment options.

INTRODUCTION: Difficult-to-treat resistance (DTR) is a newly proposed resistance phenotype characterized by resistance to all first-line drugs. The emergence of DTR as a new resistance phenotype has significant implications for clinical practice. This new concept has the potential to be widely used instead of traditional phenotypes. AREAS COVERED: This study carried out a detailed analysis about the definition, application, and evolution of various resistance phenotypes. We collected all the research articles on Gram-negative bacteria with difficult-to-treat resistance (GNB-DTR), analyzed the DTR in each region and each bacterial species. The advantages and doubts of DTR, the dilemma of GNB-DTR infections and the potential therapeutic strategies are summarized in the review. EXPERT OPINION: Available studies show that the prevalence of GNB-DTR is not optimistic. Unlike traditional resistance phenotypes, DTR is more closely aligned with the clinical treatment perspective and can help with the prompt selection of an appropriate treatment plan. Currently, potential treatment options for GNB-DTR include a number of second-line drugs and novel antibiotics. However, the definition of first-line drugs is inherently dynamic. Therefore, the DTR concept based on first-line drugs needs to be continuously updated and refined, considering the emergence of new antibiotics, resistance characteristics, and pathogen prevalence in different regions.

The efficacy and safety of ceftolozane-tazobactam in the treatment of GNB infections: a systematic review and meta-analysis of clinical studies.

BACKGROUND: Ceftolozane-tazobactam is a novel cephalosporin/ß-lactamase inhibitor combination with activity against Gram-negative bacteria (GNB). We aimed to comprehensively evaluate the clinical efficacy and safety of ceftolozane-tazobactam in treating GNB infections in adult patients. RESEARCH DESIGN AND METHODS: PubMed, Embase, and Cochrane databases were retrieved until August 2022. Randomized trials and non-randomized controlled studies evaluating ceftolozane-tazobactam and its comparators in adult patients with GNB infections were included. RESULTS: A total of 13 studies were included. Overall, patients receiving ceftolozane-tazobactam had significant advantages in clinical cure (odds ratio [OR], 1.62; 95% CI, 1.05-2.51) and microbiological eradication (OR, 1.43; 95% CI, 1.19-1.71), especially in Pseudomonas aeruginosa-infected patients. Ceftolozane-tazobactam had a significant advantage in clinical success or microbial eradication compared with polymyxin/aminoglycosides (PL/AG) or levofloxacin. There were no significant differences in adverse events (AEs), Clostridium difficile infection (CDI), and mortality between ceftolozane-tazobactam and comparators. Notably, ceftolozane-tazobactam showed a significantly lower risk of acute kidney injury compared with PL/AG. CONCLUSIONS: Ceftolozane-tazobactam showed excellent clinical and microbiological efficacy in treating GNB, especially P. aeruginosa-induced infections. The overall safety profile of ceftolozane-tazobactam was comparable to other antimicrobials, with no increased risk of CDI and obvious advantage over antibacterial agents with high nephrotoxicity.

Efficacy of vitamin D supplementation on COPD and asthma control: A systematic review and meta-analysis.

Background: The role of vitamin D (VD) in the management of chronic obstructive pulmonary disease (COPD) and asthma remains largely undetermined. In the present meta-analysis, we aimed to comprehensively investigate the efficacy of VD in the treatment of COPD and asthma according to the latest update. Methods: The PubMed, Embase, and Cochrane Library databases were searched from their inception to June 2, 2022. Randomized controlled trials (RCTs) comparing the efficacy of VD with placebo against COPD or asthma were included. Results: A total of 11 RCTs consisting of 1183 COPD patients and 19 RCTs consisting of 2025 asthmatic patients were finally included. As for pulmonary function, FEV1/FVC was not changed significantly, while FEV1% was improved in the VD group. In the asthma subgroup, FEV1% was not changed significantly, while FEV1/FVC was improved in the VD group. For the questionnaire and rating scale, the mMRC (modified Medical Research Council) dyspnoea scale score for COPD and ACT (Asthma Control Test) score for asthma were not significantly changed, while the SGRQ (St. George's Respiratory Questionnaire) score for COPD was improved in the VD group. For inflammation indicators, IL-6 and IL-10 were statistically equivalent between the VD and placebo groups, while IgE, IL-5, and IL-10 (baseline VD deficiency subgroup) were improved in the VD group. The exacerbation, length of hospital stays, and mortality were statistically equivalent between the two groups. Conclusions: VD supplementation improved the indicators of asthma and COPD, especially in pulmonary function, SGRQ scores, IL-5, and IgE. Registration: The protocol could be found at PROSPERO with the registration number of CRD42020218058.

The Efficacy of Colistin Combined with Amikacin or Levofloxacin against Pseudomonas aeruginosa Biofilm Infection.

Pseudomonas aeruginosa (PA) biofilm infection is clinically prevalent and difficult to eradicate. In the present work, we aimed to evaluate the in vitro and in vivo efficacy of colistin (COL)-based combinations against PA biofilm. MICs and fractional inhibitory concentration indexes (FICIs) of four antibiotics (COL, amikacin, levofloxacin, and meropenem) to bioluminescent strain PAO1, carbapenem-resistant PAO1 (CRPAO1), and clinically isolated strains were assessed. Minimal biofilm eradication concentrations (MBECs) of monotherapy and combinations were examined by counting the live bacteria in biofilm, accompanied by visual confirmation using confocal laser-scanning microscopy. An animal biofilm infection model was established by implanting biofilm subcutaneously, and the therapeutic effect was evaluated according to the change in luminescence through a live animal bio-photonic imaging system. In vitro, even combined with 4 or 8 mg/L COL, meropenem needed to reach 128 or 256 mg/L to eradicate the biofilm. Moreover, 2 mg/L COL combined with 32 mg/L amikacin or 4-8 mg/L levofloxacin could kill the PAO1 and CRPAO1 in biofilm within 24 h. In vivo, COL combined with amikacin or levofloxacin could shorten the eradication time of biofilm than monotherapy. For PAO1 biofilm, combination therapy could eradicate the biofilm in all mice on the 5th day, whereas monotherapy only eradicated biofilms in almost half of the mice. For CRPAO1 biofilm, the biofilm eradication rate on the 6th day in the COL+ amikacin, amikacin, or COL alone regimen was 90%, 10%, or 40%, respectively. COL combined with levofloxacin did not show a better effect than each individual antibiotic. COL-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. IMPORTANCE Infections associated with PA biofilm formation are extremely challenging. When monotherapy fails to achieve optimal efficacy, combination therapy becomes the last option. After evaluating multiple drug combinations through a series of experiments in vitro and in vivo, we confirmed that colistin-based combinations containing levofloxacin or amikacin were promising choices for treating PA biofilm infection. The efficacy of these combinations derives from the different bactericidal mechanisms and the bacterial susceptibility to each antibiotic. This study provided a new regimen to solve the incurable problem of biofilm by using COL combined with other antibiotics.

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Oral Doses of Youkenafil Hydrochloride, a Phosphodiesterase Type 5 Inhibitor, in Healthy Chinese Male Volunteers.

Youkenafil hydrochloride is a novel selective phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. Its safety, tolerability, and pharmacokinetics were evaluated in healthy Chinese male volunteers. In addition, this study explored the effect of food on the pharmacokinetic parameters of youkenafil hydrochloride. The study was divided into 3 trials: a single ascending dose (25, 50, 100, 150, or 200 mg youkenafil), multiple dose (50, 100, or 150 mg youkenafil once daily for 7 consecutive days), and food effect (50 mg youkenafil single dose). The overall tolerability of youkenafil was good. Youkenafil was rapidly absorbed after a single oral dose. Food intake impeded absorption efficiency but had no significant effect on area under the plasma concentration-time curve values. The mean accumulation ratio in area under the plasma concentration-time curve and maximum plasma concentration ranged from 1.3 to 1.6 and from 1.2 to 1.4 after once-daily dosing. There was no apparent accumulation following consecutive administration for 7 days. Less than 1% of the dose was found in urine as the intact drug for all dose groups. Single-dose youkenafil up to 200 mg and multiple doses up to 150 mg were generally safe and well tolerated.