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Chronic infections often involve biofilm-based bacteria, in which the biofilm results in significant resistance against antimicrobial agents and prevents eradication of the infection. The physicochemical barrier presented by the biofilm matrix is a major impediment to the delivery of many antibiotics. Previously, PEGylation has been shown to improve antibiotic penetration into biofilms in vitro. In these studies, PEGylating tobramycin was investigated both in vitro and in vivo. Two distinct PEGylated tobramycin molecules were synthesized (mPEG-SA-Tob and mPEG-AA-Tob). Then, in a P. aeruginosa biofilm in vitro model, we found that mPEG-SA-Tob can operate as a prodrug and showed 7 times more effectiveness than tobramycin (MIC 80 : 14 μM vs.100 μM). This improved biofilm eradication is attributable to the fact that mPEG-SA-Tob can aid tobramycin to penetrate through the biofilm and overcome the alginate-mediated antibiotic resistance. Finally, we used an in vivo biofilm-based chronic pulmonary infection rat model to confirm the therapeutic impact of mPEG-SA-Tob on biofilm-based chronic lung infection. mPEG-SA-Tob has a better therapeutic impact than tobramycin in that it cannot only stop P. aeruginosa from multiplying in the lungs but can also reduce inflammation caused by infections and prevent a recurrence infection. Overall, our findings show that PEGylated tobramycin is an effective treatment for biofilm-based chronic lung infections., Competing Interests: Declaration of competing interest Hugh D C Smyth, an author of this paper, consults for and has equity ownership in Via Therapeutics, Nob Hill Therapeutics, and Cloxero Therapeutics on inhaled product development. The terms of the arrangement have been reviewed and approved by the University of Texas at Austin following its policy on objectivity in research., (Copyright © 2024. Published by Elsevier B.V.)

Objective: Evaluation of clinical efficacy and safety of tobramycin/dexamethasone eye ointment in treating persistent corneal epithelial dysfunction (PED) after cataract surgery., Methods: 26 cases diagnosed as PED after cataract surgery accept the tobramycin/dexamethasone ophthalmic ointment and intense pulse light treatment in the Xiamen University of Xiamen eye center between September 2016 and April 2022 were retrospectively analyzed, mainly including clinical manifestations, characteristics of morphological changes imaged by in vivo confocal microscopy, meibomian glands infrared photography, lipid layer thickness (LLT), management and therapeutic effects., Results: There were 26 eyes, include 8(35%) males and 15(65%) females with an average age of 69.6 ± 5.2 years(50 to 78 years). The mean hospitalization time was (18.4 ± 7.5) days after cataract surgery. Twenty patients had meibomian gland dysfunction. Infrared photography revealed varying loss in the meibomian glands, with a mean score of 3.8 ± 1.2 for gland loss. The mean LLT was 61.6 ± 8.4 nm. After treatment, 20 patients were cured, and 3 received amniotic membrane transplantation. After treatment, the uncorrected visual acuity (UCVA) and best-corrected vision activity (BCVA) improved (P < 0.001), and there was no significant difference in intraocular pressure (IOP) before and after treatment (P > 0.05)., Conclusions: The early manifestation of PED after surgery is punctate staining of the corneal epithelium. Tobramycin and dexamethasone eye ointment bandages have a good repair effect. The meibomian gland massage combined with intense pulse light treatment can effectively shorten the course of the disease., (© 2024. The Author(s).)

Objectives: The aim of this study was to compare the effect of vancomycin/tobramycin local antibiotic powder (LAP) on surgical site infections (SSIs) after open treatment of fractures., Design: This was a retrospective comparative study with propensity matching., Setting: The study was set in an urban level 1 trauma center., Patients Selection Criteria: Patients undergoing open procedures for fracture performed by a single surgeon before and after cessation of routine LAP use were included., Outcome Measures and Comparisons: Deep and superficial SSIs were the measured outcomes., Results: There were 652 open procedures for fracture performed by a single surgeon: LAP was used in 36.7% (114/310) of procedures before stopping its use, after which 342 procedures were performed without LAP. Comparison of all procedures performed with and without routine LAP use demonstrated no difference in infection rates, although there was a trend for the group without LAP to have fewer superficial SSIs (proportional difference [PD] -2.0%, 95% confidence interval [CI] -4.1% to 0.1%; P = 0.05) and more deep SSIs (PD 3.9%, 95% CI, -0.2% to 7.9%; P = 0.06). Prematch analysis demonstrated that LAP use was associated with external fixation (PD 8.5%, 95% CI, 1.6%-16.2%; P = 0.005), longer operative times (median difference 56.0 minutes, 95% CI, 39.0-74.0; P < 0.0001), greater estimated blood loss (median difference 70.0, 95% CI, 50.0-100.0; P < 0.0001), and no difference in superficial (PD 2.4%; 95% CI, -0.8% to 6.8%; P = 0.07) or deep SSIs (PD -1.6%, 95% CI, -6.2% to 4.1%; P = 0.54). After propensity matching (108 vs. 108) to control for the above differences, the LAP group, compared with the no LAP group, had no difference in superficial SSIs and was less likely to have deep SSIs (PD -8.3%, 95% CI, -16.2% to -0.2%; P = 0.04)., Conclusions: The use of vancomycin and tobramycin LAP lowered the rate of deep SSIs after open treatment of fractures on propensity-matched analysis., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models., Competing Interests: No authors have competing interest., (Copyright: © 2024 Rouillard 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.)

Diabetic wounds pose a significant challenge due to their susceptibility to bacterial infection in a high-glucose environment, which impedes the wound healing process. To address this issue, there is a pressing need to develop suitable hydrogels that can promote the regeneration of diabetic wounds in clinical practice. In this study, we designed and fabricated a highly stretchable, adhesive, transparent, and antibacterial hydrogel through a one-pot radical polymerization of N-[Tris (hydroxymethyl) methyl] acrylamide (THMA) and acrylic acid (AA), and with chitosan and the antibiotic tobramycin as the dynamic physical crosslinkers. The copolymer contains a large number of carboxyl and hydroxyl groups, which can form an interpenetrating network structure with chitosan and tobramycin through multiple dynamic non-covalent bonds. This hydrogel exhibited over 1600 % elongation through an energy dissipation mechanism and strong adhesion to various surfaces without any chemical reaction. In vivo, studies conducted on a staphylococcus aureus-infected full-thickness diabetic skin wound model demonstrated that the hydrogel loaded with tobramycin as one of the crosslinkers had a long-lasting antibacterial activity and effectively accelerated wound healing. Therefore, the antibiotic-loaded adhesive hydrogel we proposed holds great promise as a treatment for bacteria-infected diabetic wounds., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Trauma and its associated complications, including dysregulated inflammatory responses, severe infection, and disseminated intravascular coagulation (DIC), continue to pose lethal threats worldwide. Following injury, cell-free nucleic acids (cfNAs), categorized as damage-associated molecular patterns (DAMPs), are released from dying or dead cells, triggering local and systemic inflammatory responses and coagulation abnormalities that worsen disease progression. Harnessing cfNA scavenging strategies with biomaterials has emerged as a promising approach for treating posttrauma systemic inflammation. In this study, the effectiveness of cationic hyperbranched polyaminoglycosides derived from tobramycin (HPT) and disulfide-included HPT (ss-HPT) in scavenging cfNAs to mitigate posttrauma inflammation and hypercoagulation is investigated. Both cationic polymers demonstrate the ability to suppress DAMP-induced toll-like receptor (TLR) activation, inflammatory cytokine secretion, and hypercoagulation by efficiently scavenging cfNAs. Additionally, HPT and ss-HPT exhibit potent antibacterial efficacy attributed to the presence of tobramycin in their chemical composition. Furthermore, HPT and ss-HPT exhibit favorable modulatory effects on inflammation and therapeutic outcomes in a cecal ligation puncture (CLP) mouse abdominal trauma model. Notably, in vivo studies reveal that ss-HPT displayed high accumulation and retention in injured organs of traumatized mice while maintaining a higher biodegradation rate in healthy mice, contrasting with findings for HPT. Thus, functionalized ss-HPT, a bioreducible polyaminoglycoside, holds promise as an effective option to enhance therapeutic outcomes for trauma patients by alleviating posttrauma inflammation and coagulation complications., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: New drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa , have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections., Methods: We report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression., Results: In a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO 2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5 h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits ( P <0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24 h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved C max /MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had C max /MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects., Conclusion: The rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia., Competing Interests: Authors BZ, LC, CS, AD and BS are or were employed by AstraZeneca. Author BD previously received funding from AstraZeneca, Pfizer, Merck, Arsanis, ContraFect, and Integrated Biotherapeutics for preclinical studies using earlier iterations of the rabbit model of non-ventilated pneumonia. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gras, Vu, Nguyen, Tran, Mao, Tran, Mai, Dong, Jung, Iorio, Povoa, Pinheiro, Aguiar-Alves, Weiss, Zheng, Cheng, Stover, Sellman, DiGiandomenico, Gibault, Valour and Diep.)

This study aimed to compare the efficacy of fosfomycin, colistin, tobramycin and their dual combinations in an experimental sepsis model. After sepsis was established with a Pseudomonas aeruginosa isolate (P1), antibiotic-administered rats were divided into six groups: Fosfomycin, tobramycin, colistin and their dual combinations were administered by the intravenous or intraperitoneal route to the groups. The brain, heart, lung, liver, spleen and kidney tissues of rats were cultured to investigate bacterial translocation caused by P1. Given the antibiotics and their combinations, bacterial colony counts in liver tissues were decreased in colistin alone and colistin plus tobramycin groups compared with control group, but there were no significant differences. In addition, a non-statistical decrease was found in the spleen tissues of rats in the colistin plus tobramycin group. There was a > 2 log 10 CFU/ml decrease in the number of bacterial colonies in the kidney tissues of the rats in the fosfomycin group alone, but the decrease was not statistically significant. However, there was an increase in the number of bacterial colonies in the spleen and kidney samples in the group treated with colistin as monotherapy compared to the control group. The number of bacterial colonies in the spleen samples in fosfomycin plus tobramycin groups increased compared to the control group. Bacterial colony numbers in all tissue samples in the fosfomycin plus colistin group were found to be close to those in the control group. Colistin plus tobramycin combinations are effective against P. aeruginosa in experimental sepsis, and clinical success may be achieved. New in vivo studies demonstrating the ability of P. aeruginosa to biofilm formation in tissues other than the lung are warranted in future., (© 2023. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Introduction: Infection after total knee arthroplasty (TKA) impacts the patient, surgeon, and healthcare system significantly. Surgeons routinely use antibiotic-loaded bone cement (ALBC) in attempts to mitigate infection; however, little evidence supports the efficacy of ALBC in reducing infection rates compared to non-antibiotic-loaded bone cement (non-ALBC) in primary TKA. Our study compares infection rates of patients undergoing TKA with ALBC to those with non-ALBC to assess its efficacy in primary TKA., Methods: A retrospective review of all primary, elective, cemented TKA patients over the age of 18 between 2011 and 2020 was conducted at an orthopedic specialty hospital. Patients were stratified into two cohorts based on cement type: ALBC (loaded with gentamicin or tobramycin) or non-ALBC. Baseline characteristics and infection rates determined by MSIS criteria were collected. Multilinear and multivariate logistic regressions were performed to limit significant differences in demographics. Independent samples t test and chi-squared test were used to compare means and proportions, respectively, between the two cohorts., Results: In total, 9366 patients were included in this study, 7980 (85.2%) of whom received non-ALBC and 1386 (14.8%) of whom received ALBC. There were significant differences in five of the six demographic variables analyzed; patients with higher Body Mass Index (33.40 ± 6.27 vs. 32.09 ± 6.21; kg/m 2 ) and Charlson Comorbidity Index values (4.51 ± 2.15 vs. 4.04 ± 1.92) were more likely to receive ALBC. The infection rate in the non-ALBC was 0.8% (63/7,980), while the rate in the ALBC was 0.5% (7/1,386). After adjusting for confounders, the difference in rates was not significant between the two groups (OR [95% CI]: 1.53 [0.69-3.38], p = 0.298). Furthermore, a sub-analysis comparing the infection rates within various demographic categories also showed no significant differences between the two groups., Conclusion: Compared to non-ALBC, the overall infection rate in primary TKA was slightly lower when using ALBC; however, the difference was not statistically significant. When stratifying by comorbidity, use of ALBC still showed no statistical significance in reducing the risk of periprosthetic joint infection. Therefore, the advantage of antibiotics in bone cement to prevent infection in primary TKA is not yet elucidated. Further prospective, multicenter studies regarding the clinical benefits of antibiotic use in bone cement for primary TKA are warranted., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Nebuliser systems are used to deliver medications to the lungs, to control the symptoms and the progression of lung disease in people with cystic fibrosis (CF). There are many different nebulised-medications prescribed for people with CF and there are many different types of nebuliser systems. Some of these nebulised medications are licenced for, and can be taken via only one type of nebuliser system; some are licensed for, and can be taken via more than one type of nebuliser system. This is an update to a previous systematic review., Objectives: To assess the time efficiency, effectiveness, safety, cost and impact of use (e.g. burden of care, adherence, quality of life (QoL)) of different nebuliser systems, when used with different inhaled medications for people with CF., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching of relevant journals and abstract books containing conference proceedings. We searched the reference lists of each study for additional publications and approached the manufacturers of both nebuliser systems and nebulised medications for published and unpublished data. We also searched online trial registries. Date of the most recent search: 9 August 2023., Selection Criteria: Randomised controlled trials (RCTs) or quasi-RCTs comparing nebuliser systems, including conventional nebulisers, vibrating mesh technology (VMT) systems, adaptive aerosol delivery (AAD) systems and ultrasonic nebuliser systems., Data Collection and Analysis: Two review authors independently assessed studies for inclusion. They also independently extracted data and assessed the risk of bias. A third review author assessed studies where agreement could not be reached. They assessed the certainty of the evidence using GRADE., Main Results: The search identified 216 studies with 33 of these (2270 participants) included in the review. These studies compared the delivery of tobramycin, colistin, dornase alfa, hypertonic saline and other solutions through the different nebuliser systems in children and adults with CF. This review demonstrates variability in the delivery of medication depending on the nebuliser system used. The certainty of the evidence ranged from low to very low. Some conventional nebuliser systems providing higher flows, higher respirable fractions, and smaller particles decrease treatment time, increase deposition (the amount of drug reaching the lung), and may be preferred by people with CF, as compared to other conventional nebuliser systems providing lower flows, lower respirable fractions and larger particles. Newer nebuliser systems using AAD, or VMT (or both) reduce treatment time compared to conventional systems. Deposition (as a percentage of priming dose) with AAD is greater than with conventional systems. VMT systems may give greater deposition than conventional systems when measuring sputum levels. The available data indicate that these newer systems are safe when used with an appropriate priming dose, which may be different to the priming dose used for conventional systems. There is an indication that adherence is maintained or improved and that individuals prefer AAD or VMT systems, but also that some nebuliser systems using VMT may be subject to increased system failures. There is limited, unclear evidence on the impact of different nebuliser systems on lung function and a lack of data on the impact of different nebuliser systems on our outcomes of quality of life (QoL), adverse effects, respiratory exacerbations and related implications, adherence, satisfaction, cost and device reliability., Authors' Conclusions: Newer technologies e.g. AAD and VMT have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, preference and adherence. Data are lacking for all varieties of medications which are used in CF care, including different inhaled antibiotics or hypertonic saline, with all delivery (nebuliser system) possibilities. Long-term RCTs are needed to evaluate different nebuliser systems to determine patient-focused outcomes (such as QoL and burden of care), safe and effective dosing levels of a wide variety of medications, clinical outcomes (such as hospitalisations and need for antibiotics), and an economic evaluation of their use. There are insufficient data to establish whether one nebuliser system is better than another overall. Clinicians should be aware of the variability in the performance of different nebuliser systems, compatibility with specific nebulised medication, and they must work with their patients to choose the best nebuliser system for each individual. This is likely to be an ongoing process as the needs and circumstances of each individual change over time., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objectives: To use a pre-clinical pharmacokinetic infection model to assess the antibacterial effect of ceftolozane/tazobactam alone or in combination with fosfomycin or tobramycin against Pseudomonas aeruginosa strains with MICs at or higher than the clinical breakpoint (MIC ≥ 4 mg/L)., Methods: An in vitro model was used to assess changes in bacterial load and population profiles after exposure to mean human serum concentrations of ceftolozane/tazobactam associated with doses of 2 g/1 g q8h, fosfomycin concentrations associated with doses of 8 g q8h or tobramycin at doses of 7 mg/kg q24 h over 168 h., Results: Simulations of ceftolozane/tazobactam at 2 g/1 g q8h alone produced 3.5-4.5 log reductions in count by 6 h post drug exposure for strains with MIC ≤32 mg/L. The antibacterial effect over the first 24 h was related to ceftolozane/tazobactam MIC. There was subsequent regrowth with most strains to bacterial densities of >106 CFU/mL. Addition of either fosfomycin or tobramycin resulted in suppression of regrowth and in the case of tobramycin more rapid initial bacterial killing up to 6 h. These effects could not be related to either fosfomycin or tobramycin MICs. Changes in population profiles were noted with ceftolozane/tazobactam alone often after 96 h exposure but such changes were suppressed by fosfomycin and almost abolished by the addition of tobramycin., Conclusions: The addition of either fosfomycin or tobramycin to ceftolozane/tazobactam at simulated human clinically observed concentrations reduced P. aeruginosa bacterial loads and the risk of resistance to ceftolozane/tazobactam when strains had ceftolozane/tazobactam MIC values at or above the clinical breakpoint., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Acute exacerbations of biofilm-associated Pseudomonas aeruginosa infections in cystic fibrosis (CF) have limited treatment options. Ceftolozane/tazobactam (alone and with a second antibiotic) has not yet been investigated against hypermutable clinical P. aeruginosa isolates in biofilm growth. This study aimed to evaluate, using an in vitro dynamic biofilm model, ceftolozane/tazobactam alone and in combination with tobramycin at simulated representative lung fluid pharmacokinetics against free-floating (planktonic) and biofilm states of two hypermutable P. aeruginosa epidemic strains (LES-1 and CC274) from adolescents with CF., Methods: Regimens were intravenous ceftolozane/tazobactam 4.5 g/day continuous infusion, inhaled tobramycin 300 mg 12-hourly, intravenous tobramycin 10 mg/kg 24-hourly, and both ceftolozane/tazobactam-tobramycin combinations. The isolates were susceptible to both antibiotics. Total and less-susceptible free-floating and biofilm bacteria were quantified over 120-168 h. Ceftolozane/tazobactam resistance mechanisms were investigated by whole-genome sequencing. Mechanism-based modelling of bacterial viable counts was performed., Results: Monotherapies of ceftolozane/tazobactam and tobramycin did not sufficiently suppress emergence of less-susceptible subpopulations, although inhaled tobramycin was more effective than intravenous tobramycin. Ceftolozane/tazobactam resistance development was associated with classical (AmpC overexpression plus structural modification) and novel (CpxR mutations) mechanisms depending on the strain. Against both isolates, combination regimens demonstrated synergy and completely suppressed the emergence of ceftolozane/tazobactam and tobramycin less-susceptible free-floating and biofilm bacterial subpopulations., Conclusion: Mechanism-based modelling incorporating subpopulation and mechanistic synergy well described the antibacterial effects of all regimens against free-floating and biofilm bacterial states. These findings support further investigation of ceftolozane/tazobactam in combination with tobramycin against biofilm-associated P. aeruginosa infections in adolescents with CF., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Purpose: To compare the effect of antiseptics and antibiotics on the occurrence of Infectious Keratitis (IK) secondary to Corneal Foreign Body (CFB) removal., Methods: Multicenter retrospective study conducted between June 2020 and June 2022 in patients referred for CFBs and treated with Picloxydine (Group 1) or Tobramycin (Group 2) for 7 days. A follow-up visit was scheduled on Day 3 (D3) and a phone call on D30. The primary outcome measure was the occurrence of IK., Results: 307 patients (300 men) with a mean age of 42.8 (14.8) years were included. The mean (SD) time to consultation was 43.1 (45.6) hours. Picloxydine and Tobramycin were given to 155 and 152 patients. Half of patients (n = 154, 50.2%) were building workers and 209 (68.1%) did not wear eye protections. CFBs were mainly metallic (n = 292, 95.1%). Upon referral, rust was found in 220 patients (72.1%). A burr was used in 119 (38.9%) patients. IK occurred in 15 (4.9%) patients, 8 (5.3%) in Group 1 and 7 (4.5%) in Group 2 (p = 0.797). IK was successfully treated in all cases. Persistent rust was found in 113 patients (36.9%) on D3 without difference between burr or needle use (p = 0.278). On D3, corneal healing was delayed in 154 patients (47.2%), mainly in burr-treated patients (p = 0.003). The mean (SD) work stoppage duration was 0.32 (0.98) days., Conclusion: IK rate was 4.9%. The efficacy of antibiotics and antiseptics was similar on CFB removal. Using a burr was associated with a longer healing time. CFBs had a limited social impact., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Introduction: Tobramycin inhalation solution (TIS) is a treatment option for patients with frequent exacerbations of bronchiectasis. A possible side effect of TIS is the development of chronic cough and bronchospasm, whereby the guidelines suggest a (in hospital) tolerance test with the first dose of TIS. However, data on respiratory adverse events are not consistent. In the present analysis from the BATTLE study (NCT02657473), we evaluated the added value of the tolerance test and aimed to observe the development of inhaled treatment related bronchial hyperreactivity., Methods: Fifty-seven patients from the BATTLE study were analyzed. Patients were randomized to receive TIS or placebo OD for 1 year. A tolerance test was performed with spirometry measurements before and after the first dose and with a bronchodilator in advance. Adverse events were strictly monitored., Results: Fifty-seven patients (100%) passed the tolerance test with no decrease in spirometry measurements or development of local intolerability. During the study treatment, a total of five TIS-treated patients (17.8%) withdrew due to airway hyperresponsiveness after a mean of 9.2 (SD13.9) weeks and one placebo-treated patient (3.5%) after 2 weeks (TIS vs. placebo; p = 0.66). The other TIS-related adverse events were not clinically significant., Conclusion: The use of inhaled medication is well tolerated in the heterogenous bronchiectasis population, without signs of airway hyperresponsiveness after the first dose of inhaled medication. From this observation, it can be concluded that there is no additional value for this advised tolerance test. However, closely monitoring on adverse effects during the first weeks after starting TIS is recommended., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Objective: Evaluate the species distribution and resistance patterns of bacterial pathogens causing surgical site infection (SSI) after operative fracture repair, with and without the use of intrawound powdered antibiotic (IPA) prophylaxis during the index surgery., Design: Retrospective cohort study., Setting: Academic, level 1 trauma center, 2018-2020., Patients/participants: Fifty-nine deep SSIs were identified in a sample of 734 patients with 846 fractures (IPA [n = 320], control [n = 526]; open [n = 157], closed fractures [n = 689]) who underwent orthopaedic fracture care. Among SSIs, 28 (48%) patients received IPA prophylaxis and 25 (42%) of the fractures were open., Intervention: Intrawound powdered vancomycin and tobramycin., Main Outcome Measurements: Distribution of bacterial species and resistance patterns causing deep surgical site infections requiring operative debridement., Results: Zero patients developed infections caused by resistant strains of streptococci, enterococci, gram-negative enterics, Pseudomonas , or Cutibacterium species. The only resistant strains isolated were methicillin resistance (19%) and oxacillin-resistant coagulase-negative staphylococci (16%). There was no associated statistical difference in the proportion of bacterial species isolated, their resistance profiles, or rate of polymicrobial infections between the IPA and control group. Most (93%) cases using IPAs included vancomycin and tobramycin powders. There were 59 SSIs; 28 (9%) in the IPA cohort and 31 (6%) in the control cohort ( P = 0.13)., Conclusion: The use of local antibiotic prophylaxis resulted in no measurable increase in the proportion of infections caused by resistant bacterial pathogens after operative treatment of fractures. However, the small sample size and limited time frame of these preliminary data require continued investigation into their role as an adjunct to SSI prophylaxis., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Osteomyelitis of the frontal bone is a rare but devastating complication of frontal sinusitis. Treatment involves aggressive surgery to remove all sequestra in combination with long-term antibiotic therapy. However, systemic antibiotics may struggle to penetrate any remaining infection in devascularised areas, and the morbidity associated with surgical resection of some areas of the skull base is too high. In contrast, locally implanted antibiotics provide a reliable, high concentration of treatment to these areas while also minimising potential systemic side effects. The clinical application of tobramycin beads has primarily been used in orthopaedics as an adjunct to the treatment of tibial osteomyelitis or prosthetic joint infection., Case Report: To the best of the authors' knowledge, the two cases discussed here represent the first use of tobramycin antibiotic beads in frontal sinus osteomyelitis secondary to chronic rhinosinusitis., Conclusion: These cases show promising use of tobramycin beads in recalcitrant frontal osteomyelitis.

Pseudomonas aeruginosa can form biofilms at the site of burn wound, leading to infection and the failure of treatment regimens. The previous in vitro study demonstrated that a combination of the quorum-quenching enzyme AidH A147G and the extracellular matrix hydrolase PslG was effective in inhibiting biofilm and promoting antibiotic synergy. The aim of the present study was to evaluate the efficacy of this combination of enzymes in conjunction with tobramycin in treating burn wound infected with P. aeruginosa. The results showed that this treatment was effective in quorum-quenching and biofilm inhibition on infected wounds. Compared with the tobramycin treatment only, simultaneous treatment with the enzymes and antibiotics significantly reduced the severity of tissue damage, decreased the bacterial load, and reduced the expression of the inflammatory indicators myeloperoxidase (MPO) and malondialdehyde (MDA). Topical application of the enzymes also reduced the bacterial load and inflammation to some extent. These results indicate that the combined-enzyme approach is a potentially effective treatment for P. aeruginosa biofilm infections of burn wounds.

Background: Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review., Objectives: Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022., Selection Criteria: We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials., Data Collection and Analysis: Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE., Main Results: We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cultures at 16 months between ciprofloxacin with colistin versus TNS with ciprofloxacin (OR 1.28, 95% CI 0.72 to 2.29; low-certainty evidence). TNS plus azithromycin compared to TNS plus oral placebo Adding azithromycin may make no difference to the number of participants eradicating P aeruginosa after a three-month treatment phase (risk ratio (RR) 1.01, 95% CI 0.75 to 1.35; 1 trial, 91 participants; low-certainty evidence); there was also no evidence of any difference in the time to recurrence. Ciprofloxacin and colistin versus no treatment A single trial only reported one of our planned outcomes; there were no adverse effects in either group. AZLI for 14 days plus placebo for 14 days compared to AZLI for 28 days We are uncertain whether giving 14 or 28 days of AZLI makes any difference to the proportion of participants having a negative respiratory culture at 28 days (mean difference (MD) -7.50, 95% CI -24.80 to 9.80; 1 trial, 139 participants; very low-certainty evidence). Ceftazidime with IV tobramycin compared with ciprofloxacin (both regimens in conjunction with three months colistin) IV ceftazidime with tobramycin compared with ciprofloxacin may make little or no difference to eradication of P aeruginosa at three months, sustained to 15 months, provided that inhaled antibiotics are also used (RR 0.84, 95 % CI 0.65 to 1.09; P = 0.18; 1 trial, 255 participants; high-certainty evidence). The results do not support using IV antibiotics over oral therapy to eradicate P aeruginosa, based on both eradication rate and financial cost., Authors' Conclusions: We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: Acute pancreatitis (AP) accounts for a high proportion of digestive diseases worldwide and has a high risk of infection. Pseudomonas aeruginosa, a common pathogen of hospital infections, has been observed to increase the resistance rate to several antibiotics, causing difficulties in treatments. Our study aims to investigate the impact of the multi-drug resistant Pseudomonas aeruginosa (MDR-PA) infections on AP patients., Methods: At two Chinese tertiary referral centers for AP patients infected with MDR-PA, a retrospective case-control study with a 1:2 case-control ratio was performed. Comparisons were preformed between with/without MDR-PA infections and different drug-resistance of MDR-PA infections patients, respectively. Independent risk factors of overall mortality were assessed via univariate and multivariate binary logistic regression analyses, and the distribution and antibiotic resistant rates of strains were described., Results: Mortality in AP patients with MDR-PA infections was significantly higher than in those without MDR-PA infections (7 (30.4%) vs. 4 (8.7%), P = 0.048). The rate of prophylactic use of carbapenem for 3 days (0 vs. 50%, P = 0.019) and the incidence rate of multiple organ failure (MOF) (0 vs. 57.1%, P = 0.018) were remarkably higher in the carbapenem-resistant Pseudomonas aeruginosa group compared with the carbapenem-sensitive Pseudomonas aeruginosa group. In the multivariate analysis, the severe categories of AP (OR = 13.624, 95% CIs = 1.567-118.491, P = 0.018) and MDR-PA infections (OR = 4.788, 95% CIs = 1.107-20.709, P = 0.036) were independent risk factors for mortality. The resistance rates of MDR-PA strains were low for amikacin (7.4%), tobramycin (3.7%), and gentamicin (18.5%). The resistance rates of MDR-PA strains to imipenem and meropenem were up to, 51.9% and 55.6%, respectively., Conclusion: In AP patients, severe categories of AP and MDR-PA infections were both independent risk factors for mortality. Inappropriate use of carbapenem antibiotics and MOF were related to carbapenem-resistant Pseudomonas aeruginosa infections. Amikacin, tobramycin, and gentamicin are recommended for the treatment of AP patients with MDR-PA infections., (© 2023. The Author(s).)

Introduction: The deposition of inflammatory cells on an intraocular lens (IOL) is a rare but potentially serious complication. We report a patient who presented with reversible severe deposition of inflammatory cells on the anterior surface of a hydrophobic IOL., Case Description: A 68-year-old woman with remissive uveitis presented with blurred vision in her right eye that persisted for 1 month. She had undergone cataract surgery and hydrophobic IOL (ZA9003, Johnson & Johnson Surgical Vision) implantation 3 months before presentation. Deposition of inflammatory cells was diagnosed by ocular examination. The IOL became transparent after 6 months of treatment with combined antibiotic/steroid eyedrops (tobramycin/dexamethasone eyedrops) and atropine. However, the cellular deposition recurred after either discontinuing the tobramycin/dexamethasone eyedrops or switching to steroid-only eyedrops (fluorometholone). Therefore, she was prescribed continuous tobramycin/dexamethasone eyedrops, twice-daily, and her IOL remained transparent at the time of submission of this article., Conclusions: We have reported a case of reversible severe deposition of inflammatory cells on the anterior surface of a hydrophobic IOL in a patient with uveitis that was managed by continuous administration of combined antibiotic/steroid eyedrops. The morphology of the inflammatory cells deposits and the treatment differed from those of previously reported cases.

Purpose: Tobramycin (TOB) exhibits variable pharmacokinetic properties due to the clinical condition of patients. This study aimed to investigate the AUC-guided dosing of TOB based on population pharmacokinetic analysis in the treatment of infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia., Methods: This retrospective study was conducted between January 2010 and December 2020 after obtaining approval from our institutional review board. For 53 patients who received therapeutic drug monitoring of TOB, a population pharmacokinetic model was developed with covariates of estimated glomerular filtration rate using serum creatinine (eGFRcre) on clearance (CL) and weight on both CL and V d in exponential error modeling (CL = 2.84 × [weight/70] × eGFRcre 0.568 , interindividual variability [IIV] = 31.1%; V d  = 26.3 × [weight/70], IIV = 20.2%; residual variability = 28.8%)., Findings: The final regression model for predicting 30-day mortality was developed with risk factors of AUC during a 24-hour period after the first dose to MIC ratio (odds ratio [OR] = 0.996; 95% CI, 0.968-1.003) and serum albumin (OR = 0.137; 95% CI, 0.022-0.632). The final regression model for predicting acute kidney injury was developed with the risk factors of C-reactive protein (OR = 1.136; 95% CI, 1.040-1.266) and AUC during a 72-hour period after the first dose (OR = 1.004; 95% CI, 1.000-1.001). A dose of 8 or 15 mg/kg was beneficial for achievement of AUC during a 24-hour period after the first dose/MIC >80 and trough concentration <1 µg/mL in patients with preserved kidney function and TOB CL >4.47 L/h/70 kg in the events of MIC of 1 or 2 µg/mL, respectively. We propose that the first dose of 15, 11, 10, 8, and 7 mg/kg for eGFRcre >90, 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m 2 be followed by therapeutic drug monitoring at peak and 24 hours after the first dose., Implications: This study suggests that TOB use encourages the replacement of trough- and peak-targeted dosing with AUC-guided dosing., Competing Interests: Declarations of Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Pseudomonas aeruginosa (Pa) continues to affect disease progression in cystic fibrosis (CF). However, the best eradication regimen remains unclear. This work compares three different antibiotic eradication regimens in pediatric CF: an administration according to a standard-operating procedure (SOP) order vs. administration outside of this order (ooSOP)., Methods: This observational study includes all CF patients<18 years who received one of three Pa eradication treatments in the past eight years at our center: 1) inhaled high-dose tobramycin (Hi-TOBI), 2) inhaled colistin+oral ciprofloxacin (COL/Cip), 3) inhaled low-dose tobramycin+4 intravenous 14-day Pa active antibiotic treatments (lo-Tobra/IV). We compared eradication rates of the three treatment regimens performed according to the SOP-based order vs. ooSOP. Logistic regression analysis was performed to identify risk factors for eradication failure., Results: Performed according to SOP order, Hi-TOBI showed the greatest efficacy, followed by lo-Tobra/IV and finally COL/Cip, while ooSOP lo-Tobra/IV was most successful, followed by COL/Cip and Hi-TOBI. Previous Pa-infections and Pa-therapies along with age at CF diagnosis were risk factors for eradication failure., Conclusion: Antibiotic treatment in SOP-based pre-defined order leads to significantly better eradication rates than individual modifications of the order of administration. A short course of inhalational high-dose Tobramycin is most successful at the first attempt. Prolonged antibiotic therapy seems to improve eradication after failed initial attempts., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Collateral sensitivity (CS) is an evolutionary trade-off by which acquisition of resistance to an antibiotic leads to increased susceptibility to another. This Achilles' heel of antibiotic resistance could be exploited to design evolution-based strategies for treating bacterial infections. To date, most studies in the field have focused on the identification of CS patterns in model strains. However, one of the main requirements for the clinical application of this trade-off is that it must be robust and has to emerge in different genomic backgrounds, including preexisting drug-resistant isolates, since infections are frequently caused by pathogens already resistant to antibiotics. Here, we report the first analysis of CS robustness in clinical strains of Pseudomonas aeruginosa presenting different ab initio mutational resistomes. We identified a robust CS pattern associated with short-term evolution in the presence of ciprofloxacin of clinical P. aeruginosa isolates, including representatives of high-risk epidemic clones belonging to sequence type (ST) 111, ST175, and ST244. We observed the acquisition of different ciprofloxacin resistance mutations in strains presenting varied STs and different preexisting mutational resistomes. Importantly, despite these genetic differences, the use of ciprofloxacin led to a robust CS to aztreonam and tobramycin. In addition, we describe the possible application of this evolutionary trade-off to drive P. aeruginosa infections to extinction by using the combination of ciprofloxacin-tobramycin or ciprofloxacin-aztreonam. Our results support the notion that the identification of robust patterns of CS may establish the basis for developing evolution-informed treatment strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens. IMPORTANCE Collateral sensitivity (CS) is a trade-off of antibiotic resistance evolution that could be exploited to design strategies for treating bacterial infections. Clinical application of CS requires it to robustly emerge in different genomic backgrounds. In this study, we performed an analysis to identify robust patterns of CS associated with the use of ciprofloxacin in clinical isolates of P. aeruginosa presenting different mutational resistomes and including high-risk epidemic clones (ST111, ST175, and ST244). We demonstrate the robustness of CS to tobramycin and aztreonam and the potential application of this evolutionary observation to drive P. aeruginosa infections to extinction. Our results support the notion that the identification of robust CS patterns may establish the basis for developing evolutionary strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens.

Pseudomonas aeruginosa (PA) biofilms cause many persistent chronic infections in humans, especially in cystic fibrosis (CF) patients. The biofilms form a strong barrier which may inhibit antimicrobial agents from penetrating the biofilms and killing PA bacteria that reside deep within the biofilms. Concomitant therapies based on tobramycin (TOB) and azithromycin (AZM) have demonstrated beneficial effects in CF patients with chronic PA infections. However, the co-delivery of TOB and AZM has rarely been reported. In this study, we constructed a self-assembled pH-sensitive nano-assembly (DPNA) based on a dimeric prodrug (AZM-Cit-TOB) by simply inserting citraconic amide bonds between AZM and TOB. Moreover, the cationic surface of DPNA was further modified with anionic albumin (HSA) via electrostatic interactions to form an electrostatic complex (termed HSA@DPNA) for better biocompatibility. Upon arrival at the infected tissues, the citraconic amide bonds would be cleaved at acidic pH, resulting in the release of TOB and AZM for bacteria killing and biofilm eradication. As expected, HSA@DPNA showed comparable antibacterial abilities against the P. aeruginosa strain PAO1 in both planktonic and biofilm modes of growth compared to the TOB/AZM mixture in vitro . Moreover, HSA@DPNA exhibited excellent therapeutic efficacy on mice with PAO1-induced lung infection compared to the TOB/AZM mixture, and no detectable toxicity to mammalian cells/animals was observed during the therapeutic process. In summary, our study provides a promising method for the co-delivery of AZM and TOB in concomitant therapies against PAO1-related infection.

Purpose: The study analyzes the frequency of acute endophthalmitis occurrence after cataract surgery, the risk factors, characteristic symptoms, and the effectiveness of peri-operative prevention measures., Material and Methods: The study retrospectively analyzed 59 670 cases of patients operated for cataract in 2017-2021. To prevent infections, patients received four instillations of third generation fluoroquinolone (quinolone antibiotic) in the course of two days prior to cataract phacoemulsification (PE), and two instillations immediately (1 hour and 30 minutes) before the surgery; three-minutes treatment of the cornea, conjunctival sac and periocular skin with 5% povidone iodine before the surgery; and as the last step of surgery, patients received subconjunctival injection of 0.05 g cefazolin with 2 mg dexamethasone. Follow-up after surgery included four injections of 0.5% levofloxacin in the course of 7-10 days, and 0.1% dexamethasone for two weeks, or fixed combination of tobramycin and dexamethasone four times per day for two weeks. The criteria for acute endophthalmitis are: loss of spatial vision, absence of red reflex, pronounced thickening of the choroid, suspended particulates in the retrovitreal space and the vitreous observed with ultrasonography in the early postoperative period (day 4-7 after surgery)., Results and Discussion: There were 32 patients (0.054%) diagnosed with acute endophthalmitis. Posterior capsule rupture was the main complicative risk factor of endophthalmitis development (OR=11.75, p =0.026). Main diagnostic criteria of acute endophthalmitis were hypopyon (OR=22.5, p =0.001) and absence of red reflex (OR=19.59, p <0.001). The use of the fixed combination of tobramycin and dexamethasone was associated with 5.8-times higher risk of acute endophthalmitis than separate application of levofloxacin and dexamethasone ( p =0.042)., Conclusions: Povidone iodine and third generation fluoroquinolone as a method of acute endophthalmitis prevention after cataract surgery demonstrate comparable efficacy to intracameral antibiotic injections.

The Pseudomonas aeruginosa bacterium is a common pathogen of cystic fibrosis (CF) patients due to its ability to evolve resistance to antibiotics during treatments. While P. aeruginosa resistance evolution is well-characterized in monocultures, it is less well-understood in polymicrobial CF infections. Here, we investigated how exposure to ciprofloxacin, colistin, or tobramycin antibiotics, administered at sub-minimum inhibitory concentration (MIC) doses, both alone and in combination, shaped the tolerance evolution of P. aeruginosa (PAO1 lab and clinical CF LESB58 strains) in the absence and presence of a commonly co-occurring species, Stenotrophomonas maltophilia. The increases in antibiotic tolerances were primarily driven by the presence of that antibiotic in the treatment. We observed a reciprocal cross-tolerance between ciprofloxacin and tobramycin, and, when combined, the selected antibiotics increased the MICs for all of the antibiotics. Though the presence of S. maltophilia did not affect the tolerance or the MIC evolution, it drove P. aeruginosa into extinction more frequently in the presence of tobramycin due to its relatively greater innate tobramycin tolerance. In contrast, P. aeruginosa dominated and drove S. maltophilia extinct in most other treatments. Together, our findings suggest that besides driving high-level antibiotic tolerance evolution, sub-MIC antibiotic exposure can alter competitive bacterial interactions, leading to target pathogen extinctions in multispecies communities. IMPORTANCE Cystic fibrosis (CF) is a genetic condition that results in thick mucus secretions in the lungs that are susceptible to chronic bacterial infections. The bacterial pathogen Pseudomonas aeruginosa is often associated with morbidity in CF and is difficult to treat due to its high resistance to antibiotics. The resistance evolution of Pseudomonas aeruginosa is poorly understood in polymicrobial infections that are typical of CF. To study this, we exposed P. aeruginosa to sublethal concentrations of ciprofloxacin, colistin, or tobramycin antibiotics in the absence and presence of a commonly co-occurring CF species, Stenotrophomonas maltophilia. We found that low-level antibiotic concentrations selected for high-level antibiotic resistance. While P. aeruginosa dominated in most antibiotic treatments, S. maltophilia drove it into extinction in the presence of tobramycin due to an innately higher tobramycin resistance. Our findings suggest that, besides driving high-level antibiotic tolerance evolution, sublethal antibiotic exposure can magnify competition in bacterial communities, which can lead to target pathogen extinctions in multispecies communities.

We previously demonstrated that P. aeruginosa isolates that persisted in children with cystic fibrosis (CF) despite inhaled tobramycin treatment had increased anti-Psl antibody binding in vitro compared to those successfully eradicated. We aimed to validate these findings by directly visualizing P. aeruginosa in CF sputum. This was a prospective observational study of children with CF with new-onset P. aeruginosa infection who underwent inhaled tobramycin eradication treatment. Using microbial identification passive clarity technique (MiPACT), P. aeruginosa was visualized in sputum samples obtained before treatment and classified as persistent or eradicated based on outcomes. Pre-treatment isolates were also grown as biofilms in vitro. Of 11 patients enrolled, 4 developed persistent infection and 7 eradicated infection. P. aeruginosa biovolume and the number as well as size of P. aeruginosa aggregates were greater in the sputum of those with persistent compared with eradicated infections (p < 0.01). The amount of Psl antibody binding in sputum was also greater overall (p < 0.05) in samples with increased P. aeruginosa biovolume. When visualized in sputum, P. aeruginosa had a greater biovolume, with more expressed Psl, and formed more numerous, larger aggregates in CF children who failed eradication therapy compared to those who successfully cleared their infection., (© 2022. The Author(s).)

Objective: To determine the minimum inhibitory concentration (MIC) distribution of antibacterial drugs and the susceptibility of non-tuberculous mycobacterial (NTM) isolates to provide a reference basis for the clinical selection of an effective starting regimen. Methods: The common clinical isolates of NTM in the respiratory tract, which met the standards of the American Thoracic Society for NTM lung disease, were collected. The MICs of 81 isolates were determined using the microbroth dilution method (Thermo Fisher Scientific, USA), as recommended by the Clinical and Laboratory Standards Institute, USA. Results: Included were 43 Mycobacterium avium complex (MAC) strains, 24  M. abscessus complex (MAB) strains, and 14  M. kansasii strains. The sensitivity rates of MAC to clarithromycin and amikacin were 81.4% and 79.1%, respectively, while the sensitivity rates to linezolid and moxifloxacin were only 20.9% and 9.3%; the MIC of rifabutin was the lowest (MIC50% was just 2 μg/mL). After incubation for 3-5 days, the sensitivity rate of MAB to clarithromycin was 87.5%; this decreased to 50% after 14 days' incubation. Most of them were susceptible to amikacin (91.6%), and most were resistant to moxifloxacin (95.8%), ciprofloxacin (95.8%), imipenem (95.8%), amoxicillin/clavulanate (95.8%), tobramycin (79.1%), doxycycline (95.8%) and trimethoprim/sulfamethoxazole (95.8%). intermediate (83.3%) and resistant (16.7%) to cefoxitin. The susceptibility to linezolid was only 33.3%. The sensitivity and resistance breakpoints of tigecycline were set to ≤0.5 and ≥8 μg/mL, respectively, and the sensitivity and resistance rates were 50% and 0%, respectively. M. kansasii was susceptible to clarithromycin, amikacin, linezolid, moxifloxacin, rifampicin and rifabutin (100%). Discussion: In Wenzhou, clarithromycin, amikacin and rifabutin have good antibacterial activity against MAC, while linezolid and moxifloxacin have high resistance. Amikacin and tigecycline have strong antibacterial activity against MAB, while most other antibacterial drugs are resistant to varying degrees. Most antibacterial drugs are susceptible to M . kansasii and have good antibacterial activity. Conclusion: The identification of NTM species and the detection of their MICs have certain guiding values for the treatment of NTM lung disease.Key MessageThe three most common respiratory non-tuberculous mycobacterial (NTM) isolates with clinical significance in the Wenzhou area were tested for drug susceptibility. The broth microdilution method was used to determine the minimum inhibitory concentration distribution of antibacterial drugs and the susceptibility of NTM isolates to provide a reference basis for the clinical selection of an effective starting regimen.

Cystic fibrosis (CF) disease is characterized by lifelong infections with pathogens such as Staphylococcus aureus, leading to eventual respiratory failure. Small colony variants (SCVs) of S. aureus have been linked to worse clinical outcomes for people with CF. Current studies of SCV pathology in vivo are limited, and it remains unclear whether SCVs directly impact patient outcomes or are a result of late-stage CF disease. To investigate this, we generated a stable menadione-auxotrophic SCV strain by serially passaging a CF isolate of S. aureus with tobramycin, an aminoglycoside antibiotic commonly administered for coinfecting Pseudomonas aeruginosa. This SCV was tobramycin resistant and showed increased tolerance to the anti-staphylococcal combination therapy sulfamethoxazole-trimethoprim. To better understand the dynamics of SCV infections in vivo, we infected CF rats with this strain compared with its normal colony variant (NCV). Analysis of bacterial burden at 3 days postinfection indicated that NCVs and SCVs persisted equally well in the lungs, but SCV infections ultimately led to increased weight loss and neutrophilic inflammation. Additionally, cellular and histopathological analyses showed that in CF rats, SCV infections yielded a lower macrophage response. Overall, these findings indicate that SCV infections may directly contribute to lung disease progression in people with CF.

Nowadays, antimicrobial resistance (AMR) represents a challenge for antibiotic therapy, mostly involving Gram-negative bacteria. Among the strategies activated to overcome AMR, the repurposing of already available antimicrobial molecules by encapsulating them in drug delivery systems, such as nanoparticles (NPs) and also engineered NPs, seems to be promising. Tobramycin is a powerful and effective aminoglycoside, approved for complicated infections and reinfections and indicated mainly against Gram-negative bacteria, such as Pseudomonas aeruginosa , Escherichia coli , Proteus , Klebsiella , Enterobacter , Serratia , Providencia , and Citrobacter species. However, the drug presents several side effects, mostly due to dose frequency, and for this reason, it is a good candidate for nanomedicine formulation. This review paper is focused on what has been conducted in the last 20 years for the development of Tobramycin nanosized delivery systems (nanoantibiotics), with critical discussion and comparison. Tobramycin was selected as the antimicrobial drug because it is a wide-spectrum antibiotic that is effective against both Gram-positive and Gram-negative aerobic bacteria, and it is characterized by a fast bactericidal effect, even against multidrug-resistant microorganisms (MDR).

Background: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review., Objectives: To evaluate the effects of long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug-sensitivity reactions and survival)., Search Methods: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries. Date of last search: 28 June 2022., Selection Criteria: We selected trials where people with cystic fibrosis received inhaled anti-pseudomonal antibiotic treatment for at least three months, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic)., Data Collection and Analysis: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the certainty of the evidence using the GRADE system., Main Results: The searches identified 410 citations to 125 trials; 18 trials (3042 participants aged between five and 45 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One trial (18 participants) compared an antibiotic to placebo and also to a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials. Inhaled antibiotics compared to placebo We found that inhaled antibiotics may improve lung function measured in a variety of ways (4 trials, 814 participants). Compared to placebo, inhaled antibiotics may also reduce the frequency of exacerbations (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.47 to 0.93; 3 trials, 946 participants; low-certainty evidence). Inhaled antibiotics may lead to fewer days off school or work (quality of life measure) (mean difference (MD) -5.30 days, 95% CI -8.59 to -2.01; 1 trial, 245 participants; low-certainty evidence). There were insufficient data for us to be able to report an effect on nutritional outcomes and there was no effect on survival. There was no effect on antibiotic resistance seen in the two trials that were included in meta-analyses. We are uncertain of the effect of the intervention on adverse events (very low-certainty evidence), but tinnitus and voice alteration were the only events occurring more often in the inhaled antibiotics group. The overall certainty of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates. Different antibiotics or regimens compared Of the eight trials comparing different inhaled antibiotics or different antibiotic regimens, there was only one trial for each unique comparison. We found no differences between groups for any outcomes except for the following. Aztreonam lysine for inhalation probably improved forced expiratory volume at one second (FEV 1 ) % predicted compared to tobramycin (MD -3.40%, 95% CI -6.63 to -0.17; 1 trial, 273 participants; moderate-certainty evidence). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. We found no differences in any measure of lung function in the remaining comparisons. Trials measured pulmonary exacerbations in different ways and showed no differences between groups except for aztreonam lysine probably leading to fewer people needing treatment with additional antibiotics than with tobramycin (RR 0.66, 95% CI 0.51 to 0.86; 1 trial, 273 participants; moderate-certainty evidence); and there were fewer hospitalisations due to respiratory exacerbations with levofloxacin compared to tobramycin (RR 0.62, 95% CI 0.40 to 0.98; 1 trial, 282 participants; high-certainty evidence). Important treatment-related adverse events were not very common across comparisons, but were reported less often in the tobramycin group compared to both aztreonam lysine and colistimethate. We found the certainty of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high., Authors' Conclusions: Long-term treatment with inhaled anti-pseudomonal antibiotics probably improves lung function and reduces exacerbation rates, but pooled estimates of the level of benefit were very limited. The best evidence available is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Pseudomonas aeruginosa is an important nosocomial pathogen with a capacity of resistance to multiple antibiotics and production of various extracellular and cell-associated virulence factors that clearly contribute to its pathogenicity. The objective of this study was to investigate the antibiotic susceptibility, virulence factors, and clonal relationship among clinical isolates of P. aeruginosa. Different clinical specimens from hospitalized patients were investigated for P. aeruginosa. Susceptibility of the isolates was evaluated by disc diffusion and broth microdilution methods, as described by the Clinical and Laboratory Standards Institute (CLSI) guideline. A total of 97 P. aeruginosa isolates were recovered from clinical specimens. The percentage of isolates resistant to antimicrobials was imipenem 25.77%, meropenem 15.46%, gentamicin 16.49%, tobramycin 15.46%, amikacin 16.49%, ciprofloxacin 20.61%, levofloxacin 24.74, ceftazidime 20.61%, piperacillin 15.46%, piperacillin/tazobactam 12.37%, colistin 9.27%, and polymyxin B 11.34%. Of isolates, 87.62% possessed β-hemolytic activity, 78.35% lecithinase, 59.8% elastase, 37.11% DNase, and 28.86% twitching motility. The frequency of virulence genes in isolates was lasB 82.47%, plcH 82.47%, exoA 58.76%, exoS 56.7%, and pilA 10.3%. ERIC-PCR typing clustered P. aeruginosa isolates to 19 common types (CT1-CT19) containing isolates from different hospitals and 43 single types (ST1-ST43). Colistin and polymyxin B were the most effective agents against the majority of P. aeruginosa isolates, emphasizing the effort to maintain their antibacterial activity as last-line therapy. The frequency of some virulence factors and genes was noticeably high, which is alarming. In addition, more effective strategies and surveillance are necessary to confine and prevent the inter-hospital and/or intra-hospital dissemination of P. aeruginosa between therapeutic centers., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Pseudomonas aeruginosa is the most common pathogen infecting the lungs of people with cystic fibrosis (CF), causing both acute and chronic infections. Intrinsic and acquired antibiotic resistance, coupled with the physical barriers resulting from desiccated CF sputum, allow P. aeruginosa to colonize and persist in spite of antibiotic treatment. As well as the specific difficulties in eradicating P. aeruginosa from CF lungs, P. aeruginosa is also subject to the wider, global issue of antimicrobial resistance. Glatiramer acetate (GA) is a peptide drug, used in the treatment of multiple sclerosis (MS), which has been shown to have moderate antipseudomonal activity. Other antimicrobial peptides (AMPs) have been shown to be antibiotic resistance breakers, potentiating the activities of antibiotics when given in combination, restoring and/or enhancing antibiotic efficacy. Growth, viability, MIC determinations, and synergy analysis showed that GA improved the efficacy of tobramycin (TOB) against reference strains of P. aeruginosa, reducing TOB MICs and synergizing with the aminoglycoside. This was also the case for clinical strains from people with CF. GA significantly reduced the MIC 50 of TOB for viable cells from 1.69 mg/L (95% confidence interval [CI], 0.26 to 8.97) to 0.62 mg/L (95% CI, 0.15 to 3.94; P  = 0.002) and the MIC 90 for viable cells from 7.00 mg/L (95% CI, 1.18 to 26.50) to 2.20 mg/L (95% CI, 0.99 to 15.03; P  = 0.001), compared to results with TOB only. Investigation of mechanisms of GA activity showed that GA resulted in significant disruption of outer membranes, depolarization of cytoplasmic membranes, and permeabilization of P. aeruginosa and was the only agent tested (including cationic AMPs) to significantly affect all three mechanisms. IMPORTANCE The antimicrobial resistance crisis urgently requires solutions to the lost efficacy of antibiotics. The repurposing of drugs already in clinical use, with strong safety profiles, as antibiotic adjuvants to restore the efficacy of antibiotics is an important avenue to alleviating the resistance crisis. This research shows that a clinically used drug from outside infection treatment, glatiramer acetate, reduces the concentration of tobramycin required to be effective in treating Pseudomonas aeruginosa, based on analyses of both reference and clinical respiratory isolates from people with cystic fibrosis. The two agents acted synergistically against P. aeruginosa, being more effective combined in vitro than predicted for their combination. As a peptide drug, glatiramer acetate functions similarly to many antimicrobial peptides, interacting with and disrupting the P. aeruginosa cell wall and permeabilizing bacterial cells, thereby allowing tobramycin to work. Our findings demonstrate that glatiramer acetate is a strong candidate for repurposing as an antibiotic resistance breaker of pathogenic P. aeruginosa.

Burns are a common health problem worldwide and are highly susceptible to bacterial infections that are difficult to handle with ordinary wound dressings. Therefore, burn wound repair is extremely challenging in clinical practice. Herein, a series of self-healing hydrogels (QCS/OD/TOB/PPY@PDA) with good electrical conductivity and antioxidant activity were prepared on the basis of quaternized chitosan (QCS), oxidized dextran (OD), tobramycin (TOB), and polydopamine-coated polypyrrole nanowires (PPY@PDA NWs). These Schiff base cross-links between the aminoglycoside antibiotic TOB and OD enable TOB to be slowly released and responsive to pH. Interestingly, the acidic substances during the bacteria growth process can induce the on-demand release of TOB, avoiding the abuse of antibiotics. The antibacterial results showed that the QCS/OD/TOB/PPY@PDA9 hydrogel could kill high concentrations of Pseudomonas aeruginosa (PA), Staphylococcus aureus , and Escherichia coli in a short time and showed a bactericidal effect for up to 11 days in an agar plate diffusion experiment, while showing good in vivo antibacterial activity. Excellent and long-lasting antibacterial properties make it suitable for severely infected wounds. Furthermore, the incorporation of PPY@PDA endowed the hydrogel with near-infrared (NIR) irradiation assisted bactericidal activity of drug-resistant bacteria, conductivity, and antioxidant activity. Most importantly, in the PA-infected burn wound model, the QCS/OD/TOB/PPY@PDA9 hydrogel more effectively controlled wound inflammation levels and promoted collagen deposition, vascular generation, and earlier wound closure compared to Tegaderm dressings. Therefore, the TOB smart release hydrogels with on-demand delivery are extremely advantageous for bacterial-infected burn wound healing.

Background: Cystic fibrosis is a genetic disorder in which abnormal mucus in the lungs is associated with susceptibility to persistent infection. Pulmonary exacerbations are when symptoms of infection become more severe. Antibiotics are an essential part of treatment for exacerbations and inhaled antibiotics may be used alone or in conjunction with oral antibiotics for milder exacerbations or with intravenous antibiotics for more severe infections. Inhaled antibiotics do not cause the same adverse effects as intravenous antibiotics and may prove an alternative in people with poor access to their veins. This is an update of a previously published review., Objectives: To determine if treatment of pulmonary exacerbations with inhaled antibiotics in people with cystic fibrosis improves their quality of life, reduces time off school or work, and improves their long-term lung function., Search Methods: We searched the Cochrane Cystic Fibrosis Group's Cystic Fibrosis Trials Register. Date of the last search: 7 March 2022. We also searched ClinicalTrials.gov, the Australia and New Zealand Clinical Trials Registry and WHO ICTRP for relevant trials. Date of last search: 3 May 2022., Selection Criteria: Randomised controlled trials in people with cystic fibrosis with a pulmonary exacerbation in whom treatment with inhaled antibiotics was compared to placebo, standard treatment or another inhaled antibiotic for between one and four weeks., Data Collection and Analysis: Two review authors independently selected eligible trials, assessed the risk of bias in each trial and extracted data. They assessed the certainty of the evidence using the GRADE criteria. Authors of the included trials were contacted for more information., Main Results: Five trials with 183 participants are included in the review. Two trials (77 participants) compared inhaled antibiotics alone to intravenous antibiotics alone and three trials (106 participants) compared a combination of inhaled and intravenous antibiotics to intravenous antibiotics alone. Trials were heterogenous in design and two were only available in abstract form. Risk of bias was difficult to assess in most trials but, for four out of five trials, we judged there to be a high risk from lack of blinding and an unclear risk with regards to randomisation. Results were not fully reported and only limited data were available for analysis. One trial was a cross-over design and we only included data from the first intervention arm. Inhaled antibiotics alone versus intravenous antibiotics alone Only one trial (18 participants) reported a perceived improvement in lifestyle (quality of life) in both groups (very low-certainty evidence). Neither trial reported on time off work or school. Both trials measured lung function, but there was no difference reported between treatment groups (very low-certainty evidence). With regards to our secondary outcomes, one trial (18 participants) reported no difference in the need for additional antibiotics and the second trial (59 participants) reported on the time to next exacerbation. In neither case was a difference between treatments identified (both very low-certainty evidence). The single trial (18 participants) measuring adverse events and sputum microbiology did not observe any in either treatment group for either outcome (very low-certainty  evidence). Inhaled antibiotics plus intravenous antibiotics versus intravenous antibiotics alone Inhaled antibiotics plus intravenous antibiotics may make little or no difference to quality of life compared to intravenous antibiotics alone. None of the trials reported time off work or school. All three trials measured lung function, but found no difference between groups in forced expiratory volume in one second (two trials; 44 participants; very low-certainty evidence) or vital capacity (one trial; 62 participants). None of the trials reported on the need for additional antibiotics. Inhaled plus intravenous antibiotics may make little difference to the time to next exacerbation; however, one trial (28 participants) reported on hospital admissions and found no difference between groups. There is likely no difference between groups in adverse events (very low-certainty evidence) and one trial (62 participants) reported no difference in the emergence of antibiotic-resistant organisms (very low-certainty evidence)., Authors' Conclusions: We identified only low- or very low-certainty evidence to judge the effectiveness of inhaled antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis. The included trials were not sufficiently powered to achieve their goals. Hence, we are unable to demonstrate whether one treatment was superior to the other or not. Further research is needed to establish whether inhaled tobramycin may be used as an alternative to intravenous tobramycin for some pulmonary exacerbations., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The objective of this study was to evaluate local antimicrobial delivery from temperature-responsive hydrogels for preventing infection in a rat model of intra-abdominal infection (IAI), and to determine whether delivery of tobramycin and vancomycin in combination is effective against IAI pathogens. Rats received intraperitoneal inoculation of E. coli, rat cecal contents, or cecal contents supplemented with E. coli, and received either no treatment, subcutaneous cefoxitin, or local delivery from hydrogels containing vancomycin, tobramycin, or both antimicrobials. Only the hydrogel with tobramycin and vancomycin significantly increased the infection free-rate compared to no treatment for all inocula (E. coli: 13/17, p < 0.0001; cecal contents: 11/17, p = 0.0013; cecal contents + E. coli: 15/19, p < 0.0001). Additionally, tobramycin and vancomycin displayed no synergy or antagonism against clinical isolates in vitro. Local delivery of tobramycin and vancomycin from temperature-responsive hydrogels provides broad coverage and high antimicrobial concentrations for several hours that may be effective for preventing IAIs., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Antibiotics, such as inhaled tobramycin, are used to eradicate new-onset Pseudomonas aeruginosa (PA) infections in patients with cystic fibrosis (CF) but frequently fail due to reasons poorly understood. We hypothesized that PA isolates' resistance to neutrophil antibacterial functions was associated with failed eradication in patients harboring those strains., Methods: We analyzed all PA isolates from a cohort of 39 CF children with new-onset PA infections undergoing tobramycin eradication therapy, where 30 patients had eradicated and 9 patients had persistent infection. We characterized several bacterial phenotypes and measured the isolates' susceptibility to neutrophil antibacterial functions using in vitro assays of phagocytosis and intracellular bacterial killing., Results: PA isolates from persistent infections were more resistant to neutrophil functions, with lower phagocytosis and intracellular bacterial killing compared to those from eradicated infections. In multivariable analyses, in vitro neutrophil responses were positively associated with twitching motility, and negatively with mucoidy. In vitro neutrophil phagocytosis was a predictor of persistent infection following tobramycin even after adjustment for clinical risk factors., Conclusions: PA isolates from new-onset CF infection show strain-specific susceptibility to neutrophil antibacterial functions, and infection with PA isolates resistant to neutrophil phagocytosis is an independent risk factor for failed tobramycin eradication., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Purpose: Pseudomonas aeruginosa is a leading cause of corneal infections. Recently, we discovered an antimicrobial drug combination, polymyxin B/trimethoprim (PT) + rifampin, that displayed impressive efficacy toward P. aeruginosa in both in vitro and in vivo studies. As such, this combination was further evaluated as a potential keratitis therapeutic through testing the combination's efficacy against a diverse set of P. aeruginosa clinical isolates., Methods: Minimum inhibitory concentrations (MICs) of moxifloxacin, levofloxacin, erythromycin, tobramycin, PT, polymyxin B (alone), trimethoprim (alone), and rifampin were determined for 154 ocular clinical P. aeruginosa isolates, 90% of which were derived from corneal scrapings. Additionally, the efficacy of PT + rifampin was evaluated utilizing fractional inhibitory concentration (FIC) testing., Results: While 100% of isolates were resistant to erythromycin (average MIC 224 ± 110 µg·mL-1) and trimethoprim (alone) (206 ± 67.3 µg·mL-1), antibiotic resistance was generally found to be low: moxifloxacin (2% of isolates resistant; average MIC 1.08 ± 1.61 µg·mL-1), levofloxacin (3.9%; 1.02 ± 2.96 µg·mL-1), tobramycin (1%; 0.319 ± 1.31 µg·mL-1), polymyxin B (0%; 0.539 ± 0.206 µg·mL-1), PT (0%; 0.416 ± 0.135 µg·mL-1), and rifampin (0%; 23.4 ± 6.86 µg·mL-1). Additionally, FIC testing revealed that PT + rifampin eradicated 100% of isolates demonstrating additive or synergistic activity in 95% of isolates (average FIC index 0.701 ± 0.132)., Conclusions: The drug combination of PT + rifampin was effective against a large panel of clinically relevant P. aeruginosa strains and, as such, may represent a promising therapeutic for P. aeruginosa keratitis., Translational Relevance: This work furthers the preclinical development of a novel antibiotic combination for the treatment of corneal infections (bacterial keratitis).

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis.

Acute exacerbations of chronic respiratory infections in patients with cystic fibrosis are highly challenging due to hypermutable Pseudomonas aeruginosa, biofilm formation and resistance emergence. We aimed to systematically evaluate the effects of intravenous versus inhaled tobramycin (TOB) with and without intravenous ceftazidime (CAZ). Two hypermutable P. aeruginosa isolates, CW30 (MIC CAZ , 0.5 mg/liter; MIC TOB , 2 mg/liter) and CW8 (MIC CAZ , 2 mg/liter; MIC TOB , 8 mg/liter), were investigated for 120 h in dynamic in vitro biofilm studies. Treatments were intravenous ceftazidime, 9 g/day (33% lung fluid penetration); intravenous tobramycin, 10 mg/kg of body every 24 h (50% lung fluid penetration); inhaled tobramycin, 300 mg every 12 h; and both ceftazidime-tobramycin combinations. Total and less susceptible planktonic and biofilm bacteria were quantified over 120 h. Mechanism-based modeling was performed. All monotherapies were ineffective for both isolates, with regrowth of planktonic (≥4.7 log 10 CFU/ml) and biofilm (>3.8 log 10 CFU/cm 2 ) bacteria and resistance amplification by 120 h. Both combination treatments demonstrated synergistic or enhanced bacterial killing of planktonic and biofilm bacteria. With the combination simulating tobramycin inhalation, planktonic bacterial counts of the two isolates at 120 h were 0.47% and 36% of those for the combination with intravenous tobramycin; for biofilm bacteria the corresponding values were 8.2% and 13%. Combination regimens achieved substantial suppression of resistance of planktonic and biofilm bacteria compared to each antibiotic in monotherapy for both isolates. Mechanism-based modeling well described all planktonic and biofilm counts and indicated synergy of the combination regimens despite reduced activity of tobramycin in biofilm. Combination regimens of inhaled tobramycin with ceftazidime hold promise to treat acute exacerbations caused by hypermutable P. aeruginosa strains and warrant further investigation.

Background: Present work was aimed to gather accessible evidence on the eradication rates and related postoperative complications of antibiotic-loaded calcium sulfate (CS) as an implant in the treatment of chronic osteomyelitis (COM)., Methods: Databases including PubMed, EMBASE, Medline, Ovid and Cochrane library were searched from their dates of initiation until November 2021. Two independent authors scrutinized the relevant studies based on the effectiveness of radical debridement combined with antibiotic-loaded CS for COM; data extraction and quality assessment of the Methodological Index for Non-Randomized Studies (MINORS) criteria were also performed by the authors. In addition, clinical efficacy mainly depended on the evaluation of eradication rates and complications, and all the extracted data are pooled and analyzed by STATA 16.0., Results: A total of 16 studies with 917 patients (920 locations) were recruited, with an overall eradication rate of 92%. Moreover, the overall reoperation rate, overall refracture rate, overall delayed wound healing rate, and the rate of aseptic wound leakage were 9.0%, 2.0%, 20.0%, and 12.0%, respectively. Moreover, the choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate, and the incidence of postoperative complications in COM patients (all [Formula: see text]). The general quality of the included studies was fair., Conclusions: Our meta-analysis indicated that the overall eradication rate of COM treated with antibiotic-loaded CS was 92%. Delayed healing is the most common postoperative complication. The choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate and the incidence of postoperative complications in COM patients., (© 2022. The Author(s).)

Background: Inhaled tobramycin can be used for empiric or definitive therapy of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. This is believed to minimize systemic exposure and potential adverse drug toxicities including acute kidney injury (AKI). However, detectable serum tobramycin concentrations have been reported after inhaled tobramycin therapy with AKI., Methods: This retrospective, observational study evaluated mechanically ventilated adult subjects admitted to ICUs at a large, urban academic medical center that received empiric inhaled tobramycin for VAP. Subjects were separated into detectable (ie, ≥ 0.6 mg/L) or undetectable serum tobramycin concentration groups, and characteristics were compared. Independent predictors for detectable serum tobramycin concentration and new onset AKI during or within 48 h of therapy discontinuation were assessed., Results: Fifty-nine inhaled tobramycin courses in 53 subjects were included in the analysis, of which 39 (66.1%) courses administered to 35 (66.0%) subjects had detectable serum tobramycin concentrations. Subjects with detectable serum tobramycin concentrations were older (57.1 y ± 11.4 vs 45.9 ±15.0, P = .004), had higher PEEP (9.2 cm H 2 O [7.0-11.0] vs 8.0 [5.6-8.9] , P = .049), chronic kidney disease stage ≥ 2 (10 [29.4%] vs 0 [0%], P = .009), and higher serum creatinine before inhaled tobramycin therapy (1.26 mg/dL [0.84-2.18] vs 0.76 [0.47-1.28] , P = .004). Age (odds ratio 1.09 [95% CI 1.02-1.16], P = .009) and PEEP (odds ratio 1.47 [95% CI 1.08-2.0], P =.01) were independent predictors for detectable serum tobramycin concentration. Thirty-seven subjects had no previous renal disease or injury, of which 9 (24.3%) developed an AKI. Sequential Organ Failure Assessment score (odds ratio 1.72 [95% CI 1.07-2.76], P = .03) was the only independent predictor for AKI., Conclusions: Detectable serum tobramycin concentrations were frequently observed in critically ill, mechanically ventilated subjects receiving empiric inhaled tobramycin for VAP. Subject age and PEEP were independent predictors for detectable serum tobramycin concentration. Serum monitoring and empiric dose reductions should be considered in older patients and those requiring higher PEEP., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2022 by Daedalus Enterprises.)

Pseudomonas aeruginosa is a ubiquitous human pathogen that causes severe infections. Although antibiotics, such as tobramycin, are currently used for infection therapy, their antibacterial activity has resulted in the emergence of multiple antibiotic-resistant bacteria. The 6-gingerol analog, a structural derivative of the main component of ginger, is a quorum sensing (QS) inhibitor. However, it has a lower biofilm inhibitory activity than antibiotics and the possibility to cause toxicity in humans. Therefore, novel and more effective approaches for decreasing dosing concentration and increasing biofilm inhibitory activity are required to alleviate P. aeruginosa infections. In this study, a 6-gingerol analog was combined with tobramycin to treat P. aeruginosa infections. The combined treatment of 6-gingerol analog and tobramycin showed strong inhibitory activities on biofilm formation and the production of QS-related virulence factors of P. aeruginosa compared to single treatments. Furthermore, the combined treatment alleviated the infectivity of P. aeruginosa in an insect model using Tenebrio molitor larvae without inducing any cytotoxic effects in human lung epithelial cells. The 6-gingerol analog showed these inhibitory activities at much lower concentrations when used in combination with tobramycin. Adjuvant effects were observed through increased QS-disrupting processes rather than through antibacterial action. In particular, improved RhlR inactivation by this combination is a possible target for therapeutic development in LasR-independent chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin may be considered an effective method for treating P. aeruginosa infections. IMPORTANCE Pseudomonas aeruginosa is a pathogen that causes various infectious diseases through quorum-sensing regulation. Although antibiotics are mainly used to treat P. aeruginosa infections, they cause the emergence of resistant bacteria in humans. To compensate for the disadvantages of antibiotics and increase their effectiveness, natural products were used in combination with antibiotics in this study. We discovered that combined treatment with 6-gingerol analog from naturally-derived ginger substances and tobramycin resulted in more effective reductions of biofilm formation and virulence factor production in P. aeruginosa than single treatments. Our findings support the notion that when 6-gingerol analog is combined with tobramycin, the effects of the analog can be exerted at much lower concentrations. Furthermore, its improved LasR-independent RhlR inactivation may serve as a key target for therapeutic development in chronic infections. Therefore, the combined treatment of 6-gingerol analog and tobramycin is suggested as a novel alternative for treating P. aeruginosa infections.

Background: Cystic fibrosis (CF) patients who grow Pseudomonas aeruginosa on respiratory culture are commonly prescribed inhaled tobramycin (TIS) to eradicate the organism. The objective of this study was to determine the impact of a pharmacy technician/pharmacist team, in conjunction with an integrated health-system specialty pharmacy (IHSSP), on the time from positive culture to prescribing and access to TIS in a pediatric CF clinic., Methods: A retrospective study of CF patients positive for P. aeruginosa who were prescribed TIS for eradication., Results: The study included 20 patients in the pregroup and 42 patients in the postgroup. Total median (interquartile range) days from positive culture to TIS being shipped to the patient from the pharmacy was significantly different: 15 (10.25-21) days in the pregroup and 9 (7-14) days in the post groups (p = .005). The time from positive culture to TIS prescribing was significantly different: 6 (5-12.75) days in the pregroup and 5 (3.75-6) days in the postgroup (p = .01). In the postgroup median time from prescription to the patient receiving the TIS was significantly different between the two groups 2 (2-5) days IHSSP group versus 6 (3-9) external specialty pharmacy group (p = .003). Time from prescription to prior authorization approval was the same in both groups., Conclusions: The addition of the pharmacy team reduced time from culture to TIS being received by the patient. Patients able to fill at the IHSSP received their medication sooner than an external specialty pharmacy. The study shows the benefit of an integrated pharmacy model in conjunction with an IHSSP., (© 2021 Wiley Periodicals LLC.)

Delayed healing or non-healing of wounds caused by bacterial infection is still a difficult medical problem. Nowadays, the topical application of antibiotics is a common treatment for infections. However, subinhibitory concentrations or high dose of antibiotics leads to the antibacterial effect counterproductive. So it's necessary to put forward an on-demand drug delivery to solve this tough issue. In this paper, a pH-responsive hydrogel was prepared by oxidized dextran (Dex-CHO), sulfadiazine (SD) and tobramycin (TOB). The hydrogel was designed by the environment in the early immature stage of biofilm (pH 5.0). Schiff bases can release drugs in slightly acidic environment. The hydrogel showed injectable, pH-sensitive drug release, and great biocompatibility. Released SD and TOB exhibited a synergistic effect therefore the hydrogel showed high antibacterial activity. This study provides an easy and promising strategy to develop smart hydrogels that aim at topical administration of antibiotics and come up with a new treatment of local bacterial infections., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pseudomonas aeruginosa is the predominant opportunistic bacterium that causes chronic respiratory infections in cystic fibrosis (CF) patients. This bacterium can form biofilms, which are structured communities of cells encased within a self-produced matrix. Such biofilms have a high level of resistance to multiple classes of antibiotics. A widely used treatment of P. aeruginosa lung infections in CF patients is tobramycin dry powder inhalation. The behaviour of particles in the lung has been well studied, and dry powder inhalers are optimised for optimal dispersion of the drug into different zones of the lung. However, one question that has not been addressed is whether the size of an antibiotic particle influences the antibiofilm activity against P. aeruginosa. We investigated this by fractionating tobramycin particles using a Next Generation Impactor (NGI). The fractions obtained were then tested in an in vitro model on P. aeruginosa biofilms. The results indicate that the antibiofilm activity of tobramycin dry powder inhaler can indeed be influenced by the particle size. Against P. aeruginosa biofilms of two clinical isolates, smaller tobramycin particles (aerodynamic diameter <2.82 µm) showed better efficacy by approximately 20% as compared to larger tobramycin particles (aerodynamic diameter <11.7 µm) However, this effect was only observed when biofilms were treated for 3 hours, whereas there was no difference after treatment for 24 hours. This suggests that in our model the rate of dissolution of larger particles limits the effectiveness of tobramycin over a 3-hour time period, which is relevant as this is equivalent to the time in which most tobramycin is cleared from the lung., (Copyright © 2020. Published by Elsevier B.V.)