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International Journal of Molecular... Nov 2022Nowadays, antimicrobial resistance (AMR) represents a challenge for antibiotic therapy, mostly involving Gram-negative bacteria. Among the strategies activated to... (Review)
Review
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 , , , , , , , and 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).
Topics: Tobramycin; Gentamicins; Drug Resistance, Microbial; Aminoglycosides; Anti-Bacterial Agents
PubMed: 36430555
DOI: 10.3390/ijms232214080 -
PloS One 2016Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher...
RATIONALE
Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics.
OBJECTIVES
To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose.
METHODS
Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation.
RESULTS AND DISCUSSION
Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection.
CONCLUSIONS
In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population.
Topics: Administration, Inhalation; Adult; Aged; Bronchiectasis; Cystic Fibrosis; Dose-Response Relationship, Drug; Dry Powder Inhalers; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Powders; Tobramycin
PubMed: 26959239
DOI: 10.1371/journal.pone.0149768 -
European Journal of Hospital Pharmacy :... Mar 2022Over a course of 7 months, four patients developed vestibulotoxicity after treatment with intravenous tobramycin. Since vestibulotoxicity is a serious adverse effect...
Over a course of 7 months, four patients developed vestibulotoxicity after treatment with intravenous tobramycin. Since vestibulotoxicity is a serious adverse effect which can be irreversible, an investigation was undertaken to determine if there was a cause for the toxicity and whether the quality of care had been inadequate. In this period, 26 patients with cystic fibrosis were treated with tobramycin according to valid guidelines, of which four experienced acute dizziness which disrupted their daily activities. Two patients experienced irreversible bilateral vestibular hypofunction and two unilateral loss of the right labyrinth, with decreasing dizziness over time. No apparent cause for the vestibulotoxicity was found in these four patients and the simultaneous occurrence was not due to a lack in quality of care. Symptoms of dizziness and balance disorders should be recognised by patients and caretakers at an early stage so additional diagnostics can be done to prevent further deterioration.
Topics: Cystic Fibrosis; Humans; Retrospective Studies; Tobramycin
PubMed: 33753422
DOI: 10.1136/ejhpharm-2020-002588 -
Orthopaedic Surgery Jul 2021A bone defect rat model was established to investigate the osteogenic effect of local delivery two antibiotics (vancomycin and tobramycin powder) on bone regeneration.
OBJECTIVE
A bone defect rat model was established to investigate the osteogenic effect of local delivery two antibiotics (vancomycin and tobramycin powder) on bone regeneration.
METHODS
Twenty-four Sprague-Dawley (SD) male rats (6 to 8 weeks, 200 to 250 g) were used in this study. All these rats were randomly divided into four groups. Based on dose conversion between rat and human via body surface area, the rat dose of two antibiotics was 88μg/g and 176 μg/g for vancomycin and tobramycin, respectively. Con group (no antibiotic), Van group (vancomycin, 88 μg/g), Tob group (tobramycin 176 μg/g), and Van+Tob group (vancomycin 88μg/g combined with tobramycin 176 μg/g). A 5.0-mm full-thickness standardized mandibular bone defect was performed with a drill in each rat and different antibiotic powders were placed over the bone defect space, respectively. All these animals were sacrificed after 12 weeks post-operation. The mandible bones were harvested for further radiographic and histologic analysis. The bone volume/total volume (BV/TV) ratio, bone volume (BV), and bone fractional area (BFA) in the defect area via micro-computed tomography (μCT scanning) were further analyzed. Then, we performed a histological assessment via hematoxylin and eosin (H&E) and Masson's trichrome staining to analyze bone regeneration and also analyze the number of osteoblasts per filed.
RESULTS
There were no postoperative deaths, signs of vancomycin-related or tobramycin-related toxicity, or signs of systemic illness in any of the four groups. All wounds healed well, and no complications or surgical site infection were observed in all rats. From the μCT scans analyses, there was less bone regeneration in the Van group than in the Con group (BV/TV: F = 64.29, R = 0.9602; P = 0.0052; BFA: F = 76.17, R = 0.9662, P = 0.0007; BV: F = 194.4, R = 0.9865, P = 0.0022). However, when the tobramycin and vancomycin were combined, an increase in bone defect re-ossification was found in the Van+Tob group than in the Van group (BV/TV: F = 64.29, R = 0.9602, P = 0.0033; BFA: F = 76.17, R = 0.9662, P = 0.0006; BV: F = 194.4, R = 0.9865, P = 0.0033). Routine H&E and Masson staining supported the finding of μCT scanning. Quantitative indices confirmed that both the bone regeneration and the number of osteoblasts per filed in the defect area was higher in the Van+Tob group than in the Van group (percentage of bone tissue: F = 145.7, R = 0.9562, P = 0.0008; number of osteoblasts per file; F = 67.3, R = 0.9098, P < 0.0001). There was no significant difference between the Con group and the Van+Tob group on the number of osteoblasts each field (F = 145.7, R = 0.9562, P > 0.9999).
CONCLUSION
For bone defect, local application of vancomycin combined with tobramycin was recommended over vancomycin alone. This animal study presents data suggesting that the use of local delivery of vancomycin and tobramycin should be investigated further in clinical studies.
Topics: Animals; Anti-Bacterial Agents; Bone Regeneration; Disease Models, Animal; Drug Therapy, Combination; Male; Mandible; Powders; Rats; Rats, Sprague-Dawley; Surgical Wound Infection; Tobramycin; Vancomycin; Wound Healing
PubMed: 34124847
DOI: 10.1111/os.13020 -
Medicine Dec 2022This study aimed to evaluate the risk of serum tobramycin concentrations exceeding therapeutic levels after administration of calcium sulfate (CaSO4) beads containing...
This study aimed to evaluate the risk of serum tobramycin concentrations exceeding therapeutic levels after administration of calcium sulfate (CaSO4) beads containing either 240 mg or 400 mg tobramycin and 1000 mg vancomycin. This single-center, prospective. This single-center, prospective study included included Piedmont Columbus, Regional orthopedic surgery patients. Following the implantation of tobramycin into CaSO4 beads, serially measured serum tobramycin concentrations were evaluated after 6, 12, 24, and 48 hours. In addition to that, serum tobramycin concentration was evaluated after 5 days. None of the patients who received 240 mg tobramycin-impregnated beads had a tobramycin level >2 μg/mL. Six hours after implantation, the tobramycin level in 2 out of 2 (100%) patients who received 400 mg of tobramycin-impregnated beads was >2 μg/mL. One day following the surgery, the median serum creatinine was 0.85 mg/dL, with an interquartile range of 0.73 to 1.04 mg/dL. No cases of acute kidney injury were observed. This cohort demonstrated that non-nephrotoxic serum tobramycin levels could be achieved in CaSO4 beads mixed with 240 mg or 400 mg of tobramycin.
Topics: Humans; Tobramycin; Prospective Studies; Anti-Bacterial Agents; Vancomycin; Kidney
PubMed: 36626517
DOI: 10.1097/MD.0000000000032276 -
Antimicrobial Agents and Chemotherapy May 1994The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic...
The pulmonary residence time of free and liposome-encapsulated tobramycin was studied with uninfected rats and rats infected with Pseudomonas aeruginosa. Chronic infection in lungs was established by intratracheal administration of 10(8) CFU of P. aeruginosa PA 508 prepared in agar beads. After 3 days, a single dose (300 micrograms) of free or liposome-encapsulated tobramycin was given intratracheally to both infected and uninfected rats. At various time intervals (0.25 to 16 h) after drug instillations, the remaining tobramycin was evaluated in blood, lungs, and kidneys by a microbiological assay. Intratracheal instillation of liposome-encapsulated tobramycin resulted in high and sustained levels of tobramycin in lungs of uninfected and infected rats over the 16-h period studied; however, the tobramycin levels were two times higher in uninfected rats. There was no tobramycin detected in the blood or kidneys from these animals. In contrast, the intratracheally instilled free tobramycin was cleared within 3 and 1 h from the lungs of uninfected and infected animals, respectively. These data suggest that the encapsulation of tobramycin in liposomes can result in a significant increase of its residence time within lungs. This study also shows that pulmonary infection was associated with a lowering of tobramycin levels in lungs.
Topics: Animals; Drug Carriers; Intubation, Intratracheal; Liposomes; Lung; Male; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Tobramycin
PubMed: 8067743
DOI: 10.1128/AAC.38.5.1090 -
Nucleic Acids Research Nov 2023We herein report the selection and characterization of a new riboswitch dependent on the aminoglycoside tobramycin. Its dynamic range rivals even the tetracycline...
We herein report the selection and characterization of a new riboswitch dependent on the aminoglycoside tobramycin. Its dynamic range rivals even the tetracycline dependent riboswitch to be the current best performing, synthetic riboswitch that controls translation initiation. The riboswitch was selected with RNA Capture-SELEX, a method that not only selects for binding but also for structural changes in aptamers on binding. This study demonstrates how this method can fundamentally reduce the labour required for the de novo identification of synthetic riboswitches. The initially selected riboswitch candidate harbours two distinct tobramycin binding sites with KDs of 1.1 nM and 2.4 μM, respectively, and can distinguish between tobramycin and the closely related compounds kanamycin A and B. Using detailed genetic and biochemical analyses and 1H NMR spectroscopy, the proposed secondary structure of the riboswitch was verified and the tobramycin binding sites were characterized. The two binding sites were found to be essentially non-overlapping, allowing for a separate investigation of their contribution to the activity of the riboswitch. We thereby found that only the high-affinity binding site was responsible for regulatory activity, which allowed us to engineer a riboswitch from only this site with a minimal sequence size of 33 nt and outstanding performance.
Topics: Aptamers, Nucleotide; Ligands; Nucleic Acid Conformation; Protein Synthesis Inhibitors; Riboswitch; RNA; Tetracycline; Tobramycin; Saccharomyces cerevisiae; Genetic Engineering
PubMed: 37791877
DOI: 10.1093/nar/gkad767 -
Microbes and Infection 2021Acinetobacter baumannii, a leading cause of nosocomial infections, is a serious health threat. Limited therapeutic options due to multi-drug resistance and tolerance due...
Acinetobacter baumannii, a leading cause of nosocomial infections, is a serious health threat. Limited therapeutic options due to multi-drug resistance and tolerance due to persister cells have urged the scientific community to develop new strategies to combat infections caused by this pathogen effectively. Since combination antibiotic therapy is an attractive strategy, the effect of combinations of antibiotics, belonging to four classes, was investigated on eradication of persister cells in A. baumannii. Among the antibiotics included in the study, tobramycin-based combinations were found to be the most effective. Tobramycin, in combination with colistin or ciprofloxacin, eradicated persister cells in A. baumannii in late exponential and stationary phases of growth. Mechanistically, colistin facilitated the entry of tobramycin into cells by increasing membrane permeability and inducing hyperpolarization of the inner membrane accompanied by increase in ROS production. Expression of the genes encoding universal stress protein and efflux pumps was down-regulated in response to tobramycin and colistin, suggesting increased lethality of their combination that might be responsible for eradication of persister cells. Thus, a combination of tobramycin and colistin could be explored as a promising option for preventing the relapse of A. baumannii infections due to persister cells.
Topics: Acinetobacter; Acinetobacter baumannii; Anti-Bacterial Agents; Cell Membrane; Ciprofloxacin; Colistin; Down-Regulation; Drug Therapy, Combination; Gene Expression Regulation, Bacterial; Membrane Potentials; Microbial Sensitivity Tests; Permeability; Reactive Oxygen Species; Rifampin; Tobramycin
PubMed: 33567337
DOI: 10.1016/j.micinf.2021.104795 -
British Journal of Pharmacology Mar 2013Airway inflammation in cystic fibrosis (CF) patients is characterized by accumulations of neutrophils in the airway and T cells in bronchial tissue, with activation of...
BACKGROUND AND PURPOSE
Airway inflammation in cystic fibrosis (CF) patients is characterized by accumulations of neutrophils in the airway and T cells in bronchial tissue, with activation of platelets in the circulation. CF patients are routinely treated with systemic or inhaled tobramycin for airway infection with Pseudomonas aeruginosa. Clinical trials have indicated an anti-inflammatory effect of tobramycin beyond its bactericidal activity. Here, we investigate the anti-inflammatory properties of tobramycin in vitro and consider if these relate to the ability of tobramycin to bind copper, which is elevated in blood and sputum in CF.
EXPERIMENTAL APPROACH
A copper-tobramycin complex was synthesized. The effect of tobramycin and copper-tobramycin on neutrophil activation and migration of T cells and neutrophils across human lung microvascular endothelial cells in response to thrombin-activated platelets were investigated in vitro. Tobramycin uptake was detected by immunocytochemistry. Intracellular reactive oxygen species were detected using the fluorescent indicator, 2',7'-dichlorofluorescein diacetate (DCFDA). Neutrophil superoxide, hydrogen peroxide and neutrophil elastase activity were measured using specific substrates. Copper was measured using atomic absorption spectroscopy.
KEY RESULTS
Tobramycin and copper-tobramycin were taken up by endothelial cells via a heparan sulphate-dependent mechanism and significantly inhibited T-cell and neutrophil transendothelial migration respectively. Copper-tobramycin has intracellular and extracellular superoxide dismutase-like activity. Neutrophil elastase inhibition by α1-antitrypsin is enhanced in the presence of copper-tobramycin. Tobramycin and copper-tobramycin are equally effective anti-pseudomonal antibiotics.
CONCLUSIONS AND IMPLICATIONS
Anti-inflammatory effects of tobramycin in vivo may relate to the spontaneous formation of a copper-tobramycin complex, implying that copper-tobramycin may be more effective therapy.
Topics: Anti-Inflammatory Agents; Blood Platelets; Catalase; Cell Line; Cells, Cultured; Chemokine CCL5; Copper; Endothelial Cells; Humans; Hydrogen Peroxide; Leukocyte Elastase; Neutrophils; Superoxide Dismutase; Superoxides; T-Lymphocytes; Tobramycin; Transendothelial and Transepithelial Migration
PubMed: 23072509
DOI: 10.1111/bph.12018 -
Respiratory Care Jan 2022
Topics: Humans; Tobramycin; Pneumonia, Ventilator-Associated; Anti-Bacterial Agents; Administration, Inhalation; Patients; Pseudomonas Infections
PubMed: 37068096
DOI: 10.4187/respcare.09852