RESUMO
BACKGROUND: Amikacin liposome inhalation suspension (ALIS) improved sputum culture conversion rate at 6 months for patients with refractory Mycobacterium avium complex pulmonary disease (MAC-PD) in an international phase 3 trial. Patient characteristics and chest high-resolution CT (HRCT) findings associated with ALIS effectiveness are poorly documented. OBJECTIVE: We aimed to clarify ALIS effectiveness for refractory MAC-PD at 6 months, elucidating associated patient characteristics and chest CT findings. METHODS: We reviewed medical records of 12 patients with refractory MAC-PD for whom ALIS treatment was initiated at Toho University Omori Medical Center from November 2021 through September 2022. All patients demonstrated treatment persistence for at least 3 months. They were divided into culture conversion and non-conversion groups using sputum culture conversion status after 6-month ALIS treatment initiation. Clinical and radiological characteristics were compared. RESULTS: Seven of the 12 patients (58.3%) achieved sputum culture conversion within 6 months. The culture conversion group had shorter pre-ALIS initiation treatment duration [21 months (16-25) vs. 62 months (32-69); p = 0.045]; lower cavitary lesion incidence on HRCT (28.6% vs. 100%; p = 0.028); and fewer clarithromycin (CLA)-resistant strains [0/7 (0%) vs. 3/5 (60%); p = 0.045]. Chest HRCT findings improved in 4 of 7 (57.1%) and 1 of 5 (20%) patients in the culture conversion and non-conversion groups, respectively. CONCLUSION: ALIS facilitated sputum culture conversion within 6 months in 58.3% of patients with refractory MAC-PD. Sputum culture conversion was significantly more frequent for CLA-susceptible strains and patients with fewer cavitary lesions. Improved CT findings after ALIS did not always correspond to sputum culture conversion.
Assuntos
Amicacina , Antibacterianos , Lipossomos , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Escarro , Tomografia Computadorizada por Raios X , Humanos , Amicacina/administração & dosagem , Masculino , Feminino , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Idoso , Administração por Inalação , Pessoa de Meia-Idade , Antibacterianos/administração & dosagem , Escarro/microbiologia , Estudos Retrospectivos , Resultado do Tratamento , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Idoso de 80 Anos ou mais , SuspensõesRESUMO
Exploring effective antibacterial approaches for targeted treatment of pathogenic bacterial infections with reduced drug resistance is of great significance. Combinational treatment modality that leverages different therapeutic components can improve the overall effectiveness and minimize adverse effects, thus displaying considerable potential against bacterial infections. Herein, red blood cell membrane fuses with macrophage membrane to develop hybrid cell membrane shell, which further camouflages around drug-loaded liposome to fabricate biomimetic liposome (AB@LRM) for precise antibacterial therapy. Specifically, photoactive agent black phosphorus quantum dots (BPQDs) and classical antibiotics amikacin (AM) are loaded in AB@LRM to accurately target the inflammatory sites through the guidance of macrophage membrane and long residence capability of red blood cell membrane, eventually exerting efficacious antibacterial activities. Besides, due to the excellent photothermal and photodynamic properties, BPQDs act as an efficient antibacterial agent when exposed to near-infrared laser irradiation, dramatically increasing the sensitivity of bacteria to antibiotics. Consequently, the synergistic sterilizing effect produced by AB@LRM further restricts bacterial resistance. Upon laser irradiation, AB@LRM shows superior anti-inflammatory and antibacterial properties in models of P. aeruginosa-infected pneumonia and wounds. Hence, this light-activatable antibacterial nanoplatform with good biocompatibility presents great potential to advance the clinical development in the treatment of bacterial infections.
Assuntos
Antibacterianos , Lipossomos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/farmacologia , Camundongos , Animais , Lipossomos/química , Infecções por Pseudomonas/tratamento farmacológico , Modelos Animais de Doenças , Pontos Quânticos/química , Membrana Celular/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Amicacina/farmacologia , Amicacina/administração & dosagemRESUMO
INTRODUCTION: An effective rifampicin-resistant tuberculosis (RR-TB) treatment regimen should include prevention of resistance amplification. While bedaquiline (BDQ) has been recommended in all-oral RR-TB treatment regimen since 2019, resistance is rising at alarming rates. This may be due to BDQ's delayed bactericidal effect, which increases the risk of selecting for resistance to fluoroquinolones and/or BDQ in the first week of treatment when the bacterial load is highest. We aim to strengthen the first week of treatment with the injectable drug amikacin (AMK). To limit the ototoxicity risk while maximising the bactericidal effect, we will evaluate the safety of adding a 30 mg/kg AMK injection on the first and fourth day of treatment. METHODS AND ANALYSIS: We will conduct a single-arm clinical trial on 20 RR-TB patients nested within an operational study called ShoRRT (All oral Shorter Treatment Regimen for Drug resistant Tuberculosis). In addition to all-oral RR-TB treatment, patients will receive two doses of AMK. The primary safety endpoint is any grade 3-4 adverse event during the first 2 weeks of treatment related to the use of AMK. With a sample size of 20 patients, we will have at least 80% statistical power to support the alternative hypothesis, indicating that less than 14% of patients treated with AMK experience a grade 3-4 adverse event related to its use. Safety data obtained from this study will inform a larger multicountry study on using two high doses of AMK to prevent acquired resistance. ETHICS AND DISSEMINATION: Approval was obtained from the ethics committee of Rwanda, Rwanda Food and Drug Authority, Universitair Ziekenhuis, the Institute of Tropical Medicine ethics review board. All participants will provide informed consent. Study results will be disseminated through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: NCT05555303.
Assuntos
Amicacina , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Amicacina/administração & dosagem , Amicacina/efeitos adversos , Amicacina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Rifampina/administração & dosagem , Rifampina/uso terapêutico , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Antituberculosos/uso terapêutico , Administração Oral , Adulto , Mycobacterium tuberculosis/efeitos dos fármacos , Masculino , Feminino , Esquema de MedicaçãoRESUMO
Treatment outcomes for Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating Mab disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against Mab. Since any new antibiotic effective against Mab is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary Mab clinical isolates in a mouse model of Mab lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with Mab burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced Mab levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen's effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in Mab disease patients is needed to determine the most effective omadacycline-containing regimen.IMPORTANCEMycobacteroides abscessus is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating M. abscessus disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against M. abscessus. Using a mouse model that mimics M. abscessus disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with M. abscessus patients is necessary to optimize omadacycline-based treatment strategies for this disease.
Assuntos
Amicacina , Antibacterianos , Clofazimina , Modelos Animais de Doenças , Quimioterapia Combinada , Imipenem , Linezolida , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Tetraciclinas , Animais , Clofazimina/administração & dosagem , Clofazimina/uso terapêutico , Linezolida/administração & dosagem , Linezolida/uso terapêutico , Camundongos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Amicacina/administração & dosagem , Amicacina/uso terapêutico , Tetraciclinas/administração & dosagem , Tetraciclinas/uso terapêutico , Tetraciclinas/farmacologia , Mycobacterium abscessus/efeitos dos fármacos , Imipenem/administração & dosagem , Imipenem/uso terapêutico , Imipenem/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Feminino , Resultado do Tratamento , Testes de Sensibilidade Microbiana , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Administração Oral , Pulmão/microbiologiaRESUMO
Intravenous regional limb perfusion (IVRLP) has been used in the treatment of pododermatitis and distal limb infections, which are significant causes of morbidity in avian species. This intravenous drug administration technique is designed to achieve high drug tissue concentrations while minimizing systemic toxic effects. Amikacin is commonly used for IVRLP in veterinary medicine, but dosing guidelines have not been established for its use in birds. The current study aimed to determine the tissue concentration of amikacin after a single IVRLP administration in healthy, euhydrated leghorn hen chickens (Gallus gallus domesticus). Chickens received a single IVRLP dose of 10 mg/kg amikacin and were euthanatized posttreatment at 1 hour (n = 6), 12 hours (n = 6), and 24 hours (n = 6) to assess tissue and synovial fluid concentrations of amikacin in the injected leg. Mean tissue concentrations were highest 1 hour post-IVRLP (synovial fluid = 153.0 µg/mL, metatarsal pad tissue = 26.05 µg/mL) before declining at the 12- and 24-hour time points. This indicates that administration of amikacin via IVRLP can reach minimum inhibitory concentrations of common bacterial isolates in tissues after a single treatment with 10 mg/kg amikacin. Regional limb perfusion every 24 hours is recommended, although the minimum days of treatment may be case dependent and vary based on response to therapy.
Assuntos
Amicacina , Antibacterianos , Galinhas , Animais , Amicacina/farmacocinética , Amicacina/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Líquido Sinovial/química , Perfusão/veterinária , Feminino , Membro Posterior/irrigação sanguíneaRESUMO
OBJECTIVE: To establish pilot data on the plasma concentrations of SC amikacin at 2 doses in red-eared sliders and evaluate concurrent plasma biochemistry parameters. ANIMALS: 8 adult red-eared sliders (Trachemys scripta elegans). METHODS: Amikacin was administered SC at target doses of 5 and 10 mg/kg with a 3-week washout period. Blood samples were collected at 0, 24, 48, 72, and 96 hours postadministration. Plasma amikacin concentrations were quantified using liquid chromatography tandem mass spectrometry. Plasma biochemistry analyses were performed before amikacin administration, 1 week post 5-mg/kg administration, and 1 week post 10-mg/kg administration. RESULTS: Mean maximum amikacin plasma concentrations were recorded 24 hours after 5-mg/kg and 10-mg/kg dosing and were 17.5 ± 2.32 µg/mL and 23.6 ± 2.92 µg/mL, respectively. Mean plasma concentrations after 5-mg/kg dosing steadily decreased to 9.1 ± 0.92 µg/mL by 96 hours postadministration. Amikacin remained detectable in all plasma samples 3 weeks post 5-mg/kg dosing with a mean plasma concentration of 1.04 ± 0.22 µg/mL. Mean plasma concentrations after 10-mg/kg dosing did not decrease over the 96-hour study period. There were no clinically relevant changes in biochemistry parameters. CLINICAL RELEVANCE: Amikacin persists at detectable plasma levels for at least 3 weeks after SC administration of a 5-mg/kg dose in red-eared sliders, which has not previously been reported in any species. No biochemistry changes consistent with renal toxicity occurred after either dose. Use caution with repeated amikacin dosing in this species until further studies can better characterize cumulative amikacin pharmacokinetics and toxic threshold.
Assuntos
Amicacina , Antibacterianos , Tartarugas , Animais , Amicacina/administração & dosagem , Amicacina/farmacocinética , Amicacina/sangue , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Tartarugas/sangue , Masculino , Feminino , Injeções Subcutâneas/veterinária , Projetos Piloto , Relação Dose-Resposta a DrogaRESUMO
OBJECTIVE: To report the clinical use, adverse events, and outcomes after using amikacin in 30% poloxamer 407 (amikacin-P407) during open wound management or in a closed wound application in dogs. ANIMALS: 29 client-owned dogs. METHODS: Medical records from January 2017 to August 2023 from a single hospital were reviewed for dogs that received amikacin-P407 in an open or closed wound application. Information reviewed included signalment, nature of wound and/or surgical site infection (SSI), bacterial cultures, amikacin dose, gel volume, route of administration, estimated wound surface area, biochemistry parameters, urine casts, wound progression, and general clinical outcome. RESULTS: Amikacin-P407 was applied during open wound care (10 dogs), via injection (5 dogs), and at time of wound closure (13 dogs) and was used both in open and closed wound management (1 dog). Wounds were associated with SSIs in 18 of 30 sites. Multidrug resistance was noted in 21 of 30 preapplication cultures. Median amikacin dose was 14.5 mg/kg (range, 3 to 59.5 mg/kg), median total volume was 5.0 mL (range, 1 to 12 mL), and median tissue surface area was 6.6 cm2 (range, 1.6 to 36 cm2), for a local wound dose of 62.5 mg/cm2 (range, 6.9 to 214.3 mg/cm2). No short-term adverse local or systemic effects were noted in any wounds or dogs. No dehiscence was seen in 17 of 19 closed sites. CLINICAL RELEVANCE: The results of this case series suggested that Amikacin-P407 can be applied in a variety of ways with no adverse effects. Amikacin-P407 may be considered in open wound management or in a closed setting for infected wounds and SSIs.
Assuntos
Amicacina , Antibacterianos , Doenças do Cão , Poloxâmero , Animais , Cães , Amicacina/administração & dosagem , Amicacina/uso terapêutico , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Feminino , Doenças do Cão/tratamento farmacológico , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We report the case of a female patient in her late 20s who visited the clinic with concerns about poor vision, redness, watering and a burning sensation in her left eye 2 weeks after undergoing a small incision lenticule extraction. She had no history of systemic illness or immunosuppressed status. On slit lamp examination, she was found to have corneal stromal infiltrates in the interface at multiple locations. Given the clinical diagnosis of microbial keratitis, corneal scraping of the interface infiltrate was performed and sent for microbiological examination revealing gram-positive, thin, beaded filaments that were acid-fast positive and later identified by growth in culture media as Nocardia species. This case was managed successfully with the use of topical amikacin and systemic trimethoprim-sulfamethoxazole with complete resolution of infection.
Assuntos
Antibacterianos , Infecções Oculares Bacterianas , Ceratite , Nocardiose , Humanos , Feminino , Nocardiose/diagnóstico , Nocardiose/tratamento farmacológico , Ceratite/microbiologia , Ceratite/tratamento farmacológico , Ceratite/diagnóstico , Ceratite/cirurgia , Antibacterianos/uso terapêutico , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Bacterianas/tratamento farmacológico , Amicacina/uso terapêutico , Amicacina/administração & dosagem , Adulto , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Nocardia/isolamento & purificação , Infecção da Ferida Cirúrgica/microbiologia , Infecção da Ferida Cirúrgica/tratamento farmacológico , Infecção da Ferida Cirúrgica/diagnósticoRESUMO
This study aimed to develop oral lipidic hybrids of amikacin sulfate (AMK), incorporating thiolated chitosan as a P-glycoprotein (P-gp) inhibitor to enhance intestinal absorptivity and bioavailability. Three formulations were designed: PEGylated Liposomes, Chitosan-functionalized PEGylated (Chito-PEGylated) Lipidic Hybrids, and Thiolated Chito-PEGylated Lipidic Hybrids. The physical characteristics of nanovesicles were assessed. Ex-vivo permeation and confocal laser scanning microscopy (CLSM) studies were conducted to evaluate the formulations' potential to enhance AMK intestinal permeability. In-vivo pharmacokinetic studies in rats and histological/biochemical investigations assessed the safety profile and oral bioavailability. The AMK-loaded Thiolated Chito-PEGylated Lipidic Hybrids exhibited favorable physical characteristics, higher ex-vivo permeation parameters, and verified P-gp inhibition via CLSM. They demonstrated heightened oral bioavailability (68.62% absolute bioavailability) and a sufficient safety profile. Relative bioavailability was significantly higher (1556.3% and 448.79%) compared to PEGylated Liposomes and Chito-PEGylated Lipidic Hybrids, respectively, indicating remarkable oral AMK delivery with fewer doses, reduced side effects, and enhanced patient compliance.
Assuntos
Amicacina , Antibacterianos , Disponibilidade Biológica , Quitosana , Lipídeos , Lipossomos , Polietilenoglicóis , Animais , Polietilenoglicóis/química , Masculino , Administração Oral , Quitosana/química , Amicacina/farmacocinética , Amicacina/administração & dosagem , Amicacina/química , Lipídeos/química , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ratos , Ratos Sprague-Dawley , Absorção Intestinal , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacocinética , Ratos WistarRESUMO
The development of nanoparticles (NPs) with active components with upgraded stability, and prolonged release helps in enhanced tissue regeneration. In addition, NPs are feasible strategy to boost antibiotic effectiveness and reduce drug side effects. Our study focuses on the use of amikacin (AMK) and gamma amino butyric acid (GABA) unloaded combinations or loaded on chitosan nanoparticles (CSNPs) for kidney protection. The AMK-GABA-CSNPs were prepared with the ionic gelation method, the morphology was studied using transmission electron microscopy (TEM), zetasizer and the Fourier transform-infrared spectroscopy (FT-IR) spectrum of the synthesized NPs was observed. The average size of AMK-GABA-CSNPs was 77.5 ± 16.5 nm. Zeta potential was + 38.94 ± 2.65 mV. AMK-GABA-CSNPs revealed significant in vitro antioxidant, anti-coagulation, non-hemolytic properties and good cell compatibility. To compare the effects of the unloaded AMK-GABA combination and AMK-GABA-CSNPs on the renal tissue, 42 healthy Sprague-Dawley rats were divided into seven groups. G1: normal control (NC), normal saline; G2: low-dose nephrotoxic group (LDN), AMK (20 mg/kg/day; i.p.); G3: unloaded AMK (20 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.); G4: AMK-GABA-CSNPs (20 mg/kg/day; i.p.); G5: high-dose nephrotoxic group (HDN), AMK (30 mg/kg/day; i.p.); G6: unloaded AMK (30 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.) and G7: AMK-GABA-CSNPs (30 mg/kg/day; i.p.). The results showed that AMK-GABA-CSNPs formulation is superior to unloaded AMK-GABA combination as it ameliorated kidney functions, oxidative stress and displayed a significant homeostatic role via suppression of inflammatory cytokines of Th1, Th2 and Th17 types. Hence, AMK-GABA-CSNPs could afford a potential nano-based therapeutic formula for the management of AMK-nephrotoxicity.
Assuntos
Amicacina , Quitosana , Rim , Nanopartículas , Ratos Sprague-Dawley , Ácido gama-Aminobutírico , Animais , Quitosana/química , Quitosana/farmacologia , Nanopartículas/administração & dosagem , Nanopartículas/química , Ratos , Amicacina/farmacologia , Amicacina/administração & dosagem , Masculino , Rim/efeitos dos fármacos , Rim/metabolismo , Ácido gama-Aminobutírico/farmacologia , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antioxidantes/farmacologia , Antioxidantes/administração & dosagem , Portadores de Fármacos/química , Estresse Oxidativo/efeitos dos fármacos , Tamanho da PartículaRESUMO
BACKGROUND: Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra-articular (IA) administration. HYPOTHESIS/OBJECTIVES: Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens. ANIMALS: Eight healthy neonatal foals. METHODS: Foals received 3 amikacin treatment protocols: (1) IV-only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA-only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 µg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility. RESULTS: Foal age was a significant variable. The IV-only protocol met or exceeded the 30-minute plasma concentrations considered therapeutic (mean µg/mL [95% confidence interval, CI]) in 7- to 9-day-old (54.0 [52.2-56.9]), 14- to 16-day-old (58.1 [55.2-61.0]), and 21- to 23-day-old (66.6 [63.7-69.6]) foals. Concurrent IV and IA protocol did not reach the 30-minute concentration considered therapeutic in 7- to 9-day-old foals (46.5 [43.6-49.4]) but did in 14- to 16-day-old (62.9 [60.0-65.8]) and 21-to 23-day-old (62.6 [59.7-65.6]) foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Concurrent IV and IA administration of amikacin produces 30-minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.
Assuntos
Amicacina , Animais Recém-Nascidos , Antibacterianos , Animais , Amicacina/farmacocinética , Amicacina/administração & dosagem , Amicacina/sangue , Cavalos/sangue , Injeções Intra-Articulares/veterinária , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Masculino , Feminino , Injeções Intravenosas/veterináriaRESUMO
Long-term inflammation, including those induced by bacterial infections, contributes to the superfluous accumulation of reactive oxygen species (ROS), further aggravating this condition, decreasing the local pH, and adversely affecting bone defect healing. Conventional drug delivery scaffold materials struggle to meet the demands of this complex and dynamic microenvironment. In this work, a smart gelatin methacryloyl (GelMA) hydrogel was synthesized for the dual delivery of proanthocyanidin and amikacin based on the unique pH and ROS responsiveness of boronate complexes. Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) demonstrated the co-crosslinking of two boronate complexes with GelMA. The addition of the boronate complexes improved the mechanical properties, swelling ratio, degradation kinetics and antioxidative properties of the hydrogel. The hydrogel exhibited pH and ROS responses and a synergistic control over the drug release. Proanthocyanidin was responsively released to protect mouse osteoblast precursor cells from oxidative stress and promote their osteogenic differentiation. The hydrogel responded to pH changes and released sufficient amikacin in a timely manner, thereby exerting an efficient antimicrobial effect. Overall, the hydrogel delivery system exhibited a promising strategy for solving infectious and inflammatory problems in bone defects and promoting early-stage bone healing.
Assuntos
Amicacina , Antioxidantes , Diferenciação Celular , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Gelatina , Hidrogéis , Osteogênese , Proantocianidinas , Espécies Reativas de Oxigênio , Animais , Hidrogéis/química , Camundongos , Osteogênese/efeitos dos fármacos , Proantocianidinas/administração & dosagem , Proantocianidinas/farmacologia , Proantocianidinas/química , Antioxidantes/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/química , Concentração de Íons de Hidrogênio , Espécies Reativas de Oxigênio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Gelatina/química , Amicacina/administração & dosagem , Amicacina/química , Amicacina/farmacologia , Metacrilatos/química , Osteoblastos/efeitos dos fármacos , Linhagem Celular , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Antibacterianos/química , Estresse Oxidativo/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate if a difference in synovial amikacin concentrations exists in the radiocarpal joint (RCJ) following different durations of instillation of an IV regional limb perfusion (IVRLP) perfusate. ANIMALS: 7 healthy horses. METHODS: Horses received 2 IVRLPs with 2 g amikacin diluted to 60 mL with 0.9% NaCl via the cephalic vein in a crossover study design with a wash-out period between procedures. Instillation of the perfusate was administered over a 1-minute (technique 1) and 5-minute (technique 5) period. Concentrations of amikacin within the RCJ were measured at time (T) 5, 10, 15, 20, 25, and 30 minutes after instillation of the perfusate. Systemic concentrations of amikacin were measured at T0, 5, 10, 15, 20, 25, 29 minutes, and 1 minute after tourniquet removal (T31). Amikacin concentrations were determined by fluorescence polarization immunoassay. RESULTS: The median maximum concentration (CMAX) of amikacin within the RCJ for technique 1 was 338.4 µg/mL (range, 60 to 4,925 µg/mL), while the median CMAX for technique 5 was higher at 694.8 µg/mL (range, 169.2 to 3,410 µg/mL; P = .398). There was a higher amikacin blood concentration over time for technique 1 compared to technique 5 (P = .004). CLINICAL RELEVANCE: Administration of perfusate at different rates did not significantly affect synovial concentration of amikacin within the RCJ when performing IVRLP. However, increased systemic leakage was noted when the perfusate was administered over 1 minute, which might affect synovial concentrations in a larger group of horses.
Assuntos
Amicacina , Antibacterianos , Estudos Cross-Over , Animais , Amicacina/farmacocinética , Amicacina/administração & dosagem , Cavalos , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Masculino , Feminino , Líquido Sinovial/química , Perfusão/veterinária , Fatores de Tempo , Membro AnteriorRESUMO
Introduction: During mechanical ventilation (MV), inspired gases require heat and humidification. However, such conditions may be associated with reduced aerosol delivery efficiency. The practice of turning off heated humidification before nebulization and the impact of nebulization on humidity in a dry ventilator circuit remain topics of debate. This study aimed to assess the effect of turning off heated humidification on inhaled dose and humidity with nebulizer use during adult MV. Methods: A bronchodilator (albuterol) and two antibiotics (Colistimethate sodium and Amikacin sulfate) were nebulized with a vibrating mesh nebulizer placed at the humidifier inlet and in the inspiratory limb at the Y-piece. Additionally, albuterol was nebulized using a jet nebulizer in both placements. Aerosol particle size distribution was determined through a cascade impactor. Absolute humidity (AH) and temperature of inspired gases were determined with anemometer/hygrometers before, during, and after nebulization, before, during, and up to 60 minutes after interrupting active humidification. Aerosol collected on a filter distal to the endotracheal tube and on impactor stages were eluted and assayed by spectrophotometry. Results: The inhaled dose was greater when both nebulizers were placed at the humidifier inlet than the inspiratory limb at the Y-piece. Irrespective of the nebulizer types and placements, the inhaled dose either decreased or showed no significant change after the humidifier was turned off. The aerosol particle size ranged from 1.1 to 2.7 µm. With interruption of active humidification, humidity of inspired gas quickly dropped below recommended levels, and nebulization in dry ventilator circuit produced an AH between 10 and 20 mgH2O/L, lower than the recommended minimum of 30 mgH2O/L. Conclusion: Interrupting active humidification during MV before nebulization did not improve aerosol delivery efficiency for bronchodilator or antibiotics, but did reduce humidity below recommended levels.
Assuntos
Aerossóis , Albuterol , Antibacterianos , Broncodilatadores , Sistemas de Liberação de Medicamentos , Temperatura Alta , Umidade , Nebulizadores e Vaporizadores , Tamanho da Partícula , Respiração Artificial , Temperatura , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Administração por Inalação , Antibacterianos/administração & dosagem , Amicacina/administração & dosagem , Colistina/administração & dosagem , Humanos , Desenho de Equipamento , Umidificadores , Fatores de TempoRESUMO
Amikacin liposome inhalation suspension (ALIS) is known to cause drug-related pneumonitis, which has been described as "hypersensitivity pneumonitis (HP)". However, its clinical and pathological characteristics have never been reported. We retrospectively evaluated 18 patients treated with ALIS. Three (16.7%) patients developed HP-pattern pneumonitis on high-resolution computed tomography. Serum eosinophil counts were elevated up to above 1000/µL in these three patients, which decreased with ALIS discontinuation only. Of note, the specimen obtained by transbronchial lung cryobiopsy in one patient revealed a mild degree of lymphocyte and eosinophil infiltration. Rather, the findings of acute lung injury such as an edematous thickening of the alveolar walls, and an accumulation of foamy degenerative macrophages in the alveolar lumina was prominent. A pulmonary alveolar proteinosis reaction was also observed. HP-pattern pneumonitis due to ALIS may pathologically correspond to acute lung injury and a pulmonary alveolar proteinosis reaction despite increasing serum eosinophil counts.
Assuntos
Amicacina , Eosinófilos , Lipossomos , Humanos , Masculino , Amicacina/administração & dosagem , Amicacina/efeitos adversos , Administração por Inalação , Idoso , Feminino , Estudos Retrospectivos , Eosinófilos/patologia , Pessoa de Meia-Idade , Suspensões , Tomografia Computadorizada por Raios X , Alveolite Alérgica Extrínseca/induzido quimicamente , Contagem de Leucócitos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/diagnóstico por imagemRESUMO
Catheter-related bloodstream infection (CRBSI) is one of the common healthcare-acquired infections imposing a high burden of morbidity and mortality on the patients. Non-tuberculous mycobacterium is a rare aetiology for CRBSI and poses challenges in laboratory diagnosis and clinical management. This is a case of a woman in her early 60s with underlying end-stage renal failure, diabetes mellitus and hypertension presented with a 2-week history of high-grade fever postregular haemodialysis, vomiting, lethargy and altered mental status.Blood cultures from a permanent catheter and peripheral taken concurrently yielded Mycobacterium senegalense, identified by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry, which established the diagnosis of CRBSI atypically presented with concurrent acute intracranial bleeding and cerebrovascular infarction at initial presentation. She was started on a combination of oral azithromycin, oral amikacin and intravenous imipenem, and the permanent catheter was removed. Despite the treatments instituted, she developed septicaemia, acute myocardial infarction and macrophage activation-like syndrome, causing the patient's death.
Assuntos
Antibacterianos , Infecções Relacionadas a Cateter , Infecções por Mycobacterium não Tuberculosas , Humanos , Feminino , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/diagnóstico , Infecções Relacionadas a Cateter/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Evolução Fatal , Bacteriemia/tratamento farmacológico , Bacteriemia/diagnóstico , Bacteriemia/microbiologia , Diálise Renal , Falência Renal Crônica/terapia , Falência Renal Crônica/complicações , Amicacina/uso terapêutico , Amicacina/administração & dosagemRESUMO
Bacterial corneal keratitis is a damage to the corneal tissue that if not treated, can cause various complications like severe vision loss or even blindness. Combination therapy with two antibiotics which are effective against Gram-positive and Gram-negative bacteria offers sufficient broad-spectrum antibiotic coverage for the treatment of keratitis. Nanofibers can be a potential carrier in dual drug delivery due to their structural characteristics, specific surface area and high porosity. In order to achieve a sustained delivery of amikacin (AMK) and vancomycin (VAN), the current study designed, assessed, and compared nanofibrous inserts utilizing polyvinyl alcohol (PVA) and polycaprolactone (PCL) as biocompatible polymers. Electrospinning method was utilized to prepare two different formulations, PVA-VAN/AMK and PCL/PVA-VAN/AMK, with 351.8 ± 53.59 nm and 383.85 ± 49 nm diameters, respectively. The nanofibers were simply inserted in the cul-de-sac as a noninvasive approach for in vivo studies. The data obtained from the physicochemical and mechanical properties studies confirmed the suitability of the formulations. Antimicrobial investigations showed the antibacterial properties of synthesized nanofibers against Staphylococcus aureus and Pseudomonas aeruginosa. Both in vitro and animal studies demonstrated sustained drug release of the prepared nanofibers for 120 h. Based on the in vivo findings, the prepared nanofibers' AUC0-120 was found to be 20 to 31 times greater than the VAN and AMK solutions. Considering the results, the nanofibrous inserts can be utilized as an effective and safe system in drug delivery.
Assuntos
Administração Oftálmica , Amicacina , Antibacterianos , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Nanofibras , Poliésteres , Álcool de Polivinil , Pseudomonas aeruginosa , Staphylococcus aureus , Vancomicina , Animais , Coelhos , Nanofibras/química , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antibacterianos/química , Álcool de Polivinil/química , Staphylococcus aureus/efeitos dos fármacos , Poliésteres/química , Pseudomonas aeruginosa/efeitos dos fármacos , Vancomicina/administração & dosagem , Vancomicina/farmacocinética , Vancomicina/química , Amicacina/farmacocinética , Amicacina/administração & dosagem , Amicacina/química , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química , MasculinoRESUMO
Nosocomial infections with drug resistant bacteria impact morbidity and mortality, length of therapy and stay and the overall cost of treatment. Key pathogens with ventilator associated pneumonia may be drug-susceptible or multi-drug resistant and inhaled amikacin has been investigated as an adjunctive therapy option. High pulmonary drug concentrations (epithelial lining fluid [ELF]) along with minimal systemic toxicity is seen as an advantage to inhaled formulations. In vitro killing of bacteria using clinically relevant drug concentrations provide insight on bug-drug interactions. The aim of this study was to measure killing of clinical isolates of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and methicillin-susceptible S. aureus using the minimum inhibitory concentration (MIC), mutant prevention concentration (MPC) and median (976 µg/ml) ELF drug concentration for amikacin. Overall killing took longer at the MIC drug concentration and was inconsistent amongst the pathogens tested with the percentage of bacteria killed following 180 min of drug exposure ranging from growth in the presence of the drug to 95% kill. At the MPC drug concentrations, killing ranged from 55-88% for all pathogens following 30 min of drug exposure and increased to 99-100% following 180 min of drug exposure. At the ELF amikacin tested, killing was 81-100% following 20 min and 94-100% by 30 min of drug exposure. Rapid killing against MDR respiratory pathogens by amikacin ELF drug concentrations is encouraging.
Assuntos
Amicacina , Antibacterianos , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade Microbiana , Amicacina/farmacologia , Amicacina/farmacocinética , Amicacina/administração & dosagem , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Humanos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Administração por Inalação , Klebsiella pneumoniae/efeitos dos fármacosRESUMO
AIMS: Amikacin requires therapeutic drug monitoring for optimum efficacy; however, the optimal model-informed precision dosing strategy for the area under the concentration-time curve (AUC) of amikacin is uncertain. This simulation study aimed to determine the efficient blood sampling points using the Bayesian forecasting approach for early achievement of the target AUC range for amikacin in critically ill patients. METHODS: We generated a virtual population of 3000 individuals using 2 validated population pharmacokinetic models identified using a systematic literature search. AUC for each blood sampling point was evaluated using the probability of achieving a ratio of estimated/reference AUC at steady state in the 0.8-1.2 range. RESULTS: On day 1, the 1-point samplings for population pharmacokinetic models showed a priori probabilities of 26.3 and 45.6%, which increased to 47.3 and 94.4% at 23 and 15 h, respectively. Using 2-point sampling at the peak (3 and 4 h) and trough (24 h) on day 1, these probabilities further increased to 72.3 and 99.5%, respectively. These probabilities were comparable on days 2 and 3, regardless of 3 and 6 sampling points or estimated glomerular filtration rate. These results indicated the higher predictive accuracy of 2-point sampling than 1-point sampling on day 1 for amikacin AUC estimation. Moreover, 2-point sampling was a more reasonable approach than rich sampling. CONCLUSIONS: This study contributes to the development of an efficient model-informed precision dosing strategy for early targeting of amikacin AUC in critically ill patients.
Assuntos
Amicacina , Antibacterianos , Área Sob a Curva , Teorema de Bayes , Simulação por Computador , Estado Terminal , Monitoramento de Medicamentos , Modelos Biológicos , Amicacina/farmacocinética , Amicacina/administração & dosagem , Amicacina/sangue , Humanos , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Monitoramento de Medicamentos/métodos , Taxa de Filtração Glomerular , Medicina de Precisão/métodos , Relação Dose-Resposta a DrogaRESUMO
OBJECTIVES: Urinary tract infections (UTIs) are very common infections in humans, and Escherichia coli (E. coli) is the commonest pathogen leading to UTIs. The generation of beta-lactamase enzymes in this bacterium results in its resistance against many antibiotics. This study compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli in a double-blind clinical trial. METHODS: The current double-blind clinical trial compares three doses of amikacin on alternate days with a daily dose of meropenem in the same period for the treatment of UTIs with E. coli. The patients were assigned to two groups: Intervention (receiving a single dose of amikacin once a day at 48-h intervals for a week, three doses) and control (receiving meropenem for 1/TDS for a week). RESULTS: The E. coli infection frequency was 61 (21 cases of non-ESBL and 40 cases of ESBL-positive infections) and the frequency of the other infections was 52 (46%). In the patients with ESBL E. coli infection, ciprofloxacin (21; 70%) showed the highest antibiotic resistance, and nitrofurantoin (33; 91.7%) showed the highest sensitivity. The baseline variables between the control and intervention groups indicated no significant difference (p > 0.05). The frequency of signs and symptoms showed no significant difference between the amikacin and meropenem groups in the first 24 h and the first week. In the second week of follow-up, no clinical signs or symptoms were observed in the two groups. CONCLUSION: The results of this study showed that treatment with amikacin, 1 g q48h, for one week (three doses) has the same result as meropenem, 1 g q8h, for one week (21 doses). The results are the same for the treatment of UTIs with ESBL positive and ESBL negative. Amikacin can be used once every 48 h to treat UTIs, is less expensive and can be administered on an outpatient basis. TRIAL REGISTRATION: This study was registered in the Iranian Registry of Clinical Trials (IRCT) with ID number: IRCT20170417033483N2 on the date 2018-02-13.