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1.
J Infect Chemother ; 28(1): 91-94, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34518095

RESUMO

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


Assuntos
Transplante de Células-Tronco Hematopoéticas , Pneumonia , Infecções por Pseudomonas , Amicacina/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Colistina/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pessoa de Meia-Idade , Pneumonia/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Terapia Respiratória
2.
Expert Rev Respir Med ; 15(11): 1387-1401, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34612115

RESUMO

INTRODUCTION: Nontuberculous mycobacterial (NTM) lung disease (LD) is the most common clinical manifestation of NTM infection and is a growing health concern. Up to 85% of NTM-LD cases are caused by Mycobacterium avium complex (MAC). Increased awareness of NTM-LD caused by MAC is needed as patients with this disease experience substantial burden and unmet treatment needs. AREAS COVERED: This review provides clinicians and regulatory and healthcare decision makers an overview of the clinical, economic, and humanistic burden of NTM-LD and the unmet treatment needs faced by patients and clinicians. The review focuses on NTM-LD caused by MAC. A summary of the 2020 NTM guidelines specifically for MAC-LD and an overview of novel treatment options, including amikacin liposome inhalation suspension (ALIS) as the first approved therapy for refractory MAC-LD, and investigational drugs in testing phase are provided. EXPERT OPINION: Key advancements in NTM-LD management include recent updates to clinical practice guidelines, approval of ALIS for the treatment of refractory MAC-LD, and ongoing clinical trials of investigational treatments. Yet opportunities still exist to improve patient outcomes, including development of better screening tools, such as reliable and responsive biomarkers to help identify high-risk patients, and addressing unmet treatment needs.


Assuntos
Infecção por Mycobacterium avium-intracellulare , Pneumonia , Amicacina , Efeitos Psicossociais da Doença , Humanos , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/diagnóstico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico
3.
Int J Mycobacteriol ; 10(3): 293-300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34494569

RESUMO

Background: Rapidly growing mycobacteria (RGM) are increasingly being recognized as potential pathogens. RGM, particularly Mycobacterium abscessus, Mycobacterium fortuitum, and Mycobacterium chelonae, have been observed in both pulmonary and extrapulmonary infections including cutaneous, soft-tissue, and wound infections. However, there are limited reports of these potential pathogens from skin and soft-tissue infections. Moreover, the drug susceptibility profile of RGM is largely unknown in several regions of the world. Methods: We analyzed reports on RGM isolated from skin and soft-tissue infections globally for details of RGM species and drug susceptibility profile. We also analyzed the drug susceptibility profile of four RGM isolates, obtained from skin and soft-tissue infections in our laboratory, by broth microdilution method. Results: In the reports reviewed, the most common RGM isolated from skin and soft-tissue infections were M. abscessus (184/475, 38.7%), M. fortuitum (150/475, 31.5%), M. chelonae (72/475, 15%), and M. chelonae-M. abscessus complex (46/475, 9.6%). However, drug susceptibility was tested only in 26/39 (66.6%) reports. In our own laboratory, we obtained three isolates of M. abscessus and one isolate of M. fortuitum from one case of breast abscess and three cases of postsurgical wound infections. Maximum susceptibility of M. abscessus was observed to clarithromycin, amikacin, and linezolid. The M. fortuitum isolate was susceptible to clarithromycin, amikacin, clofazimine, and linezolid. Conclusion: Paucity of information available on RGM isolated from skin and soft-tissue infections highlights the need to be aware of the pathogenic potential and the drug susceptibility profile of these organisms.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium , Amicacina , Antibacterianos/farmacologia , Claritromicina , Humanos , Testes de Sensibilidade Microbiana , Micobactérias não Tuberculosas
4.
BMJ Open ; 11(9): e048591, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521664

RESUMO

INTRODUCTION: Pre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia. METHODS AND ANALYSIS: Academic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee. ETHICS AND DISSEMINATION: The protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2016-001054-17 and NCT03149640.


Assuntos
Amicacina , Pneumonia Associada à Ventilação Mecânica , Administração por Inalação , Amicacina/administração & dosagem , Método Duplo-Cego , Humanos , Estudos Multicêntricos como Assunto , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial/efeitos adversos , Resultado do Tratamento
5.
Can Vet J ; 62(9): 975-981, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34475583

RESUMO

This study investigated the pharmacokinetics of ceftiofur after intravenous regional limb perfusion (IVRLP). Six horses were involved in 3 IVRLP sessions. For each session, operators with varying clinical experience placed the tourniquet. A wide-rubber tourniquet was applied in the antebrachium as 2 g of ceftiofur in a total volume of 100 mL was injected into the cephalic vein. Plasma and metacarpophalangeal synovial fluid samples were obtained to evaluate perfusate leakage and synovial fluid concentrations of ceftiofur over 24 h. Overall, mean plasma concentrations were not significantly different before and after tourniquet removal. Mean synovial fluid ceftiofur concentrations were significantly higher 5 min and 8 h after tourniquet removal versus 24 h, after which values above the minimum inhibitory concentration (MIC) (1 µg/mL) were not detected. Concentrations above the MIC were detected in 72% and 50% of the horses at 5 min and 8 h, respectively. Overall, higher synovial fluid concentrations were obtained for the operator with the most recent clinical experience performing IVRLP.


Assuntos
Amicacina , Membro Anterior , Animais , Antibacterianos , Cefalosporinas , Cavalos , Articulação Metacarpofalângica , Perfusão/veterinária , Líquido Sinovial
6.
Rev Chilena Infectol ; 38(3): 317-323, 2021 Jun.
Artigo em Espanhol | MEDLINE | ID: mdl-34479286

RESUMO

BACKGROUND: The monitoring of antimicrobial therapy through plasma levels makes it possible to determine the optimal dosage of antimicrobials, an essential approach in pediatrics. AIM: To describe the monitoring of plasma antimicrobial levels and dose adjustment in the pediatric population to determine if the doses used reach therapeutic ranges. METHODS: Retrospective, descriptive study using a database with measurement of plasma levels of amikacin and vancomycin in pediatric patients at San Borja Arriarán Hospital between 2015-2018. The number of patients who reached the therapeutic range with the initial dose, how many required adjustment and their characteristics were determined. RESULTS: 104 total levels were monitored. For vancomycin 65 plasmatic levels were baseline, being outside the therapeutic range 56.5%; 25% of those requiring adjustment were neonates with a higher probability of being out of range versus others (p = 0.022). For amikacin, Cpeak was in range in 60% of measurements; 15.4% required adjustment, including patients with cystic fibrosis and cancer, without adjustments in patients without comorbidity. CONCLUSION: Measurement of plasma levels is necessary to individually adjust the dose, especially in pediatric patients with cystic fibrosis, oncology and in neonatology where it is more likely not to reach a therapeutic range with initial doses.


Assuntos
Pediatria , Vancomicina , Amicacina , Antibacterianos/uso terapêutico , Criança , Monitoramento de Medicamentos , Humanos , Recém-Nascido , Estudos Retrospectivos
7.
J Laryngol Otol ; 135(10): 911-917, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34399860

RESUMO

OBJECTIVE: This study aimed to identify pathogens isolated in acute external otitis cases and determine their distribution according to ages and seasons as well as investigate the susceptibility or resistance to the aminoglycoside and quinolone group antibiotics of which topical forms are available. METHOD: A total of 168 patients diagnosed with acute external otitis were evaluated retrospectively. Growing bacteria were identified according to the species by conventional methods. Antibiotic susceptibility status was determined for the growing bacteria. RESULTS: The most common bacteria detected were pseudomonas group bacteria (38.7 per cent). Resistance to the amikacin group of antibiotics was found to be the lowest and resistance to the ciprofloxacin group of antibiotics was the highest. CONCLUSION: External auditory canal cultures should be taken simultaneously with empirical treatment. Seasonal effect and age group should be taken into consideration in the choice of treatment and after questioning about chronic exposure to water. Empirical treatment should then be started.


Assuntos
Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Otite Externa/tratamento farmacológico , Otite Externa/microbiologia , Doença Aguda , Administração Tópica , Adulto , Fatores Etários , Amicacina/administração & dosagem , Amicacina/uso terapêutico , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Bactérias/crescimento & desenvolvimento , Ciprofloxacina/administração & dosagem , Ciprofloxacina/uso terapêutico , Resistência Microbiana a Medicamentos/fisiologia , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Pessoa de Meia-Idade , Otite Externa/diagnóstico , Pseudomonas/isolamento & purificação , Quinolonas/administração & dosagem , Quinolonas/uso terapêutico , Estudos Retrospectivos , Estações do Ano
8.
Life Sci ; 284: 119883, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34390724

RESUMO

Hypodermic delivery of amikacin is a widely adopted treatment modality for severe infections, including bacterial septicemia, meningitis, intra-abdominal infections, burns, postoperative complications, and urinary tract infections in both paediatric and adult populations. In most instances, the course of treatment requires repeated bolus doses of amikacin, prolonged hospitalization, and the presence of a skilled healthcare worker for administration and continuous therapeutic monitoring to manage the severe adverse effects. Amikacin is hydrophilic and exhibits a short half-life, which further challenges the delivery of sufficient systemic concentrations when administered by the oral or transdermal route. In this purview, the exploitation of novel controlled and sustained release drug delivery platforms is warranted. Furthermore, it has been shown that novel delivery systems are capable of increasing the antibacterial activity of amikacin at lower doses when compared to the conventional formulations and also aid in overcoming the development of drug-resistance, which currently is a significant threat to the healthcare system worldwide. The current review presents a comprehensive overview of the developmental history of amikacin, the mechanism of action in virulent strains as well as the occurrence of resistance, and various emerging drug delivery solutions developed both by the academia and the industry. The examples outlined within the review provides significant pieces of evidence on novel amikacin formulations in the field of antimicrobial research paving the path for future therapeutic interventions that will result in improved clinical outcome.


Assuntos
Amicacina/administração & dosagem , Sistemas de Liberação de Medicamentos , Amicacina/química , Amicacina/farmacocinética , Animais , Ensaios Clínicos como Assunto , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Nanopartículas/química , Nanopartículas/ultraestrutura
9.
Antimicrob Agents Chemother ; 65(11): e0116421, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34460306

RESUMO

Antibiotic resistance among bacterial pathogens poses a major global health threat. Mycobacterium tuberculosis complex (MTBC) is estimated to have the highest resistance rates of any pathogen globally. Given the low growth rate and the need for a biosafety level 3 laboratory, the only realistic avenue to scale up drug susceptibility testing (DST) for this pathogen is to rely on genotypic techniques. This raises the fundamental question of whether a mutation is a reliable surrogate for phenotypic resistance or whether the presence of a second mutation can completely counteract its effect, resulting in major diagnostic errors (i.e., systematic false resistance results). To date, such epistatic interactions have only been reported for streptomycin that is now rarely used. By analyzing more than 31,000 MTBC genomes, we demonstrated that the eis C-14T promoter mutation, which is interrogated by several genotypic DST assays endorsed by the World Health Organization, cannot confer resistance to amikacin and kanamycin if it coincides with loss-of-function (LoF) mutations in the coding region of eis. To our knowledge, this represents the first definitive example of antibiotic reversion in MTBC. Moreover, we raise the possibility that mmpR (Rv0678) mutations are not valid markers of resistance to bedaquiline and clofazimine if these coincide with an LoF mutation in the efflux pump encoded by mmpS5 (Rv0677c) and mmpL5 (Rv0676c).


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Amicacina/farmacologia , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Clofazimina/farmacologia , Diarilquinolinas , Farmacorresistência Bacteriana Múltipla/genética , Epistasia Genética , Humanos , Canamicina/farmacologia , Testes de Sensibilidade Microbiana , Mutação , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/genética
10.
Sci Rep ; 11(1): 15878, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354181

RESUMO

Bacterial endophthalmitis is a rare intraocular infection, and prompt administration of intravitreal antibiotics is crucial for preventing severe vision loss. The retrospective study is to investigate the in vitro susceptibility to the antibiotics vancomycin, amikacin, and ceftazidime of bacterial endophthalmitis isolates in specimens at a tertiary referral center from January 1996 to April 2019 in Taiwan. Overall, 450 (49.9%) isolates were Gram positive, 447 (49.6%) were Gram negative, and 4 (0.4%) were Gram variable. In Gram-positive isolates, coagulase-negative staphylococci were the most commonly cultured bacteria (158, 35.1%), followed by Streptococci (100, 22.2%), Enterococci (75, 16.7%), and Staphylococcus aureus (70, 15.6%). In Gram-negative isolates, they were Klebsiella pneumoniae (166, 37.1%) and Pseudomonas aeruginosa (131, 29.3%). All Gram-positive organisms were susceptible to vancomycin, with the exception of one Enterococcus faecium isolate (1/450, 0.2%). Of the Gram-negative isolates, 96.9% and 93.7% were susceptible to ceftazidime and amikacin, respectively. Nine isolates (9/447, 2.0%) were multidrug-resistant Gram-negative bacteria, comprising K. pneumoniae (4/164, 2.4%), Acinetobacter baumannii (2/3, 67%), and Stenotrophomonas maltophilia (3/18, 17%). In conclusion, in vitro susceptibility testing revealed that vancomycin remains the suitable antibiotic treatment for Gram-positive endophthalmitis. Ceftazidime and amikacin provide approximately the same degree of Gram-negative coverage. Multidrug-resistant bacterial endophthalmitis was uncommon.


Assuntos
Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Endoftalmite/tratamento farmacológico , Amicacina/uso terapêutico , Bactérias/isolamento & purificação , Ceftazidima/uso terapêutico , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Endoftalmite/metabolismo , Endoftalmite/microbiologia , Infecções Oculares Bacterianas/tratamento farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Vancomicina/uso terapêutico
11.
Microb Pathog ; 160: 105162, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34461245

RESUMO

Heteroresistance is a poorly understood mechanism of resistance which refers to a phenomenon where there are different subpopulations of seemingly isogenic bacteria which exhibit a range of susceptibilities to a particular antibiotic. In the current study, we identified a multidrug-resistant, carbapenemase-positive K. pneumoniae strain SWMUF35 which was classified as susceptible to amikacin and resistant to meropenem by clinical diagnostics yet harbored different subpopulations of phenotypically resistant cells, and has the ability to form biofilm. Population analysis profile (PAP) indicated that SWMUF35 showed heteroresistance towards amikacin and meropenem which was considered as co-heteroresistant K. pneumoniae strain. In vitro experiments such as dual PAP, dual Times-killing assays and checkerboard assay showed that antibiotic combination therapy (amikacin combined with meropenem) can effectively combat SWMUF35. Importantly, using an in vivo mouse model of peritonitis, we found that amikacin or meropenem monotherapy was unable to rescue mice infected with SWMUF35. Antibiotic combination therapy could be a rational strategy to use clinically approved antibiotics when monotherapy would fail. Furthermore, our data warn that antibiotic susceptibility testing results may be unreliable due to undetected heteroresistance which can lead to treatment failure and the detection of this phenotype is a prerequisite for a proper choice of antibiotic to support a successful treatment outcome.


Assuntos
Amicacina , Carbapenêmicos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Klebsiella pneumoniae , Meropeném/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Falha de Tratamento
12.
Expert Opin Pharmacother ; 22(15): 1961-1974, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34292097

RESUMO

Introduction: Guidelines recommend the use of amikacin in the treatment of nontuberculous mycobacterial (NTM) disease. The authors have evaluated the evidence for the position of amikacin in NTM disease treatment.Areas covered: The authors performed a literature search for original research on amikacin in NTM disease, including its mechanism of action, emergence of resistance, pre-clinical and clinical investigations.Expert opinion: Amikacin shows moderate in vitro activity against the clinically most relevant NTM species (M. avium complex and M. abscessus). It is synergistic with ethambutol, clofazimine, and macrolides and these combinations are effective in animal models. Liposomal encapsulation increases amikacin efficacy. Clinically, the recommended dose of 15 mg/kg intravenous amikacin does not lead to PK/PD target attainment in all patients and a positive impact on long-term treatment outcomes remains unproven in both M. avium complex and M. abscessus disease. Adding the amikacin liposome inhalation suspension did prove to be effective in short and long term in patients not responding to recommended treatment for M. avium complex pulmonary disease. Its optimal use in M. avium complex and M. abscessus pulmonary disease warrants further evaluation.


Assuntos
Amicacina , Infecções por Mycobacterium não Tuberculosas , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Exercício Físico , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas
13.
Int J Infect Dis ; 110: 272-278, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34274509

RESUMO

OBJECTIVE: Nocardia can be introduced accidentally causing non-healing surgical wounds. METHOD: From February 2017 to January 2021 samples from wounds were collected. Nocardia identification and susceptibility testing were carried out by standard procedure. RESULTS: Seventeen (35.4 %) Nocardia spp. and 20 other pathogens (41.7%) were recovered by culture. Drug susceptibility among Nocardia was >70% to amikacin, amoxicillin-clavulanic acid, levofloxacin, linezolid, and imipenem, 47% to cephalosporins and 41% to trimethoprim/sulfamethoxazole. CONCLUSIONS: Infections with Nocardia spp. should be considered in non-healing surgical wounds.


Assuntos
Nocardiose , Nocardia , Ferida Cirúrgica , Amicacina/uso terapêutico , Antibacterianos/uso terapêutico , Bangladesh/epidemiologia , Humanos , Testes de Sensibilidade Microbiana , Nocardiose/diagnóstico , Nocardiose/tratamento farmacológico , Nocardiose/epidemiologia , Ferida Cirúrgica/tratamento farmacológico
14.
J Antibiot (Tokyo) ; 74(9): 580-592, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34253885

RESUMO

Amikacin (AMK) is one of the most effective aminoglycoside antibiotics. However, nephrotoxicity is a major deleterious and dose-limiting side effect associated with its clinical use especially in high dose AMK-treated patients. The present study assessed the ability of taurine (TAU) to alleviate or prevent AMK-induced nephrotoxicity if co-administrated with AMK focusing on inflammation, apoptosis, and fibrosis. Male Sprague Dawley rats were assigned to six equal groups. Group 1: rats received saline (normal control), group 2: normal rats received 50 mg kg-1 TAU intraperitoneally (i.p.). Groups 3 and 4: received AMK (25 or 50 mg kg-1; i.p.). Groups 5 and 6: received TAU (50 mg kg-1; i.p.) concurrently with AMK (25 or 50 mg kg-1; i.p.) for 3 weeks. AMK-induced nephrotoxicity is evidenced by elevated levels of serum creatinine (CRE), blood urea nitrogen (BUN), and uric acid (UA). Histopathological investigations provoked damaging changes in the renal tissues. Heat shock proteins (HSP)25 and Toll-like receptor-4 (TLR-4) elevated levels were involved in the induction of inflammatory reactions and focal fibrosis. The improved activation of TLR-4 may stimulate monocytes to upgrade Interleukin (IL)-18 production rather than IL-10. TAU proved therapeutic effectiveness against AMK-induced renal toxicity through downregulation of HSP25, TLR-4, caspase-3, and IL-18 with up-regulation of IL-10 levels.


Assuntos
Amicacina/toxicidade , Antibacterianos/toxicidade , Nefropatias/prevenção & controle , Taurina/farmacologia , Amicacina/administração & dosagem , Animais , Antibacterianos/administração & dosagem , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Relação Dose-Resposta a Droga , Fibrose/induzido quimicamente , Fibrose/prevenção & controle , Proteínas de Choque Térmico HSP27/metabolismo , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Nefropatias/induzido quimicamente , Masculino , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Taurina/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Ácido Úrico/sangue
15.
Ther Drug Monit ; 43(4): 461-471, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34250963

RESUMO

ABSTRACT: Using pharmacokinetic (PK) models and Bayesian methods in dosing software facilitates the analysis of individual PK data and precision dosing. Several Bayesian methods are available for computing Bayesian posterior distributions using nonparametric population models. The objective of this study was to compare the performance of the maximum a posteriori (MAP) model, multiple model (MM), interacting MM (IMM), and novel hybrid MM(HMM) in estimating past concentrations and predicting future concentrations during therapy. Amikacin and vancomycin PK data were analyzed in older hospitalized patients using 2 strategies. First, the entire data set of each patient was fitted using each of the 4 methods implemented in BestDose software. Then, the 4 methods were used in each therapeutic drug monitoring occasion to estimate the past concentrations available at this time and to predict the subsequent concentrations to be observed on the next occasion. The bias and precision of the model predictions were compared among the methods. A total of 406 amikacin concentrations from 96 patients and 718 vancomycin concentrations from 133 patients were available for analysis. Overall, significant differences were observed in the predictive performance of the 4 Bayesian methods. The IMM method showed the best fit to past concentration data of amikacin and vancomycin, whereas the MM method was the least precise. However, MM best predicted the future concentrations of amikacin. The MAP and HMM methods showed a similar predictive performance and seemed to be more appropriate for the prediction of future vancomycin concentrations than the other models were. The richness of the prior distribution may explain the discrepancies between the results of the 2 drugs. Although further research with other drugs and models is necessary to confirm our findings, these results challenge the widely accepted assumption in PK modeling that a better data fit indicates better forecasting of future observations.


Assuntos
Amicacina , Teorema de Bayes , Monitoramento de Medicamentos/métodos , Vancomicina , Idoso , Amicacina/farmacocinética , Humanos , Software , Vancomicina/farmacocinética
16.
Sci Rep ; 11(1): 11614, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078922

RESUMO

Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2')-Ia from Providencia stuartii. As the clinical use of plazomicin begins to increase, the spread of resistance factors will undoubtedly accelerate, rendering this aminoglycoside increasingly obsolete. Understanding resistance to plazomicin is an important step to ensure this aminoglycoside remains a viable treatment option for the foreseeable future. Here, we present three crystal structures of AAC(2')-Ia from P. stuartii, two in complex with acetylated aminoglycosides tobramycin and netilmicin, and one in complex with a non-substrate aminoglycoside, amikacin. Together, with our previously reported AAC(2')-Ia-acetylated plazomicin complex, these structures outline AAC(2')-Ia's specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2')-I homologues highlights the conservation of residues predicted to be involved in aminoglycoside binding, and identifies the presence of plasmid-encoded enzymes in environmental strains that confer resistance to the latest next-generation aminoglycoside. These results forecast the likely spread of plazomicin resistance and highlight the urgency for advancements in next-generation aminoglycoside design.


Assuntos
Acetiltransferases/química , Antibacterianos/química , Proteínas de Bactérias/química , Farmacorresistência Bacteriana/genética , Providencia/enzimologia , Sisomicina/análogos & derivados , Acetiltransferases/genética , Acetiltransferases/metabolismo , Amicacina/química , Amicacina/metabolismo , Amicacina/farmacologia , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Cinética , Modelos Moleculares , Netilmicina/química , Netilmicina/metabolismo , Netilmicina/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Providencia/química , Providencia/efeitos dos fármacos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sisomicina/química , Sisomicina/metabolismo , Sisomicina/farmacologia , Especificidade por Substrato , Tobramicina/química , Tobramicina/metabolismo , Tobramicina/farmacologia
17.
BMC Infect Dis ; 21(1): 600, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162341

RESUMO

BACKGROUND: This antimicrobial surveillance study reports in vitro antimicrobial activity and susceptibility data for a panel of agents against respiratory isolates of Enterobacterales and Pseudomonas aeruginosa. METHODS: Isolates from respiratory specimens were collected in Africa/Middle East, Asia/South Pacific, Europe and Latin America between 2016 and 2018, as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program. Broth microdilution methodology was used to quantify minimum inhibitory concentrations, from which rates of susceptibility were determined using EUCAST breakpoints (version 10). Rates of subsets with genes encoding ß-lactamases (extended-spectrum ß-lactamases [ESBLs], serine carbapenemases and metallo-ß-lactamases [MBLs]) were also determined, as well as rates of multidrug-resistant (MDR) P. aeruginosa. RESULTS: Among all respiratory Enterobacterales isolates, susceptibility to ceftazidime-avibactam, meropenem, colistin and amikacin was ≥94.4% in each region. For Enterobacterales isolates that were ESBL-positive or carbapenemase-positive/MBL-negative, ceftazidime-avibactam susceptibility was 93.6 and 98.9%, respectively. Fewer than 42.7% of MBL-positive Enterobacterales isolates were susceptible to any agents, except colistin (89.0% susceptible). Tigecycline susceptibility was ≥90.0% among Citrobacter koseri and Escherichia coli isolates, including all ß-lactamase-positive subsets. ESBL-positive Enterobacterales were more commonly identified in each region than isolates that were ESBL/carbapenemase-positive; carbapenemase-positive/MBL-negative; or MBL-positive. Among all respiratory P. aeruginosa isolates, the combined susceptibility rates (susceptible at standard dosing regimen plus susceptible at increased exposure) were highest to ceftazidime-avibactam, colistin and amikacin (≥82.4% in each region). Susceptibility to colistin was ≥98.1% for all ß-lactamase-positive subsets of P. aeruginosa. The lowest rates of antimicrobial susceptibility were observed among MBL-positive isolates of P. aeruginosa (≤56.6%), with the exception of colistin (100% susceptible). MDR P. aeruginosa were most frequently identified in each region (18.7-28.7%), compared with the subsets of ESBL-positive; carbapenemase-positive/MBL-negative; or MBL-positive isolates. CONCLUSIONS: Rates of susceptibility among the collections of respiratory Enterobacterales and P. aeruginosa isolates were highest to ceftazidime-avibactam, colistin and amikacin in each region. Tigecycline was active against all subsets of C. koseri and E. coli, and colistin was active against all subsets of P. aeruginosa. The findings of this study indicate the need for continued antimicrobial surveillance among respiratory Gram-negative pathogens, in particular those with genes encoding MBLs.


Assuntos
Antibacterianos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/isolamento & purificação , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Amicacina/farmacologia , Compostos Azabicíclicos/farmacologia , Proteínas de Bactérias/genética , Ceftazidima/farmacologia , Citrobacter koseri/efeitos dos fármacos , Citrobacter koseri/isolamento & purificação , Colistina/farmacologia , Combinação de Medicamentos , Monitoramento Epidemiológico , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Humanos , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Tigeciclina/farmacologia , beta-Lactamases/genética
18.
Sci Rep ; 11(1): 12208, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108590

RESUMO

This study aimed to identify effective treatments against rapidly growing mycobacteria (RGM) infections by investigating the minimum inhibitory concentrations (MIC) of 24 antimicrobial agents and their molecular mechanisms of resistance. In total, 509 clinical RGM isolates were identified by analyzing the sequences of three housekeeping genes (hsp65, rpoB, and sodA), and their susceptibilities to 24 antimicrobial agents were tested. We also performed sequencing analysis of antimicrobial resistance genes (rrl, rrs, gyrA, and gyrB). To identify Mycobacteroides abscessus group subspecies, we performed PCR-based typing and determined the sequevar of erm(41). We identified 15 RGM species, most of which were susceptible to amikacin and linezolid. Among these species, arbekacin and sitafloxacin had the lowest MIC among the same class of antimicrobials. The MIC of rifabutin for M. abscessus subsp. abscessus (MAB) was lower than that for M. abscessus subsp. massiliense (MMA). The proportion of MAB isolates with MIC ≤ 2 mg/L for rifabutin was significantly higher than that of MMA [MAB: 50/178 (28.1%) vs. MMA: 23/130 (17.7%); p = 0.041]. In summary, our study revealed the antimicrobial susceptibility profile of 15 RGM species isolated in Japan and indicated that arbekacin, sitafloxacin, and rifabutin may be possible therapeutic options for RGM infections.


Assuntos
Amicacina/farmacologia , Antibacterianos/farmacologia , Claritromicina/farmacologia , Farmacorresistência Bacteriana , Linezolida/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas/efeitos dos fármacos , Humanos , Japão/epidemiologia , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas/genética , Micobactérias não Tuberculosas/crescimento & desenvolvimento , Micobactérias não Tuberculosas/isolamento & purificação
19.
Paediatr Drugs ; 23(4): 395-401, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34142330

RESUMO

OBJECTIVES: This study aimed to assess the incidence of amikacin plasma peak concentration (Cmax) below 60 mg·L-1 in critically ill children receiving an amikacin dosing regimen of 30 mg kg-1·day-1. Secondary objectives were to identify factors associated with low Cmax and to assess the incidence of acute kidney injury (AKI). METHODS: A retrospective observational study was performed in two French pediatric intensive care units. All admitted children who received 30 mg·kg-1 amikacin and had a Cmax measurement were eligible. Clinical and biological data, amikacin dose, and concentrations were collected. RESULTS: In total, 30 patients were included, aged from 3 weeks to 7 years. They received a median amikacin dosage of 30 mg kg-1·day-1 (range 29-33) based on admission body weight (BW), corresponding to 27 mg kg-1·day-1 (range 24-30) based on actual BW. Cmax was < 60 mg·L-1 in 21 (70%) children and none had a Cmax ≥ 80 mg·L-1. Among the 15 patients with a measured minimum inhibitory concentration (MIC), 13 (87%) had a Cmax/MIC ratio > 8. Univariate analysis showed that factors associated with Cmax < 60 mg·L-1 were high estimated glomerular filtration rate (p = 0.015) and low blood urea concentration (p = 0.001). AKI progression or occurrence was observed after amikacin administration in two (7%) and six (21%) patients, respectively. CONCLUSIONS: Despite the administration of the maximal recommended amikacin dose, Cmax was below the pharmacokinetic target in 70% of our pediatric population. Further studies are needed to develop a pharmacokinetic model in a population of critically ill children to optimize target attainment.


Assuntos
Amicacina/administração & dosagem , Amicacina/sangue , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Estado Terminal/terapia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Amicacina/efeitos adversos , Antibacterianos/efeitos adversos , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana/métodos , Estudos Retrospectivos
20.
Int J Infect Dis ; 108: 510-512, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34091004

RESUMO

We describe a challenging case of patient with metallo-beta-lactamase-producing Pseudomonas aeruginosa sternal osteomyelitis following aortic valve replacement with biological prosthesis. The strain exhibited a multidrug-resistance phenotype carrying the blaVIM-1 gene and belonged to the high-risk clone sequence type ST235. The patient was successfully treated with surgical debridement plus antibiotic therapy with ceftazidime/avibactam, aztreonam, and amikacin. Time-kill curves showed that this triple antibiotic combination at 1 × MIC was strongly synergic after 8 h, achieving 99.9% killing and maintaining this until 48 h.


Assuntos
Amicacina/uso terapêutico , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Aztreonam/uso terapêutico , Ceftazidima/uso terapêutico , Osteomielite/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Idoso , Desbridamento , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/genética , Quimioterapia Combinada , Feminino , Humanos , Osteomielite/microbiologia , Osteomielite/cirurgia , Infecções por Pseudomonas/cirurgia
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