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1.
Antimicrob Agents Chemother ; 67(4): e0239721, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-36916956

RESUMO

Omadacycline is approved in the United States for the treatment of patients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections. Analyses were undertaken to evaluate pharmacokinetic differences among subjects or patients stratified by comorbidities. Differences in clearance by smoking status, history of diabetes mellitus, chronic lung disease, hypertension, heart failure, or coronary artery disease were evaluated using a Welch two-sample t test. Smoking was the only significant comorbidity after correction for sex, with a clinically insignificant difference of 13%. Omadacycline dose adjustments based on these comorbidities do not appear to be warranted.


Assuntos
Antibacterianos , Infecções Comunitárias Adquiridas , Humanos , Antibacterianos/uso terapêutico , Antibacterianos/farmacocinética , Bactérias , Tetraciclinas/uso terapêutico , Tetraciclinas/farmacocinética , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Comorbidade
2.
Eur J Drug Metab Pharmacokinet ; 46(1): 85-92, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33180250

RESUMO

BACKGROUND: Omadacycline is a semisynthetic aminomethylcycline antibacterial derived from the tetracycline class. It is approved in the USA to treat adults with acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia. OBJECTIVES: This phase I, open-label study evaluated the effect of a potential drug-drug interaction of verapamil-a known P-glycoprotein (P-gp) inhibitor-with omadacycline on the pharmacokinetic profile of omadacycline in healthy adults. The safety and tolerability of omadacycline taken alone and in combination with verapamil were also evaluated. METHODS: A single oral dose of 240 mg verapamil extended release (ER) was given 2 h prior to a single oral dose of 300 mg omadacycline. RESULTS: Ten (83.3%) of the 12 participants enrolled in the study completed the study, and all enrolled participants were included in the safety and pharmacokinetic populations. An increase of 14-25% in systemic exposure to omadacycline was seen when administered following a single oral dose of 240 mg verapamil ER compared with omadacycline alone, as measured by the area under the concentration-time curve (AUC) from time 0 to 24 h after dosing (AUC0-24), from time 0 to the last quantifiable concentration (AUC0-t), from time 0 extrapolated to infinity (AUC0-inf), and by maximum (peak) observed plasma concentration (Cmax). Treatment-emergent adverse events were reported by one participant (nausea and headache). CONCLUSIONS: These findings suggest that, if given with a known P-gp inhibitor, dose adjustment of oral omadacycline is not warranted based on small increases in absorption and systemic exposure. No safety signals were identified.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antibacterianos/farmacocinética , Interações Medicamentosas/fisiologia , Voluntários Saudáveis , Tetraciclinas/farmacocinética , Verapamil/farmacocinética , Adulto , Antibacterianos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Tetraciclinas/administração & dosagem , Verapamil/administração & dosagem , Adulto Jovem
3.
Future Microbiol ; 15: 1319-1333, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32959689

RESUMO

Omadacycline is a novel aminomethylcycline antimicrobial, US FDA approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is not susceptible to common tetracycline resistance mechanisms, and has demonstrated efficacy against a broad spectrum of pathogens including resistant isolates, which are increasing in prevalence and complexity. It is available in both intravenous and oral formats, and can be administered in single, once daily doses or multiple doses, with no dosing adjustments required for sex, age, hepatic or renal impairment. It can be a good option for patients with low treatment adherence, and oral therapy may be used to reduce length of hospitalization for iv. treatment. This article reviews the in vitro and in vivo activity, PK/PD profile, integrated data from clinical trials including clinical efficacy and safety profile, and looks to future application of omadacycline.


Assuntos
Antibacterianos/uso terapêutico , Pneumonia Bacteriana/tratamento farmacológico , Dermatopatias Bacterianas/tratamento farmacológico , Tetraciclinas/uso terapêutico , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Ensaios Clínicos como Assunto , Infecções Comunitárias Adquiridas/tratamento farmacológico , Farmacorresistência Bacteriana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Segurança , Tetraciclinas/química , Tetraciclinas/farmacocinética , Tetraciclinas/farmacologia
4.
Pharmacotherapy ; 40(3): 221-238, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31944332

RESUMO

Eravacycline (ERV), formerly known as TP-434, is a novel tetracycline (TET) antibiotic that exhibits in vitro activity against various gram-positive, gram-negative aerobic and anaerobic pathogens, including those exhibiting TET-specific acquired resistance mechanisms. Similar to other TETs, it inhibits protein synthesis through binding to the 30S ribosomal subunit. Eravacycline was approved by the United States Food and Drug Administration (FDA) in August 2018 for the treatment of complicated intraabdominal infections (cIAIs) in adults following the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE)1 and IGNITE4 phase III trials. In these two, double-blind, multicenter clinical trials, ERV was proven noninferior in terms of clinical response in comparison to ertapenem and meropenem, respectively. Eravacycline was well tolerated with nausea, vomiting, and infusion site reactions being the most commonly reported adverse reactions. Clinicians now have ERV as a novel therapeutic option for the treatment of adults with intraabdominal infections, allergies to ß-lactam agents, Clostridioides difficile-associated diarrhea, or if tolerability to other agents is a concern.


Assuntos
Antibacterianos/uso terapêutico , Ensaios Clínicos como Assunto , Tetraciclinas/uso terapêutico , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Humanos , Tetraciclinas/farmacocinética , Tetraciclinas/farmacologia
5.
Clin Pharmacokinet ; 59(4): 409-425, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31773505

RESUMO

Omadacycline is a novel aminomethylcycline antibiotic (antibacterial). Omadacycline has had chemical structure modifications at the C9 and C7 positions of the core tetracycline rings that allow stability in the efflux pump and ribosomal protection protein mechanisms of tetracycline resistance. The systemic exposure (i.e., maximum plasma concentrations [Cmax] and area under the plasma concentration-time curve [AUC]) after intravenous (IV) administration were linear and predictable over the dose range of 25 and 600 mg in healthy subjects. The oral bioavailability of omadacycline was 34.5% under fasted conditions (no food intake 6 h before and 4 h after dosing). Both AUC and Cmax values significantly decreased (41-61%) when a high-fat meal, with and without dairy, were administered 2 h before oral dosing of omadacycline. Similar to other tetracyclines, it is advisable to avoid concurrent administration of divalent- or trivalent cation-containing products (e.g., antacids and iron-containing preparations) for at least 4 h after oral administration of omadacycline. Omadacycline has a large volume of distribution (190 L) and low plasma protein binding (21.3%) that was concentration independent. Systemic exposure of omadacycline in epithelial lining fluid (ELF) and alveolar macrophages was greater than in plasma in healthy adult subjects. Omadacycline is excreted unchanged in the feces (81.1%) and urine (14.4%), and has a low potential for drug-drug interactions since it was not a substrate, inhibitor, or inducer of major cytochrome-metabolizing enzymes or organic anion transporters (OATs). No clinically significant differences in the pharmacokinetics of omadacycline have been observed for age, sex, and renal or hepatic impairment. Pharmacokinetic-pharmacodynamic studies have confirmed that the AUC from time zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) ratio was the best index for correlating unbound plasma and total-drug ELF concentrations with the efficacy of omadacycline. A population pharmacokinetic model was developed with data from healthy subjects and infected patients and used to establish interpretive criteria for in vitro susceptibility testing and dosing regimens of omadacycline for treating acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.


Assuntos
Bactérias/efeitos dos fármacos , Infecções Comunitárias Adquiridas/tratamento farmacológico , Tetraciclinas/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/sangue , Antibacterianos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Interações Medicamentosas/fisiologia , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tetraciclinas/sangue
6.
Expert Rev Anti Infect Ther ; 17(11): 851-863, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31622119

RESUMO

Introduction: Complicated intra-abdominal infections (cIAIs) are among the most frequent infections, contributing to significant morbidity and healthcare costs. Several medical needs remain unmet, related to the pharmacokinetic capacities of the available drugs and their limited spectrum of activity for targeting multidrug-resistant Gram-negative and Gram-positive bacteria. Eravacycline, a new synthetic fluorocycline, could have useful properties in cIAIs.Areas covered: The antimicrobial activity of eravacycline against the microorganisms most frequently cultured in cIAIs has been confirmed in worldwide panels of clinical isolates, including enterococci, ESBL-producing Enterobacteriaceae, Acinetobacter baumannii and anaerobes. Pharmacokinetic data demonstrate interesting characteristics with good tissue concentrations including biliary tract and digestive tissues. At a conventional dosage of 1 mg/kg q12h, no adjustment is required on the basis of race or gender, or in elderly (≥ 65 years old) patients, patients with renal impairment or patients undergoing hemodialysis. Phase 2 and 3 trials assessing the clinical efficacy and safety of eravacycline demonstrated non-inferiority versus carbapenems and a good safety profile.Expert opinion: Eravacycline may be particularly suitable for the treatment of cIAIs. Results from clinical trials and real-world data are now expected in specific subgroups of patients to confirm the safety profile and efficacy observed in registration trials.


Assuntos
Antibacterianos/administração & dosagem , Infecções Intra-Abdominais/tratamento farmacológico , Tetraciclinas/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Infecções Intra-Abdominais/microbiologia , Testes de Sensibilidade Microbiana , Tetraciclinas/efeitos adversos , Tetraciclinas/farmacocinética
7.
Clin Infect Dis ; 69(Suppl 1): S16-S22, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31367744

RESUMO

Oral and intravenous (IV) omadacycline formulations are approved in the United States for treating acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in adults. Oral omadacycline bioavailability is 34.5%; similar exposures are obtained following 300 mg oral and 100 mg IV doses. Oral administration should be in a fasted state, with dairy products, antacids, or multivitamins avoided for ≥4 hours after dosing. Low protein binding (21%), large volume of distribution (190 L), low systemic clearance (10 L/hour), and long elimination half-life (16-17 hours) support once-daily dosing. Omadacycline is excreted unchanged in feces (81.1%) and urine (14.4%), with low potential for drug-drug interactions. Dose adjustments are unnecessary for age, sex, and renal or hepatic impairment. Pharmacokinetic-pharmacodynamic studies identify fAUC0-24/MIC ratio as the parameter that correlates with in vivo efficacy. Systemic exposure of omadacycline in epithelial lining fluid is greater than/equal to plasma concentrations in healthy adults.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Tetraciclinas/farmacocinética , Tetraciclinas/uso terapêutico , Administração Intravenosa , Administração Oral , Fatores Etários , Antibacterianos/administração & dosagem , Área Sob a Curva , Infecções Comunitárias Adquiridas/tratamento farmacológico , Esquema de Medicação , Interações Medicamentosas , Humanos , Fatores Sexuais , Tetraciclinas/administração & dosagem
8.
Clin Pharmacokinet ; 58(9): 1149-1153, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31049869

RESUMO

On 27 August, 2018, the US Food and Drug Administration approved eravacycline, a fluorocycline antimicrobial agent within the tetracycline class of antibacterial drugs, for the treatment of complicated intra-abdominal infections in patients aged 18 years and older. This decision was based on substantial clinical and pre-clinical data, including rigorous pharmacokinetic and pharmacodynamic work. This paper examines the in-vivo pharmacokinetic/pharmacodynamic work that led to the approval of eravacycline and explores how this important new antibiotic may be used to treat aggressive multidrug-resistant infections in the years ahead.


Assuntos
Antibacterianos/farmacocinética , Infecções Intra-Abdominais/tratamento farmacológico , Tetraciclinas/farmacocinética , Administração Intravenosa , Adulto , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Interações Medicamentosas , Resistência a Múltiplos Medicamentos , Humanos , Infecções Intra-Abdominais/microbiologia , Camundongos , Testes de Sensibilidade Microbiana/métodos , Modelos Animais , Coelhos , Tetraciclinas/administração & dosagem , Tetraciclinas/farmacologia
10.
Ann Pharmacother ; 53(5): 486-500, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30917674

RESUMO

OBJECTIVE: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of omadacycline, a new tetracycline antibiotic. DATA SOURCES: A literature search through PubMed, Google Scholar, and clinicaltrials.gov was conducted (2008 to October 2018) using the search terms omadacycline and PTK-0796. Abstracts presented at recent conferences, prescribing information and information from the FDA and the manufacturer's website were reviewed. STUDY SELECTION AND DATA EXTRACTION: Preclinical data and published phase 1, 2, and 3 studies were evaluated. DATA SYNTHESIS: Omadacycline displays in vitro activity against a wide range of bacteria. Clinical trials have shown that omadacycline is noninferior to linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). A loading dose of 200 mg intravenously (IV) once or 100 mg IV twice or 450 mg orally once is recommended followed by a maintenance dose of 100 mg IV or 300 mg orally once daily. No dosage adjustment is needed in patients with renal or hepatic impairment. Omadacycline is well tolerated, with nausea being a common adverse effect, but is associated with food and drug interactions. Relevance to Patient Care and Clinical Practice: Omadacycline is active against staphylococci, including methicillin-resistant strains, and streptococci, including tetracycline-resistant strains, as well as atypical bacteria. Omadacycline provides clinicians with an additional parenteral and oral option for the treatment of adults with ABSSSI and CABP. CONCLUSION: Omadacycline is an alternative treatment option for ABSSSI and CABP.


Assuntos
Antibacterianos/classificação , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Tetraciclinas/uso terapêutico , Doença Aguda , Administração Intravenosa , Adulto , Antibacterianos/farmacocinética , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/epidemiologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/epidemiologia , Tetraciclinas/classificação , Tetraciclinas/farmacocinética , Resultado do Tratamento
11.
Artigo em Inglês | MEDLINE | ID: mdl-30559132

RESUMO

Eravacycline is a novel, fully synthetic fluorocycline that is approved for the treatment of complicated intra-abdominal infections (cIAI) in adult patients. We report results from three studies in healthy subjects that investigated the distribution, metabolism, and excretion of intravenous (i.v.) eravacycline and the effect of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of i.v. eravacycline. In the mass balance study, the majority of total radioactivity from [14C]eravacycline was recovered in the feces, suggesting biliary/fecal elimination is the major route of excretion for eravacycline and its metabolites after IV administration. The volume of distribution (217 liters) was greater than that of extracellular fluid, which suggests distribution beyond the central compartment. In the drug-drug interaction studies, mean area under the concentration-time curve from 0 h to the last time point (AUC0-t ) and half-life were increased approximately 30% to 40% after a concomitant dose of i.v. eravacycline and itraconazole and clearance (CL) was decreased. A reduction in total eravacycline exposure (AUC) of approximately 25% to 35% and an increase in CL of approximately 50% occurred with concomitant eravacycline and rifampin treatment. The dose of eravacycline should be increased to 1.5 mg/kg of body weight every 12 h when coadministered with a strong CYP3A inducer.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Tetraciclinas/farmacologia , Tetraciclinas/farmacocinética , Adulto , Antibacterianos/efeitos adversos , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Itraconazol/farmacologia , Masculino , Pessoa de Meia-Idade , Rifampina/farmacologia , Tetraciclinas/efeitos adversos
12.
Artigo em Inglês | MEDLINE | ID: mdl-30150464

RESUMO

Eravacycline is a novel, fully synthetic fluorocycline antibiotic with in vitro activity against aerobic and anaerobic Gram-positive and Gram-negative pathogens, including multidrug-resistant (MDR) bacteria. The pharmacokinetics (PK), urinary excretion, and safety/tolerability of intravenous (i.v.) eravacycline were evaluated in single- and multiple-ascending-dose studies. Healthy subjects received single i.v. doses of 0.1 to 3 mg/kg of body weight or 10 days of treatment with 0.5 or 1.5 mg/kg every 24 h (q24h) over 30 min, 1.5 mg/kg q24h over 60 min, or 1 mg/kg q12h over 60 min. After single doses, total exposure (the area under the plasma concentration-time curve [AUC]) and the maximum plasma concentrations (Cmax) of eravacycline increased in an approximately dose-proportional manner. After multiple doses, steady state was achieved within 5 to 7 days. Accumulation ranged from approximately 7% to 38% with the q24h dosing regimens and was 45% with 1 mg/kg q12h. Eravacycline was generally well tolerated, with dose-related nausea, infusion site effects, and superficial phlebitis that were mild or moderate occurring. These results provide support for the 1-mg/kg q12h regimen used in clinical studies of eravacycline.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Tetraciclinas/efeitos adversos , Tetraciclinas/farmacocinética , Adolescente , Adulto , Antibacterianos/administração & dosagem , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Tetraciclinas/administração & dosagem , Adulto Jovem
13.
Artigo em Inglês | MEDLINE | ID: mdl-29941646

RESUMO

Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant Enterobacteriaceae We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was administered to New Zealand White (NZW) rabbits at 1, 2, 4, 8, and 10 mg/kg of body weight intravenously (i.v.) once a day (QD) (n = 20). For multidose pharmacokinetic analysis, eravacycline was administered at 0.5, 1, 2, and 4 mg/kg i.v. QD (n = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by a liquid chromatography-tandem mass spectrometry assay. Mean areas under the concentration-time curves (AUCs) following a single eravacycline dose ranged from 5.39 µg · h/ml to 183.53 µg · h/ml. Within the multidose study, mean AUCs ranged from 2.53 µg · h/ml to 29.89 µg · h/ml. AUCs correlated linearly within the dosage range (r = 0.97; P = 0.0001). In the cardiopulmonary system, the concentrations were the highest in the lung, followed by the heart > pulmonary alveolar macrophages > bronchoalveolar lavage fluid; for the intra-abdominal system, the concentrations were the highest in bile, followed by the liver > gallbladder > spleen > pancreas; for the renal system, the concentrations were the highest in urine, followed by those in the renal cortex > renal medulla; for the musculoskeletal tissues, the concentrations were the highest in muscle psoas, followed by those in the bone marrow > adipose tissue; for the central nervous system, the concentrations were the highest in cerebrum, followed by those in the aqueous humor > cerebrospinal fluid > choroid > vitreous. The prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields an exposure comparable to that in humans (1 or 2 mg/kg every 12 h) and demonstrates target tissue concentrations in most sites.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Enterobacteriaceae/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Tetraciclinas/farmacologia , Tetraciclinas/farmacocinética , Distribuição Tecidual/fisiologia , Animais , Área Sob a Curva , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Masculino , Testes de Sensibilidade Microbiana/métodos , Coelhos
14.
Drugs Today (Barc) ; 54(4): 245-254, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29869646

RESUMO

Eravacycline is a novel, broad-spectrum, synthetic fluorocycline antibiotic for the treatment of complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) due to multidrug-resistant Gram-positive, Gram-negative and anaerobic bacteria that has demonstrated superior potency to that of currently marketed antibiotics. Tetraphase Pharmaceuticals has submitted a new drug application for eravacycline for the treatment of cIAI due to drug-resistant bacteria. In 2013, the U.S. Food and Drug Administration (FDA) granted eravacycline qualified infectious disease product designation for the treatment of cUTI and cIAI.


Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Intra-Abdominais/tratamento farmacológico , Tetraciclinas/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Antibacterianos/efeitos adversos , Antibacterianos/química , Antibacterianos/farmacocinética , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/microbiologia , Composição de Medicamentos , Interações Medicamentosas , Humanos , Infecções Intra-Abdominais/diagnóstico , Infecções Intra-Abdominais/microbiologia , Tetraciclinas/efeitos adversos , Tetraciclinas/química , Tetraciclinas/farmacocinética , Resultado do Tratamento , Infecções Urinárias/diagnóstico , Infecções Urinárias/microbiologia
15.
Drugs Today (Barc) ; 54(3): 209-217, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29771255

RESUMO

Omadacycline is a novel aminomethylcycline antimicrobial agent that is available in both oral and intravenous formulations. The distinguishing structural characteristics of omadacycline from other tetracyclines allow for its continued antimicrobial activity in the presence of traditional tetracycline resistance mechanisms (efflux pumps and ribosomal protection proteins). Omadacycline has been found to have potent activity against antibiotic-resistant pathogens including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, extended spectrum beta-lactamase-producing Escherichia coli and multidrug-resistant Streptococcus pneumoniae. Currently available data indicate that omadacycline is generally well tolerated with the most common adverse effects being gastrointestinal symptoms. Omadacycline seems to be a promising new agent for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Studies for the treatment of cystitis in adult females are currently underway, and future results of these studies will further help delineate the antibacterial role of omadacycline.


Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Tetraciclinas/uso terapêutico , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/microbiologia , Interações Medicamentosas , Humanos , Tetraciclinas/efeitos adversos , Tetraciclinas/farmacocinética , Resultado do Tratamento
16.
AAPS PharmSciTech ; 19(3): 1287-1296, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29318467

RESUMO

Several authors have studied the release profile of drugs incorporated in different devices. However, to the best of our knowledge, although many studies have been done on the release of tetracycline, in these release devices, no study has investigated if the released compound is actually the tetracycline, or, instead, a degraded product. This approach is exploited here. In this work, we analyse the influence of two drying methods on the tetracycline delivery behaviour of synthesised glasses using the sol-gel process. We compare the drying methods results using both theoretical models and practical essays, and analyse the chemical characteristic of the released product in order to verify if it remains tetracycline. Samples were freeze-dried or dried in an oven at 37°C and characterised by several methods such as Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TG), differential thermogravimetric analysis (DTG), differential thermal analyses (DTA) and gas adsorption analysis (BET). The released concentration of tetracycline hydrochloride was studied as a function of time, and it was measured by ultraviolet spectrophotometry in the tetracycline wavelength. The drug delivery profiles were reasonably consistent with a diffusion model analysis. In addition, we observed higher release rates for the freeze-dried compared to those dried in an oven at 37°C. This higher release can be attributed to larger pore size for the freeze-dried sample systems with tetracycline, which promoted more water penetration, improving the drug diffusion. The analysis of the solution obtained in the release tests using high-performance liquid chromatography- mass spectrometry (HPLC-MS) confirmed that tetracycline was being released.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Tetraciclinas/síntese química , Antibacterianos/administração & dosagem , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Difusão , Composição de Medicamentos/métodos , Liofilização/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Tetraciclinas/administração & dosagem , Tetraciclinas/farmacocinética
17.
Int J Antimicrob Agents ; 51(5): 727-732, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29325762

RESUMO

After the pharmacokinetic (PK) profile of eravacycline, a novel fluorocycline, was defined, understanding its pharmacodynamic (PD) profile became essential. This study aimed to assess the correlation of the PK/PD index fAUC/MIC (ratio of area under the free drug concentration-time curve to MIC) and its magnitude with eravacycline's efficacy against Enterobacteriaceae using an immunocompetent murine thigh infection model to resemble the immunocompetent environment in eravacycline's clinical trials. Eight Enterobacteriaceae isolates with various resistance mechanisms were tested. Eravacycline doses ranged from 1-10 mg/kg/day and were given either once daily (q24h) or divided into doses every 12 h (q12h) over the 24-h treatment period. Antibacterial efficacy was measured as the change in log10CFU at 24 h compared with 0 h controls. Composite data were modelled using a sigmoid Emax model. Eravacycline MICs ranged from 0.125-0.5 µg/mL. The mean fAUC/MIC magnitudes required for stasis and 1-log reduction for the eight isolates were 2.9 ± 3.1 and 5.6 ± 5.0, respectively. Whilst the humanised eravacycline regimen (2.5 mg/kg q12h) pharmacokinetically achieves an fAUC0-24 that is higher than the fAUC0-24 achieved with the 5 mg/kg q24h dose, the latter was associated with greater efficacy, raising a suggestive correlation of the peak free drug concentration to MIC (fCmax/MIC) ratio with eravacycline's efficacy. This study showed that the magnitudes associated with eravacycline's efficacy in an immunocompetent murine thigh model appear to be close to achievable targets in human. These data support further development of eravacycline for treatment of infections caused by drug-resistant Enterobacteriaceae.


Assuntos
Enterobacteriaceae/efeitos dos fármacos , Tetraciclinas/administração & dosagem , Tetraciclinas/farmacocinética , Animais , Área Sob a Curva , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana , Enterobacteriaceae/patogenicidade , Infecções por Enterobacteriaceae/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana
18.
Artigo em Inglês | MEDLINE | ID: mdl-29180524

RESUMO

Omadacycline, a first-in-class aminomethylcycline antibiotic, is related to tetracyclines but is structurally modified to circumvent mechanisms of resistance to tetracyclines. Omadacycline demonstrates potent activity against a broad range of pathogens, including drug-resistant strains, and is in late-stage development for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Previous studies support an intravenous-to-oral transition regimen with 300-mg once-daily oral dosing. This phase 1 study investigated the pharmacokinetics and safety/tolerability of multiple oral omadacycline doses higher than 300 mg. Using a 3-period crossover design, healthy adults were randomized to receive oral omadacycline at 300, 450, and 600 mg in variable sequence (n = 26) or placebo (n = 7) once daily for 5 consecutive days per period. In plasma, omadacycline maximum concentration and total exposure increased with increasing dose but were less than dose proportional. The kinetics of omadacycline plasma accumulation were similar between dose levels; exposure on day 5 was ∼50% higher than that on day 1. Omadacycline plasma concentrations on day 1 of 450-mg dosing were similar to those on day 5 of 300-mg dosing. All doses were generally well tolerated, but the 600-mg dose was associated with more gastrointestinal adverse events.


Assuntos
Antibacterianos/farmacocinética , Tetraciclinas/farmacocinética , Administração Oral , Adolescente , Adulto , Antibacterianos/sangue , Área Sob a Curva , Método Duplo-Cego , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Tetraciclinas/sangue
19.
Artigo em Inglês | MEDLINE | ID: mdl-29158281

RESUMO

Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 µg · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 µg · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 µg · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 µg/ml when it was administered after dialysis and 2.33 µg/ml when it was administered before dialysis, and in healthy subjects it was 1.92 µg/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.


Assuntos
Antibacterianos/farmacocinética , Insuficiência Renal/metabolismo , Tetraciclinas/efeitos adversos , Tetraciclinas/farmacocinética , Administração Intravenosa/métodos , Adulto , Idoso , Antibacterianos/efeitos adversos , Área Sob a Curva , Bactérias/efeitos dos fármacos , Estudos de Casos e Controles , Feminino , Humanos , Falência Renal Crônica/metabolismo , Masculino , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Diálise Renal/métodos , Tetraciclinas/administração & dosagem
20.
Curr Opin Infect Dis ; 31(2): 148-154, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29251672

RESUMO

PURPOSE OF REVIEW: Skin and soft tissue infections (SSTIs) are among the most frequent infections, contributing to significant morbidity and healthcare costs. Although numerous antibiotics are available for this indication, several medical needs remain unmet, especially for treating methicillin-resistant Staphylococcus aureus (MRSA) or mixed infections. This review summarizes the results achieved in the development of omadacycline, a new aminomethylcycline, which could have useful properties for the treatment of SSTIs. RECENT FINDINGS: The antimicrobial activity of omadacycline against the micro-organisms most frequently cultured in SSTIs has been confirmed in worldwide panels of clinical isolates, including MRSA, Gram-negative aerobes and some anaerobes. Pharmacokinetic data demonstrate interesting characteristics, allowing intravenous and oral administration. The Phase 3 OASIS-1 trial assessed the clinical efficacy and safety of omadacycline versus linezolid in SSTIs and demonstrated noninferiority and a good safety profile especially with regard to gastrointestinal effects. Analyses of subgroups of patients from this trial showed similar activity to that of the comparator drug, good safety and no dosage adjustments for age, sex or hepatic or renal impairment. SUMMARY: Because of its microbiological activities and pharmacokinetic profile, omadacycline may be particularly suitable for the treatment of SSTIs, whether managed in hospital or on an outpatient basis.


Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Dermatopatias Infecciosas/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Tetraciclinas/uso terapêutico , Administração Intravenosa , Administração Oral , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Ensaios Clínicos como Assunto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Tetraciclinas/efeitos adversos , Tetraciclinas/farmacocinética , Resultado do Tratamento
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