RESUMO
This was a phase I, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of oral ceftibuten to describe the pharmacokinetics (PK) of cis-ceftibuten (administered form) and trans-ceftibuten (metabolite), and to describe safety and tolerability at higher than licensed doses. Subjects received single 400, 600, or 800 mg doses of ceftibuten on Days 1 and 4, followed by 7 days of twice-daily dosing from Days 4 to 10. Non-compartmental methods were used to describe parent drug and metabolite PK in plasma and urine. Dose proportionality was examined using C max, AUC0-12, and AUC0-INF. Accumulation was calculated as the ratio of AUC0-12 on Days 4 and 10. Adverse events (AEs) were monitored throughout the study. Following single ascending doses, mean cis- and trans-ceftibuten C max were 17.6, 24.1, and 28.1 mg/L, and 1.1, 1.5, and 2.2 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 64.3%-86.9% of the administered dose over 48 h. Following multiple ascending doses, mean cis- and trans-ceftibuten C max were 21.7, 28.1, and 38.8 mg/L, and 1.4, 1.9, and 2.8 mg/L, respectively; cis-ceftibuten urinary recovery accounted for 72.2%-96.4% of the administered dose at steady state. The exposure of cis- and trans-ceftibuten increased proportionally with increasing doses. Cis- and trans-ceftibuten accumulation factor was 1.14-1.19 and 1.28-1.32. The most common gastrointestinal treatment emergent AEs were mild and resolved without intervention. Ceftibuten was well tolerated. Dose proportionality and accumulation of cis- and trans-ceftibuten were observed. These results support the ongoing development of ceftibuten at doses up to 800 mg twice-daily. (The study was registered at ClinicalTrials.gov under the identifier NCT03939429.).
Assuntos
Ceftibuteno , Adulto , Humanos , Área Sob a Curva , Método Duplo-Cego , Voluntários Saudáveis , Administração Oral , Relação Dose-Resposta a DrogaRESUMO
The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single and multiple-ascending dose study using doses from 250 to 1250 mg administered three times a day using 3-hour infusions. Maximum concentrations for biapenem were achieved at the end of the 3-hour infusion. Biapenem exposure (AUC) increased in a slightly greater than dose-proportional manner following single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg*h/L at 250 mg to 150 mg*h/L at 1250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1250 mg. Biapenem was well tolerated up to 1000 mg administered every 8 hours by 3-hour infusion for 7 days; however, a higher incidence of nausea, vomiting, and rash was reported at 1250 mg. There were no serious adverse events (SAEs) reported following either single or multiple doses of biapenem and all AEs were mild or moderate in severity.
RESUMO
Early efforts to broaden the spectrum and potency of cyclic boronic acid ß-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important ß-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).
Assuntos
Pró-Fármacos , Inibidores de beta-Lactamases , Antibacterianos/química , Antibacterianos/farmacologia , Disponibilidade Biológica , Pró-Fármacos/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismoRESUMO
Burkholderia cepacia complex is an opportunistic pathogen capable of causing chronic pulmonary infections. These studies were conducted to demonstrate the activity of aerosolized levofloxacin in a chronic mouse lung infection model caused by B. cepacia isolates from patients with cystic fibrosis. Treatment with aerosolized levofloxacin for 4 days produced at least 1 log CFU of bacterial killing against all strains tested, suggesting possible utility in the treatment of lung infections caused by B. cepacia isolates.
Assuntos
Antibacterianos/administração & dosagem , Infecções por Burkholderia/tratamento farmacológico , Complexo Burkholderia cepacia/efeitos dos fármacos , Fibrose Cística/complicações , Levofloxacino/administração & dosagem , Infecções Respiratórias/tratamento farmacológico , Administração por Inalação , Animais , Infecções por Burkholderia/complicações , Infecções por Burkholderia/microbiologia , Doença Crônica , Feminino , Humanos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções Respiratórias/complicações , Infecções Respiratórias/microbiologiaRESUMO
Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.
Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Klebsiella pneumoniae , Animais , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/genética , beta-LactamasRESUMO
Acinetobacter baumannii infections are difficult to treat and have limited treatment options. Carbapenems, including meropenem, are currently considered the first-line agents for the treatment of infections caused by Acinetobacter spp. The percentage of a 24-hour period that the concentration of free drug in plasma is above the MIC (%24-h fT>MIC) to achieve stasis, 1 log CFU, or 2 log CFU of bacterial killing against A. baumannii has not been studied previously for meropenem. The objective of this study was to determine these parameters for meropenem against A. baumannii in a neutropenic mouse thigh infection model. Six A. baumannii clinical isolates with MICs ranging from 0.25 to 16 mg/liter were tested. Meropenem produced a bacteriostatic effect with a %24-h fT>MIC of 7 to 24% and produced 1 log CFU of bacterial killing with a %24-h fT>MIC of 15 to 37%.
Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacocinética , Meropeném/farmacocinética , Infecções por Acinetobacter/microbiologia , Animais , Antibacterianos/sangue , Antibacterianos/farmacologia , Carga Bacteriana , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Feminino , Meropeném/sangue , Meropeném/farmacologia , Camundongos , Testes de Sensibilidade MicrobianaRESUMO
We have evaluated the activity of meropenem-vaborbactam against clinical isolates of Pseudomonas aeruginosaandAcinetobacter baumannii in a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-h infusions every 8 h with 2 g meropenem and 2 g vaborbactam produced bacterial killing against strains with MICs of 2 to 16 mg/liter and suggests that this combination may have utility in the treatment of infections caused by P. aeruginosa and A. baumannii.
Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Meropeném/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Acinetobacter baumannii/isolamento & purificação , Animais , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/isolamento & purificaçãoRESUMO
Minocycline is currently approved in the United States for the treatment of infections caused by susceptible isolates of Acinetobacter spp. The objective of these studies was to determine the minocycline exposures associated with an antibacterial effect against Acinetobacter baumannii in a rat pneumonia model. Rats received minocycline doses as 30-min intravenous infusions. In the rat pneumonia model, six clinical isolates of A. baumannii with MICs ranging from 0.03 to 4 mg/liter were studied. In this model, minocycline produced a bacteriostatic effect with a free 24-h area under the concentration-time curve (AUC)/MIC ratio of 10 to 16 and produced 1 log of bacterial killing with a free 24-h AUC/MIC of 13 to 24. These exposures can be achieved with the current FDA-approved dosage regimens of intravenous minocycline.
Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Minociclina/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Animais , Ciclofosfamida/farmacocinética , Ciclofosfamida/uso terapêutico , Masculino , Minociclina/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550 mg · h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.
Assuntos
Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Ácidos Borônicos/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacocinética , Meropeném/farmacologia , Meropeném/farmacocinética , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/farmacocinética , Animais , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Modelos Animais de Doenças , Combinação de Medicamentos , Enterobacter cloacae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Feminino , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Neutropenia/microbiologia , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Infecções Urinárias/microbiologiaRESUMO
Nonclinical studies have suggested that oxidative damage, caspase-mediated apoptosis, and inducible nitric oxide synthase levels may be involved in the pathogenesis of colistin (CST)-associated acute renal failure. MIN inhibits caspase 1, caspase 3, and inducible nitric oxide synthase, leading to the hypothesis that coadministration of CST with MIN (CST-MIN) may reduce the incidence of acute renal failure as well as produce additive or synergistic antimicrobial effects. A multicenter retrospective cohort study was conducted using the Premier Research database to examine the impact of CST-MIN on acute renal failure. Inclusion criteria were as follows: age of ≥18 years, intensive care unit admission at CST initiation, primary International Classification of Diseases 9 (ICD-9) diagnosis of pneumonia or sepsis, nondialysis at hospital admission, and discharge between January 2010 and December 2015. ICD-9 code 584.XX or ICD-10 code N17 was used to define acute renal failure. Baseline comparisons, 1:8 propensity score matching, and confirmatory logistic regression analyses were conducted. In total, 4,817 patients received CST and met inclusion criteria; 93 received CST-MIN. Unadjusted frequency of acute renal failure was significantly lower in patients receiving CST-MIN than CST (11.8% versus 23.7%, P = 0.007). Similar results were seen in propensity score matching (12.0% versus 22.3%, P = 0.031) and logistic regression analyses (odds ratio of 0.403, P = 0.006). Mortalities and 30-day readmission rates were similar between groups. The acute renal failure rate was not impacted by prevalence of baseline renal disease. CST-MIN in critically ill patients may reduce CST-associated acute renal failure. Further evaluation of this combination in prospective clinical studies is warranted.
Assuntos
Injúria Renal Aguda/prevenção & controle , Colistina/administração & dosagem , Minociclina/administração & dosagem , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Adulto , Idoso , Estudos de Coortes , Colistina/uso terapêutico , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Minociclina/uso terapêutico , Readmissão do Paciente/estatística & dados numéricos , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, â¼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.
Assuntos
Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Infecções por Enterobacteriaceae/tratamento farmacológico , Meropeném/farmacologia , Proteínas de Bactérias/metabolismo , Infecções por Enterobacteriaceae/metabolismo , Humanos , Testes de Sensibilidade Microbiana/métodosRESUMO
Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.
Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacter cloacae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Animais , Antibacterianos/farmacocinética , Proteínas de Bactérias/metabolismo , Ácidos Borônicos/farmacocinética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Humanos , Meropeném/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/patologia , Infecções dos Tecidos Moles/microbiologia , Coxa da Perna/microbiologia , Coxa da Perna/patologia , Inibidores de beta-Lactamases/farmacocinética , beta-Lactamases/metabolismoRESUMO
Vaborbactam is a member of a new class of ß-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g., Klebsiella pneumoniae carbapenemase) that has been developed in combination with meropenem. The pharmacokinetics of the combination was evaluated in 41 subjects with chronic renal impairment in a phase 1, open-label, single-dose study. Subjects were assigned to one of five groups based on renal function: normal (creatinine clearance of ≥90 ml/min), mild (estimated glomerular filtration rate [eGFR] of 60 to 89 ml/min/1.73 m2), moderate (eGFR of 30 to <60), or severe (eGFR of <30) impairment plus end-stage renal disease (ESRD) patients on hemodialysis. Subjects received a single intravenous dose of 1 g of meropenem plus 1 g of vaborbactam by 3-h infusion. The ESRD group received two doses (on and off dialysis) separated by a washout. Pharmacokinetic parameters were estimated by standard noncompartmental methods. For both meropenem and vaborbactam, the area under the concentration-time curve was larger and the elimination half-life was longer with decreasing renal function. Meropenem and vaborbactam total plasma clearance (CLt) rates were similar and decreased with decreasing renal function. Slopes of the linear relationship between eGFR and CLt were similar, indicating a similar proportional reduction in CLt with decreasing renal function. Hemodialysis significantly increased drug clearance of meropenem (mean of 2.21-fold increase in CLt, P < 0.001) and vaborbactam (mean of 5.11-fold increase, P = 0.0235) relative to drug administration off dialysis, consistent with dose recovery rates of 38.3% and 52.9% for meropenem and vaborbactam, respectively, in dialysate. Plasma clearance of meropenem and vaborbactam is reduced with renal impairment, requiring dose adjustment. Hemodialysis removes both drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT02020434.).
Assuntos
Antibacterianos/farmacocinética , Ácidos Borônicos/farmacocinética , Falência Renal Crônica/sangue , Meropeném/farmacocinética , Diálise Renal , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Antibacterianos/sangue , Antibacterianos/urina , Área Sob a Curva , Ácidos Borônicos/sangue , Ácidos Borônicos/urina , Creatinina/sangue , Esquema de Medicação , Combinação de Medicamentos , Feminino , Taxa de Filtração Glomerular/fisiologia , Meia-Vida , Humanos , Injeções Intravenosas , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Falência Renal Crônica/urina , Masculino , Meropeném/sangue , Meropeném/urina , Pessoa de Meia-Idade , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/urinaRESUMO
Meropenem-vaborbactam is a fixed combination of the novel ß-lactamase inhibitor vaborbactam and the carbapenem antibiotic meropenem, developed for the treatment of serious infections caused by drug-resistant Gram-negative bacteria. The safety, tolerability, and pharmacokinetics (PK) of vaborbactam and meropenem following single and multiple ascending doses of each study drug administered alone or combined were evaluated in 76 healthy adult subjects in a randomized, placebo-controlled, double-blind study. Subjects were enrolled in 1 of 5 dose cohorts (receiving 250 to 2,000 mg vaborbactam and/or 1,000 to 2,000 mg meropenem) alone or in combination. No subjects discontinued the study due to adverse events (AEs), and no serious AEs were observed. The pharmacokinetics of meropenem and vaborbactam were similar when given alone or in combination; all evaluated plasma PK exposure measures (peak plasma concentration, area under the plasma concentration-time curve [AUC] from time zero to the last measurable concentration area under the plasma concentration-time curve, and AUC from time zero to infinity) were similar for the study drugs alone versus those in combination, indicating no pharmacokinetic interaction between meropenem and vaborbactam. Across all treatments, 47 to 64% of an administered meropenem dose and 75 to 95% of vaborbactam was excreted unchanged in the urine over 48 h postdose. Meropenem and vaborbactam, when given alone or in combination, have similar pharmacokinetic properties, with no plasma or urine PK drug-drug interactions, and are well tolerated. These findings supported further clinical investigation of the combination product. (This study is registered at ClinicalTrials.gov under registration no. NCT01897779.).
Assuntos
Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Meropeném/efeitos adversos , Meropeném/farmacocinética , Adolescente , Adulto , Método Duplo-Cego , Esquema de Medicação , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine pyelonephritis model. The data indicate that the combination of meropenem and vaborbactam significantly increased bacterial killing compared to that with the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.
Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/uso terapêutico , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Animais , Proteínas de Bactérias/metabolismo , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Klebsiella pneumoniae/isolamento & purificação , Klebsiella pneumoniae/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Pielonefrite/microbiologia , Infecções Urinárias/microbiologia , beta-Lactamases/metabolismoRESUMO
Vaborbactam (formerly RPX7009) is a new beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore. The spectrum of beta-lactamase inhibition by vaborbactam and the impact of bacterial efflux and permeability on its activity were determined using a panel of strains with beta-lactamases cloned from various classes and a panel of Klebsiella pneumoniae carbapenemase 3 (KPC-3)-producing isogenic strains with various combinations of efflux and porin mutations. Vaborbactam is a potent inhibitor of class A carbapenemases, such as KPC, as well as an inhibitor of other class A (CTX-M, SHV, TEM) and class C (P99, MIR, FOX) beta-lactamases. Vaborbactam does not inhibit class D or class B carbapenemases. When combined with meropenem, vaborbactam had the highest potency compared to the potencies of vaborbactam in combination with other antibiotics against strains producing the KPC beta-lactamase. Consistent with broad-spectrum beta-lactamase inhibition, vaborbactam reduced the meropenem MICs for engineered isogenic strains of K. pneumoniae with increased meropenem MICs due to a combination of extended-spectrum beta-lactamase production, class C beta-lactamase production, and reduced permeability due to porin mutations. Vaborbactam crosses the outer membrane of K. pneumoniae using both OmpK35 and OmpK36, but OmpK36 is the preferred porin. Efflux by the multidrug resistance efflux pump AcrAB-TolC had a minimal impact on vaborbactam activity. Investigation of the vaborbactam concentration necessary for restoration of meropenem potency showed that vaborbactam at 8 µg/ml results in meropenem MICs of ≤2 µg/ml in the most resistant engineered strains containing multiple mutations. Vaborbactam is a highly active beta-lactamase inhibitor that restores the activity of meropenem and other beta-lactam antibiotics in beta-lactamase-producing bacteria, particularly KPC-producing carbapenem-resistant Enterobacteriaceae.
Assuntos
Ácidos Borônicos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , Resistência beta-Lactâmica/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Carbapenêmicos/farmacologia , Conjugação Genética , Quimioterapia Combinada , Enterobacteriaceae/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Meropeném , Testes de Sensibilidade Microbiana , Mutação , Porinas/genética , Tienamicinas/farmacologia , beta-Lactamases/genética , beta-Lactamases/metabolismoRESUMO
With the increasing proportion of youth living with human immunodeficiency virus (YLHIV) and the aging of the perinatally infected population, there is a need for clinical services that are "youth friendly" to address the multiple challenges YLHIV face in terms of engagement in care and maintenance of combination antiretroviral therapy (cART). Little is known about how and where YLHIV receive their care. Further, the impact of the care structure on engagement and retention outcomes for YLHIV is ill defined. In order to better classify how YLHIV receive care in the United States, we performed a review of published literature characterizing the structure and outcomes of care for YLHIV. Several key concepts emerged: 1. The majority of YLHIV (13-24 years old) are cared for at adult sites, 2. Clinics providing care to YLHIV are varied in terms of the services offered and the types of services offered can impact outcomes, 3. YLHIV cared for in adult clinical sites have poor retention and antiretroviral treatment initiation, and 4. YLHIV cared for at adult sites had poorer retention and cART outcomes compared to YLHIV cared for at pediatric sites. There were no studies identified that specifically examined "youth friendly" care for YLHIV within the context of adult clinical sites. The results of this review highlight disparities for YLHIV and the need for interventions to improve outcomes for YLHIV in the context of adult care.
Assuntos
Continuidade da Assistência ao Paciente/organização & administração , Atenção à Saúde/organização & administração , Infecções por HIV/tratamento farmacológico , Adolescente , Feminino , Infecções por HIV/psicologia , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Transição para Assistência do Adulto , Estados Unidos , Adulto JovemRESUMO
Vaborbactam (formerly RPX7009) is a member of a new class of ß-lactamase inhibitor with pharmacokinetic properties similar to those of many ß-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmax and area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of â¼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0-∞) was 144.00 ± 13.90 mg · h/liter, and the Vss was 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistant Enterobacteriaceae (CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.).
Assuntos
Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/farmacocinética , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/farmacocinética , Administração Intravenosa , Adulto , Ácidos Borônicos/efeitos adversos , Feminino , Meia-Vida , Voluntários Saudáveis , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , MasculinoRESUMO
The steady-state concentrations of meropenem and the ß-lactamase inhibitor RPX7009 in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows: Cmax = 58.2 ± 10.8 and 59.0 ± 8.4 µg/ml, Vss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t1/2 = 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC0-8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 µg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.
Assuntos
Antibacterianos/farmacocinética , Ácidos Borônicos/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Pulmão/química , Macrófagos Alveolares/química , Mucosa Respiratória/química , Tienamicinas/farmacocinética , Adulto , Antibacterianos/sangue , Área Sob a Curva , Ácidos Borônicos/sangue , Líquido da Lavagem Broncoalveolar/química , Broncoscopia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Compostos Heterocíclicos com 1 Anel/sangue , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Meropeném , Pessoa de Meia-Idade , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Tienamicinas/sangueRESUMO
The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.