RESUMO
BACKGROUND: Carbapenemase-producing Enterobacterales represent a major therapeutic challenge. MBLs, requiring zinc at their catalytic site, could be inhibited by meso-dimercaptosuccinic acid (DMSA), a heavy metal chelator already widely used for treating lead intoxication. OBJECTIVES: To evaluate the activity of carbapenems alone or combined with DMSA against MBL-producing Escherichia coli in a severe murine peritonitis model. METHODS: Isogenic strains of wild-type E. coli CFT073 producing the MBLs NDM-1, VIM-2 and IMP-1, and the control serine carbapenemases OXA-48 and KPC-3 were constructed. MIC determinations and time-kill assays were performed for imipenem, meropenem and ertapenem alone or in combination with DMSA. Infected mice were treated intraperitoneally for 24 h with imipenem, DMSA or their combination. Bacterial counts in peritoneal fluid and spleen were assessed at 24 h. RESULTS: DMSA in combination with each carbapenem caused a significant decrease in the MICs for all MBL-producing strains, in a concentration-dependent manner, but did not provide benefit against non-MBL strains. In mice infected with the NDM-1-producing strain, the combination of imipenem and DMSA significantly reduced bacterial counts in peritoneal fluid (P = 0.0006) and spleen (P < 0.0001), as compared with imipenem alone, with no benefit against the KPC-3-producing and CFT073 strains. DMSA concentrations in plasma of mice were comparable to those obtained in humans with a standard oral dose. CONCLUSIONS: DMSA restores the activity of carbapenems against MBL-producing strains, and its combination with carbapenems appears to be a promising strategy for the treatment of NDM-producing E. coli infections.
Assuntos
Carbapenêmicos , Peritonite , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Escherichia coli/genética , Camundongos , Testes de Sensibilidade Microbiana , Peritonite/tratamento farmacológico , Succímero , beta-Lactamases/genéticaRESUMO
BACKGROUND: Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. MATERIALS AND METHODS: Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC-tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. RESULTS: Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT>MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). CONCLUSIONS: Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.
Assuntos
Combinação Amoxicilina e Clavulanato de Potássio , Amoxicilina , Adulto , Antibacterianos , Ácido Clavulânico , Humanos , Obesidade/complicações , Obesidade/tratamento farmacológico , Estudos ProspectivosRESUMO
Background: Alternative therapeutic regimens are urgently needed against carbapenemase-producing Enterobacteriaceae. Fosfomycin often remains active against KPC and OXA-48 producers, but emergence of resistance is a major limitation. Our aim was to determine whether the association of temocillin with fosfomycin might be useful to treat KPC- or OXA-48-producing Escherichia coli infections. Methods: Isogenic derivatives of E. coli CFT073 with blaKPC-3- or blaOXA-48-harbouring plasmids (named CFT073-KPC-3 and CFT073-OXA-48, respectively) were used. The addition of temocillin to fosfomycin was tested using the chequerboard method and time-kill curves as well as in a fatal peritonitis murine model. Mice were treated for 24 h with fosfomycin alone or in combination with temocillin. Bacterial loads, before and after treatment, were determined in the peritoneal fluid and fosfomycin-resistant mutants were detected. Results: Temocillin MICs were 8, 32 and 256 mg/L for CFT073 (WT), CFT073-KPC-3 and CFT073-OXA-48, respectively. Fosfomycin MIC was 0.5 mg/L for all strains. The chequerboard experiments demonstrated synergy for all three strains. In time-kill curves, combining temocillin with fosfomycin was synergistic, bactericidal and prevented emergence of resistance for CFT073-pTOPO and CFT073-KPC-3, but not CFT073-OXA-48. In vivo, for the three strains, bacterial counts were lower in peritoneal fluid with the combination compared with fosfomycin alone (P < 0.001) and inhibited growth of resistant mutants in all cases. Conclusions: The combination of fosfomycin and temocillin demonstrated a benefit in vitro and in vivo against E. coli strains producing KPC-3 or OXA-48-type carbapenemases. This combination prevented the emergence of fosfomycin resistance and proved to be more bactericidal than fosfomycin alone.
Assuntos
Antibacterianos/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Fosfomicina/farmacologia , Penicilinas/farmacologia , Peritonite/tratamento farmacológico , Animais , Carga Bacteriana/efeitos dos fármacos , Proteínas de Bactérias , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Escherichia coli/enzimologia , Proteínas de Escherichia coli , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Peritonite/microbiologia , beta-LactamasesRESUMO
Background: Only limited pharmacokinetic data are available for anidulafungin in ICU patients, especially in patients treated for severe intra-abdominal infection (IAI). Methods: This was a prospective multicentre observational study in ICU patients with suspected yeast IAI. All patients received an intravenous loading dose of 200 mg of anidulafungin, followed by 100 mg/day. Thirteen blood samples were drawn between day 1 and day 5 for pharmacokinetic analysis. Samples were analysed by an HPLC-tandem MS method. Demographics and SAPS2 and SOFA scores were recorded. Results: Fourteen patients with a median age (IQR) of 62 years (48-70) and with a mean BMI of 30.5 kg/m 2 were included from three centres; 57.1% were women. Their median (IQR) SAPS2 score was 54 (45-67) and their median (IQR) SOFA score was 8 (7-12). Six patients with community-acquired IAI and eight patients with nosocomial-acquired IAI were included. Twelve yeasts were isolated: six Candida albicans , two Candida glabrata , two Candida tropicalis , one Candida parapsilosis and one Candida krusei . Pharmacokinetic parameters were as follows [mean (% coefficient of variation)]: C max (mg/L) = 6.0 (29%); T max (h) = 1.6 (25.8%); C min (mg/L) = 3.2 (36.8%); AUC 0-24 (mg·h/L) = 88.9 (38.6%); t 1/2 (h) = 42.1 (68.2%); CL (L/h) = 1.2 (42.3%); and V (L) = 72.8 (87.8%). A two-compartment model best described the anidulafungin concentrations in the population pharmacokinetic study. Conclusions: The pharmacokinetic parameters of anidulafungin in critically ill ICU patients with complicated IAI are similar to those observed in the literature. However, an increased V and a longer t 1/2 were observed in this study. (EudraCT No. 2010-018695-25).
Assuntos
Antifúngicos/farmacocinética , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Equinocandinas/farmacocinética , Unidades de Terapia Intensiva , Infecções Intra-Abdominais/tratamento farmacológico , Administração Intravenosa , Idoso , Anidulafungina , Antifúngicos/administração & dosagem , Antifúngicos/sangue , Antifúngicos/uso terapêutico , Candida/isolamento & purificação , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Candida glabrata/efeitos dos fármacos , Candida glabrata/isolamento & purificação , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/isolamento & purificação , Candidíase/microbiologia , Cromatografia Líquida de Alta Pressão , Estado Terminal , Equinocandinas/administração & dosagem , Equinocandinas/sangue , Equinocandinas/uso terapêutico , Feminino , Humanos , Infecções Intra-Abdominais/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX)-clavulanate (CLA) (AMC) against extended-spectrum-ß-lactamase (ESBL)-producing Escherichia coli in vitro and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore the in vitro synergism between cefotaxime and amoxicillin-clavulanate against two isogenic E. coli strains-CFT073-RR and its transconjugant, CFT073-RR Tc bla(CTX-M-15)-harboring a bla(CTX-M-15) plasmid and a bla(OXA-1) plasmid. For in vivo experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (fT≥MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tc bla(CTX-M-15), respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tc bla(CTX-M-15) to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed an in vitro synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tc bla(CTX-M-15). In vivo, this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin-clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains.
Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/farmacologia , Antibacterianos/farmacologia , Cefotaxima/farmacologia , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Escherichia coli Uropatogênica/efeitos dos fármacos , beta-Lactamases/genética , Combinação Amoxicilina e Clavulanato de Potássio/sangue , Combinação Amoxicilina e Clavulanato de Potássio/farmacocinética , Animais , Antibacterianos/sangue , Antibacterianos/farmacocinética , Cefotaxima/sangue , Cefotaxima/farmacocinética , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Expressão Gênica , Humanos , Imipenem/farmacologia , Camundongos , Camundongos Endogâmicos CBA , Testes de Sensibilidade Microbiana , Plasmídeos/química , Plasmídeos/metabolismo , Pielonefrite/sangue , Pielonefrite/microbiologia , Pielonefrite/patologia , Infecções Urinárias/sangue , Infecções Urinárias/microbiologia , Infecções Urinárias/patologia , Escherichia coli Uropatogênica/enzimologia , Escherichia coli Uropatogênica/genética , Resistência beta-Lactâmica/genética , beta-Lactamases/metabolismoRESUMO
OBJECTIVES: Temocillin is a 6-α-methoxy derivative of ticarcillin that shows in vitro activity against Enterobacteriaceae producing Klebsiella pneumoniae carbapenemase (KPC). Our objective was to assess in vivo temocillin activity against KPC-producing Escherichia coli. METHODS: Isogenic derivatives of the WT E. coli CFT073 producing KPC-2, KPC-3 or OXA-48 were constructed. An experimental murine model of intra-abdominal infection with sepsis was used. Mice were treated subcutaneously with temocillin 200 mg/kg every 2 h for 24 h, reproducing the duration of time that the free serum concentration of temocillin exceeded the MIC in humans with a regimen of 2 g every 12 h or 2 g every 8 h. Blood, peritoneal fluid (PF) and spleen were collected; 24 h survival and sterility rates were assessed. RESULTS: Temocillin MICs were 8, 16, 32, and 256 mg/L for the susceptible strain and KPC-2-, KPC-3-, and OXA-48-producing strains, respectively. In mice treated with temocillin, significant bacterial reduction was obtained in PF, blood, and spleen for the susceptible strain and KPC-2- and KPC-3-producing strains (Pâ<â0.001) but not for the OXA-48-producing strain. Sterility rates in PF were 53%, 10%, 0% and 0% (Pâ<â0.001) and sterility rates in blood were 77%, 40%, 3% and 0% (Pâ<â0.001), while survival rates were 97%, 97%, 57%, 0% (Pâ<â0.001) for mice infected with the susceptible strain and KPC-2-, KPC-3- and OXA-48-producing strains, respectively. CONCLUSIONS: In a lethal-infection model with bacteraemia from intra-abdominal origin, temocillin retained significant activity in PF, blood and spleen and prevented death in mice by effectively working against KPC-producing E. coli with temocillin MICs ≤16 mg/L.
Assuntos
Antibacterianos/administração & dosagem , Bacteriemia/tratamento farmacológico , Proteínas de Bactérias/metabolismo , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/enzimologia , Infecções Intra-Abdominais/complicações , Penicilinas/administração & dosagem , beta-Lactamases/metabolismo , Animais , Antibacterianos/farmacocinética , Líquido Ascítico/química , Modelos Animais de Doenças , Escherichia coli/efeitos dos fármacos , Feminino , Injeções Subcutâneas , Infecções Intra-Abdominais/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Penicilinas/farmacocinética , Plasma/química , Baço/patologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: Temocillin is a 6α-methoxy derivative of ticarcillin that is resilient to ESBLs. Prospective data about its in vivo activity remain scarce. Our aims were: (i) to evaluate the activity of temocillin in a urinary tract infection (UTI) model due to ESBL-producing Escherichia coli and compare it with that of imipenem; and (ii) to define in vivo susceptibility breakpoints. METHODS: Mice were infected with a susceptible E. coli CFT073-RR or its transconjugant (CFT073-RR Tc) harbouring a blaCTX-M-15-carrying plasmid, using an ascending UTI model. Therapeutic regimens were chosen in order to reproduce percentage of time of free drug concentrations above MIC (fT>MIC) obtained in humans with standard regimens of temocillin (200 mg/kg every 2 h for 2 g every 12 h) or imipenem (100 mg/kg every 2 h for 1 g every 8 h). Additional regimens of temocillin (200 mg/kg every 4 and 6 h) with reduced fT>MIC were studied. RESULTS: MICs of temocillin and imipenem were 4/8 and 0.5/0.5 mg/L, for CFT073-RR and CFT073-RR Tc, respectively. In vivo, when given every 2 h (fT>MICâ=â82% and 70%), temocillin was bactericidal and as effective as imipenem in kidneys against both strains without selecting resistant mutants. Temocillin remained active even when given every 4 h, generating an fT>MIC of 41% and 35%, which corresponded to a breakpoint of 16 mg/L in humans with the standard regimen. CONCLUSIONS: Our observations support the consideration of a standard regimen of temocillin as an alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains with an MIC of 16 mg/L or less.
Assuntos
Antibacterianos/administração & dosagem , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/enzimologia , Penicilinas/administração & dosagem , Infecções Urinárias/tratamento farmacológico , beta-Lactamases/metabolismo , Animais , Modelos Animais de Doenças , Infecções por Escherichia coli/microbiologia , Feminino , Imipenem/administração & dosagem , Camundongos Endogâmicos CBA , Testes de Sensibilidade Microbiana , Resultado do TratamentoRESUMO
OBJECTIVES: Despite recent advances, antibiotic therapy of ventilator-associated pneumonia (VAP) in ICU patients is still challenging. We assessed the impact of imipenem and amikacin pharmacokinetic and pharmacodynamic parameters on microbiological outcome in these patients. PATIENTS AND METHODS: Patients with Gram-negative bacilli (GNB) VAP were prospectively included. Blood samples for pharmacokinetic analysis were collected after empirical administration of a combination of imipenem three times daily and one single dose of amikacin. MICs were estimated for each GNB obtained from respiratory samples. Microbiological success was defined as a ≥10(3) cfu/mL decrease in bacterial count in quantitative cultures between baseline and the third day of treatment. RESULTS: Thirty-nine patients [median (min-max) ageâ=â60 years (28-84) and median SAPS2 at inclusionâ=â40 (19-73)] were included. Median MICs of imipenem and amikacin were 0.25 mg/L (0.094-16) and 2 mg/L (1-32), respectively. Median times over MIC and over 5× MIC for imipenem were 100% (8-100) and 74% (3-100), respectively. The median C1/MIC ratio for amikacin was 23 (1-76); 34 patients (87%) achieved a C1/MIC ≥10. Microbiological success occurred in 29 patients (74%). No imipenem pharmacodynamic parameter was significantly associated with the microbiological success. For amikacin, C1/MIC was significantly higher in the microbiological success group: 26 (1-76) versus 11 (3-26) (Pâ=â0.004). CONCLUSIONS: In ICU patients with VAP, classic imipenem pharmacodynamic targets are easily reached with usual dosing regimens. In this context, for amikacin, a higher C1/MIC ratio than previously described might be necessary.
Assuntos
Amicacina/uso terapêutico , Antibacterianos/uso terapêutico , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Imipenem/uso terapêutico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Amicacina/farmacocinética , Amicacina/farmacologia , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Carga Bacteriana , Quimioterapia Combinada/métodos , Feminino , Humanos , Imipenem/farmacocinética , Imipenem/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
Venovenous extracorporeal membrane oxygenation (ECMO) is increasingly used in patients with respiratory failure who fail conventional treatment. Postoperative pneumonia is the most common infection after lung transplantation (40%). Imipenem is frequently used for empirical treatment of nosocomial pneumonia in the intensive care unit. Nevertheless, few data are available on the impact of ECMO on pharmacokinetics, and no data on imipenem dosing during ECMO. Currently, no guidelines exist for antibiotic dosing during ECMO support. We report the cases of 2 patients supported with venovenous ECMO for refractory acute respiratory distress syndrome following single lung transplantation for pulmonary fibrosis, treated empirically with 1 g of imipenem intravenously every 6 h. Enterobacter cloacae was isolated from the respiratory sample of Patient 1 and Klebsiella pneumoniae was isolated from the respiratory sample of Patient 2. Minimum inhibitory concentrations of the 2 isolated strains were 0.125 and 0.25 mg/L, respectively. Both patients were still alive on day 28. This is the first report, to our knowledge, of imipenem concentrations in lung transplantation patients supported with ECMO. This study confirms high variability in imipenem trough concentrations in patients on ECMO and with preserved renal function. An elevated dosing regimen (4 g/24 h) is more likely to optimize drug exposure, and therapeutic drug monitoring is recommended, where available. Population pharmacokinetic studies are indicated to develop evidence-based dosing guidelines for ECMO patients.
Assuntos
Antibacterianos/farmacocinética , Imipenem/farmacocinética , Transplante de Pulmão/efeitos adversos , Síndrome do Desconforto Respiratório/terapia , Insuficiência Respiratória/terapia , Antibacterianos/administração & dosagem , Creatinina/sangue , Infecção Hospitalar , Oxigenação por Membrana Extracorpórea , Humanos , Imipenem/administração & dosagem , Masculino , Pessoa de Meia-Idade , TransplantadosRESUMO
AIMS: Modifications of antimicrobials' pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We characterized amikacin pharmacokinetic variability in critically ill patients with ventilator-associated pneumonia (VAP) and evaluated several dosing regimens. METHODS: We conducted a prospective multicenter study in critically ill patients with presumptive diagnosis of Gram-negative bacilli (GNB) VAP. Patients empirically received imipenem and a single-dose of amikacin, which was administered as a 30-min infusion (20 mg/kg). Concentrations were measured 0.5, 1, 8, 16, and 24 h after beginning of infusion. Pharmacokinetic parameters were estimated using a population approach. Main pharmacodynamic target was a ratio ≥ 10 between the concentration achieved 1 h after beginning of infusion (C 1h) and the minimal inhibitory concentration of the liable bacteria (MIC). We simulated individual C 1h for several dosing regimens by Monte Carlo method and computed C 1h/MIC ratios for MICs from 0.5 to 64 mg/L. RESULTS: Sixty patients (47 males), median (range) age, and body weight, 61.5 years (28-84) and 78 kg (45-126), respectively, were included. Amikacin median C 1h was 45 mg/L (22-87). Mean value (between-patients variability) for CL, V1, Q, and V2 were 4.3 L/h (31 %), 15.9 L (22 %), 12.1 L/h (27 %), and 21.4 L (47 %), respectively. CL increased with CrCL (p<0.001) and V1 with body weight (p<0.001) and PaO2/FIO2 ratio (p<0.001). With a 25 mg/kg regimen, the pharmacodynamic target was achieved in 20 and 96 % for a MICs of 8 and 4 mg/L, respectively. CONCLUSION: Amikacin clearance was decreased and its volume of distribution was increased as previously reported. A ≥ 25 mg/kg single-dose is needed for empirical treatment of GNB-VAP.
Assuntos
Amicacina/farmacocinética , Antibacterianos/farmacocinética , Modelos Biológicos , Pneumonia Associada à Ventilação Mecânica/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Amicacina/farmacologia , Amicacina/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Estado Terminal , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologiaRESUMO
WHAT IS KNOWN AND OBJECTIVE: Azole antifungals, prescribed prophylactically to avoid severe infections in immunosuppressed organ transplant recipients, can interact with drug substrates of CYP3A4. We report serious adverse effects due to interaction between orally administered voriconazole and everolimus in a renal transplant recipient. CASE DESCRIPTION: Despite reduction of the dose of everolimus by a third, the blood trough concentration of everolimus increased considerably in a kidney transplant recipient upon oral administration of voriconazole. Everolimus was then discontinued. Pneumonia secondary to pulmonary aspergillosis worsened, possibly due to the excessive immunosuppression. WHAT IS NEW AND CONCLUSION: Orally administered voriconazole inhibits intestinal and hepatic cytochrome P450-3A4 activity and thereby reduces everolimus metabolism. An 80% decrease in dose or discontinuation of everolimus is required when concomitant voriconazole is introduced. Daily blood monitoring of everolimus is warranted until a steady state of concentrations is reached.
Assuntos
Antifúngicos/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Micoses/prevenção & controle , Pneumonia/induzido quimicamente , Sirolimo/análogos & derivados , Voriconazol/efeitos adversos , Administração Oral , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Interações Medicamentosas , Everolimo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Masculino , Micoses/imunologia , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Voriconazol/administração & dosagem , Voriconazol/farmacocinéticaRESUMO
Linezolid is an antimicrobial agent for the treatment of multiresistant Gram-positive infections. We assessed the impact of linezolid on the microbiota and the emergence of resistance and investigated its relationship with plasma pharmacokinetics of the antibiotic. Twenty-eight patients were treated for the first time with linezolid administered orally (n = 17) or parenterally (n = 11) at 600 mg twice a day. Linezolid plasma pharmacokinetic analysis was performed on day 7. Colonization by fecal enterococci, pharyngeal streptococci, and nasal staphylococci were assessed using selective media with or without supplemental linezolid. The resistance to linezolid was characterized. The treatment led to a decrease of enterococci, staphylococci, and streptococci in the fecal (P = 0.03), nasal, and pharyngeal (P < 0.01) microbiotas. The appearance of resistant strains was observed only in enterococci from the fecal microbiota between the 7th and 21st days of treatment in four patients (14.3%). The resistance was mainly due for the first time to the mutation G2447T in the 23S rRNA gene. No pharmacokinetic parameters were significantly different between the patients, regardless of the appearance of resistance. The emergence of linezolid resistance during treatment was observed only in the intestinal microbiota and unrelated to pharmacokinetic parameters. However, colonization by Gram-positive bacteria was reduced as a result of treatment in all microbiotas.
Assuntos
Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Enterococcus/patogenicidade , Intestinos/microbiologia , Oxazolidinonas/farmacocinética , Oxazolidinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Farmacorresistência Bacteriana , Feminino , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Linezolida , Masculino , Pessoa de Meia-Idade , Staphylococcus/efeitos dos fármacos , Staphylococcus/patogenicidade , Streptococcus/efeitos dos fármacos , Streptococcus/patogenicidadeRESUMO
AAC(6')-Ib-cr is a plasmid-mediated quinolone resistance mechanism described worldwide for Escherichia coli. Since it confers in vitro only a low level of resistance to ciprofloxacin, we evaluated its impact on the in vivo activity of ciprofloxacin. Isogenic strains were obtained by transferring plasmid p449, harboring aac(6')-Ib-cr, into the quinolone-susceptible strain E. coli CFT073-RR and its D87G gyrA mutant. MICs were 0.015, 0.06, 0.25, and 0.5 µg/ml against E. coli strains CFT073-RR, CFT073-RR/p449, CFT073-RR GyrA(r), and CFT073-RR GyrA(r)/p449, respectively. Bactericidal activity was reduced at 1× the MIC for the three resistant derivatives, while at a fixed concentration of 0.5 µg/ml, 99.9% killing was observed for all strains except E. coli CFT073-RR GyrA(r)/p449. In the murine model of pyelonephritis, an optimal regimen of ciprofloxacin (10 mg/kg of body weight twice a day [b.i.d.]) significantly decreased the bacterial count in the kidneys of mice infected with E. coli CFT073 (1.6 versus 4.3 log10 CFU/g of kidney compared to untreated controls; P = 0.0001), while no significant decrease was observed for E. coli CFT073-RR/p449 (2.7 versus 3.1 log10 CFU/g; P = 0.84), E. coli CFT073-RR GyrA(r) (4.2 versus 4.1 log10 CFU/g; P = 0.35), or E. coli CFT073-RR GyrA(r)/p449 (2.9 versus 3.6 log10 CFU/g; P = 0.47). While pharmacokinetic and pharmacodynamic (PK/PD) parameters accounted for ciprofloxacin failure against gyrA-containing mutants, this was not the case for the aac(6')-Ib-cr-containing strains, suggesting an in situ hydrolysis of ciprofloxacin in the latter case.
Assuntos
Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/genética , Plasmídeos , Pielonefrite/tratamento farmacológico , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Ciprofloxacina/metabolismo , Ciprofloxacina/farmacocinética , DNA Girase/genética , Modelos Animais de Doenças , Esquema de Medicação , Farmacorresistência Bacteriana/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Feminino , Hidrólise , Camundongos , Camundongos Endogâmicos CBA , Testes de Sensibilidade Microbiana , Mutação , Pielonefrite/microbiologia , Transformação Bacteriana , Falha de TratamentoRESUMO
Concerns have recently emerged about the potency and the quality of generic vancomycin (VAN) products approved for use in humans, based on experiments in a neutropenic mouse thigh infection model. However, other animal models may be more appropriate to decipher the bactericidal activities of VAN generics in vivo and to predict their efficacy in humans. We aimed to compare the bactericidal activities of six generic VAN products currently used in France (Mylan and Sandoz), Spain (Hospira), Switzerland (Teva), and the United States (Akorn-Strides and American Pharmaceutical Products [APP]) in a rabbit model of aortic valve endocarditis induced by 8 × 10(7) CFU of methicillin-resistant Staphylococcus aureus (MRSA) strain COL (VAN MIC, 1.5 µg/ml). In vitro, there were no significant differences in the time-kill curve studies performed with the six generic VAN products. Ten rabbits in each group were treated with intravenous (i.v.) VAN, 60 mg/kg of body weight twice a day (b.i.d.) for 4 days. Mean peak serum VAN levels, measured 45 min after the last injection, ranged from 35.5 (APP) to 45.9 µg/ml (Teva). Mean trough serum VAN levels, measured 12 h after the last injection, ranged from 2.3 (Hospira) to 9.2 (APP) µg/ml. All generic VAN products were superior to controls (no treatment) in terms of residual organisms in vegetations (P < 0.02 for each comparison) and in the spleen (P < 0.005 for each comparison). Pairwise comparisons of generic VAN products found no significant differences. In conclusion, a stringent MRSA endocarditis model found no significant differences in the bactericidal activities of six generic VAN products currently used in Europe and America.
Assuntos
Antibacterianos/farmacocinética , Medicamentos Genéricos/farmacocinética , Endocardite Bacteriana/tratamento farmacológico , Cardiopatias Congênitas/tratamento farmacológico , Doenças das Valvas Cardíacas/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/farmacocinética , Animais , Valva Aórtica/microbiologia , Doença da Válvula Aórtica Bicúspide , Endocardite Bacteriana/microbiologia , Cardiopatias Congênitas/microbiologia , Doenças das Valvas Cardíacas/microbiologia , Humanos , Injeções Intravenosas , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Coelhos , Infecções Estafilocócicas/microbiologia , Equivalência TerapêuticaRESUMO
The purpose of this study was to investigate Poloxamer 407 25% (w/w) formulations aimed at prolonging the residence time of vancomycin, a time-dependent antibiotic, in a body site with a high infectious risk. Reversible thermal gelation of the formulations permitted their local injection in liquid form and in situ gelation as they warmed to body temperature. Neither the rheological properties of the Poloxamer matrices nor the antibacterial activity of vancomycin was altered by their combination. In vitro, the dispersed form exhibited prolonged release, with a lower diffusion coefficient of vancomycin compared to the solubilized form (4.7x10(-8) vs 2. 1x10(-7) cm(2) s(-1)131 mg l(-1) for the solubilized form), followed by lower but effective antibacterial levels for at least 8 days. Controlled-release profiles, good preservation of vancomycin activity, good tolerability in rats, and ease of administration suggest that Poloxamer 407 may be useful as a vancomycin delivery vehicle for local prophylaxis of infections, especially in prosthetic surgery.
Assuntos
Antibacterianos/farmacocinética , Géis/química , Géis/síntese química , Poloxâmero/química , Vancomicina/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada , Difusão , Estabilidade de Medicamentos , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Reologia , Temperatura , Fatores de Tempo , Vancomicina/efeitos adversos , Vancomicina/análise , Vancomicina/farmacologiaAssuntos
Antibacterianos/administração & dosagem , Daptomicina/administração & dosagem , Endocardite/tratamento farmacológico , Infecção dos Ferimentos/tratamento farmacológico , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Endocardite/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Infecção dos Ferimentos/microbiologiaRESUMO
Chronic cavitary pulmonary aspergillosis requires a first-line prolonged treatment with itraconazole or voriconazole. We report a 71-year-old immunocompetent man with polyarteritis and history of multiple lung surgery procedures, who developed a peripheral axonal neuropathy 1 month after voriconazole therapy was started for a chronic cavitary pulmonary aspergillosis. After discontinuation of the treatment and a switch to posaconazole, the neuropathy partly improved. Three other cases of peripheral neuropathy with voriconazole have been already published, all reversible after voriconazole discontinuation.
Assuntos
Antifúngicos/efeitos adversos , Aspergilose Broncopulmonar Alérgica/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Pirimidinas/efeitos adversos , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Idoso , Antifúngicos/uso terapêutico , Doença Crônica , Humanos , Masculino , Dor/induzido quimicamente , Dor/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Pirimidinas/uso terapêutico , Resultado do Tratamento , VoriconazolRESUMO
OBJECTIVE: The anhepatic phase of orthotopic liver transplantation (OLT) is associated with significant changes in pharmacokinetics. The aim of this study was to compare the influence of this phase on propofol target concentrations during BIS guided target controlled infusion (TCI). STUDY DESIGN: Prospective study. PATIENTS AND METHODS: Eight patients aged 25 to 65 years, Child-Pugh status A-B scheduled for OLT were prospectively included. Anesthesia was performed using TCI of propofol (Diprifusor, Marsh pharmacokinetic model), sufentanil and cisatracurium. Propofol target concentration was adjusted to maintain BIS values between 40 and 50. RESULTS: To maintain stable BIS values, propofol target concentrations should be decreased during the anhepatic phase versus the dissection one (2.0 microg/ml+/-0.8 versus 3.0 microg/ml+/-0.9, p<0.0001). CONCLUSION: BIS could be useful to titrate propofol infusion during the anhepatic phase of OLT.
Assuntos
Anestésicos Intravenosos/administração & dosagem , Eletroencefalografia , Transplante de Fígado , Monitorização Intraoperatória/métodos , Propofol/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Infusões Intravenosas/métodos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Formation of free radicals and lipoperoxidation occur at the onset of cellular damage. These effects are produced during normal metabolism and in pathological states. The peroxidation of polyunsaturated fatty acids, i.e. linoleic acid and linolenic acid, which are both cellular membrane compounds, induces ethane and pentane formation in pulmonary air exhalation. These two volatile hydrocarbons can be considered as potential lipoperoxidation markers. Methodological difficulties limit the use of these gases for assessment of free oxygen radical activity but we have developed and validated a non-invasive technique. A study was performed with ten healthy volunteers.
Assuntos
Etano/análise , Peroxidação de Lipídeos/fisiologia , Pentanos/análise , Biomarcadores , Testes Respiratórios , Cromatografia Gasosa , Feminino , Humanos , MasculinoRESUMO
Two nonfatal models of peritonitis differing by the duration and the severity of the disease were studied in rats by implantation of Escherichia coli and Bacteroides fragilis with or without increasing concentrations of Enterococcus faecalis. Results were evaluated at 3 or 6 days after inoculation. The highest enterococcal concentrations (10(9) cfu/mL) enhanced the severity of the infection, evident by increased emaciation, increased peritoneal counts of E. coli and B. fragilis, and increased frequency of E. coli and B. fragilis bacteremia compared with enterococcus-free animals. Six therapeutic regimens (low-dose amoxicillin + low-dose gentamicin, high-dose amoxicillin + high-dose gentamicin, pefloxacin, ornidazole, pefloxacin + ornidazole, imipenem + gentamicin) were tested. All treatments failed to eradicate E. faecalis except the combination pefloxacin + ornidazole, which achieved a significant reduction of local bacterial counts and suppressed bacteremia. Enterococcus played an important role in the mechanisms of bacterial synergy in experimental peritonitis. However, eradication of enterococcus did not seem possible by conventional antienterococcal therapy.