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1.
Crit Care ; 24(1): 55, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066497

RESUMO

BACKGROUND: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia. METHODS: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. RESULTS: The median (IQR) of meropenem AUC0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L. CONCLUSIONS: An increase in the dose of meropenem administered by CI achieved a higher exposure in the plasma and ELF. The use of the highest licensed dose of 6 g/day may be necessary to achieve an optimal coverage in ELF for all susceptible isolates (MIC ≤ 2 mg/L) in patients with conserved renal function. An alternative therapy should be considered when the presence of microorganisms with a MIC greater than 2 mg/L is suspected. TRIAL REGISTRATION: The trial was registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT-no. 2016-002796-10). Registered on 27 December 2016.


Assuntos
Antibacterianos , Infecção Hospitalar , Pneumonia Associada a Assistência à Saúde , Meropeném , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Infecção Hospitalar/tratamento farmacológico , Feminino , Pneumonia Associada a Assistência à Saúde/tratamento farmacológico , Humanos , Infusões Intravenosas , Masculino , Meropeném/administração & dosagem , Meropeném/farmacocinética , Pessoa de Meia-Idade , Estudos Prospectivos
2.
Yakugaku Zasshi ; 139(12): 1609-1614, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31787651

RESUMO

It has been reported that the risk of acute kidney injury (AKI) is higher during treatment with vancomycin and piperacillin/tazobactam compared to use of vancomycin and cefepim or meropenem. We investigated the risk of AKI in patients receiving vancomycin and piperacillin/tazobactam versus those receiving vancomycin and meropenem or doripenem. The subjects were patients over 18 years old who received either vancomycin and piperacillin/tazobactam (V+P/T therapy) or vancomycin and carbapenems (meropenem or doripenem) (V+C therapy) for at least 48 h between 1 May 2013 and 28 February 2019. The primary endpoint was the incidence of AKI in patients receiving V+P/T or V+C therapy, while the secondary outcome was the timing of AKI in each group. The incidence of AKI was 33.3% (9/27) in patients receiving V+P/T therapy versus 9.1% (5/55) in those receiving V+C therapy, and its incidence was significantly higher with the former regimen (χ2=5.90, p=0.015). Multiple logistic regression analysis confirmed that V+P/T therapy was associated with an increased risk of AKI compared to V+C therapy (adjusted odds ratio: 5.05, 95% confidence interval: 1.46-17.5, p=0.01). The time to onset of AKI after initiation of treatment was not significantly different between patients receiving V+T/P or V+C therapy [median (interquartile range): 4 d (2-6 d) versus 7 d (3-10 d); p=0.282]. V+P/T therapy was associated with a significantly higher incidence of AKI than alternative regimens, suggesting that it should be avoided. When broad spectrum antibacterial therapy is required, V+C therapy should be considered instead.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Doripenem/efeitos adversos , Meropeném/efeitos adversos , Combinação Piperacilina e Tazobactam/efeitos adversos , Vancomicina/efeitos adversos , Lesão Renal Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Estudos de Coortes , Doripenem/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Meropeném/administração & dosagem , Pessoa de Meia-Idade , Combinação Piperacilina e Tazobactam/administração & dosagem , Estudos Retrospectivos , Risco , Vancomicina/administração & dosagem
3.
Rinsho Shinkeigaku ; 59(10): 666-668, 2019 Oct 26.
Artigo em Japonês | MEDLINE | ID: mdl-31564706

RESUMO

A 17-year-old woman was admitted to our hospital because of a high fever, consciousness disturbance, and delirious behavior. Methicillin susceptible Staphylococcus aureus (MSSA) infection was confirmed by blood culture. Transthoracic echocardiogram showed no abnormality at first. Diffusion-weighted brain MRI showed a high intensity lesion in the middle portion of the splenium, which was shown as low intensity on apparent diffusion coefficient map. Then, antibiotics therapy was started against suspected bacterial meningitis, while the lumbar puncture was not performed because of the decreased number of platelets. Since the systolic murmur appeared at the apex on day 12, the diagnosis with infectious endocarditis was made by transthoracic echocardiogram. The MRI abnormalities disappeared on day 16 and we diagnosed her with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with infectious endocarditis. This case suggests that MERS can occur associated with infectious endocarditis caused by Staphylococcus aureus.


Assuntos
Endocardite Bacteriana/microbiologia , Endocardite Bacteriana/terapia , Encefalite Infecciosa/microbiologia , Infecções Estafilocócicas , Staphylococcus aureus , Adolescente , Antibacterianos/administração & dosagem , Corpo Caloso/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Quimioterapia Combinada , Ecocardiografia , Endocardite Bacteriana/complicações , Endocardite Bacteriana/diagnóstico por imagem , Feminino , Humanos , Encefalite Infecciosa/diagnóstico por imagem , Encefalite Infecciosa/tratamento farmacológico , Encefalite Infecciosa/etiologia , Meropeném/administração & dosagem , Anuloplastia da Valva Mitral , Índice de Gravidade de Doença , Resultado do Tratamento , Vancomicina/administração & dosagem
4.
J Med Microbiol ; 68(12): 1699-1706, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31647407

RESUMO

Background. This study was conducted to understand the effect of fosfomycin in combination with amikacin, ciprofloxacin or meropenem on biofilm formation by multidrug-resistant urinary isolates of Escherichia coli.Methods. Fifty urinary tract multidrug-resistant E. coli isolates that were known biofilm producers were studied. The MIC was determined using the agar dilution method for amikacin, ciprofloxacin, meropenem and fosfomycin. The fractional inhibitory concentration was determined for the combination of antibiotics followed by a time-kill assay. A tissue culture plate method was used to study the effect of the combination of antibiotics on biofilm formation.Results. The MICs of the isolates tested ranged from 0.25 to 32 µg ml-1 for fosfomycin, 1 to 1024 µg ml-1 for ciprofloxacin, 4 to 1024 µg ml-1 for amikacin, and 0.25 to 512 µg ml-1 for meropenem. The combination of fosfomycin with meropenem showed 68 % synergy, fosfomycin with amikacin 58 % synergy and fosfomycin with ciprofloxacin 6 % synergy. The combination also reduced the MIC of each antibiotic and none showed an antagonistic effect. Biofilm inhibition was best observed with the combination of fosfomycin with meropenem.Conclusion. The combination of fosfomycin with amikacin and fosfomycin with meropenem yielded a high percentage of synergy alongside an increased capacity to reduce biofilm formation when compared to combination with ciprofloxacin against multidrug-resistant E. coli. Fosfomycin in combination with other classes of antimicrobial agents has potential beneficial effects.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Escherichia coli/fisiologia , Infecções Urinárias/microbiologia , Amicacina/administração & dosagem , Amicacina/farmacologia , Ciprofloxacino/administração & dosagem , Ciprofloxacino/farmacologia , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Fosfomicina/administração & dosagem , Fosfomicina/farmacologia , Humanos , Meropeném/administração & dosagem , Meropeném/farmacologia , Testes de Sensibilidade Microbiana
6.
Am J Health Syst Pharm ; 76(18): 1383-1394, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31505562

RESUMO

PURPOSE: To summarize the current literature on the use and clinical efficacy of extended-infusion (EI) beta-lactam antibiotics, including piperacillin-tazobactam, meropenem, and cefepime. SUMMARY: Gram-negative infections are a serious concern among hospitalized patients and require innovative pharmacokinetic dosing strategies to achieve clinical success, especially as the emergence of resistant gram-negative pathogens has outpaced the development of new antibiotics. Beta-lactam antibiotics exhibit time-dependent activity, which means that optimal efficacy is achieved when free drug concentrations stay above the minimum inhibitory concentration for an extended duration of the recommended dosage interval. EI piperacillin-tazobactam therapy has demonstrated improved clinical outcomes and decrease mortality in critically ill patients with gram-negative infections, particularly Pseudomonas aeruginosa infections. EI meropenem has shown higher therapeutic success rates for patients with febrile neutropenia and shorter intensive care unit (ICU) length of stay (LOS) with a reduction in ventilator days in patients with multidrug-resistant ventilator-associated pneumonia. However, a larger study showed no difference in clinical outcomes between standard-infusion and EI meropenem. EI cefepime has been associated with decreased mortality and shorter ICU LOS in patients with Pseudomonas aeruginosa infections. Common challenges associated with EI beta-lactam antibiotics include Y-site incompatibilities, lack of intravenous access, and tubing residuals. It is important to note that factors such as diverse patient populations and study methodology, along with various antibiotic dose regimens, may have contributed to conflicting data on EI beta-lactam therapy. CONCLUSION: Based on most published literature, there appears to be a favorable trend toward use of EI beta-lactam therapy in clinical practice, particularly in critically ill patients with gram-negative infections.


Assuntos
Antibacterianos/administração & dosagem , Infusões Intravenosas/métodos , Infecções por Pseudomonas/tratamento farmacológico , Cefepima/administração & dosagem , Estado Terminal/mortalidade , Estado Terminal/terapia , Relação Dose-Resposta a Droga , Esquema de Medicação , Farmacorresistência Bacteriana Múltipla , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Meropeném/administração & dosagem , Testes de Sensibilidade Microbiana , Combinação Piperacilina e Tazobactam/administração & dosagem , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/mortalidade , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Fatores de Tempo , Resultado do Tratamento
8.
Farm Hosp ; 43(5): 151-157, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469627

RESUMO

OBJECTIVE: To determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous  infusion who achieved the target pharmacokinetic/pharmacodynamic  (PK/PD) index, which was defined as free concentrations four times  more than the minimum inhibitory concentration (CMI) for 100% of the  dosing interval (100% fT≥ 4 x MIC). METHOD: Preliminary data from a larger prospective clinical study  analysing the PK/PD behaviour of ß-lactams antibiotics continuous  infusion (CI) in critical patients. The study was conducted in the  intensive care units of a tertiary university hospital for adults (June  2015-May 2017). Inclusion criteria: normal renal function (glomerular  renal function (GFR) CKD-EPI formula ≥ 60 mL/min/1.73 m2) and  treatment with standard dose ß-lactams CI. Concentrations at steady  state (Css) conditions were determined using UHPLC-MS/MS. We  selected the highest susceptible MIC for all likely organisms according to  European Commitee on Antimicrobial Susceptibility Testing's (i.e.  piperacillin/tazobactam: 8 mg/L for enterobacteriaceae and 16 mg/L for  Pseudomonas aeruginosa; meropenem: 2 mg/L for any  microorganism). In addition, a subanalysis of patients was conducted using actual MIC values. RESULTS: 61 patients were enrolled (25 to meropenem and 36 to  piperacillin/tazobactam). Average age was 59 (15) years and median  GFR rate was 95 mL/min/1.73 m2 (83-115). Median meropenem and  piperacillin free concentrations were 16 mg/L (11-29) and 40 mg/L (21- 51), respectively. 88% of patients treated with meropenem reached the  PK/PD target, without differences between both microorganisms. For  piperacillin/tazobactam, 61% and 11% of patients reached the target,  with enterobacteriaceae and Pseudomonas as suspected  microorganisms, respectively. The pathogen was isolated in 35 (57%)  patients: 94% reached the target PK/PD, without differences between  both antibiotic therapies. CONCLUSIONS: Standard doses of meropenem CI are sufficient to  achieve a PK/PD target of 100% fT≥ 4 x MIC in suspected infections  with high MICs (Pseudomonas aeruginosa or enterobacteriaceae).  However, higher doses of piperacillin/tazobactam could be considered to  achieve this goal. In patients with isolated microorganisms, a  standard dose of both antibiotic therapies would be sufficient to achieve  the target. Therapeutic drug monitoring is highly recommended for  therapeutic optimization.


Assuntos
Antibacterianos/administração & dosagem , Estado Terminal/terapia , Meropeném/administração & dosagem , Combinação Piperacilina e Tazobactam/administração & dosagem , Adulto , Idoso , Antibacterianos/sangue , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Estudos Clínicos como Assunto/estatística & dados numéricos , Infecção Hospitalar/tratamento farmacológico , Infecções por Enterobacteriaceae/tratamento farmacológico , Feminino , Hospitais Universitários , Humanos , Infusões Intravenosas , Unidades de Terapia Intensiva , Masculino , Meropeném/sangue , Meropeném/farmacocinética , Meropeném/uso terapêutico , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Combinação Piperacilina e Tazobactam/sangue , Combinação Piperacilina e Tazobactam/farmacocinética , Combinação Piperacilina e Tazobactam/uso terapêutico , Estudos Prospectivos , Infecções por Pseudomonas/tratamento farmacológico , Centros de Atenção Terciária
9.
BMJ Case Rep ; 12(8)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31377717

RESUMO

We present a case of a 55-year-old Filipino man who was transferred from another institution where he was recently diagnosed with Crohn's disease but not started on any immunosuppressants. He underwent laparoscopic cholecystectomy with T-tube placement a few weeks prior to admission. On workup, abdominal CT scan was unremarkable, but blood cultures on the third hospital day grew Burkholderia cepacia Antibiotic regimen was shifted to ceftazidime and levofloxacin. The bacteraemia and febrile episodes persisted despite removal of the central line and T tube. White blood cell scan and chest CT scan showed left-sided consolidation pneumonia. Blood cultures continued to grow B. cepacia despite shifting to meropenem and trimethoprim-sulfamethoxazole. Meropenem nebulisation at 250 mg every 12 hours was added to the regimen on the third week then oral minocycline was added on the fourth week due to persistence of bacteraemia. He subsequently developed a small vegetation on the aortic valve, so amikacin was added. Fever lysed on the sixth week, but the B. cepacia bacteraemia persisted, clearing only on the 51st hospital day. The patient was discharged with a plan to continue antibiotics, including meropenem nebulisation, for 6 more weeks. On follow-up, the patient had no recurrence of fever. There was also resolution of consolidation on chest CT scan and disappearance of vegetation on echocardiography.


Assuntos
Antibacterianos/administração & dosagem , Bacteriemia/tratamento farmacológico , Infecções por Burkholderia/tratamento farmacológico , Meropeném/administração & dosagem , Pneumonia/tratamento farmacológico , Antibacterianos/uso terapêutico , Burkholderia cepacia/isolamento & purificação , Quimioterapia Combinada/métodos , Humanos , Masculino , Meropeném/uso terapêutico , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Pneumonia/microbiologia , Resultado do Tratamento
10.
Eur J Clin Microbiol Infect Dis ; 38(10): 1925-1931, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31278562

RESUMO

Combination therapies are frequently used in the treatment of multidrug-resistant Klebsiella pneumoniae infection without consensus regarding which combination is the most effective. We compared bactericidal titres from sera collected from critically ill patients receiving meropenem plus tigecycline (n = 5), meropenem plus colistin (n = 5), or meropenem, colistin and tigecycline (n = 5) against K. pneumoniae isolates that included ESBL-producing (n = 7) and KPC-producing strains (n = 14) with varying sensitivity patterns to colistin and tigecycline. Meropenem concentrations (Cmin) were measured in all samples by LC-MS/MS, and indexed to respective pathogen MICs to explore differences in patterns of bactericidal activity for two versus three drug combination regimens. All combination regimens achieved higher SBTs against ESBL (median reciprocal titre 128, IQR 32-256) versus KPC (4, IQR 2-32) strains. Sera from patients treated with meropenem-colistin yielded higher median SBTs (256, IQR 64-512) than either meropenem-tigecycline (32, IQR 8-256; P < 0.001). The addition of tigecycline was associated with a lower probability of achieving a reciprocal SBT above 8 when meropenem concentrations were below the MIC (P = 0.04). Although the clinical significance is unknown, sera from patients receiving tigecycline-based combination regimens produce lower serum bactericidal titres against ESBL or KPC-producing K. pneumoniae. SBTs may represent a useful complimentary endpoint for comparing pharmacodynamics of combinations regimens for MDR Enterobacteriaceae.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/administração & dosagem , Meropeném/farmacocinética , beta-Lactamases/metabolismo , Idoso , Cromatografia Líquida , Colistina/administração & dosagem , Estado Terminal , Quimioterapia Combinada/métodos , Feminino , Humanos , Klebsiella pneumoniae/enzimologia , Masculino , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Pessoa de Meia-Idade , Soro/química , Espectrometria de Massas em Tandem , Tigeciclina/administração & dosagem
11.
Int J Antimicrob Agents ; 54(3): 292-300, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279154

RESUMO

BACKGROUND: Meropenem is widely used for the treatment of paediatric patients with bacterial meningitis, but the pharmacodynamic (PD) basis for this has not been fully elucidated. OBJECTIVES: A cerebrospinal pharmacokinetic (PK) and PD analysis was performed to identify the optimal dosage regimen for paediatric patients with inflamed central nervous system disease (bacterial men-ingitis). PATIENTS AND METHODS: Paediatric data from three clinical studies were used to build a novel population PK model with a cerebrospinal fluid (CSF) compartment, assuming CSF clearance of 0.021 L/h from a physical-anatomical perspective. The bactericidal target attainment rates in CSF [50%T>MIC(CSF)], after various dosage regimens, were simulated on the basis of reported or observed minimum inhibitory concentration (MIC) distributions and a newly developed population PK model including CSF concentrations. The effects of increased dose and/or prolonged infusion on target attainment were investigated. RESULTS: Clinical data from 154 patients {mean age 30.6 [standard deviation (SD) 34.4] months, mean body weight 12.4 (SD 7.6) kg} were used for the population PK analysis. The flat profile of the CSF concentration-time curve and attainment of 50%T>MIC(CSF) did not change markedly when the duration of infusion was increased, whereas attainment of 50%T>MIC(CSF) was improved by increasing the dose from 20 to 40 mg/kg q8h for penicillin-resistant Streptococcus pneumoniae and Pseudomonas aeruginosa. Thirty-six patients who achieved satisfactory clinical cure showed at least 75.3%T>MIC(CSF). CONCLUSIONS: A high dose of meropenem (40 mg/kg q8h) is necessary to achieve clinical efficacy in paediatric patients with bacterial meningitis.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Líquido Cefalorraquidiano/química , Meningites Bacterianas/tratamento farmacológico , Meropeném/farmacologia , Meropeném/farmacocinética , Antibacterianos/administração & dosagem , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Meropeném/administração & dosagem , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Infecções Pneumocócicas/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos
12.
Rinsho Shinkeigaku ; 59(7): 448-450, 2019 Jul 31.
Artigo em Japonês | MEDLINE | ID: mdl-31243251

RESUMO

A 39-year-old previously healthy man was referred to our hospital because of acute onset of fever and consciousness disturbance. Neurological examinations revealed deteriorated consciousness, nuchal rigidity and Kernig's sign. A lumbar puncture yielded clouded fluid with a WBC 1,012/µl (polynuclear cell 96%), 147.3 mg/dl of protein, 44 mg/dl of glucose and Gram positive cocci. At first, he was treated with ceftriaxon and ampicillin. At Day 2, meropenem was added. Streptococcus agalactiae was isolated from blood and cerebrospinal fluid. He responded promptly to antimicrobial therapy, and within 2 days, he became lucid and afebrile. S. agalactiae was sensitive to ceftriaxone, ampicillin and meropenem. After Day 3, he was treated with meropenem only. We diagnosed his condition as S. agalactiae meningitis and was discharged from our hospital at Day 18. Many cases of S. agalactiae meningitis are known to occur in neonates, pregnant women, elderly, and persons with underlying disease such as diabetes, malignant disorders, liver dysfunction. But cases occurring in a previously healthy adult are rare. Neurologists should be aware that S. agalactiae may be cause bacterial meningitis in a previously healthy adults.


Assuntos
Imunocompetência , Meningites Bacterianas/diagnóstico , Meningites Bacterianas/microbiologia , Infecções Estreptocócicas , Streptococcus agalactiae/isolamento & purificação , Adulto , Ampicilina/administração & dosagem , Antibacterianos/administração & dosagem , Ceftriaxona/administração & dosagem , Transtornos da Consciência/etiologia , Quimioterapia Combinada , Febre/etiologia , Humanos , Masculino , Meningites Bacterianas/complicações , Meningites Bacterianas/tratamento farmacológico , Meropeném/administração & dosagem , Resultado do Tratamento
13.
Mater Sci Eng C Mater Biol Appl ; 102: 634-645, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31147035

RESUMO

A square wave voltammetric method for selective determination of meropenem (MRP) and ertapenem (ERP) was developed using pencil graphite electrode modified with poly (bromocresol green) (PGE/PBCG). The modified electrode film was characterized by scanning electron microscopy and electro-chemical impedance spectroscopy. Under the optimized conditions, the prepared electrode has good linearity over concentration range 1.0-60.0 and 0.3.0-75.0 µM for MRP and ERP, respectively. The developed method was validated according to ICH guidelines. In addition, the diffusion co-efficients of MRP and ERP were estimated to be 1.24 × 10-6 and 9.09 × 10-6 cm2 s-1, respectively using chronoamperometric technique. The developed method was highly sensitive and selective for the determination of MRP or ERP in the presence of their corresponding open beta-lactam ring degradation products. Consequently, it was successfully utilized for in-vitro and in-vivo applications in spiked and real plasma samples of healthy rabbits for their pharmacokinetic studies. Furthermore, the method was applied for the assay of the available dosage forms of both drugs.


Assuntos
Técnicas Biossensoriais/métodos , Verde de Bromocresol/química , Técnicas Eletroquímicas/métodos , Ertapenem/farmacocinética , Grafite/química , Meropeném/farmacocinética , Animais , Eletrodos , Ertapenem/administração & dosagem , Ertapenem/sangue , Concentração de Íons de Hidrogênio , Limite de Detecção , Masculino , Meropeném/administração & dosagem , Meropeném/sangue , Oxirredução , Coelhos , Fatores de Tempo
14.
Int J Antimicrob Agents ; 54(3): 309-317, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31229669

RESUMO

Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharmacokinetic (PK) modelling was performed in NONMEM®7.3 based on densely sampled meropenem serum samples (npatients = 48; nsamples = 1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000-6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft-Gault creatinine clearance (CLCRCG) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCRCG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3(-MIC), pathogen and susceptibility known; L3(+MIC), MIC known). Whereas patients with higher CLCRCG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information.


Assuntos
Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Estado Terminal , Meropeném/administração & dosagem , Algoritmos , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Humanos , Meropeném/farmacocinética , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Modelos Estatísticos , Soro/química
15.
J Vet Pharmacol Ther ; 42(5): 525-529, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31222751

RESUMO

The objective of this study was to determine the pharmacokinetics of meropenem in horses after intravenous (IV) administration. A single IV dose of meropenem was administered to six adult horses at 10 mg/kg. Plasma and synovial fluid samples were collected for 6 hr following administration. Meropenem concentrations were determined by bioassay. Plasma and synovial fluid data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean ± SD values for elimination half-life, volume of distribution at steady-state, and clearance after IV administration for plasma samples were 0.78 ± 0.176 hr, 136.1 ± 19.69 ml/kg, and 165.2 ± 29.72 ml hr-1  kg-1 , respectively. Meropenem in synovial fluid had a slower elimination than plasma with a terminal half-life of 2.4 ± 1.16 hr. Plasma protein binding was estimated at 11%. Based on a 3-compartment open pharmacokinetic model of simultaneously fit plasma and synovial fluid, dosage simulations were performed. An intermittent dosage of meropenem at 5 mg/kg IV every 8 hr or a constant rate IV infusion at 0.5 mg/kg per hour should maintain adequate time above the MIC target of 1 µg/ml. Carbapenems are antibiotics of last resort in humans and should only be used in horses when no other antimicrobial would likely be effective.


Assuntos
Antibacterianos/farmacocinética , Cavalos/sangue , Meropeném/farmacocinética , Líquido Sinovial/química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/química , Área Sob a Curva , Meia-Vida , Meropeném/administração & dosagem , Meropeném/sangue , Meropeném/química
16.
Ann Otol Rhinol Laryngol ; 128(9): 848-854, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31043072

RESUMO

INTRODUCTION: Necrotizing otitis externa resolves best with antimicrobial treatment. How to care for these patients and monitor their resolution remains a problem. Our protocol in Bangalore can manage these patients inexpensively and well. MATERIALS AND METHODS: Patients who were referred to our patients became the subjects for this paper. They were managed through our protocol, which consists of IV ciprofloxacin and meropenem, weekly labs, weekly examinations, and photodocumention. RESULTS: Fifty-one people presented with necrotizing otitis externa (NOE) between October 2015 and November 2017 and completed our entire protocol. Forty-six had complete resolution of their disease, while 5 had to undergo surgical removal of necrotic bone. Six of 8 patients with facial weakness had improvement in their House-Brackmann scores. Reduction of self-reported nocturnal pain, dissolution of ear canal granulations, and normalization of the erythrocyte sedimentation rate (ESR) proved to be the most accurate indicators of disease regression. CONCLUSION: Patients are monitored closely with review of their otalgia, examination of their canal, repeated ESRs, effective control of their diabetes, and radiological imaging. All this can be done in a resource-poor country, which in turn serves as a model for the wealthier nations.


Assuntos
Ciprofloxacino/administração & dosagem , Dor de Orelha , Meropeném/administração & dosagem , Osteomielite , Otite Externa , Antibacterianos/administração & dosagem , Dor de Orelha/diagnóstico , Dor de Orelha/tratamento farmacológico , Dor de Orelha/etiologia , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Necrose , Osteomielite/diagnóstico , Osteomielite/etiologia , Osteomielite/cirurgia , Otite Externa/tratamento farmacológico , Otite Externa/patologia , Otite Externa/fisiopatologia , Otite Externa/cirurgia , Base do Crânio/diagnóstico por imagem , Base do Crânio/patologia , Resultado do Tratamento
17.
Drugs R D ; 19(2): 177-189, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31090024

RESUMO

OBJECTIVE: The objective of this study was to develop a physiologically based pharmacokinetic model for meropenem using a retrograde approach, which could serve as a basis for prediction of the systemic and infection-site drug exposures in different populations and indications. We intended this model to be a useful tool to inform (local) pharmacokinetic-based optimal dosing of meropenem in different settings. METHODS: We developed a reduced physiologically based pharmacokinetic model with NONMEM software using a top-down approach. We used historical (previously published) data for model development and qualification. We used steady-state systemic and infection-site concentrations from 60 adult patients diagnosed with severe lung infection for model development and internal evaluation. The data included rich plasma and sparse epithelial lining fluid samples. We based the internal validation of the model on successful numerical convergence, adequate precision in parameter estimation, acceptable goodness-of-fit plot with no indication of bias, and acceptable performance of visual predictive checks. We performed external validation by fitting the model to independent data from five previously published studies: four studies in patients with pneumonia, with different grades of renal impairment, and one study in morbidly obese patients. RESULTS: We successfully fitted a reduced physiologically based pharmacokinetic model with six compartments (arterial and venous pools, infection site [lungs], liver, kidneys and rest of the body) to the data and adequately estimated model parameters. We successfully qualified the model (internally and externally) using established methods. Estimated values for tissue-to-plasma partition coefficients were 0.2629 and 0.1946 for lungs and non-fat tissues (kidneys and liver), respectively. Estimated total clearance was 8.174 L/h for a typical patient with a glomerular filtration rate of 65 mL/min. Consistent with the known mechanism of meropenem elimination and previously published models, renal clearance accounted for 70% of total clearance. The model had good predictive performances on data from five different sources including populations with different characteristics with regard to body size, renal function and morbidity. CONCLUSIONS: We successfully developed a physiologically based pharmacokinetic model for meropenem in adult patients to be used as a basis for prediction of concentrations in different groups of patients, and eventually for effective dose individualisation in different subgroups of the population.


Assuntos
Antibacterianos/farmacocinética , Meropeném/farmacocinética , Modelos Biológicos , Pneumonia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Conjuntos de Dados como Assunto , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Infusões Intravenosas , Masculino , Meropeném/administração & dosagem , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Eliminação Renal/fisiologia , Distribuição Tecidual , Adulto Jovem
18.
Crit Care Resusc ; 21(1): 63-68, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30857514

RESUMO

BACKGROUND AND RATIONALE: ß-Lactam antibiotics display a time-dependent mechanism of action, with evidence suggesting improved outcomes when administering these drugs via continuous infusion compared with standard intermittent infusion. However, there is no phase 3 randomised controlled trial (RCT) evidence to support one method of administration over another in critically ill patients with sepsis. DESIGN AND SETTING: The ß-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 RCT to compare continuous infusion with standard intermittent infusion of ß-lactam antibiotics in critically ill patients with sepsis. The study will be conducted in about 70 intensive care units (ICUs) in Australia, New Zealand, the United Kingdom, Belgium and selected other countries, from 2018 to 2021. PARTICIPANTS AND INTERVENTIONS: BLING III will recruit 7000 critically ill patients with sepsis being treated with one of two ß-lactam antibiotics (piperacillin-tazobactam or meropenem) to receive the ß-lactam antibiotic by either continuous or intermittent infusion. MAIN OUTCOME MEASURES: The primary outcome is allcause mortality within 90 days after randomisation. Secondary outcomes are clinical cure at Day 14 after randomisation, new acquisition, colonisation or infection with a multiresistant organism or Clostridium difficile diarrhoea up to 14 days after randomisation, all-cause ICU mortality and all-cause hospital mortality. Tertiary outcomes are ICU length of stay, hospital length of stay and duration of mechanical ventilation and duration of renal replacement therapy up to 90 days after randomisation. RESULTS AND CONCLUSIONS: The BLING III study will compare the effect on 90-day mortality of ß-lactam antibiotics administered via continuous versus intermittent infusion in 7000 critically ill patients with sepsis. TRIAL REGISTRATION: ClinicalTrials.gov Registry (NCT03213990).


Assuntos
Antibacterianos/administração & dosagem , Estado Terminal/terapia , Meropeném/administração & dosagem , Combinação Piperacilina e Tazobactam/administração & dosagem , Sepse/tratamento farmacológico , beta-Lactamas/administração & dosagem , Antibacterianos/uso terapêutico , Austrália , Esquema de Medicação , Humanos , Infusões Intravenosas , Meropeném/uso terapêutico , Nova Zelândia , Combinação Piperacilina e Tazobactam/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento , Reino Unido , beta-Lactamas/uso terapêutico
19.
BMJ Case Rep ; 12(3)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30898950

RESUMO

Malignant infantile osteopetrosis (MIOP), an autosomal-recessive disorder, is extremely rare, presenting early in life with extreme sclerosis of the skeleton and reduced activity of osteoclasts. It was first described by Albers Schonberg in 1904. Disease manifestations include compensatory extramedullary haematopoiesis at sites such as the liver and spleen, hepatosplenomegaly, anaemia and thrombocytopaenia. Neurological manifestations can also occur due to narrowing of osseous foramina resulting in visual impairment, hearing loss, facial palsy and hydrocephalus. In addition, growth retardation and recurrent infections requiring long-term antibiotic use are common. The incidence of MIOP is 1/2 000 000 and if untreated, then it has a fatal outcome, with the majority of cases occurring within the first 5 years of life. At present, the only potentially curative option is a haematopoietic stem cell transplant. We present a 21-year-old woman, diagnosed with malignant infantile osteopetrosis, due to a mutation in the T-cell immune regulator 1 gene when aged 6 weeks, presenting with chronic osteomyelitis of her left mandible. As malignant infantile osteopetrosis has a high mortality in infancy, we felt it prudent to report this rare case in a patient surviving to adulthood.


Assuntos
Mandíbula/patologia , Osteomielite/patologia , Osteopetrose/complicações , Antibacterianos/administração & dosagem , Feminino , Humanos , Mandíbula/diagnóstico por imagem , Meropeném/administração & dosagem , Osteomielite/complicações , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Streptococcus constellatus/isolamento & purificação , Streptococcus mitis/isolamento & purificação , Streptococcus oralis/isolamento & purificação , Adulto Jovem
20.
Ann Hematol ; 98(5): 1209-1216, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30824955

RESUMO

Febrile neutropenia is often observed in patients with hematologic malignancies, especially in those with acute leukemia. Meropenem has potent and broad antibacterial activity against gram-positive and gram-negative bacteria, and is recommended as first-line empiric therapy for febrile neutropenia. In contrast, the safety and efficacy of doripenem in patients with febrile neutropenia and hematologic malignancies is limited. In this randomized, prospective, cooperative, open-label trial, we compared doripenem (1.0 g every 8 h) to meropenem (1.0 g every 8 h) as first-line empiric antibacterial treatment of febrile neutropenia. To evaluate efficacy and safety, 133 hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed febrile neutropenia during or after chemotherapy, were randomized to each drug. Resolution of fever within 3 to 5 days without treatment modification (i.e., the primary endpoint) did not significantly differ between the doripenem and meropenem groups (60.0% vs. 45.6%, respectively; P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the doripenem group than in the meropenem group (78.4% vs. 60.2%, respectively; P = 0.037). Similar rates of adverse events (grades 1-2) were observed in both groups. Thus, we conclude that both drugs are safe and well-tolerated for the treatment of febrile neutropenia in patients with acute leukemia or high-risk myelodysplastic syndrome, and that the clinical efficacy of doripenem is noninferior to that of meropenem. UMIN Clinical Trial Registry number: 000006124.


Assuntos
Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Doripenem/administração & dosagem , Leucemia/tratamento farmacológico , Meropeném/administração & dosagem , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doripenem/efeitos adversos , Feminino , Febre/tratamento farmacológico , Humanos , Masculino , Meropeném/efeitos adversos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Estudos Prospectivos
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