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1.
J Antimicrob Chemother ; 77(5): 1365-1371, 2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35178567

RESUMO

OBJECTIVES: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. RESULTS: Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. CONCLUSIONS: Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.


Assuntos
Infecções Bacterianas , Estado Terminal , Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Estado Terminal/terapia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Tigeciclina/farmacocinética
2.
BMC Infect Dis ; 21(1): 307, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771113

RESUMO

BACKGROUND: Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. RESULTS: The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75-91%). CONCLUSIONS: The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.


Assuntos
Antibacterianos/farmacocinética , Rim/fisiopatologia , Infecções por Klebsiella/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Colistina/farmacocinética , Colistina/uso terapêutico , Estado Terminal , Feminino , Fosfomicina/farmacocinética , Fosfomicina/uso terapêutico , Humanos , Testes de Função Renal , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Tigeciclina/farmacocinética , Tigeciclina/uso terapêutico
3.
Eur J Clin Pharmacol ; 77(2): 197-205, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32975650

RESUMO

PURPOSE: Tigecycline is one of few antibiotics active against multidrug-resistant bacteria; however, the assessment of dosing strategies to optimize its activity is needed. The purpose was to use Monte Carlo Simulation (MCS) to determine if safe tigecycline dosing options attaining breakpoints for pharmacokinetic/pharmacodynamic (PK-PD) targets in non-critically ill adults could be identified. METHODS: Publications that evaluated tigecycline dosing regimens and provided mean PK variables of interest (minimum 2 of: elimination rate constant or half-life and volume of distribution or clearance), with SDs, were included. Weighted mean (±SDs) for each PK parameter were determined. Food and Drug Administration minimum inhibitory concentration (MIC) tigecycline breakpoints for susceptible (MIC ≤ 2 µg/mL), intermediate (MIC 4 µg/mL), and resistant (MIC ≥ 8 µg/mL) Enterobacteriaceae were used. MCS probability distributions for PK-PD target attainment of AUC for total tigecycline plasma concentration from 0 to 24 h following an intravenous dose (AUCtotal, 0-24h) to MIC ratios of ≥ 18, 7, and 4.5 were generated, with success defined as ≥ 80% probability of target attainment at a given MIC. RESULTS: Ten studies (n = 442) were eligible. Tigecycline 150 mg IV q12h for ward patients with resistant bacteria up to a MIC of 0.48, 1, and 2 µg/mL for an AUCtotal, 0-24h/MIC target attainment of 18, 7, and 4.5, respectively, may be appropriate. CONCLUSION: Bacterial infections with tigecycline MICs ≥ 0.48-2 µg/mL, depending on AUCtotal, 0-24h/MIC target, may require treatment with alternate antibiotics due to target attainment failure.


Assuntos
Antibacterianos/administração & dosagem , Infecções por Enterobacteriaceae/tratamento farmacológico , Enterobacteriaceae/efeitos dos fármacos , Tigeciclina/administração & dosagem , Adulto , Antibacterianos/farmacocinética , Área Sob a Curva , Simulação por Computador , Conjuntos de Dados como Assunto , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana Múltipla , Enterobacteriaceae/isolamento & purificação , Enterobacteriaceae/fisiologia , Infecções por Enterobacteriaceae/sangue , Infecções por Enterobacteriaceae/microbiologia , Meia-Vida , Humanos , Infusões Intravenosas , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Tigeciclina/farmacocinética
4.
J Chemother ; 32(8): 420-428, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32757849

RESUMO

OBJECTIVE: The objective of this study was to investigate the cumulative fraction of response (CFR) of various tigecycline dosing regimens in patients with hepatic or renal impairment. METHODS: Monte Carlo simulations were performed using pharmacokinetic parameters and microbiological data to evaluate various tigecycline regimens in patients with hepatic or renal impairment. RESULTS: For HAP and cIAI, the regimen of 25 mg q12h achieved CFR values of >90% in Child-Pugh C patients against Gram-positive bacteria and partial Gram-negative bacteria (Escherichia coli and Klebsiella oxytoca). However, dose increases of tigecycline was mostly required for Enterobacter cloacae, Klebsiella pneumoniae and Acinetobacter baumanni. The conventional tigecycline regimen (50 mg q12h) was effective for HAP and cIAI caused by Gram-positive bacteria and Escherichia coli in patients with renal impairment. For HAP caused by Klebsiella pneumoniae and Enterobacter cloacae, patients with severe renal failure can use the standard dose regimen 50 mg q12h, and other patients need to increase the dose of tigecycline. However, when treating cSSSI caused by Acinetobacter baumannii, Enterobacter cloacae and Klebsiella pneumoniae, all tigecycline maintenance doses have a CFR <90%. CONCLUSIONS: It is necessary to optimize tigecycline dosage regimens in patients with hepatic or renal impairment in order to maximise clinical response and minimise the probability of exposure-related toxicity.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Falência Hepática/metabolismo , Insuficiência Renal/metabolismo , Tigeciclina/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Taxa de Depuração Metabólica , Testes de Sensibilidade Microbiana , Método de Monte Carlo , Tigeciclina/administração & dosagem , Tigeciclina/farmacocinética
5.
J Antimicrob Chemother ; 74(6): 1607-1617, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30820554

RESUMO

BACKGROUND: MDR-TB and XDR-TB have poor outcomes. OBJECTIVES: To examine the efficacy of tigecycline monotherapy in the hollow fibre system model of TB. METHODS: We performed pharmacokinetic/pharmacodynamic studies using tigecycline human-like concentration-time profiles in the hollow fibre system model of TB in five separate experiments using Mycobacterium tuberculosis in log-phase growth or as semi-dormant or intracellular bacilli, as monotherapy. We also compared efficacy with the isoniazid/rifampicin/pyrazinamide combination (standard therapy). We then applied extinction mathematics, morphisms and Latin hypercube sampling to identify duration of therapy with tigecycline monotherapy. RESULTS: The median tigecycline MIC for 30 M. tuberculosis clinical and laboratory isolates (67% MDR/XDR) was 2 mg/L. Tigecycline monotherapy was highly effective in killing M. tuberculosis in log-phase-growth and semi-dormant and intracellular M. tuberculosis. Once-a-week dosing had the same efficacy as daily therapy for the same cumulative dose; thus, tigecycline efficacy was linked to the AUC0-24/MIC ratio. Tigecycline replacement by daily minocycline after 4 weeks of therapy was effective in sterilizing bacilli. The AUC0-24/MIC ratio associated with optimal kill was 42.3. Tigecycline monotherapy had a maximum sterilizing effect (day 0 minus day 28) of 3.06 ±âŸ0.20 log10 cfu/mL (r2 = 0.92) compared with 3.92 ±âŸ0.45 log10 cfu/mL (r2 = 0.80) with optimized standard therapy. In our modelling, at a tigecycline monotherapy duration of 12 months, the proportion of patients with XDR-TB who reached bacterial population extinction was 64.51%. CONCLUSIONS: Tigecycline could cure patients with XDR-TB or MDR-TB who have failed recommended therapy. Once-a-week tigecycline could also replace second-line injectables in MDR-TB regimens.


Assuntos
Antituberculosos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Tigeciclina/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Antituberculosos/farmacocinética , Esquema de Medicação , Monitoramento de Medicamentos , Quimioterapia Combinada , Humanos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Método de Monte Carlo , Tigeciclina/farmacocinética , Distribuição Tecidual
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