Introduction: Guidelines recommend the use of amikacin in the treatment of nontuberculous mycobacterial (NTM) disease. The authors have evaluated the evidence for the position of amikacin in NTM disease treatment. Areas covered: The authors performed a literature search for original research on amikacin in NTM disease, including its mechanism of action, emergence of resistance, pre-clinical and clinical investigations. Expert opinion: Amikacin shows moderate in vitro activity against the clinically most relevant NTM species (M. avium complex and M. abscessus). It is synergistic with ethambutol, clofazimine, and macrolides and these combinations are effective in animal models. Liposomal encapsulation increases amikacin efficacy. Clinically, the recommended dose of 15 mg/kg intravenous amikacin does not lead to PK/PD target attainment in all patients and a positive impact on long-term treatment outcomes remains unproven in both M. avium complex and M. abscessus disease. Adding the amikacin liposome inhalation suspension did prove to be effective in short and long term in patients not responding to recommended treatment for M. avium complex pulmonary disease. Its optimal use in M. avium complex and M. abscessus pulmonary disease warrants further evaluation.
Background and Objectives
Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine.
Methods
In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin–tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function.
Results
A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100%
f
T
>1×MIC
(minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100%
f
T
>5×MIC
with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively.
Conclusions
A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by
Escherichia coli
and
Klebsiella pneumoniae
with MICs ≤ 8 mg/L
.
In case of infections caused by
Pseudomonas aeruginosa
with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases.
ClinicalTrials.gov identifier
NCT03738683.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40262-022-01113-6.
Mycobacterium avium complex pulmonary disease shows limited efficacy in an open source hollow fiber system that simulates human plasma and epithelial lining fluid pharmacokinetics, Clinical Microbiology and Infection,
Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. Hence, new compounds are being developed, available drugs are repurposed, and the dosing of existing drugs is optimized, resulting in the largest drug development portfolio in TB history. This review highlights a selection of clinically available drug candidates that could be part of future TB regimens, including bedaquiline, delamanid, pretomanid, linezolid, clofazimine, optimized (high dose) rifampicin, rifapentine, and para-aminosalicylic acid. The review covers drug development history, preclinical data, PK, and current clinical development.
This is a corrigendum to Clin Pharmacokinet. 2022 Apr 4 An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients concerning a correction in the simulations of piperacillin and tazobactam concentrations with the developed pharmacokinetic model. In the original simulation dataset, by accident double doses were entered. The exposure of both piperacillin and tazobactam based on the new corrected simulations is 50% of the exposure presented in the original publication. This applies to the following sections of the article: abstract, results, discussion, conclusion, Figs. 3, 4, 5 and Tables 3 and 4. Therefore, all simulated piperacillin and tazobactam concentrations in the original manuscript should be divided by 2. The published model does not contain any errors, as the error concerns only the performed simulations. Although
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