Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

Beraldi-Magalhães, Francisco; Parker, Suzanne L.; Sanches, Cristina; Garcia, Leandro Sousa; Carvalho, Brenda K.S.; Fachi, Mariana Millan; Liz, Marcus Vinícius de; Pontarolo, Roberto; Lipman, Jeffrey; Cordeiro-Santos, Marcelo; Roberts, Jason A.

doi:10.3390/antibiotics10121559

Cited by 4 publications

(2 citation statements)

References 41 publications

(85 reference statements)

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“…Ethambutol clearance was significantly affected by creatinine clearance, which has been previously reported. 66 Most participants within our study had normal renal function (see Table 1 ). For this reason, the effect of creatinine clearance on ethambutol clearance could not be fully characterized, and extrapolation with this model outside the observed creatinine clearance range should be interpreted with caution.…”

Section: Discussionmentioning

confidence: 86%

The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs

Wijk,

Gausi,

Malatesta

et al. 2024

Journal of Antimicrobial Chemotherapy

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Background In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics. Objectives To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB. Methods We prospectively enrolled participants ≥15 years old, without HIV, and initiating drug-susceptible TB treatment in Worcester, South Africa. Alcohol use was measured via self-report and blood biomarkers. Other illicit substances were captured through a urine drug test. Plasma samples were drawn 1 month into treatment pre-dose, and 1.5, 3, 5 and 8 h post-dose. Non-linear mixed-effects modelling was used to describe the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol. Alcohol and drug use were tested as covariates. Results The study included 104 participants, of whom 70% were male, with a median age of 37 years (IQR 27–48). Alcohol use was high, with 42% and 28% of participants having moderate and high alcohol use, respectively. Rifampicin and isoniazid had slightly lower pharmacokinetics compared with previous reports, whereas pyrazinamide and ethambutol were consistent. No significant alcohol use effect was detected, other than 13% higher ethambutol clearance in participants with high alcohol use. Methaqualone use reduced rifampicin bioavailability by 19%. Conclusion No clinically relevant effect of alcohol use was observed on the pharmacokinetics of first-line TB drugs, suggesting that poor treatment outcome is unlikely due to pharmacokinetic alterations. That methaqualone reduced rifampicin means dose adjustment may be beneficial.

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Section: Discussionmentioning

confidence: 86%

The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs

Wijk,

Gausi,

Malatesta

et al. 2024

Journal of Antimicrobial Chemotherapy

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“…The initial phase aims to quickly reduce bacillary population, decreasing contagiousness and patient symptoms [ 10 ]. For this early phase to be effective in TB patients admitted to ICU, the pharmacokinetic–pharmacodynamic (PK/PD) targets for all first-line TB antimicrobial must be achieved; otherwise, patient outcomes may be compromised and selective pressure applied for the emergence of antimicrobial resistance [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis

et al. 2023

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Background: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. Methods: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. Results: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. Conclusions: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

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Antibiotics in the management of tuberculosis and cancer

Koirala

Butnariu²,

Panthi

et al. 2023

Antibiotics - Therapeutic Spectrum and Limitations

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Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

Cited by 4 publications

References 41 publications

The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs

The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs

Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis

Antibiotics in the management of tuberculosis and cancer

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