Critically ill patients with tuberculosis (TB) receiving enteral feeding and standard-dose rifampicin have lower-than-optimal rifampicin concentrations, a situation that can be remediated through a rifampicin minimum starting dose of at least 20 mg/kg orally and the use of dose escalation guided by therapeutic drug monitoring (TDM). These were among study findings published in the International Journal of Infectious Diseases.
Researchers sought to assess the effect of enteral feeding patterns on rifampicin absorption in critically ill patients with TB, as well as the potential for TDM-guided dose escalation to achieve optimal pharmacokinetic (PK) rifampicin targets in these patients.
The researchers conducted a randomized, sequential, pharmacokinetic (PK) study of adult patients with drug-susceptible TB who required intensive care at a hospital in Cape Town, South Africa, between May 1, 2019 and April 30, 2020. The participants were initiated on standard fixed-dose combination, weight-based TB treatment of rifampicin (150 mg), isoniazid (75 mg), pyrazinamide (400 mg), and ethambutol (275 mg).
The patients were randomly assigned 1:1 to pharmacokinetic sampling in 1 of 2 sequences: (1) fed-to-fasted: enteral feeding during TB treatment on day 1 of PK study, followed by repeated sampling on the next day, when the TB drugs were given after a 4-hour pre-dose hold on enteral feeding; or (2) fasted-to-fed: a 4-hour pre-dose hold on enteral feeding on day 1 of PK study, followed by continuous enteral feeding during dose administration the following day.
A total of 20 patients (median age, 35.5 years; 55% male) were included. All participants had microbiologically confirmed TB, and 40% were HIV positive.
The median maximum serum concentration (Cmax) was 5.1 µg/mL in the fasted state and 3.3 µg/mL in the fed state (P <.0001). The median Cmax in the fasted state was 5.5 µg/mL in the fed-to-fasted sequence and 4.7 µg/mL in the fasted-to-fed sequence. The median Cmax in the fed state was 3.1 µg/mL in the fed-to-fasted sequence and 3.4 µg/mL in the fasted-to-fed sequence. The geometric mean ratio of Cmax was 1.95 in the fasted state compared with the fed state (90% CI, 1.46-2.60).
The proportion of patients who had a low Cmax in the fasted state was 80% compared with 100% in the fed state (P =.1336).
The TDM analysis included 12 participants, and iterative dose escalation was conducted up to a maximum of 40 mg/kg. The median optimized dose of rifampicin was 1200 mg (24.6 mg/kg). No patients achieved target drug concentrations with standard-dose rifampicin, and 83% achieved target concentrations after dose escalation (P =.0044). After 1, 2, and 3 dose iterations, a target drug concentration was achieved in 7, 1, and 2 participants, respectively. The 2 participants who did not meet target attainment for rifampicin exposure had a dose increase to 1200 mg (20 mg/kg) and 1800 mg (30 mg/kg), respectively, although they died from refractory hypoxemia before further dose escalation.
Participants’ median Cmax increased from 2.4 µg/mL on the standard dose to 17.8 µg/mL on an optimized dose. The geometric mean Cmax on optimized dosing was 8.29 compared with standard dosing (90% CI, 3.88-17.74).
The investigators noted that their study was not powered to assess the impact of rifampicin exposure target attainment on clinical outcomes. In addition, they did not perform protocolized gastric aspiration before dosing to establish gastric residual volumes. Furthermore, TDM was performed with use of a limited sampling strategy, which may have led to an underestimation of drug exposure.
“We found low rifampicin concentrations in all patients receiving continuous enteral feeding. TDM-guided dose-escalation provided an effective strategy to achieve target drug exposure in these critically ill TB patients,” the study authors concluded. “[T]he minimum dose sufficient to achieve target rifampicin concentrations was 20mg/kg – approximately double the standard dose. A higher starting dose and the use of TDM may significantly improve the pharmacokinetic-pharmacodynamic profiles and treatment outcomes in critically ill patients,” the study authors added.
Perumal R, Naidoo K, Naidoo A, et al. The impact of enteral feeding and therapeutic monitoring of rifampicin with dose-escalation in critically ill patients with tuberculosis. Int J Infect Dis. 2023;126:174-180. doi:10.1016/j.ijid.2022.11.033