Drug exposure of moxifloxacin and levofloxacin in patients with multi-drug-resistant tuberculosis, which one is more serious?

Adequate drug exposure is very important to ensure the treatment effect of tuberculosis (TB) and avoid acquired drug resistance.

Although the exposure of most anti-tuberculosis drugs is relatively low, there are few data on drug exposure with regard to the minimum inhibitory concentration (MIC).

Because Mycobacterium tuberculosis (Mtb) is resistant to rifampicin and isoniazid, fluoroquinolone is the cornerstone of the treatment of multidrug-resistant tuberculosis (MDR-TB).

The activity of fluoroquinolones can be described by the area under the concentration-time curve of free drug and minimum inhibitory concentration (fAUC/MIC).

Professor Hu Yi’s team from the School of Public Health of Fudan University in Shanghai reported on the individual drug exposure of moxifloxacin and levofloxacin relative to the MIC of the Mtb isolate, and discussed the pharmacokinetic/pharmacodynamic (PK/PD) indicators Achievement of the goal.

 Research methods In 2016-2018, the investigators conducted a prospective cohort study at a designated tuberculosis hospital in Xiamen, China.
The subjects were HIV-negative adult patients with MDR-TB.

The individual MIC of moxifloxacin was detected by the micro broth dilution method, and exploratory epidemiological cut points were used for the fluoroquinolone sensitive strains that did not obtain MIC (ECOFFs: moxifloxacin 0.
5 mg/L and levofloxacin 1 mg/L).

Then the drug concentration was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) before administration and 1, 2, 4, 6, 8 and 10 hours after administration.

 Study results ➤ The average age of the included 32 patients was 32.
5 years old (IQR was 25.
8-43.
3), and 20 patients took moxifloxacin 400 mg/d daily.

The median AUC from 0-24h was 36.
1 mg*h/L, and the median fAUC was 18.
0 mg*h/L. Seven patients were given levofloxacin 500 mg/d.

The median AUC from 0-24 h was 63.
7 mg*h/L, and the median fAUC was 44.
6 mg*h/L.

The drug exposure levels of all patients were lower than the recommended dose (750-1000 mg/d) of 100-200 mg*h/L AUC.

 ➤For the MIC of levofloxacin (0.
125 mg/L, 0.
25 mg/L, 0.
50 mg/L and 1 mg/L), only when the MIC is ≤0.
125 mg/L can it be ensured that more than 90% of patients taking 500 mg of levofloxacin achieve fAUC/MIC≥ 146 goals.

Similarly, to make the target of fAUC / MIC ≥ 42 reach more than 90%, moxifloxacin MIC ≤ 0.
25 mg/L is necessary.

 ➤When 400 mg of moxifloxacin and 500 mg of levofloxacin are used daily, the target achievement rate is low.
Only 45-55% of patients have reached the tentative PK/PD target of moxifloxacin, and no patient has reached the PK/PD target of levofloxacin.
.

 Research conclusions For patients with MDR-TB, the target achievement rate of moxifloxacin treatment is low, while the dose of levofloxacin treatment is insufficient.

The researchers recommend that higher doses of fluoroquinolones (moxifloxacin 600-800 mg or levofloxacin 1250-1500 mg daily) should be considered for low-level resistance mutations.

Therefore, in the future standard treatment plan, the use of high-dose fluoroquinolones should be combined with therapeutic drug monitoring to further evaluate the effectiveness and safety of the combined treatment.

 Yimaitong compiled from: DaviesFL, Niward K, Kuhlin J, et al.
Suboptimal moxifloxacin and levofloxacin drugexposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China[J].
Eur Respir J, 2021, 57(3).