Suboptimal moxifloxacin and levofloxacin drug exposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China

To the Editor:

Adequate drug exposure is important to ensure tuberculosis (TB) treatment efficacy and to avoid acquired drug resistance. Although low drug exposure has been reported for most anti-TB drugs, data on drug exposure in relation to minimum inhibitory concentration (MIC) are scarce [1, 2]. A fluoroquinolone is a cornerstone in the treatment of multidrug-resistant (MDR)-TB, which results when Mycobacterium tuberculosis is resistant to rifampicin and isoniazid. The activity of fluoroquinolones is best described by the area under the concentration–time curve based on free drug in relation to MIC (fAUC/MIC) [3, 4].

Therefore, we report the individual drug exposure of moxifloxacin and levofloxacin in relation to MICs of the infecting M. tuberculosis isolate and explore target attainment of previously suggested pharmacokinetic/pharmacodynamic (PK/PD) indices [3, 4].

We performed a prospective cohort study including HIV-negative adult patients with MDR-TB in a designated TB hospital in Xiamen, China, during 2016–2018. Ethics approval (IRB 2015-09-0565) and informed consent were obtained; see the published study protocol [5]. Drug regimens were designed according to World Health Organization (WHO) recommendations at the time. No patient received linezolid or bedaquiline. Individual MIC testing for moxifloxacin was performed using broth microdilution (MYCOTB, Thermo Fisher Scientific, MA, USA) and tentative epidemiological cut-offs (ECOFFs; moxifloxacin 0.5 mg·L⁻¹ and levofloxacin 1 mg·L⁻¹) were used for fluoroquinolone-susceptible isolates where MICs were unavailable. Drug concentrations were measured at pre-dose and 1, 2, 4, 6, 8 and 10 h post-dose with a validated LC-MS/MS assay, as previously described [6]. Non-compartmental analysis was performed to estimate AUC_0–24h and previously suggested targets of optimal microbial kill and prevention of acquired resistance from hollow fibre system (HFS) of ≥42 and ≥53 for moxifloxacin as well as ≥146 and ≥360 for levofloxacin were explored, in addition to minimal kill (1 log₁₀ CFU·mL⁻¹) [3, 4, 7, 8].

The 32 included patients had a median age of 33 years (interquartile range 25.8–43.3 years), 17 were female (53.1%) and two had diabetes mellitus type II. Five patients had non-evaluable PK data, leaving 20 patients treated with moxifloxacin 400 mg daily (median 7.8 mg·kg⁻¹, range 5.9–9.5 mg·kg⁻¹). The median (range) of AUC_0–24h was 36.1 mg·h·L⁻¹ (19.3–60.3 mg·h·L⁻¹) and fAUC_0–24h was 18.0 mg·h·L⁻¹ (9.6–30.1 mg·h·L⁻¹). Excluding the five fluoroquinolone resistant isolates by routine drug susceptibility testing, moxifloxacin MICs ranged from 0.125 to 1 mg·L⁻¹ (median 0.25 mg·L⁻¹).

Seven patients received levofloxacin 500 mg daily (median 10.0 mg·kg⁻¹, range 6.7–11.9 mg·kg⁻¹) according to Chinese national guidelines. The median (range) of AUC_0–24h was 63.7 mg·h·L⁻¹ (47.8–75.3 mg·h·L⁻¹) and fAUC_0–24h was 44.6 mg·h·L⁻¹ (33.5–52.7 mg·h·L⁻¹). All patients had lower drug exposure than the AUC of 100–200 mg·h·L⁻¹ described for recommended doses of 750–1000 mg daily [7]. The fAUC_0–24h/MIC of moxifloxacin and levofloxacin in relation to previously suggested PK/PD indices are shown in figure 1.

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FIGURE 1

Fluoroquinolone (FQ) drug exposure in relation to minimum inhibitory concentration (MIC) for 27 patients on multidrug-resistant tuberculosis treatment. Median (range) for moxifloxacin (MFX, n=20) AUC_0–24h/MIC was 104 (15–430) and fAUC_0–24h/MIC 52 (8–215) and without the five fluoroquinolone resistant (Löwenstein–Jensen, ofloxacin/levofloxacin 2 mg·L⁻¹) Mycobacterium tuberculosis isolates (black circles); 145 (19–430) and 73 (10–215), respectively. In four isolates, moxifloxacin epidemiological cut-off level (ECOFF) of 0.5 mg·L⁻¹ was used. We applied the 0.5 mg·L⁻¹ ECOFF as previous studies implied the clinical breakpoint of moxifloxacin 2 mg·L⁻¹ to be too high [21]. Levofloxacin (LFX, n=7) median (range) fAUC_0-24h/MIC was 45 (33–53) when using an MIC of levofloxacin 1 mg·L⁻¹ (tentative ECOFF in microbroth dilution), given fluoroquinolone susceptibility [22]. A protein binding of 50% for moxifloxacin and 30% for levofloxacin were applied to calculate fAUC_0-24h/MIC. fAUC/MIC: area under the concentration–time curve based on free drug in relation to minimum inhibitory concentration.

Exploration of target attainment across MICs for levofloxacin (0.125, 0.25, 0.5 and 1 mg·L⁻¹) showed that only MICs of ≤0.125 mg·L⁻¹ ensured that >90% of patients on levofloxacin 500 mg daily reach target attainment of fAUC/MIC ≥146. Similarly, a moxifloxacin MIC of ≤0.25 mg·L⁻¹ was needed for >90% target attainment of fAUC/MIC ≥42. At the median levofloxacin fAUC/MIC of 45 achieved in our study, only a minimal kill of 1 log₁₀ CFU·mL⁻¹ is to be expected according to HFS data using monotherapy from Deshpande et al. [3]. Less than three quarters of the patients with fluoroquinolone-susceptible isolates reached the moxifloxacin fAUC/MIC targets 42 and 53 (11/15 (73%) and 9/15 (60%), respectively) [4]. Two patients reported arthralgia and no serious adverse events occurred. A successful treatment outcome was seen for 28/32 patients (87.5%), with one failure and three patients lost to follow-up (WHO 2008 definitions). All patients with a fluoroquinolone resistant M. tuberculosis isolate had a successful treatment outcome.

In summary, we found low target attainment using moxifloxacin 400 mg once daily and the recommended Chinese levofloxacin dosing at the time of the study (500 mg daily), where only 45–55% of patients reached tentative PK/PD targets for moxifloxacin and none for levofloxacin. Determination of individual moxifloxacin MICs confirmed that low drug exposure and/or moxifloxacin MIC close to the breakpoint resulted in low PK/PD ratios (i.e. fAUC_0–24h/MIC).

Low and variable drug exposure have been seen in previous studies, although few included individual MICs [1, 2, 9]. Our median moxifloxacin AUC_0–24h of 36.1 mg·h·L⁻¹ is comparable to previous studies from Europe (24.8 mg·h·L⁻¹) and South Africa (38.7 mg·h·L⁻¹) [2, 9] and we found no pharmacogenetic explanation in the English or Chinese literature. Low drug exposure may pose some risk of treatment failure or, occasionally, acquired drug resistance in MDR-TB as well as drug-susceptible TB [4, 10, 11]. Unfortunately, the study reporting on acquired fluoroquinolone resistance did not evaluate drug exposure [11]. Furthermore, drug penetration in caseous granulomas is poor [12].

As MICs cannot be changed, increased doses of fluoroquinolones have been suggested to ensure drug efficacy [2, 4, 9], even if adverse events are a concern. Indeed, a moxifloxacin dose of 800 mg is recommended in the MDR-TB short-course regimen by the WHO [13], but higher dosages show more adverse drug events [14]. A previous analysis regarding levofloxacin suggested the need for increased dosing from currently 10–15 mg·kg⁻¹ to 17–20 mg·kg⁻¹ to ensure target attainment at MICs from 0.25 to 0.5 mg·L⁻¹ [1]. Even higher doses of levofloxacin, 25 mg·kg⁻¹ or 1500 mg daily, have been suggested from HFS studies [3], although the benefit and safety of higher doses needs to be confirmed in clinical studies.

Therapeutic drug monitoring (TDM) has been recommended because of variable PK, especially if risk factors for resistance exist or levofloxacin MICs ≥0.5 mg·L⁻¹ or moxifloxacin MICs ≥0.25 mg·L⁻¹ (critical concentrations for Mycobacteria Growth Indicator Tube) [15]. Limited-sampling strategies have been developed for both drugs to support fAUC guided dosing [16, 17].

We emphasise, in line with the WHO's technical PK/PD report [18], the importance of including both drug exposure and level of resistance when assessing the individual fluoroquinolone dose. In adult MDR-TB, we suggest considering higher doses of fluoroquinolones (moxifloxacin 600–800 mg or levofloxacin 1250–1500 mg daily) in cases of low-level resistance mutations, such as A90 V of gyrA corresponding to borderline fluoroquinolone MICs.

If increased fluoroquinolone dosing is considered, it needs to be carefully weighed against individual safety aspects and, if applied, be combined with active TB drug safety monitoring and management and preferably TDM to detect unexpected drug exposure [19]. The STREAM trial using moxifloxacin 800 mg daily showed no major safety concerns, although QTc-prolongation and hepatobiliary disorders were seen, thus highlighting the need of monitoring. Likewise, the dose-ranging study of levofloxacin 11–20 mg·kg⁻¹ showed no dose-limiting toxicity [20]. However, safety data for high-dose fluoroquinolones, especially in combination with bedaquiline, are limited. Furthermore, high-dose fluoroquinolones might be ill-suited to vulnerable subpopulations, such as patients with cardiac failure or hypokalaemia.

Study limitations include small sample size, lack of individual MICs of levofloxacin, a low levofloxacin dose and that PK/PD targets may need refinement as they are derived from pre-clinical models. As MIC determination is method dependent, we used a methodology similar to the EUCAST reference method, including a quality control (H37Rv). Despite suboptimal drug exposure, some activity can be expected at lower concentrations [3, 4] due to drug synergy and an adequate host immune response, partly explaining the successful treatment outcomes in our study. Optimising doses while taking safety into careful consideration might enable future treatment shortening, although the PK/PD thresholds need clinical validation, especially in bedaquiline-containing combination regimens.

In conclusion, target attainment of moxifloxacin was low in patients with MDR-TB and levofloxacin was under-dosed. We advocate for further clinical evaluation of the efficacy and safety of high-dose fluoroquinolone combined with TDM, not only in short-course but also in standard regimens.

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