Sitafloxacin Demonstrated Superior In Vitro Activity against MDR and XDR-Tuberculosis Compared with Other Fluoroquinolones

24 October, 2017

Since the introduction of quinolones in the 1960s, and their subsequent development into fluoroquinolones, they have continued to expand their spectrum of activity, with later agents possessing activity against drug-resistant Mycobacterium tuberculosis. This is of great clinical importance, as tuberculosis, and particularly its drug-resistant isolates, continues to be a major global health threat. However, alongside the greater potency some fluoroquinolones had unacceptable toxicity, necessitating their withdrawal from the market. Fortunately, one new agent that possesses excellent activity coupled with an acceptable safety profile is sitafloxacin, a fourth-generation fluoroquinolone that possesses excellent penetration into respiratory tissues as well as tissue granuloma. 

While sitafloxacin has been proven to have a broad range of Gram-positive, Gram-negative and anaerobic activity, as well as potency against M. tuberculosis and M. avium, there is less data available outlining its activity against drug-resistant M. tuberculosis. However, a recent Thai study determined the in vitro activity of sitafloxacin against all groups of drug-resistant M. tuberculosis, including those that are multidrug-resistant (MDR-TB), MDR-TB with quinolone-resistance (pre-XDR), and extensively drug-resistant (XDR) strains. Additional analysis included determination of MICs and mutations associated with quinolone resistance.

The study tested 374 drug-resistant M. tuberculosis strains isolated over a three-year period (July 2013-2016) for first and second-line anti-TB drug susceptibility using the proportional method. Among those, 315 strains were identified as MDR-TB, 59 were non-MDR-TB. Of the 315 MDR-TB isolates, 73 were classed as pre-XDR and 41 as XDR-TB. MICs were determined using the Microplate Alamar Blue Assay, and DNA isolation was carried out with amplification and sequencing of gyrA and gyrB genes.

Sitafloxacin was shown to be the most active of the fluoroquinolones tested (ofloxacin, levofloxacin, moxifloxacin, gatifloxacin), with all tested isolates susceptible to sitafloxacin. Of the 274 MDR-TB strains, 19% were resistant to ofloxacin, 9.1% to levofloxacin, 10.2% to moxifloxacin and 1.4% to gatifloxacin.  Sitafloxacin was also the most active against XDR-TB. All of the non-MDR-TB strains were susceptible to sitafloxacin.

MIC values were determined from 95 randomly selected clinical strains (35 MDR-TB, 33 pre-XDR and 27 XDR-TB)  . The majority of the strains (85%) had MICs of sitafloxacin of <0.25 μg/ml and all drug-resistant strains were susceptible to sitafloxacin at a concentration of 2 μg/ml. MIC90 for MDR-TB strains was 0.0625 μg/ml while pre-XDR and XDR-TB strains both had MIC90 values of 0.5 μg/ml.

Nucleotide sequencing was carried out in 53 strains with 90.7% of the mutations found at the quinolone resistance determining region (QRDR) of gyrA. Of particular note was the fact that double mutations of gyrA at Ala90Val and Asp94Ala were identified in strains with MIC of 1.0 μg/ml.

These results confirm sitafloxacin to be the most active fluoroquinolone tested against MDR-TB, with a greater in vitro activity against MDR-TB, pre-XDR and XDR-TB than moxifloxacin, gatifloxacin and levofloxacin. It was also stressed that all XDR-TB strains tested were susceptible to sitafloxacin, which was not the case for moxifloxacin, gatifloxacin and levofloxacin. Based on these very positive results the authors advocated carrying out a RCT to evaluate the clinical effectiveness of sitafloxacin in treating MDR- and XDR-TB.

PMID: 29061759

Antimicrob Agents Chemother. 2017 Oct 23. pii: AAC.00825-17. doi: 10.1128/AAC.00825-17. [Epub ahead of print]