First-line TB treatment: Faropenem rivals ethambutol in efficacy, with fewer side effects

Faropenem, when used in combination with the other standard treatment drugs for the first-line treatment of tuberculosis (TB) infection, appears to be noninferior to ethambutol, with faropenem having the added benefit of lower frequency of adverse events (AEs), according to the results of an open-label study in China.

When faropenem was used instead of ethambutol in the first-line background regimen (isoniazid, rifampicin, pyrazinamide, and ethambutol), the difference in the 6-month treatment success rate ranged from 2.1 percent (95 percent confidence interval [CI], −5.31 to 5.72) to 2.2 percent (95 percent CI, −6.73 to 11.13). [Int J Infect Dis 2023;doi:10.1016/j.ijid.2023.04.388]

In the modified intention-to-treat (mITT) population, 88.18 percent of patients in the faropenem group and 85.98 percent of those in the control ethambutol group achieved treatment success at 6 months. The corresponding treatment success rates in the per-protocol (PP) population were 96.04 percent and 95.83 percent.

Additionally, the faropenem and ethambutol groups had comparable sputum examination results and cure rates.  Culture conversion by the end of 8 weeks was reported in 81.81 percent of patients with faropenem and 78.50 percent with ethambutol in the mITT population (p=0.61), and in 85.15 percent and 83.33 percent, respectively, in the PP population (p=0.84).

Meanwhile, cure at 6 months was documented in 79.09 percent of patients in the faropenem group and in 71.03 percent in the ethambutol group in the mITT population (p=0.21), and in 86.14 percent and 79.17 percent, respectively, in the PP population (p=0.26). 

Ethambutol-associated ocular toxicity averted

“An interesting observation of the study is that the faropenem [regimen] had a significantly fewer total number of AEs than the [standard] control regimen (31.81 percent vs 49.53 percent; p<0.01),” according to the investigators.

Hepatoxicity was the most common AE, with three patients in the faropenem group and five in the control group experiencing grade 3 hepatotoxicity.

“Almost all the hepatotoxicity events occurred within the first month of treatment, and the patients experienced mildly elevated transaminases, which reverted back to normal after glycopyrrolate treatment,” they added.

Other AEs included loss of appetite, leukopenia, rash, diarrhoea, and nausea and vomiting, among others. The frequency of these AEs did not differ between the two treatment groups.

The only difference was found in the frequency of visual impairment, which is a side effect of ethambutol. None of the patients in the faropenem group experienced any visual impairment, whereas five patients in the ethambutol did (0 percent vs 4.67 percent; p=0.02). [Int Ophthalmol 2010;30:63-72]

“Of note, the proportion of visual impairment in our study with ethambutol was … higher than the optic neuropathy expected, which is about 1 percent, at a dose of 15 mg/kg ethambutol. The reason for [this] was that [all] patients with subjective symptoms, such as blurred vision, reduced visual acuity, visual fatigue, and eye dryness but no objective ophthalmologic abnormalities, were included in the AE reports for safety concerns,” according to the investigators.

“Also, the dosage of ethambutol was adjusted according to body weight (15-20 mg/kg), which is higher than the dose of 15 mg/kg,” they added.

Clinicians have expressed concerns about the ocular toxicity associated with ethambutol, particularly in patients who are at high risk, such as those with older age, underweight, or kidney disease. So, the finding that replacing ethambutol with faropenem can not only achieve a comparable therapeutic effect on TB but also avoid ethambutol-associated ocular toxicity with fewer side effects has important implications, the investigators pointed out.

Potential drawbacks

Faropenem is a novel oral beta-lactam antibiotic that belongs to the penem group, which is structurally similar to the carbapenems. The drug has previously shown clinical activity against nonreplicating Mycobacterium tuberculosis (Mtb) strains in vitro. [Antimicrob Agents Chemother 2015;59:5714-5720]

“The reason that the faropenem group had a similar cure rate to the control group may be due to the strong bactericidal effect of faropenem or the presence of a synergistic bactericidal effect of faropenem with other drugs, such as rifampin,” the investigators said. [J Antimicrob Chemother 2017;72:2012-2019; Antimicrob Agents Chemother 2015;59:6561-6567]

“Our study reveals the potential of faropenem in the treatment of TB and provides some basis for further study,” they added.

However, the investigators admitted that replacing ethambutol in the standard regimen with faropenem may come with certain disadvantages, such as the lack of a fixed dose combination and the impact of widespread use of a broad-spectrum antibiotic on the development of drug resistance.

“More clinical experience needs to be accumulated for the application of faropenem in anti-TB treatment,” they said.