Quinolones show promise of much shorter therapy; a match with RFP seen
Drugs pack big punch — with staying power
TB researchers are taking a hard new look at an old friend — a family of antibiotics known as quinolones. The drugs may have star potential as first-line agents, many experts have begun to believe, thanks to data suggesting many quinolones have potent sterilizing activity. As an added bonus, they have long half-lives, suggesting they may be good companion drugs for rifapentine (RFP).
At a recent meeting of TB researchers at the National Institutes for Health in Bethesda, MD, recently published data from a trial in Chennai, India, was one cause for excitement.1 In the trial, Indian researchers added ofloxacin — an older quinolone well-known to TB clinicians — to induction regimens containing three other first-line agents. The results were impressive: Following durations of treatment ranging from the usual six months to just three, the two-month culture conversion rates ranged from 92% to 98%.
"That’s unprecedented," says William J. Burman, MD, an infectious disease specialist at the Denver Medical Health Center. The two-month conversion rates of the Chennai study, along with some convincing unpublished data, suggest that most quinolones may have kill-power rivaling that of rifampin (RIF). "Rifampin’s king, and I don’t know whether even a quinolone could dethrone it," Burman says. Still, he adds, "if something like the Chennai trials could be repeated here, does that mean we could increase two-month conversion rates by 10%?"
If so, quinolones might point the way to shorter therapy. Alternatively, and maybe just as good, quinolones might serve as linchpins for regimens entailing markedly less frequent therapy.
Researchers at the Tuberculosis Trials Consortium (TBTC) are also keen to team a quinolone with RFP, the drug with the long-half life approved in 1998 for TB treatment. The TBTC is the investigator-led collaboration funded by the Centers for Disease Control and Prevention in Atlanta.
Two scenarios combining RFP with a quinolone (plus two other first-line agents) pop up in conversations with Burman and with Rick O’Brien, MD, head of the research and evaluation branch at the CDC’s Division of TB Elimination.
Burman envisions a three-month regimen of daily therapy — period. In the Chennai trial, for example, one group of patients was treated for just three months with daily doses of ofloxacin, INH, RIF, and PZA. That group’s culture negativity at two months was 92%.
O’Brien thinks it might be possible to use a quinolone along with RFP to achieve a super-short induction phase of perhaps just two weeks, followed by once-weekly therapy for six months.
Along with their apparent talent for sterilization, the other compelling aspect of quinolones is their long half-life.
According to Burman, unpublished data suggest that adding a quinolone to once-weekly RFP therapy might close the performance gap TBTC researchers uncovered when they teamed RFP with isoniazid (INH) in once-weekly doses during the continuation phase of therapy. When analysts mulled over possible causes for the shortfall between that intervention and standard twice-weekly therapy, some decided the problem was that the RFP dose wasn’t high enough.
But others, Burman among them, are starting to think the problem isn’t RFP at all, but instead INH, with a half-life much shorter than that of RFP. "INH may not be the right companion drug," Burman explains. "It’s a tremendous mismatch in terms of half-life."
One of the newer quinolones, moxifloxacin, has a half life that almost equals that of rifapentine. Another newcomer, gatifloxacin, has a half-life that’s just a little less. Unpublished data from animal experiments show adding moxifloxacin to once-weekly RFP therapy "adds a lot of punch," Burman notes.
Ironically, the drugs causing all the fuss are already quite familiar to TB clinicians. Ofloxacin and levofloxacin in particular are well-respected members of the battery of second-line agents available for treating patients with drug-resistant disease. There are plenty of safety data on levofloxacin. Unfortunately, data are scanty for long-term use of most other quinolones.
That poses a problem that will have to be addressed before work can proceed further, says Burman. "We’ve tried telling the FDA and the drug companies how we use quinolones in TB treatment all the time for long-term treatment," he says. "But they say they’re still worried about side effects, and that they need more data."
That means the first work the TBTC does on quinolones will probably have to be a small Phase II safety and tolerability trial that looks at two-month culture conversion rates as well as safety. Given that several quinolones have been pulled from the market because of serious side effects, being patient makes good sense, Burman concedes.
The other question that needs to be answered before bigger trials can proceed is which quinolone to use. In animal studies, moxifloxacin and gatifloxacin seem to be more pharmacologically active than ofloxacin, says Burman; they also appear to out-perform levofloxacin in low doses. At the higher dose, levofloxacin looks as if it works about as well as the two newer quinolones, says Burman.
The other hurdle, predictably, is money. "If we don’t get more of it, we won’t be doing any trials at all on quinolones this year," says Burman.
Meanwhile, the TBTC is poised to start enrolling patients in a trial of RFP and INH given in 12 once-weekly doses to those latently infected with TB. The trial will enroll 8,000 patients. The comparison arm will be nine months of daily INH, O’Brien says.
Reference
1. Controlled clinical trial for the treatment of sputum positive pulmonary tuberculosis with regimens containing ofloxacin. TRC Annual Report 1999-2000: 24.
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