One expert’s solution: Skip the PZA
A group of 17 patients being treated for possible multidrug-resistant TB infection had so many aches, pains, stomach troubles, and other miseries with the regimen of levofloxacin and pyrazinamide that all 17 had to stop treatment, according to a study published recently by a group of Canadian researchers.1
Similar difficulties have popped up before with the same regimen, says Rick O’Brien, MD, chief of the research and evaluation branch of the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention. Current guidelines on the subject concede the absence of expert agreement over how to treat latent MDR-TB, adding that "watchful waiting" is an acceptable alternative to treatment, at least when contacts are immune-competent and otherwise not at high risk, O’Brien adds.2
Better yet, just give the levofloxacin, but hold that pesky pyrazinamide (PZA), says John Sbarbaro, MD, professor of medicine at the university of Colorado Health Sciences Center in Denver. Not only is PZA the culprit behind the side effects, it also fails to add anything of value, he contends. "What are you killing with PZA?" he asks rhetorically. "In every study we’ve ever done looking at what happens at the molecular level, we’ve found the bugs have to be outside the cell for PZA to work; but with latent infection, all the bugs are inside the macrophages."
Call out the Mounties: 1,500 contacts
What triggered the events that led to the Canadian study was the discovery of two patients with MDR-TB. The index case was found to be resistant to five drugs, including ethambutol — which meant that using that drug in combination with PZA, the other combination the guidelines suggest — wasn’t going to work. In addition, the index case had active TB since he’d arrived in the country nine months earlier — leaving plenty of time for him to expose some 1,500 contacts, all of whom had to be identified and screened. Of the 17 contacts who ultimately began treatment for latent TB, all suffered at least one adverse event, researchers report — from aching joints to gastro-intestinal complaints to headaches and skin problems. Five contacts also had a rise in liver enzymes more than twice the upper limit of normal, the researchers note.
The problem, the Canadians conjecture — and the Americans agree — is that both drugs are competing for the same transport mechanism in the kidneys, inhibiting excretion and allowing blood levels to rise. "The levo blocks the PZA, with the result that you get an elevated PZA level," says Sbarbaro. "The solution is to just skip the PZA. But for contacts where the risk is high, you want to use something that’s going to work. So just give the levo" — or, he adds, maybe moxifloxacin, which some clinicians feel is even more powerful against TB.
References
1. Papastavros T, Dolovich LR, Holbrook A, et al. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis. CMAJ 2002; 167:131-136.
2. ATS/CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000; 49(RR06):1-54.
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