Older antibiotics should be reviewed for potential labeling updates regarding their efficacy against certain pathogens, members of FDA's Anti-Infective Drugs Advisory Committee said July 11.

"What within the regulatory process would enable the agency to reconsider looking backwards for drugs that may be approved now for indications that in our heart of hearts we have great questions about [whether] they do what they say they do?" Anti-Infective Drugs Advisory Committee Chair Barth Reller, MD, Duke University Medical Center, asked at a July 11 meeting. "Maybe this is for a future meeting," Reller added.

Anti-Infective Drug Products Division Director Janice Soreth, MD, responded, "I think there are a couple mechanisms and a couple of databases to try to answer" the question about whether products, "which we approve at one point in time [continue to be] safe and efficacious in current times."

FDA is looking into using its spontaneous adverse event reporting system and surveillance data on infectious isolates to evaluate the continued efficacy or lack of efficacy of antibiotics.

Queries can be done "of this spontaneous reporting system and [FDA can] marry that information to usage data in a crude attempt to...understand within a drug class or across drug classes, etc., whether or not something that used to work might not still be working." Soreth said.

FDA has "surveillance data that tell us [about] recurrent isolates and recurrent antibiotics and old antibiotics: what theoretically should still be covered and what ought not to be covered from isolates from those people who had real infections," she added.

The spontaneous reporting system codes for "lack of efficacy, for infections one may get as the result of taking an antibiotic," Soreth said.

FDA has already proposed to remove in vitro data from labeling if the data have not been clinically validated (¹ Also see "In Vitro Data Not Relevant To Clinical Use Should Be Cleared From Label - FDA" - Pink Sheet, 1 January, 2001., p. 15).

The committee met to discuss clinical study designs for antibiotics to treat acute otitis media. [For a ² webcast of the meeting, visit FDAAdvisoryCommittee.com].

Few agents are currently marketed that cover the three major pathogens in acute otitis media (H. influenzae, S. pneumoniae, M. catarrhalis), Michael Jacobs, MD, PhD, Case Western Reserve University, told committee members.

"We have a great need for new drugs. Hopefully [with] the situation with pneumococcals, as we expect, resistance will decrease because of the [pneumococcal conjugate] vaccine," Jacobs said. Wyeth's seven-valent pneumococcal conjugate vaccine Prevnar was introduced in February 2000. However, "we don't know whether replacement organisms are going to develop resistance," he added.

Currently available agents vary significantly in achieving parameters necessary for bacterial eradication, Jacobs noted. However, it has been difficult to show differences between agents in most clinical outcomes trials conducted to date. He urged the committee to consider the use of pharmacokinetic and pharmacodynamic parameters that correlate with bacteriological and clinical outcomes to distinguish therapies.

Jacobs presented PK/PD microbiological data on certain drugs to show the variation in potential resistance.

"Ciprofloxacin ( Cipro and generics), one of the original quinolones, is very active against H. influenzae, but [has] inadequate activity against S. pneumococcus," Jacobs noted. However, "I know it is still approved for pneumococcal infections to this day."

Microbiological data show that Pfizer's Zithromax (azithromycin) has activity against many S. pneumoniae and M. catarrhalis strains but much less against H. influenzae, Jacobs noted. Zithromax, however, is approved for H. influenzae infections.

Aventis' Ketek (telithromycin), which is still in development in the U.S., has microbiological activity "very similar to that of azithromycin, potency wise, but again, the PK/PD breakpoint has not been fairly well-established. There's a lot of potential for resistance to emerge," Jacobs maintained.

Aventis has completed a 24,000-patient respiratory tract infection study to support approval of Ketek.

Antibiotic Labeling Revisions For Changes In Efficacy Suggested By Cmte.

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