Learning from our failures: the antifungal treatment conundrum.

Received 30 January 2008; accepted 30 January 2008; electronically published 24 March 2008. Reprints or correspondence: Dr. John R. Wingard, 1376 Mowry Rd., Ste. 145, PO Box 103633, Gainesville, FL 326103633 ([email protected]). Clinical Infectious Diseases 2008; 46:1434–5 2008 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2008/4609-0017$15.00 DOI: 10.1086/587102 It is often said that we learn more from our failures than from our successes. Certainly, there is truth to this adage with regard to antifungal therapy. There is much for us to learn from antifungal treatment failure. Although it is hard to accept failure, all too often, it is even harder to recognize failure in antifungal therapy. Clinical and radiological criteria of treatment response are flawe by considerable subjectivity, and they have not been well validated in clinical studies. The criteria commonly used in clinical practice and in clinical trials have been developed largely from the judgments of “experts.” Although such criteria are well reasoned, they are imprecise, and sometimes, reliance on such criteria may unwittingly mislead us. Clinical deterioration often occurs as immune reconstitution in the host occurs, which, ironically, is one of the most important facets of ultimate recovery and therapy success, not failure. This has been observed in cryptococcal meningitis in several different types of patients [1–3]. Moreover, radiological studies of tissueinvasive fungal infections, such as invasive aspergillosis, show that infiltrate attributable to the infection typically worsen during treatment before eventual improvement; such “worsening” is as much attributable to host inflammatio as to microbial activity [4, 5]. Are microbiological indicators of response much better? Results of follow-up cultures of blood samples from patients with bloodstream or disseminated fungal infections may be negative during therapy, yet these results do not reliably indicate microbial eradication in deep tissues. Moreover, serial cultures are often not an option for judging the microbiological status of deep-tissue infections, because invasive tests to obtain tissue samples at repeated intervals are not practical. Why does antifungal treatment failure occur? One obvious reason may be that antimicrobial resistance and failure attributable to drug resistance clearly do occur. But there is a gap between the numbers of instances in which resistant fungal pathogens are isolated before or during the course of therapy (relatively infrequent) and the numbers of instances of treatment failures (much more frequent). This gap indicates that many therapy failures are not attributable to drug resistance. A drug may fail even when it is active against the pathogen if there are insufficien drug concentrations systemically or at the site of infection; certainly, this may account for some of this gap between drug resistance and treatment failure. Yet, in many instances of treatment failure, the host may be responsible for treatment failure. In the absence of some measure of host defenses (more than a modicum) to figh infection, no antifungal drug will keep an invasive infection at bay for long. Unfortunately, criteria of attribution of treatment failure to either the drug or the host are not well developed, and criteria are certainly not well validated. Again, we rely on expert opinion all too often to arbitrate this in the context of clinical trials. How long should a clinician wait to see whether response is occurring, and what are the optimal criteria by which a clinician should judge success and failure? Waiting too long is bad: if the infection is too far advanced, a midcourse corrective action is unlikely to succeed. Being precipitous in declaring failure is also bad: abandoning effective first-lin therapy needlessly is risky, because the prospect for success with a second-line therapy is likely to be lower (or the treatment more toxic), and if an investigational therapy is chosen, the prospects are uncertain at best. Moreover, we may attribute the eventual success to the “salvage” therapy when it was actually the primary therapy that set the stage for recovery, although the salvage therapy was initiated before