Reply to Datta, “Is static or cidal antibiotic falsifiable?”

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REPLY

We would like to thank Dr. Datta (1) for his interest in our article (2). Dr. Datta wishes to defend the static vs. cidal antibiotic model against “absolutist framing.” He invokes “mono-parametric” assays like “MBC/MIC ratios or…reactive oxygen species generation” to suggest that in vitro static vs. cidal phenomenology may be phenotypically real.

However, MBC/MIC ratios and reactive oxygen species generation have never been demonstrated to predict different efficacy in vivo. Indeed, as we summarized, 60 randomized controlled trials (RCTs) definitively demonstrated that the static/cidal framing of antibiotics specifically does not predict differences in clinical efficacy (2). RCTs are the most reliable means of dealing with complexity when evaluating the effect of an intervention (i.e., a drug). Ironically, the points Dr. Datta raised actually reinforce our central message: in vivo clinical efficacy depends on pharmacokinetic/pharmacodynamic parameters, site of infection, immune status, and tissue penetration, and not on the static/cidal classification of an antibiotic.

More fundamentally, as we emphasized in our letter, static antibiotics do kill bacteria, contrary to the connotation of the term “static.” The term “bacteriostatic” originated in the 1920s, before even sulfonamides were available, based on crude, macroscopic visualization of the effect of colored dyes on bacterial colonies (3). The term was never subsequently updated, such that it is still incorrectly used to imply that an antibiotic inhibits bacterial replication without killing the bacteria.

Thus, irrespective of any assays based on “mono-”, “multi-”, or any other Latin multiple of “-parametric,” we reiterate that the terms static and cidal are archaic, misleading, and incorrect. Furthermore, given their tendency to push clinicians toward potentially harmful care decisions—such as adding aminoglycosides to improve a presumed “cidal effect,” or refusing to use static linezolid to treat bacteremia or endocarditis despite compelling data demonstrating its clinical efficacy (4–6)—this classification should be abandoned.

Finally, Datta quotes the philosopher Popper to make the point that the hallmark of a scientific hypothesis is falsifiability and suggests that we have not left the question of static/cidal open to future evidence. However, given how often in vitro constructs have failed to translate to clinical efficacy, the burden of proof must shift to those who wish to advance the relevance of in vitro paradigms. Indeed, Popper also said, “Every scientific theory must be subjected to severe tests; it must be put to the test to see whether it withstands attempts at falsification.” (7). That is precisely what we did, thereby demonstrably falsifying the static/cidal theorem via rigorous investigation.

Thus, the static vs. cidal myth should be retired until new, compelling data become available that somehow are able to supersede 60 concordant RCTs demonstrating that it is of no clinical relevance. And even in the highly unlikely event that were to occur, the term “static” would need to be rebranded so as to avoid the false implication that the antibiotic inhibits cell division without killing the bacteria.