An important—but sometimes difficult to quantify—characteristic of a drug is ‘‘forgiveness.’’ Forgiveness (F) is defined as the difference between the medication’s postdose duration of beneficial action (D) and the prescribed dosing interval (I): F 5 D – I [1]. In plain words, it directly relates to the number of doses that can be skipped without causing detectable disease relapse. Forgiveness arises by 2 major mechanisms: prolonged inhibitory effect of the drug on its target (pharmacodynamics [PD]) and/or prolonged halflife of the drug at the site of action (pharmacokinetics [PK]). Drug forgiveness has been characterized in several disease areas in which rebound can be measured noninvasively with a readout that accurately reflects the pharmacological effect of the drug in real time. Examples are b blockers, antihypertension drugs, and anti–human immunodeficiency virus (HIV) agents. The emergence of drug-resistant bacteria is a special form of such rebound. When antimicrobial treatment is too short to achieve complete sterilization, but long enough to eradicate the more drugsensitive microbes, it leaves the less sensitive ones able to multiply when treatment lapses. This phenomenon has been observed during drug holidays with an HIV protease inhibitor [2], and it is well accepted— although not formally proven—as a major factor in the emergence of multidrugresistant tuberculosis [3–5]. Nonadherence to a recommended antituberculosis regimen is not a spotty phenomenon but an integral part of long-term pharmacotherapy with multiple agents, each having its own set of adverse effects. In an attempt to mitigate this issue, the World Health Organization implemented the Directly Observed Therapy program in the 1990s, to ensure adherence by integrating the supervision of antituberculous drug administration by a healthcare worker, family, or community member, as 1 of 5 components to improve disease control (http://www.health.state. mn.us/divs/idepc/diseases/tb/dot.html). Measuring the impact of omitted doses on drug action classically requires blinded substitution of placebo for active drug, combined with frequent pharmacological measurements. Anti-tuberculosis drug forgiveness has not been explored for ethical, technical, and clinical reasons. Quantifying drug action is challenging because of the difficulty of measuring real-time bacterial regrowth or emergence of drugresistant populations in pulmonary lesions, and the lack of validated surrogate markers in circulating fluids. The problem is further compounded by the combinatorial nature of anti-tuberculosis therapy, the presence of multiple bacterial populations that are likely to be killed more or less effectively by any given drug [6], the slow and largely unknown regrowth rate of Mycobacterium tuberculosis in various lesion types, and the fact that disease severity is driven by the immune system in response to pathogen exposure (rather than by the bacterial load per se). In this issue of the Journal, the group of Tawanda Gumbo (Srivastava et al) reports the surprising results of a study in which an elegant in vitro model was used to evaluate, for the first time, the forgiveness of a standard tuberculosis drug regimen (isoniazid, rifampicin, and pyrazinamide). The hollow fiber system is an in vitro PD model, in which M. tuberculosis is exposed to simulated serum concentration-time profiles that mimic those encountered in humans. In this case, daily administration of the 3-drug combination was simulated for 4–6 weeks. The objective was to determine whether poor adherence, in the form of simulated drug holidays, would lead to incomplete sterilization and/or emergence of drug resistance. Interestingly, none of the nonadherence schemes mimicked in the hollow fiber system led to the development of resistance to any of the 3 study drugs, with resistance defined as .1% of the total bacterial population. Even more surprising, .60% of simulated nonadherence was required to observe incomplete Received and accepted 1 September 2011. Correspondence: Veronique Dartois, PhD, Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01, Singapore 138670 (veronique.dartois@novartis.com). The Journal of Infectious Diseases 2011;204:1827–9 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com 0022-1899 (print)/1537-6613 (online)/2011/20412-0003$14.00 DOI: 10.1093/infdis/jir662