Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.

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Isoniazid, administered as part of combination antituberculosis therapy, is responsible for most of the early bactericidal activity (EBA) of the regimen. However, the emergence of Mycobacterium tuberculosis resistance to isoniazid is a major problem. We examined the relationship between isoniazid exposure and M. tuberculosis microbial kill, as well as the emergence of resistance, in our in vitro pharmacodynamic model of tuberculosis. Since single-nucleotide polymorphisms of the N-acetyltransferase-2 gene lead to two different clearances of isoniazid from serum in patients, we simulated the isoniazid concentration-time profiles encountered in both slow and fast acetylators. Both microbial kill and the emergence of resistance during monotherapy were associated with the ratio of the area under the isoniazid concentration-time curve from 0 to 24 h (AUC 0-24 ) to the isoniazid MIC. The time in mutant selection window hypothesis was rejected. Next, we utilized the in vitro relationship between the isoniazid AUC 0-24 /MIC ratio and microbial kill, the distributions of isoniazid clearance in populations with different percentages of slow and fast acetylators, and the distribution of isoniazid MICs for isonazid-susceptible M. tuberculosis clinical isolates in Monte Carlo simulations to calculate the EBA expected for ϳ10,000 patients treated with 300 mg of isoniazid. For those patient populations in which the proportion of fast acetylators and the isoniazid MICs were high, the average EBA of the standard dose was ϳ0.3 log 10 CFU/ml/day and was thus suboptimal. Our approach, which utilizes preclinical pharmacodynamics and the genetically determined multimodal distributions of serum clearances, is a preclinical tool that may be able to predict the EBAs of various doses of new antituberculosis drugs.In the 21st century, tuberculosis is still responsible for 3% of all human deaths (45). First-line antituberculosis therapy consists of isoniazid, pyrazinamide, and rifampin. It is thought that isoniazid kills the largest population of Mycobacterium tuberculosis, which represents bacilli in log-phase growth, after which pyrazinamide kills the slower-growing population of bacilli in acidic milieus and rifampin kills nonreplicating bacilli (4,23,29,33). Isoniazid microbial kill ceases after 2 to 3 days of therapy. As a result, isoniazid's microbial kill in patients is measured using an index termed early bactericidal activity (EBA), which is the average rate of sputum bacillary decline during the first 2 days of therapy (10, 23). It is also believed that the cessation of kill is due to depletion of bacilli in the log phase of growth. However, we recently demonstrated that this early cessation of kill by isoniazid is due to the emergence of an isoniazid-resistant population (20). The pharmacokineticpharmacodynamic (PK-PD) relationship between isoniazid exposure and the emergence of resistance is, as yet, unknown.The pharmacokinetics and pharmacogenomics of isoniazid in humans have been well characterized. The concentration of isonia...

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