W e read with great interest the mathematical model presented by Fofana et al. (1) on the role of pyrazinamide (PZA) in the emergence of multidrug-resistant tuberculosis (MDR TB), particularly as the results of their model mirror our concerns regarding the amplification of PZA resistance during inappropriate first-line therapy and the dramatic negative consequences that this can have on the subsequent response to second-line therapy. Indeed recent data from Belarus suggest that approximately 50% of PZA resistance is acquired de novo (2). Fofana et al. (1) propose that this problem, a result of using the same important agent in first-and second-line therapy, might be circumvented by using an as-yet-unidentified new agent with characteristics similar to those of PZA in a new second-line regimen. Although considerable effort is being applied to the development of new targets for such agents (3), it is far from certain when or even if these miraculous drugs will be available for routine use. Consequently, PZA is currently a uniquely valuable agent, which we speculate will be very difficult to replace (4, 5). We therefore suggest that in settings where the a priori risk of MDR TB due to transmission is above a certain level, such as in Belarus, prescribing PZA to new patients before they have been screened for rifampin and isoniazid resistance is likely counterproductive. Screening for PZA resistance is still complicated and not in reach for many laboratories. Of course, in an ideal world, a full drug susceptibility test (DST) profile would be available for all patients before TB therapy is prescribed. Unfortunately, in reality, this is seldom the case; at best, there is a considerable delay before DST results are communicated to the physician, and at worst, DST is not performed at all until there is evidence of treatment failure, which may be between 2 and 6 months after starting the patient on first-line agents. As this scenario appears to account for 50% of the PZA resistance seen in MDR-TB cases in many settings (5), action is required now to prevent transmissible PZA-resistant mutants from becoming widely established (6, 7). Thus, we propose that, in settings with a high proportion of MDR-TB patients, PZA be withheld until there is evidence of susceptibility to other first-line agents, because of either a clinical response (acid-fast bacillus [AFB] smear conversion) or a solid laboratory diagnosis. Modeling the exact proportion of primary MDR-TB patients in whom PZA resistance was prevented, a population benefitting from this change, and discussion of the ethics of this approach would be highly informative. Delaying action Citation Anthony RM, Cynamon M, Hoffner S, Werngren J, den Hertog AL, van Soolingen D. 2017. Protecting pyrazinamide, a priority for improving outcomes in multidrug-resistant tuberculosis treatment. Antimicrob Agents Chemother 61:e00258-17. https://doi.

Mycobacterium tuberculosis strains resistant to almost all available anti-tuberculosis drugs are an increasing threat to public health worldwide. Among existing drugs with potential antimycobacterial effects, the combination of meropenem with clavulanate has been shown to have potent in vitro bactericidal activity against extensively drug-resistant tuberculosis (XDR-TB). To explore its potential clinical efficacy, a meropenem-clavulanate-containing salvage regimen was started in six patients with severe pulmonary XDR-TB, in association with the only one or two remaining active second-line drugs. Encouraging preliminary data are detailed and discussed.

Ongoing transmission, high levels of drug resistance, and poor diagnostic

The combination of meropenem with clavulanate has high antimycobacterial activity in vitro against extensively drug-resistant Mycobacterium tuberculosis strains. We report the successful use of this combination in association with linezolid in the management of an advanced extensively drug-resistant tuberculosis disease with complex second-line drug resistance in a 14-year-old teenager.

Background: Immunotherapy represents a recent milestone in the treatment of lung cancer, particularly with the rapidly expanding development of monoclonal antibodies targeting checkpoint inhibitors in the programmed cell death-1 (PD-1) pathway, such as nivolumab and pembrolizumab. Classical auto-immune side effects of these treatments, often called immune-related adverse events (irAEs), can affect multiple organs, including the lungs in which potentially life-threatening pneumonitis may require rapid treatment with high doses of corticosteroids. Nevertheless, the occurrence of severe infections in cancer patients treated with nivolumab, outside the context of immunosuppressive therapy, is a complication that has rarely been reported in the literature. Clinical cases: We report two cases of severe pulmonary infection with unusual microbes, Mycobacterium tuberculosis and Aspergillus fumigatus, in patients treated with nivolumab for non-small cell lung cancer. Conclusion: Ruling out pulmonary infections may require extensive investigation, as these may have an atypical presentation due to immunomodulation. Furthermore, treating the patient with corticosteroids for immune-related pneumonia could lead to a fatal outcome in this context. This report highlights the importance of excluding the presence of opportunistic infections and tuberculosis before considering immune-related pulmonary toxicity with or without a history of prior corticosteroid use. These cases also emphasize the potential value of tuberculosis screening in patients treated with PD-1 checkpoint inhibitors.