Novel treatment strategies for multidrug-resistant tuberculosis

Tuberculosis is the leading cause of death from a single infectious agent in the world, surpassing the annual death toll of both malaria and HIV combined. The rise in multidrug-resistant tuberculosis (MDR-TB) has further exacerbated the situation, as this form of TB is more difficult and time-consuming to treat, with dismal cure rates. There is an urgent need to improve treatment of MDR-TB and to avoid the development of resistance during TB treatment. This thesis will delve deeper into the intricate relationship of bacterial resistance, drug exposure and host response, with the aim of exploring the role of repurposed drugs, the importance of the level of drug resistance of TB-drugs as well as therapeutic drug monitoring in the fight against TB and MDR-TB.

Repurposing already approved drugs may accelerate the availability of new drug alternatives and two such alternatives were explored in Study I & II. The minimum inhibitory concentration (MIC) in vitro was determined for trimethoprim-sulfamethoxazole and meropenem-clavulanic acid, showing good activity against highly drug-resistant Mycobacterium tuberculosis (M.tuberculosis) isolates. Explorative pharmacometric modelling showed a high probability of target attainment for clinically achievable doses of trimethoprim-sulfamethoxazole (800 mg sulfamethoxazole thrice daily). However, there are no clinical trials evaluating the effect of trimethoprim-sulfamethoxazole in MDR-TB treatment. Meropenem-clavulanic acid is recommended by World Health Organization as an add-on agent in difficult to treat cases.

The importance of the level of bacterial resistance was explored in Study III, a national cohort study in Sweden including all MDR-TB cases from 1992-2014 (no= 158). Increments of MIC for fluoroquinolones, rather than binary resistance testing, were associated with increased risk of unsuccessful treatment outcome. A similar association was seen for increasing age and patients with diabetes. Furthermore, pyrazinamide treatment was associated with reduced time to sputum culture conversion for patients with pyrazinamide-susceptible M.tuberculosis isolates. Bacterial resistance, as well as individual drug exposure, were studied in Study IV, where drug concentrations were measured in a prospective cohort study of susceptible TB. The drug exposure of first-line drugs in TB-patients was often lower than recommended (16-42%), despite the use of recommended dosages. The number of patients with low drug concentrations of rifampicin was particularly pronounced (13/31, 42%), with great inter-individual variability. When taking individual MICs into account, the ratios of drug exposure and the MICs were still low, possibly contributing to the overall successful treatment outcome. Subtherapeutic drug exposure can be revealed by therapeutic drug monitoring. The result of this study has led to the development of a prospective cohort study in China, studying drug exposure in relation to bacterial MIC in MDR-TB patients.

In conclusion, a more holistic approach, taking the level of bacterial susceptibility, individual drug exposure as well as comorbidities into account, is needed for an individualised, improved treatment of TB. For clinicians, therapeutic drug monitoring might be a useful tool for selected patients, with the aim of preventing acquired drug resistance and improving treatment outcome of TB and MDR-TB.

List of scientific papers

I. Davies Forsman L, Schon T, Simonsson USH, Bruchfeld J, Larsson M, Jureen P, Sturegård E, Giske CG, Ängeby K. Intra- and extracellular activities of trimethoprim-sulfamethoxazole against susceptible and multidrug-resistant Myobacterium tuberculosis. Antimicrobial agents and chemotherapy. 2014;58(12):7557-9.
https://doi.org/10.1128/AAC.02995-14

II. Davies Forsman L, Giske CG, Bruchfeld J, Schon T, Jureen P, Angeby K. Meropenem-clavulanic acid has high in vitro activity against multidrug- resistant Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy. 2015;59(6):3630-2.
https://doi.org/10.1128/AAC.00171-15

III. Davies Forsman L, Jonsson J, Wagrell C, Werngren J, Mansjö M, Wijkander M, Groenheit R, Hammar U, Giske CG, Schön S, Bruchfeld J. Minimum inhibitory concentrations versus clinical outcome in MDR-TB patients - a nationwide Swedish cohort study over two decades. [Submitted]

IV. Niward K, Davies Forsman L, Bruchfeld J, Chryssanthou E, Carlstrom O, Alomari T, Carlsson B, Pohanka A, Mansjö M, Jonsson Nordvall M, Johansson AG, Eliasson E, Werngren J, Paues J, Simonsson USH, Schön T. Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting. J Antimicrob Chemother. 2018;73(10):2838-45.
https://doi.org/10.1093/jac/dky268