4.3.2. Sanfetrinem

*Activity.* Sanfetrinem is a tricyclic β-lactam developed by GlaxoSmithKline in the 1990s. Sanfetrinem has broad-spectrum activity against Gram-negative and Gram-positive bacteria. Sanfetrinem is also very stable to β-lactamases and to human renal dehydropeptidase (DHP) [258]. The MICs for sanfetrinem against *M. tuberculosis* H37Rv ranged from 1.25 to 5 μm with clavulanate (2.5 to 7.5 μm without clavulanate). In a checkerboard assay, the combination of sanfetrinem with RIF or amoxicillin was synergistic, but not with delamanid or ethambutol. Sanfetrinem cilexetil is an oral prodrug ester of sanfetrinem and has an MIC ranging from 5 to 20 μm with clavulanate (7.5 to 20 μm without clavulanate) against *M. tuberculosis*. The compounds performed better against intracellular *M. tuberculosis*. In THP1 monocytes, the MIC for sanfetrinem and sanfetrinem cilexetil ranged from 2.1 to 7.7 μm without clavulanate (6.1 to 8.8 μm with clavulanate) and 3.4 to 7.0 μm without clavulanate (4.6 to 5.3 μm with clavulanate), respectively. In a mouse model of acute *M. tuberculosis* infection, DHP-1 KO mice were infected intratracheally with *M. tuberculosis* H37Rv. Treatment started 9 days post infection, twice a day, for 5 days. Sanfetrinem was given subcutaneously, while sanfetrinem cilexetil

and clavulanate were given orally. Growth arrest but not killing of *M. tuberculosis* was observed during this five-day treatment [259].

*Clinical trial.* A phase 2a clinical study is projected to start the first quarter of 2021 [260].
