In a series of studies, we have recently formulated a simple QM/MM model based on an electrostatic embedding coupling in periodic boundary conditions (PBC) between ab initio density functional theory (DFT) and fixed-charge MM forcefields, allowing efficient MD simulations using the microcanonical (NVE), canonical (NVT) and isobaric isothermal (NPT) thermodynamic ensembles. Analytic derivatives in our model scale linearly with the number of MM atoms. Still, long dynamics are usually limited by the computational cost of DFT, which is one of the main bottlenecks of ab initio QM/MM MD. Semi-empirical based QM/MM methods have been extensively exploited in the literature to alleviate the electronic structure bottlenecks. Among them, density functional-based tight-binding (DFTB) has been shown to predict relatively accurate free energy barriers compared to ab initio calculations in the gas phase, or at the QM/MM level. Nam, Gao, and York proposed a coupling of a semiempirical QM/MM scheme with PBC for the first time in 2005. The method described the representation of QM density in the replica cells by employing Mulliken charges and used the Ewald summation method, which has since then become a gold standard to handle the long-range character of electrostatic interactions in QM/MM methods adapted to PBC. Since then, PBC-adapted QM/MM models using semi-empirical methods flourished, with several implementations using either methods derived from Hartree-Fock, or DFTB. Here, we formulate a new electrostatic embedding model based on DFTB coupled to a fixed-charge MM environment in PBC, including the energy and analytic gradients, and allowing covalently bonded QM-MM interfaces. The combined efficiency of DFTB and the linear-scaling electrostatic embedding QM/MM formulation allows for a proper model equilibration and sampling of phase space, especially suited for the reactivity of enzymes and other biomacromolecules. To show this, we apply the DFTB/MM in PBC to three types of mechanisms in aqueous solution: (i) the cis/trans isomerization of proline, (ii) the water-assisted proton transfer in pterin, and (iii) the SN2 reaction of sodium fluoride with chloromethane.