Bacterial resistance to the cephalosporin compounds can take place by three mechanisms.
* Modifications in target PBP
* Drug inactivation by bacterial β-lactamases
* Drug not being able to reach target PBP in the bacterial cell
Cephalosporins must get through the bacterial cell wall in order to reach the target PBP. In comparison, it is easier to penetrate the cell wall of gram-positive bacteria than the cell wall of gram-negative bacteria. The cell wall structure of gram-positive bacteria is made routinely up by peptidoglycan which allows the passage of cephalosporin-sized molecules. The cell wall structure of gram-negative bacteria is more complex, composed of polysaccharides, lipids and proteins, and is harder to penetrate.  Particles get through the outer membrane through water-filled channels, or porins, which are trans membrane proteins.
During exposure to cephalosporins the bacteria can form resistance by itself or as selection of the next generation of bacteria after reproducing itself, by mutation.
Bacteria species such as pneumococci and meningococci can acquire exogenous genetic material, and incorporate it into their own chromosomes which leads to antimicrobial resistance.
In that manner the target PBP can be altered to have their attraction for cephalosporins and other β-lactam antibiotics lowered. The bacteria can also replace the PBP that is vulnerable to Beta-lactam antibiotics with PBP that is less vulnerable.
β-lactam antibiotics can be inactivated by many types of β-lactamases, which are produced by bacteria. The enzymes hydrolyze the bond between the carbon and nitrogen atom of the β-lactam ring.  There are many beta lactamases which vary in substrate specificity and host range. The enzymes active site is easily regenerated hydrolytically so it is re-usable many times, in that way can a comparatively small amount of beta-lactamases destroy a large amount of drug. Gram-positive bacteria, such as a staphylococci,  have a high release of beta-lactamases into their extracellular space, where they meet the drug outside the cell wall. Gram-negative bacteria on the other hand follow a more conservative course. They secrete their beta-lactamases into the periplasmic space between the inner and outer membrane so they cant easily escape into the extracellular space, and dont have to be biosynthesized in high quantities.