this hydrolytic activity is inhibited when piperacillin works in conjunction with tazobactam. Tazobactam binds to these enzymes to form a stable acyl-enzyme complex; similar to one formed during the hydrolysis of the β-lactam ring. Thus, protecting piperacillin from hydrolysis. The inclusion of a β-lactamase inhibitor does not always increase drug efficacy. Some bacteria may produce certain types of β-lactamase such as AmpC, which are intrinsically resistant to tazobactam. Mechanisms of resistance A major mechanism of resistance against piperacillin-tazobactam is Gram-negative bacteria producing β-lactamases. Other currently known mechanisms include mutations in the active site of penicillin-binding proteins, changes in membrane efflux, or bacteria permeability. Some enzymes, such as extended-spectrum β-lactamase (ESBL) have evolved from narrow-spectrum β-lactamases due to genetic mutations, increasing their capabilities to hydrolyze much broader spectrum penicillin. Due to prior conflicting reports on the drug's affinity with ESBL-producing bacteria, piperacillin-tazobactam treatment for such is not recommended. Antibiotic resistance occurs sporadically, conferred by the continuous use of piperacillin-tazobactam in situations where it may prove to be ineffective, leading to cases where plasmid-mediated β-lactamases are being produced in bacteria that do not naturally produce it. Some Gram-positive bacteria penicillin-binding proteins such as Enterococcus faecium (PBP-5) or Staphylococcus aureus (PBP-2a) are intrinsically antibiotic resistant, consisting of relatively low affinity with piperacillin and therefore high resistance to piperacillin-tazobactam. Furthermore, mutations in penicillin-binding proteins cause fluctuations in piperacillin affinity, whereas Streptococcus pneumoniae (PBP-2b) autolytic response is significantly reduced due to decreased affinity with piperacillin. Although membrane permeability changes are less common as a mechanism of resistance, studies investigating Klebsiella pneumoniae have reported a correlation between decreased permeability of piperacillin and increased SHV-1 β-lactamase production. Pharmacokinetics Piperacillin is generally available in their stable form as crystallized potassium or sodium salt, quickly losing bactericidal activity upon dissolution due to their short half-lives. As the gastrointestinal tract does not absorb piperacillin and tazobactam, they are dissolved in a solution before being administered to a patient, through parenteral means. Excreted through renal mechanisms like glomerular or tubular filtration as a component of urine, uncontrolled dosages of the drug can cause renal dysfunction and competitive inhibition of excretion, delaying piperacillin-tazobactam excretion, and endangering patients to drug exposure. Although the distribution of the drug remained the same, the half-life for elimination increased by three to five folds for patients diagnosed with renal dysfunction. Measured by creatinine clearance (CrCl), patients with less than 30ml/min of clearance had significantly reduced levels of