<unk>  irreversibly binds to the enzyme penicillin-binding proteins, inhibiting the biosynthesis of bacterial cell walls. Mechanism of action As a β-lactam antibiotic,<unk>  inhibits penicillin-binding proteins, preventing the spread of bacteria and infections. Responsible for catalyzing the cross-linkage between peptidoglycan strands that protect the bacterial cell from osmotic rupture, penicillin-binding proteins are unique to bacterial organisms, where every known bacteria with a peptidoglycan cell wall consists of homologous sub-families. By sharing a similar stereochemistry with the substrates that bind to penicillin-binding proteins,<unk>  is able to bind to serine residues found at the active site of the enzyme through the formation of a covalent complex, preventing other substrates from binding. Moreover, this leads to the release of autolysins that break down the bacteria's cell wall. Some β-lactamase enzymes also consist of residue at their active site, enabling them to hydrolyze the β-lactam ring found within these antibiotics. However, this hydrolytic activity is inhibited when<unk>  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<unk>  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<unk> -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,<unk> -tazobactam treatment for such is not recommended. Antibiotic resistance occurs sporadically, conferred by the continuous use of<unk> -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<unk>  and therefore high resistance to<unk> -tazobactam. Furthermore, mutations in penicillin-binding proteins cause fluctuations in<unk>  affinity, whereas Streptococcus pneumoniae (PBP-2b) autolytic response is significantly reduced due to decreased affinity with<unk> . Although membrane permeability changes are less common as a mechanism of resistance, studies investigating Klebsiella pneumoniae have reported a correlation between decreased permeability of<unk>  and increased SHV-1 β-lactamase production. Pharmacokinetics<unk>  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<unk>  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<unk> -tazobactam excretion, and endangering patients to drug exposure. 2.25g vial of<unk> -tazobactam power used in IV injection. Produced by SANDOZ. 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<unk> /tazobactam excretion, measuring down to 35% of the initial dosage, while the area under the curve (AUC) for<unk>  increased by about three folds for those with less than 20ml/min. A reduced dosage or alteration in the interval of administration is recommended for patients lying under 40ml/min of CrCl, depending on the severity of dysfunction. Renal is the main pathway for drug elimination for both tazobactam and<unk>  in the body. While there are other non-renal means of drug elimination like Hepatobiliary excretion, they occur less frequently. A substantial amount (~80%) of<unk>  found in urine when excreted through glomerular and tubular filtration is unmetabolized. Tazobactam renal elimination may be significantly reduced through<unk>  interaction, dropping from 63.7% to 56.8% of the administered dose over a 24-hour period.<unk>  may be actively diffused through filtration into the biliary tract during renal clearing, indicated by a generally higher concentration of<unk>  than tazobactam in the bile. The metabolites that make up the remaining percentage in the excreted urine are composed of M1 (inactive) and N-desethyl-piperacillin (active), formed from the division of β-lactam rings of both tazobactam and<unk>  respectively. Due to the hydrophilic nature of<unk> -tazobactam, a volume distribution of ~15 L amounting to various sites (tissues) is desired, as hydrophilic compounds are not able to pass through plasma membranes as easily as hydrophobic compounds. Concentrations often in the range of 90 MIC or above are located in specific areas including the gallbladder, lung, muscle, and skin, making up 16 - 85% of the plasma concentrations. The concentration of<unk> -tazobactam is especially lower in fatty tissue, making up less than 10% of the plasma concentrations. Pharmacodynamics Compared to concentration dependent bactericidal antibiotics like aminoglycosides and fluoroquinolones, the antibacterial activity of β-lactam antibiotics are generally more time dependent. Unlike the former, when<unk> -tazobactam concentrations exceed minimum inhibitory concentrations (MIC) of a pathogen by five folds, the exponential relationship between concentration and activity begins to level off. Otherwise,<unk> -tazobactam bactericidal efficacy is shown to consist of a strong association with the duration of time the concentration exceeds minimum inhibitory concentrations (T>MIC). When the T>MIC in the serum equates to 60 - 70% of the frequency for drug administration (dosing interval), maximal activity is achieved against Gram-negative bacteria, while for Gram-positive bacteria it occurs at around 40 - 50%. Within a 24-hour period in one clinical study, a T>MIC surpassing 60% was found for<unk> -susceptible bacteria including Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus in two dosing regimes (4.5g every 8 hours and 3.375g every 8 hours). The evidence for this was obtained through Monte Carlo experiments procured by a special program (OPTAMA), where for several different scenarios (e.g. hospital acquired infections, secondary peritonitis, skin or soft tissue infections), the probability of attaining those figures were in the ranges of 85 - 95% and 90 - 89% respectively for the two regimes. In addition, two similar dosing regimes (3.375g and 4.5g every 6 hours) both had lower chances of reaching the 90% T>MIC threshold compared to the 50% threshold against hospital acquired pneumonia pathogens. The optimization of<unk> -tazobactam drug efficiency has been covered by various studies, limiting the focus down to two types of infusions; continuous and intermittent. A comparison using the two administration methods under the same dosage regime of 13.5g per day highlighted no major differences when treating complex intra-abdominal infections. Furthermore, a follow-up analyzation of this trial deduced that both methods of administration lead to higher concentrations compared to the MIC of the pathogens that were used. Similar results are found in a study where a select number of β-lactam susceptible pathogens consisting of Enterococcus faecalis, Klebsiella pneumoniae and Citrobacter freundii were used to test a ~10g every 24 hour dosing interval for continuous infusion. Organisms with a<unk> -tazobactam MIC values equal to 32 or less than 16ml/I lead to 50% T>MIC when extended-interval intermittent administrations under two different dosing intervals (8.1g and 6.75g every 12 hours) were used against them. The pharmacodynamic target attainments corresponding to pathogens with MIC values of 16 mg/I are found to reach 92% when a more traditional 4 hour dosing regime is utilized to administer at irregular intervals. One study using the Monte Carlo simulation produced contradicting results to the previous studies, deducing that inadequate pharmacodynamic targets were achieved (T>MIC > 50%) for similar ESBL-producing bacteria, applying to both continuous and high dosage intermittent infusion.
Piperacillin
Cloxacillin
Resistin
Carbenicillin
Cefazolin
Ampicillin
Dicloxacillin
Vancomycin