Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of penicillins, including beta-lactamase inhibitors.

ATC Classification: J01CR05

Mechanism of action:
Piperacillin, a broad spectrum, semisynthetic penicillin active against many Gram-positive and Gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many beta-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of tazobactam in the Piperacillin/Tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many beta-lactamase producing bacteria normally resistant to it and other beta-lactam antibiotics. Thus, Piperacillin/Tazobactam combines the properties of a broad spectrum antibiotic and a beta-lactamase inhibitor.

Mechanism of resistance:

The presence of tazobactam expands the spectrum of activity of piperacillin to include microorganisms that would otherwise, due to the formation of beta-lactamase, be resistant to piperacillin and other beta-lactam antibiotics. In vitro investigation has demonstrated that the type I beta-lactamase inducing ability of tazobactam is insignificant with regard to Gram- negative bacteria. In vitro studies have demonstrated a synergetic effect of Piperacillin/Tazobactam and aminoglycosides against Pseudomonas aeruginosa and other bacteria, including beta-lactamase producing strains.

Breakpoints

The minimum inhibitory concentration (MIC) breakpoints separating susceptible, intermediately susceptible and resistant organisms have been defined as follows: 
EUCAST clinical MIC breakpoints 2008 (version 1.2):

For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/L
Pathogen                                          Species-related breakpoints (S) 
Enterobacteriaceae                                8/16

Pseudomonas                                       16/16
Gram-negative and Gram-positive anaerobes         8/16

Non-species related breakpoints                   4/16

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Gram positive aerobes
Brevibacterium spp

Enterococcus faecalis

Listeria monocytogenes
Staphylococcus spp. methicillin-sensitive

Streptococcus pneumoniae

Streptococcus pyogenes
Group B streptococci
Streptococcus spp*

Gram negative aerobes

Branhamella catarrhalis
Citrobacter koseri

Haemophilus influenzae*

Haemophilus spp.
Proteus mirabilis

Salmonella spp.

Shigella spp.
Gram positive anaerobes

Clostridium spp.

Eubacterium spp.
Peptococcus spp.

Peptostreptococcus spp.

Gram negative anaerobes
Bacteroides fragilis*

Bacteroides fragilis group

Fusobacterium spp.
Porphyromonas spp.

Prevotella spp*

Species for which resistance may be a problem
Gram positive aerobes

Staphylococcus aureus, methicillin-sensitive

Staphylococcus epidermis, methicillin-sensitive
Enterococcus avium ($)

Enterococcus faecium (+ $)

Propionibacterium acnes ($)
Viridans streptococci
Gram negative aerobes

Actinobacter spp (+ $)

Burkholderia cepacia
Citrobacter freundii

Enterobacter spp.

Escherichia coli *
Klebsiella spp.

Proteus, indole positive

Pseudomonas aeruginosa*
Pseudomonas spp. *

Pseudomonas stutzeri $

Serratia spp.
Gram negative anaerobes

Bacteroides spp. *

Inherently resistant organisms
Gram positive aerobes

Corynebacterium jeikeium
Staphylococcus spp. methicillin resistant

Gram negative aerobes
Legionella spp
Stenotrophomonas maltophilia +$

* Clinical effectiveness against this has been demonstrated in the registered indications.

($) Species showing natural intermediate susceptibility
(+) Species for which high resistance rates (more than 50%) have been observed in one or more areas/countries/regions within the EU.


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Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Distribution
Peak piperacillin and tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion or injection. Piperacillin plasma levels produced when given with tazobactam are similar to those attained when equivalent doses of piperacillin are administered alone.

There is a greater proportional (approximately 28%) increase in plasma levels of piperacillin and tazobactam with increasing dose over the dosage range of piperacillin/tazobactam 2000/250 mg to piperacillin/tazobactam 4000/500 mg.

Both piperacillin and tazobactam are 20 to 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.

Piperacillin/Tazobactam is widely distributed in tissue and body fluids including intestinal mucosa, gallbladder, lung, bile and bone.

Biotransformation

Piperacillin is metabolised to a minor microbiologically active desethyl metabolite.
Tazobactam is metabolised to a single metabolite, which has been found to be micro- biologically inactive.

Elimination

Piperacillin and tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion.

Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose appearing as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile.

Following single or multiple doses of Piperacillin/Tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. The elimination half-lives of both piperacillin and tazobactam are increased with decreasing renal clearance.

There are no significant changes in piperacillin pharmacokinetics due to tazobactam.
Piperacillin appears to reduce the rate of elimination of tazobactam.

Impaired Renal Function
Piperacillin and tazobactam are haemodialysable: 31% (piperacillin) and 39% (tazobactam) of administered doses are filtrated. During peritoneal dialysis, 5% of administered piperacillin and 12% of administered tazobactam are found in the dialysis liquid. Patients treated by chronic ambulatory peritoneal dialysis should receive the same dose as non dialysed patients with severe renal insufficiency.

Impaired Liver Function

Plasma concentrations of piperacillin and tazobactam are prolonged in hepatically impaired patients. The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, dosage adjustments in patients with hepatic impairment are not necessary.
Paediatric patients

The pharmacokinetics of Piperacillin/Tazobactam has been studied in paediatric patients with intra-abdominal infections and other kinds of infections. In every age group, renal fraction of elimination of piperacillin and tazobactam was approximately 70% and 80%, respectively, like in adults.

Mean pharmacokinetic parameters of Piperacillin/Tazobactam of paediatric patients of different age groups.
Piperacillin                                           Tazobactam 
Age group             Half-life      Clearance         Half-life          Clearance (ml/min/kg)                          (ml/min/kg)

2-5 years             0.7            5.5               0.8                5.5

6-12 years            0.7            5.9               0.9                6.2 

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