Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Combinations of penicillins incl. beta-lactamase inhibitors; ATC code: J01C R05 


Mechanism of action
Piperacillin, a broad spectrum, semisynthetic penicillin exerts bactericidal activity by inhibition of both septum and cell-wall synthesis.

Tazobactam, a beta-lactam structurally related to penicillins, is an inhibitor of many beta-lactamases which commonly cause resistance to penicillins and cephalosporins but it does not inhibit AmpC enzymes or metallo beta-lactamases. Tazobactam extends the antibiotic spectrum of piperacillin to include many beta-lactamase- producing bacteria that have acquired resistance to piperacillin alone.

Phamacokinetic / Pharmacodynamic relationship

The time above the minimum inhibitory concentration (T>MIC) is considered to be the major pharmacodynamic determinant of efficacy for piperacillin.

Mechanism of resistance

The two main mechanisms of resistance to piperacillin/tazobactam are: 
• Inactivation of the piperacillin component by those beta-lactamases that are not inhibited by tazobactam: beta-lactamases in the Molecular class B, C and D. In addition, tazobactam does not provide protection against extended-spectrum beta- lactamases (ESBLs) in the Molecular class A and D enzyme groups.

• Alteration of penicillin-binding proteins (PBPs), which results in the reduction of the affinity of piperacillin for the molecular target in bacteria.

Additionally, alterations in bacterial membrane permeability, as well as expression of multi-drug efflux pumps, may cause or contribute to bacterial resistance to piperacillin/tazobactam, especially in Gram-negative bacteria.

Breakpoints

EUCAST Clinical MIC Breakpoints for Piperacillin/Tazobactam (2009-12-02, v 1). For Susceptibility Testing Purposes, the Concentration of Tazobactam is Fixed at 4 mg/l Pathogen                  Species-related breakpoints (S /R>) Enterobacteriaceae                                            8/16 Pseudomonas                                                   16/16 Gram-negative and                                             8/16 Gram-positive anaerobes
Non-species related                                           4/16 breakpoints
The susceptibility of streptococci is inferred from the penicillin susceptibility.
The susceptibility of staphylococci is inferred from the oxacillin susceptibility.

Susceptibility

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.

Groupings of relevant species according to piperacillin/tazobactam susceptibility
COMMONLY SUSCEPTIBLE SPECIES
Aerobic Gram-positive micro-organisms
Enterococcus faecalis
Listeria monocytogenes
Staphylococcus aureus, methicillin-susceptible£
Staphylococcus species, coagulase negative, methicillin-susceptible Streptococcus pyogenes
Group B streptococci
Aerobic Gram-negative micro-organisms
Citrobacter koseri
Haemophilus influenza
Moraxella catarrhalis
Proteus mirabilis
Anaerobic Gram-positive micro-organisms
Clostridium species
Eubacterium species
Peptostreptococcus species
Anaerobic Gram-negative micro-organisms
Bacteroides fragilis group
Fusobacterium species
Porphyromonas species
Prevotella species
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive micro-organisms
Enterococcus faecium$,+
Streptococcus pneumonia
Streptococcus viridans group
Aerobic Gram-negative micro-organisms
Acinetobacter baumannii$
Burkholderia cepacia
Citrobacter freundii
Enterobacter species
Escherichia coli
Klebsiella pneumonia
Morganella morganii
Proteus vulgaris
Providencia ssp.
Pseudomonas aeruginosa
Serratia species
INHERENTLY RESISTANT ORGANISMS
Aerobic Gram-positive micro-organisms
Corynebacterium jeikeium
Aerobic Gram-negative micro-organisms
Legionella species
Stenotrophomonas maltophilia+,$
Other microorganisms
Chlamydophilia pneumonia
Mycoplasma pneumonia
$ 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.
£ All methicillin-resistant staphylococci are resistant to piperacillin/tazobactam.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
The peak piperacillin and tazobactam concentrations after 4 g / 0.5 g administered over 30 minutes by intravenous infusion are 298 µg/ml and 34 µg/ml respectively.

Distribution

Both piperacillin and tazobactam are approximately 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, gall bladder, lung, bile and bone. Mean tissue concentrations are generally 50 to 100% of those in plasma. Distribution into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins.

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

Elimination

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

Piperacillin is excreted rapidly as unchanged substance 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 substance 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 slightly reduce the clearance of tazobactam.

Special populations
The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects.

The half-life of piperacillin and tazobactam increases with decreasing creatinine clearance. The increase in half-life is two-fold and four-fold for piperacillin and tazobactam, respectively, at creatinine clearance below 20 ml/min compared to patients with normal renal function.

Haemodialysis removes 30% to 50% of piperacillin/tazobactam, with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 18% of the tazobactam dose removed as the tazobactam metabolite.


Paediatric population
In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) ml/min/kg. The piperacillin clearance estimate is 80% of this value for paediatric patients 2-9 months of age. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) l/kg and is independent of age.

Elderly patients
The mean half-life for piperacillin and tazobactam were 32% and 55% longer, respectively, in the elderly compared with younger subjects. This difference may be due to age-related changes in creatinine clearance.
Race
No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4 g / 0.5 g doses.