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. Tazobactum 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 (EUCAST Clinical Breakpoint Table Version 10.0, valid from 2020-01-01)
For Susceptibility Testing Purposes, the Concentration of Tazobactam is Fixed at 4 mg/l 

Pathogen                                   Species-related breakpoints (S≤/R>) ,mg/L of piperacillin
Enterobacterales (formerly                                      8/16
Enterobacteriaceae )
Pseudomonas aeruginosa                                        <0.001/16 ¹ Staphylococcus species                                             -2 Enterococcus species                                                              -3 


Streptococcus Groups A,B,C,and G                                                  -4 


Sreptococcus pneumoniae                                                           -5 


Viridans group streptococci                                                       -6 


Haemophilus influenza                                                         0.25/0.25 

Moraxella catarrhalis                                                             -7 


Gram -positive anaerobes (except                                                8/16 Clostridioides difficile)

Gram -negative anaerobes                                                         8/16 
Non-species related (PK/PD)                                                     4/16 breakpoints
1 For several agents, EUCAST has introduced breakpoints which categorise wild-type organisms (organisms without phenotypically detectable acquired resistance mechanisms to the agent) as "Susceptible, increased exposure (I)" instead of "Susceptible, standard dosing regimen (S)". Susceptible breakpoints for these organism-agent combinations are listed as arbitrary, "off scale" breakpoints of S ≤ 0.001 mg/L.
2 Most staphylococci are penicillinase producers, and some are methicillin resistant. Either mechanism renders
 them resistant to benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, piperacillin and ticarcillin. Staphylococci that test susceptible to benzylpenicillin and cefoxitin can be reported susceptible to all penicillins. Staphylococci that test resistant to benzylpenicillin but susceptible to cefoxitin are susceptible to β-lactamase inhibitor combinations, the isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin) and nafcillin. For agents given orally, care to achieve sufficient exposure at the site of the infection should be exercised. Staphylococci that test resistant to cefoxitin are resistant to all penicillins.
Ampicillin susceptible S. saprophyticus are mecA-negative and susceptible to ampicillin, amoxicillin and piperacillin (without or with a beta-lactamase inhibitor).
3 Susceptibility to ampicillin, amoxicillin and piperacillin (with and without beta-lactamase inhibitor) can be  inferred from ampicillin. Ampicillin resistance is uncommon in E. faecalis (confirm with MIC) but common in E. faecium.
4 The susceptibility of Streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin
 susceptibility with the exception of phenoxymethylpenicillin and isoxazolylpenicillins for Streptococcus group B. Streptococcus groups A, B, C and G do not produce beta-lactamase. The addition of a beta-lactamase inhibitor does not add clinical benefit.
5
The oxacillin 1 μg disk screen test or a benzylpenicillin MIC test shall be used to exclude beta-lactam resistance mechanisms. When the screen is negative (oxacillin inhibition zone ≥20 mm, or benzylpenicillin MIC ≤0.06 mg/L) all beta-lactam agents for which clinical breakpoints are available, including those with “Note” can be reported susceptible without further testing, except for cefaclor, which if reported, should be reported as “susceptible, increased exposure” (I). Streptococcus pneumoniae do not produce beta-lactamase.
The addition of a beta-lactamase inhibitor does not add clinical benefit. Susceptibility inferred from ampicillin (MIC or zone diameter).
6 For isolates susceptible to benzylpenicillin, susceptibility can be inferred from benzylpenicillin or ampicillin.

For isolates resistant to benzylpenicillin, susceptibility is inferred from ampicillin.
7 Susceptibility can be inferred from amoxicillin-clavulanic acid.
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 (ampicillin -or penicillin -susceptible isolates only) Listeria monocytogenes
Staphylococcus aureus, )methicillin-susceptible isolates only(
Staphylococcus species, coagulase negative, (methicillin-susceptible isolates only) Streptococcus agalactiae (Goup B streptococci) †
Streptococcus pyogenes (GoupA streptococci) †
Aerobic Gram-negative micro-organisms
Citrobacter koseri
Haemophilus influenza
Moraxella catarrhalis
Proteus mirabilis
Anaerobic Gram-positive micro-organisms
Clostridium species
Eubacterium species
Anaerobic gram -positive cocci ††
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
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
Burkholderia cepacian
Legionella species
Ochrobactrum anthropi
Stenotrophomonas maltophilia
Other microorganisms
Chlamydophilia pneumonia
Mycoplasma pneumonia
†
Streptococci are not β-lactamase producing bacteria; resistance in these organisms is due to alterations in penicillin-binding proteins (PBPs) and, therefore, susceptible isolates are susceptible to piperacillin alone. Penicillin resistance has not been reported in S. pyogenes.

††
Including Anaerococcus, Finegoldia, Parvimonas, Peptoniphilus, and Peptostreptococcus spp.

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 tissues and body fluids including intestinal mucosa, gallbladder, 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 that 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.