Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties
Pharmacotherapeutic group
Benzylpenicillin (Penicillin G) is a semi-synthetic, beta-lactamase-sensitive, beta-lactam antibiotic.

ATC code: J01CE01

Mechanism of action
The For benzylpenicillin, the mechanism of action is based on inhibition of bacterial cell wall synthesis (during the growth phase) through a blockade of penicillin-binding proteins (PBPs) such as transpeptidases. This results in a bactericidal action.
 pharmacokinetic /pharmacodynamic relationship
Efficacy largely depends on the length of time that the active substance level remains above the pathogen`s MIC.

Resistance mechanisms
Resistance to benzylpenicillin may be due to the following mechanisms: − Inactivation by beta-lactamases: Benzylpenicillin is sensitive to beta-lactamase and is therefore inactive against beta-lactamase-producing bacteria (e.g. staphylococci or gonococci).


−   Reduced affinity of PBPs for benzylpenicillin: The acquired resistance in pneumococci and a few other streptococci to benzylpenicillin is due to modifications of existing PBPs as a result of a mutation. However, the formation of an additional PBP with reduced affinity for benzylpenicillin is responsible for resistance in methicillin (oxacillin)-resistant staphylococci .
−   In Gram-negative bacteria, inadequate penetration of benzylpenicillin through the outer cell wall can lead to an insufficient inhibition of PBPs.
−   Benzylpenicillin can be actively transported from the cell by efflux pumps. .
Benzylpenicillin is partially or completely cross-resistant to other penicillins and cephalosporins.

Breakpoints
Testing of benzylpenicillin is performed using the standard dilution series. results are evaluated on the basis of breakpoints for benzylpenicillin. The following minimum inhibitory concentrations have been established for susceptible and resistant germs: 


EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints (version 10.0)
PATHOGEN                                        SUSCEPTIBLE     RESISTANT 
Staphylococcus aureus                     ≤ 0.125 mg/L          > 0.125 mg/L Streptococcus spp.
(Groups A, B, C, G)                        ≤ 0.25 mg/L          > 0.25 mg/L 
Streptococcus pneumoniae
(indications other than                    ≤ 0.06 mg/L          > 2 mg/L meningitis)

Streptococcus pneumoniae
≤ 0.06 mg/L          > 0.06 mg/L
(meningitis)

Streptococci of the "viridans" group                                      ≤ 0.25 mg/L          > 2 mg/L Neisseria meningitidis                     ≤ 0.06 mg/L          > 0.25 mg/L Neisseria gonorrhoeae                      ≤ 0.06 mg/L          > 1 mg/L Gram-negative anaerobes                    ≤ 0.25 mg/L          > 0.5 mg/L Gram-positive anaerobes                    ≤ 0.25 mg/L          > 0.5 mg/L Listeria monocytogenes                         ≤ 1 mg/L         > 1 mg/L Pasteurella multocida                        ≤ 0.5 mg/L         > 0.5 mg/L Corynebacterium spp.                      ≤ 0.125 mg/L          > 0.125 mg/L Aerococcus sanguinicola and               ≤ 0.125 mg/L          > 0.125 mg/L Kingella kingae                            ≤ 0.03 mg/L          > 0.03 mg/L PK/PD (Non-species related) breakpoints *                              ≤ 0.25 mg/L          > 2 mg/L 

Prevalence of acquired resistance
The prevalence of acquired resistance in individual species may vary geographically and over time. Thus, local information on the resistance situation is required, particularly for the adequate treatment of severe infections. If based on the local resistance situation, the efficacy of benzylpenicillin is questionable, expert therapeutic advice should be sought.
Particularly in cases of serious infection or unsuccessful therapy, a, microbiological diagnosis should be sought, with the detection of the pathogen and its susceptibility to benzylpenicillin.
Prevalence of acquired resistance based on data from the past 5 years from national resistance monitoring projects and studies (version: April 2019):
Commonly susceptible species
Aerobic Gram-positive micro-organisms
Actinomyces israeli °
Corynebacterium diphtheriae °
Erysipelothrix rhusiopathiae °
Gardnerella vaginalis °
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Streptococcus dysgalactiae subsp. equisimilis (group
C & G streptococci)
Streptococci of the “viridians” group ° ∧
Aerobic Gram-negative micro-organisms
Borrelia burgdorferi°
Eikenella corrodens ° $
Haemophilus influenzae ° $
Neisseria meningitidis °
Anaerobic micro-organisms
Clostridium perfringens °
Clostridium tetani °
Fusobacterium spp. °
Peptoniphilus spp. °
Peptostreptococcus spp. °
Veillonella parvula °
Other micro-organisms
Treponema pallidum °
Species in which acquired resistance may pose a problem during use
Aerobic Gram-positive micro-organisms
Enterococcus faecalis $
Staphylococcus aureus +
Staphylococcus epidermidis +
Staphylococcus haemolyticus +
Staphylococcus hominis +
Aerobic Gram-negative micro-organisms
Neisseria gonorrhoeae $
Naturally resistant species
Aerobic Gram-positive micro-organisms
Enterococcus faecium
Nocardia asteroides
Aerobic Gram-negative micro-organisms
All Enterobacterales species
Legionella pneumophila
Moraxella catarrhalis
Pseudomonas aeruginosa
Anaerobic micro-organisms
Bacteroides spp.
Other micro-organisms
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.
° At the time of the publishing of the table, no current data were available. . Susceptibility is assumed in the primary literature, standard works and therapeutic recommendations.
$ The natural susceptibility of most isolates is within the intermediate range.
+ In at least one region, the resistance rate is over 50%.
∧
Collective name for a heterogeneous group of streptococci species. The resistance rate can vary depending on the streptococci species present.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties
Absorption
Benzylpenicillin is not acid-stable and can therefore only be administered parenterally The alkali salts of benzylpenicillin are rapidly and completely absorbed after IM. injection.
Peak plasma levels of 150-200 1U/mL are reached 15 - 30 min. after IM. injection of 10 MU of Penicillin G-Sodium. After a short infusion (30 min.), peak levels of up to 500 IU/mL may be reached. About 55% of the administered dose is bound to plasma proteins.

Distribution
When administering high-dose penicillin therapy, therapeutically effective concentrations are reached even in poorly accessible tissues such as cardiac valves, bone, cerebrospinal fluid or empyema, etc.
Benzylpenicillin crosses the placenta. 10-30% of maternal plasma concentrations are found in the fetal circulation. High concentrations are also attained in the amniotic fluid. On the other hand, passage into breast milk is low. The volume of distribution is about 0.3-0.4 l/kg; in children, about 0.75 l/kg. Plasma protein binding is approximately 55%.

Biotransformation and elimination
Elimination occurs largely (50–80%) as unchanged substance via the kidneys (85–95%) and, to a lesser degree, in active form with the bile (approximately 5%).
The plasma half-life is approximately 30 minutes in adults with healthy kidneys.

Kinetics of special patient groups
 Diabetics Absorption from the intramuscular depot is likely to be delayed in diabetics. .
 Pre-term and newborn infants: Due to the immaturity of the kidney and liver at this age, the serum half-life can be up to three hours (or more). The dosing interval should therefore be no less than 8–12 hours (depending on maturity).
 Elderly: Equally, elimination processes may be delayed with advanced age; the dosage should therefore be adjusted to renal function in each individual case.