Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterial for systemic use

ATC code: J01GB03

Gentamicin is an aminoglycoside antibiotic extracted from Micromonospora purpurea.
It represents a mixture of the structurally very similar homologues gentamicin C1, C1a and C2. The gentamicin homologue C2 is classified as the component with the highest toxicity. The antibacterial activity of gentamicin sulfate is determined both on the basis of units and also on the basis of mass (weight).

Mechanism of action
Gentamicin has bactericidal efficacy both in the proliferation and in the resting stage of bacteria. It forms a bond with the proteins of the 30S subunits of the bacterial ribosomes, which causes “misreading” of the mRNA.
PK/PD relationship

The aminoglycosides show a concentration dependent anti-bacterial effect Gentamicin and other aminoglycosides show a clear post-antibiotic effect in vitro and in vivo in most experimental models of infection. Provided sufficiently high doses are administered, these drugs are therefore efficacious against infections with many susceptible micro-organisms even if the concentration in plasma and tissues remains below the MIC during part of the dosage interval. The post-antibiotic effect permits the dosage interval to be extended without loss of efficacy against most Gram-negative bacilli.

Mechanism of resistance
Resistance may be due to a failure of permeation, low affinity for the bacterial ribosome or inactivation of gentamicin by microbial enzymes. The emergence of resistance during therapy is unusual.

Breakpoints
According to EUCAST, the following limit values apply for gentamicin: 
Pathogen                   Susceptible              Resistant
Enterobacteriaceae                           2 mg/l                > 4 mg/l Pseudomonas spp.                             4 mg/l                > 4 mg/l Acinetobacter spp.                           4 mg/l                > 4 mg/l Staphylococcus spp.                          1 mg/l                > 1 mg/l Non-species-related breakpoints*             2 mg/l                > 4 mg/l 
* 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. Especially in such circumstances, samples should be obtained in order to identify the causal micro- organism and to measure its sensitivity to gentamicin.

Commonly susceptible species (according to EUCAST)
Aerobic Gram-positive micro-organisms
Listeria monocytogenes
Staphylococcus aureus (MSSA)
Aerobic Gram-negative micro-organisms
Campylobacter coli
Campylobacter jejuni
Citrobacter koseri
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Francisella tularensis
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus vulgaris
Salmonella enterica subsp. enterica
Serratia marcescens
Yersinia enterocolitica
Yersinia pseudotuberculosis
Species for which acquired resistance may be a problem
Aerobic Gram-positive micro-organisms
Staphylococcus aureus (MRSA)
Staphylococcus epidermidis
Staphylococcus haemolyticus                    Staphylococcus hominis
Aerobic Gram-negative micro-organisms
Acinetobacter spp.
Citrobacter freundii
Morganella morganii
Proteus mirabilis
Pseudomonas aeruginosa
Inherently resistant organisms
Aerobic Gram-positive micro-organisms
Enterococcus faecalis
Enterococcus faecium
Streptococcus spp.
Aerobic Gram-negative micro-organisms
Burkholderia cepacia
Legionella pneumophila
Stenotrophomonas maltophilia
Anaerobic micro-organisms
Bacteroides spp.
Clostridium difficile
Others
Atypical pathogens
Chlamydia spp.
Chlamydophila spp.
Mycoplasma spp.
Ureaplasma urealyticum

Abbreviations:
MSSA = Methicillin-sensitive Staphylococcus aureus
MRSA = Methicillin-resistant Staphylococcus aureus
Infections caused by Streptococci or Enterococci:
Aminoglycosides are suitable combination partners for other antibiotics against Gram-positive cocci. For some indications (endocarditis), synergistic effects with beta-lactams have been described. This synergy is abolished when Streptococci or Enterococci present a high level acquired resistance to gentamicin.
Other notes:
Synergistic effects have been described with acylamino penicillins (e.g. piperacillin) on Pseudomonas aeruginosa and with cephalosporins on Klebsiella pneumoniae.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Like all aminoglycoside antibiotics, gentamicin is barely absorbed by healthy intestinal mucosa after oral administration. Therefore, therapeutic application is parenteral.

Higher peak and lower trough levels are found when the total daily dose is given as a single daily infusion. When gentamicin is administered by intravenous short infusion of 30 minutes at 4 mg/kg body weight per day in three divided doses, peak and trough gentamicin concentrations measured in adult patients were 4.7 µg/ml and 1.0 µg/ml, respectively. With the same daily dose administered once daily, peak and trough concentrations of 9.5 µg/ml and 0.4 µg/ml were measured.

Therapeutic serum concentrations generally lie between 2 and 8 µg/ml. Therapeutic peak serum concentrations are in the range of 5 – 10 µg/ml for multiple daily dosing and 20 – 30 µg/ml for once daily dosing. Maximum serum concentrations of 10 – 12 µg/ml should not be exceeded when administered conventionally, in several doses per day. Before another dose is administered, the serum concentration when administered conventionally, in several doses per day, should have fallen below 2 µg/ml.

Distribution
The distribution volume of gentamicin is about equivalent to the volume of extracellular water. In the newborn water makes up 70 to 75% of body weight, compared with 50 to 55% in adults. The extracellular water compartment is larger (40% of body weight compared with 25% of body weight in adults). Therefore, the volume of distribution of gentamicin per kg body weight is affected and decreases with increasing age from 0.5 to 0.7 l/kg for a premature newborn to 0.25 l/kg for an adolescent. The larger volume of distribution per kg body weight means that for adequate peak blood concentration, a higher dose per kg body weight needs to be administered.

The distribution of gentamicin to the individual organs results in varying tissue concentrations; the highest concentrations appear in the renal tissue. Smaller concentrations are found in the liver and gall bladder, the lung and spleen.

Gentamicin crosses the placenta; the fetal concentrations can be 30% of the maternal plasma concentrations. Gentamicin is excreted in small quantities in breast milk (1/3 of the concentration is found here, as in the case of the maternal plasma).

After repeated injection of gentamicin, approximately 50% of the concentrations reached in plasma is measured in the synovial, pleural, pericardial and peritoneal fluid.
The penetration of gentamicin into the cerebrospinal fluid is poor in un-inflamed meninges. In inflamed meninges, concentrations reach up to 30% of the concentrations measured in plasma.

Plasma protein binding: less than 10%.
Biotransformation
Gentamicin is not metabolised in the organism but is excreted unchanged in microbiologically active form.

Elimination
Gentamicin is eliminated unchanged in microbiologically active form principally in the urine by glomerular filtration. The dominant elimination half-life in patients with normal renal function is around 2 – 3 hours. Elderly patients eliminate gentamicin more slowly than younger adults.