Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other aminoglycosides, 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 sulphate is determined both on the basis of units and also on the basis of mass (weight). The following relationships apply: 
1 mg is equivalent to 628 I.U. or 1 I.U. is equivalent to 0.00159 mg gentamicin sulphate.

For its international standard substance, the WHO specifies a specific activity of 614 I.U./mg gentamicin sulphate.

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
 2 mg/l               > 4 mg/l breakpoints*

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 enterolitica
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 (septicaemia, 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 bodyweight, 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 bodyweight 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 bodyweight means that for adequate peak blood concentration a higher dose per kg bodyweight 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 foetal 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.

Children have a shorter half-life and higher clearance rates compared to adult patients.
In neonates up to three weeks of age, the serum half-life is extended by about 1/3 and the elimination rate is reduced because of immature renal function. Elimination half life averages approximately 8 hours in neonates at a gestational age of 26 to 34 weeks compared with about 6.7 hours in neonates at a gestational age of 35 to 37 weeks. Correspondingly, clearance values increase from about 0.05 l/h in neonates at a gestational age of 27 to 0.2 l/h in neonates at a gestational age of 40 weeks.

An accumulation of gentamicin occurs in the tubular cells of the renal cortex. A terminal half-life of 100 – 150 hours results from a release of gentamicin from this deep compartment.

Elimination occurs independent of dose. Far in excess of 90% of the substance is eliminated via the kidneys.
Only about 2% of the dose administered is excreted extrarenally in normal renal function. The total clearance is approximately 0.73 ml × min-1 × kg-1.
In patients with impaired renal function the elimination half-life is prolonged depending on the degree of renal impairment. Adherence to the standard treatment program results in accumulation of the drug.

Gentamicin is dialysable.
During extracorporeal haemodialysis, depending on the duration of the dialysis, 50% - 80% of the gentamicin is removed from the serum. Peritoneal dialysis is also possible; here the elimination half-lifes are between 12.5 and 28.5 hours and 25% of the dose is removed within 48 to 72 hours (see section 4.2).