Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, tetracyclines, ATC code: J01A A08

Minocycline is a broad spectrum antibiotic used for the treatment of infections caused by tetracycline-sensitive organisms. Some tetracycline-resistant strains of Staphylococci are also sensitive.

Minocycline should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.


Mechanism of action
Minocycline inhibits protein synthesis in susceptible bacteria. In common with other tetracyclines it is primarily bacteriostatic and has a similar spectrum of activity to other tetracyclines.

Breakpoints
The general MIC breakpoint to identify organisms susceptible to minocycline is < 0.5 mg/l. All organisms for which the MIC of minocycline is > 1 mg/l are considered resistant (European Committee on Antimicrobial Susceptibility Testing (EUCAST)).
EUCAST Recommendations

Organi sm/Species                  MIC breakpoints (mg/L)
Susceptible,     Resistant (R >) standard dosing regimen (S <)

Staphylococcus spp.                      0.51                 0.51 Streptococcus groups A, B, C             0.51                 0.51 and G
Streptococcus pneumoniae                 0.51                 0.51 Haemophilus influenzae                    11                   11 Moraxella catarrhalis                     11                   11 Neisseria meningitidis                    12                   12 
1
Isolates susceptible to tetracycline are also susceptible to doxycycline and minocycline, but some resistant to tetracycline may be susceptible to minocycline and/or doxycycline. An MIC method should be used to test minocycline susceptibility of tetracycline resistant isolates if required.
2
Tetracycline can be used to predict susceptibility to minocycline for prophylaxis against N. meningitidis infections.


Susceptibility testing for Enterobacterales, Pseudomonas spp., Enterococcus spp.
and Viridans group streptococci is not recommended as the species is a poor target for therapy with the agent. Isolates may be reported as R without prior testing.

For Acinetobacter spp. Neisseria gonorrhoeae and PK-PD (Non-species related) breakpoints there is insufficient evidence that the organism or group is a good target for therapy with the agent. An MIC with a comment but without an accompanying S, I or R categorisation may be reported.

For anaerobic bacteria there is clinical evidence of activity in mixed intraabdominal infections, but no correlation between MIC values, PK-PD data and clinical outcome.
Therefore no breakpoints for susceptibility testing are given.

Susceptibility
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable. Minocycline is usually active in vitro against Propionibacterium acnes, which is implicated in the pathogenesis of acne.


Resistance
Bacterial resistance to the tetracyclines is now common in some species and usually involves cross-resistance between the different tetracyclines.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption:
Minocycline is readily absorbed from the GI tract and is not significantly affected by the presence of food or moderate amounts of milk as other tetracyclines. Absorption may be impaired by the concomitant administration of iron salts or antacids containing calcium, magnesium or aluminium salts. Normal doses of 200mg followed by 100mg every 12 hours produced plasma concentrations within the range of 1- 4μg/ml.

Distribution:
Minocycline is reported to be more lipid-soluble than doxycycline and the other tetracyclines and to be widely distributed in body tissues and fluids. High concentrations being achieved in the hepatobiliary tract, lungs, sinuses and tonsils, as well as in tears, saliva, and sputum. Penetration into cerebrospinal fluid is relatively poor, although a higher ratio of CSF to blood concentrations has been reported with minocycline than with doxycycline. It crosses the placenta and diffuses into milk of nursing mothers. About 75% of minocycline in the circulation is bound to plasma proteins. The plasma half-life tends to be prolonged in patients with severe renal impairment. It has a lower renal clearance than doxycycline and its plasma half- life ranges from 11-23 hours.

Biotransformation:
In contrast to most tetracyclines, minocycline appears to undergo some metabolism in the liver, mainly to 9-hydroxyminocycline. It is also excreted in bile.

Elimination:
About a third of the drug may be excreted unchanged and although figures vary widely, about a third of this unchanged drug may appear in the urine and two thirds in the faeces.