TETRALYSAL Hard capsule Ref.[27953] Active ingredients:

Pharmacotherapeutic group: Tetracyclines
ATC code: J01AA04

Mode of action

Tetracyclines provide bacteriostatic action at the available plasma and tissue concentrations and are effective against intracellular and extracellular organisms. Their mechanism of action is based on an inhibition of ribosomal protein synthesis. Tetracyclines block the access of the bacterial aminoacyl-tRNA to the mRNA-ribosome complex by binding to the 30S subunit of the ribosome, thus preventing the addition of amino acids to the growing peptide chain in protein synthesis. When given at therapeutically attainable concentrations their toxic effect is limited to the bacterial cells.

The exact mechanisms by which tetracyclines reduce lesions of acne vulgaris have not been fully elucidated; however, the effect appears to result in part from the antibacterial activity of the drugs. Following oral administration, the drugs inhibit the growth of susceptible organisms (mainly Propionibacterium acnes) on the surface of the skin and reduce the concentration of free fatty acids in sebum. The reduction in free fatty acids in sebum may be an indirect result of the inhibition of lipase-producing organisms which convert triglycerides into free fatty acids or may be a direct result of interference with lipase production in these organisms. Free fatty acids are comedogenic and are believed to be a possible cause of the inflammatory lesions, e.g. papules, pustules, nodules, cysts, of acne. However, other mechanisms also appear to be involved because clinical improvement of acne vulgaris with oral tetracycline therapy does not necessarily correspond with a reduction in the bacterial flora of the skin or a decrease in the free fatty acid content of sebum.

Mechanism of resistance

Tetracycline resistance in propionibacteria is usually associated with a single point mutation within the gene encoding 16S rRNA. Clinical isolates resistant to tetracycline were found to have cytosine instead of guanine at a position cognate with Escherichia coli base 1058. There is no evidence that ribosome mutations can be transferred between different strains or species of propionibacteria, or between propionibacteria and other skin commensals.

Resistance to the tetracyclines is associated with mobile resistance determinants in both staphylococci and coryneform bacteria. These determinants are potentially transmissible between different species and even different genera of bacteria.

In all three genera, cross-resistance with the macrolide-lincosamide-streptogramin group of antibiotics cannot be ruled out.

Strains of propionibacteria resistant to the hydrophilic tetracyclines are cross-resistant to doxycycline and may or may not show reduced susceptibility to minocycline.

Breakpoints

For tetracycline resistance in anaerobic and most aerobic bacteria, the breakpoints as set by the NCCLS are:

Susceptible – MIC <4 mg/L
Intermediate – MIC 8 mg/L
Resistant – MIC >16 mg/L

In cutaneous propionibacteria, mutational resistance is associated with MICs of tetracycline >2mg/L.

Susceptibility table

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.

Susceptibility to tetracyclines of species relevant to the approved indication.

Commonly susceptible species::

Gram-positive aerobes:
None of relevance

Gram-negative aerobes:
None of relevance

Anaerobes:
Propionbacterium acnes (clinical isolates)*

Other:
None of relevance

Species for which acquired resistance may be a problem (defined as >10% resistant within any European country):

Gram-positive aerobes:
S. aureus (methicillin susceptible)
S. aureus (methicillin resistant)⁺
Coagulase-negative staphylococci (methicillin susceptible)
Coagulase-negative staphylococci (methicillin resistant)⁺
Corynebacterium spp

Species for which acquired resistance may be a problem (defined as >10% resistant within any European country):

Gram-negative aerobes:
None of relevance

Anaerobes:
Propionibacterium acnes (isolates from acne)* +

Other (microaerophile):
None of relevance

Inherently resistant species:
None of relevance

However, even if resistance to cutaneous propionibacteria is detected, this does not automatically translate into therapeutic failure, since the antiinflammatory activity of the tetracyclines is not compromised by resistance in the target bacteria.