Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: hameln pharma plus gmbh, Langes Feld 13, 31789, Hameln, Germany
Pharmacotherapeutic group: Antibacterial for systemic use, macrolide
ATC code: J01FA09
Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It exerts its antibacterial action by selectively binding to the 50s ribosomal sub-unit of susceptible bacteria preventing translocation of activated amino acids. It inhibits the intracellular protein synthesis of susceptible bacteria.
The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism also has anti-microbial activity. The metabolite is less active than the parent compound for most organisms, including mycobacterium spp. An exception is Haemophilus influenza where the 14-hydroxy metabolite is two-fold more active than the parent compound.
The following breakpoints have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST):
| Breakpoints (MIC, mg/l) | ||
|---|---|---|
| Microorganism | Susceptible (≤) | Resistant (>) |
| Staphylococcus spp.1 | 1 mg/l | 2 mg/l |
| Streptococcus (A, B, C and G)1 | 0.25 mg/l | 0.5 mg/l |
| Streptococcus pneumoniae1 | 0.25 mg/l | 0.5 mg/l |
| Haemophilus influenzae. | Note | Note |
| Moraxella catarrhalis1 | 0.25 mg/l | 0.5 mg/l |
1 Erythromycin can be used to determine susceptibility to clarithromycin
Note: Clinical evidence for the efficacy of macrolides in H. influenzae respiratory infections is conflicting due to high spontaneous cure rates. Should there be a need to test clarithromycin against this species, an epidemiological cut-off (ECOFF) of 32 mg/l should be used to detect strains with acquired resistance.
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an appropriate guidance on the probabilities whether micro-organisms will be susceptible to clarithromycin or not.
Aerobic, Gram-positive microorganisms:
Streptococcus agalactiae
Streptococcus pyogenes (Group A beta-hemolytic streptococci)
Streptococcus viridans
Streptococcus (Diplococcus) pneumoniae
Staphylococcus aureus (methicillin susceptible)
Listeria monocytogenes
Aerobic, Gram-negative microorganisms:
Bordetella pertusis
Haemophilus influenzae
Haemophilus parainfluenzae
Helicobacter pylori
Campylobacter jejuni
Moraxella (Branhamella) catarrhalis
Neisseria gonorrhoeae
Legionella spp.
Anaerobic microorganisms:
Clostridium perfrigens
Bacterioides fragilis
Peptococcus/Peptostreptococcus spp.
Propionibacterium acnes
Other microorganisms:
Mycoplasma pneumoniae
Chlamydia trachomatis
Chlamydia pneumoniae
Ureaplasma urealyticum
Mycobacterium spp.
Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to clarithromycin can be predicted by testing erythromycin.
The mechanisms of acquired resistance in macrolides are: efflux of drug by an active pump mechanism, inducible or constitutive production of a methylase enzyme that modifies the ribosomal target, hydrolysis of macrolides by esterases, chromosomal mutations that alter a 50 S ribosomal protein. Cross-resistance between clarithromycin and other macrolides and clindamycin and lincomycin may therefore occur. Methicillin-resistant and oxacillin-resistant staphylococci (MRSA) and penicillin-resistant Streptococcus pneumoniae are resistant to all currently available Beta- lactam antibiotics and macrolides such as clarithromycin.
Following IV administration, the blood levels of clarithromycin achieved are well in excess of the MIC 90s for the common pathogens and the levels of 14-hydroxyclarithromycin exceed the necessary concentrations for important pathogens, e.g. H. influenzae. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first pass metabolism as indicated by lower biovailability of the metabolite following IV administration.
Clarithromycin gives good penetration into different compartments. Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin also penetrates the gastric mucus.
Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
The serum half-life of the active 14-®-hydroxy metabolite ranges between 5 to 6 hours.
Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism involves mainly N-dealkylation, oxidation and stereospecific hydroxylation at position C 14.
The pharmacokinetics of clarithromycin and the 14-hydroxy metabolite are non-linear; steady state is achieved by day 3 of IV dosing. Following a single 500 mg IV dose over 60 minutes, about 33% clarithromycin and 11% 14-hydroxyclarithromycin is excreted in the urine at 24 hours.
Clarithromycin 500 mg powder for concentrate for solution for infusion does not contain tartrazine or other azo dyes, lactose or gluten.
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.
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