Chemical formula: C₁₈H₃₃ClN₂O₅S Molecular mass: 424.98 g/mol PubChem compound: 446598
Clindamycin is a lincosamide antibiotic with a primarily bacteriostatic action against Gram-positive aerobes and a wide range of anaerobic bacteria. Lincosamides such as clindamycin bind to the 50S subunit of the bacterial ribosome similarly to macrolides such as erythromycin and inhibit the early stages of protein synthesis. The action of clindamycin is predominantly bacteriostatic although high concentrations may be slowly bactericidal against sensitive strains.
Resistance to clindamycin usually occurs via macrolide-lincosamide-streptogramin B (MLSB) type of resistance, which may be constitutive or inducible. Clindamycin demonstrates cross-resistance with lincomycin. When tested by in vitro methods, some staphylococcal strains originally resistant to erythromycin rapidly developed resistance to clindamycin. The mechanisms for resistance are the same as for erythromycin, namely methylation of the ribosome binding site, chromosomal mutation of the ribosomal protein and in a few staphylococcal isolates emzymatic inactivation by a plasmid-mediated adenyltransferase.
Resistance to clindamycin in Propionibacterium acnes can be caused by mutations at the rRNA antibiotic binding site or by methylation of specific nucleotides in the 23S RNA of the 50S ribosomal subunit. These alterations can determine cross resistance to macrolides and streptogramins B (MLSB phenotype). Macrolide-resistant isolates should be tested for inducible resistance to clindamycin using the D zone test.
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. Particularly in severe infections or therapy failure microbiological diagnosis with verification of the pathogen and its susceptibility to clindamycin is recommended.
Resistance is usually defined by susceptibility interpretive criteria (breakpoints) established by EUCAST for systemically administered antibiotics. These breakpoints may be less relevant for topically administered clindamycin. Although clindamycin is not specifically cited, EUCAST has suggested that, for topically applied antimicrobials, resistance might be better defined by epidemiological cut-off values (ECOFFS) rather than the clinical breakpoints determined for systemic administration. However, MIC distributions and ECOFFS have not been published by EUCAST for P. acnes. Based on correlations between clinical results in acne patients and the clindamycin MICs for their P. acnes isolates, values as high as 256 mg/L are considered susceptible for topically administered clindamycin.
A Belgian surveillance study (2011-2012) of anaerobic bacteria included 22 P. acnes isolates; 95.5% were susceptible to clindamycin. An earlier European surveillance study, which included 304 isolates of P. acnes, had reported a resistance rate of 15% to clindamycin. However, this study used a breakpoint of 0.12 mg/L; using the current breakpoint of 4 mg/L, there were no resistant isolates.
The minimum inhibitory concentrations (MIC) breakpoints are as follows:
Eucast
Staphylococci: sensitive ≤0.5 resistant >0.5
Streptococci ABCG and pneumoniae: sensitive ≤0.5 resistant >0.5
Gram positive anaerobes: sensitive ≤4 resistant >4
Gram negative anaerobes: sensitive ≤4 resistant >4
Clindamycin is active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:
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 local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Following multiple topical applications of clindamycin phosphate at a concentration equivalent to 10 mg clindamycin per mL in an isopropyl alcohol and water solution, very low levels of clindamycin are present in the serum (0–3 ng/mL) and less than 0.2% of the dose is recovered in urine as clindamycin.
Clindamycin concentrations have been demonstrated in comedones from acne patients. The mean (±SD) concentration of clindamycin in extracted comedones after application of clindamycin topical solution for 4 weeks was 0.60 ± 0.11 mcg/mg.
Following a once a day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered to 6 healthy female volunteers for 7 days, approximately 4% (range 0.6% to 11%) of the administered dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 18 ng/mL (range 4 to 47 ng/mL) and on day 7 it averaged 25 ng/mL (range 6 to 61 ng/mL). These peak concentrations were attained approximately 10 hours post-dosing (range 4–24 hours).
Following a once a day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered for 7 consecutive days to 5 women with bacterial vaginosis, absorption was slower and less variable than that observed in healthy females. Approximately 4% (range 2% to 8%) of the dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 13 ng/mL (range 6 to 34 ng/mL) and on day 7 it averaged 16 ng/mL (range 7 to 26 ng/mL). These peak concentrations were attained approximately 14 hours post-dosing (range 4–24 hours).
There was little or no systemic accumulation of clindamycin after repeated (7 day) vaginal dosing of clindamycin phosphate vaginal cream 2%. The systemic half-life was 1.5 to 2.6 hours.
After oral administration clindamycin is absorbed quickly and almost completely (>90%). The absorption is not affected by food. The peak plasma concentration is achieved within approximately 45 minutes after oral administration. The bioavailability is non-linear and decreases with increasing doses. Following a 600 mg dose the absolute bioavailability is 53±14%.
Following parenteral administration, the biologically inactive clindamycin phosphate is hydrolysed to clindamycin. When the equivalent of 300mg of clindamycin is injected intramuscularly, a mean peak plasma concentration of 6 microgram/ml is achieved within three hours; 600mg gives a peak concentration of 9 microgram/ml. In children, peak concentration may be reached within one hour. When the same doses are infused intravenously, peak concentrations of 7 and 10 micrograms per ml respectively are achieved by the end of infusion.
Clindamycin is widely distributed in body fluids and tissues. It diffuses across the placenta but not the healthy blood-brain barrier. 68–93% of clindamycin in the circulation is bound to plasma proteins. Clindamycin is distributed very highly intracellular due to the lipophilic properties. The intracellular concentrations are 10-50 times higher than the extracellular concentrations.
Clindamycin is widely distributed in body fluids and tissues, including bone, but it does not reach the cerebrospinal fluid in significant concentrations. It diffuses across the placenta into the foetal circulation and appears in breast milk. High concentrations occur in bile. It accumulates in leucocytes and macrophages. Over 90% of clindamycin in the circulation is bound to plasma proteins. The half-life is 2 to 3 hours, although this may be prolonged in pre-term neonates and patients with severe renal impairment.
Clindamycin undergoes metabolism, presumably in the liver, to the active N-demethyl and sulphoxide metabolites, and also some inactive metabolites and about 4% in the faeces: the remainder is excreted as inactive metabolites.
Half-life is approximately two and a half hour in children and approximately 3 hours in adults. Clindamycin is excreted as biological active and biological inactive metabolites in faeces, urine and bile. Faecal excretion is predominant. About 10% of the drug is excreted in the urine as active drug and about 4% in the faeces; the remainder is excreted as inactive metabolites.
Clindamycin undergoes metabolism, to the active N-demethyl and sulphoxide metabolites and also some inactive metabolites. About 10% of the drug is excreted in the urine as active drug or metabolites and about 4% in the faeces; the remainder is excreted as inactive metabolites. Excretion is slow and takes place over several days. It is not effectively removed from the blood by dialysis.
The half-life, volume of distribution and clearance, and extent of absorption after administration of clindamycin phosphate are not altered by increased age.
In the presence of renal impairment, elimination half-life is prolonged; however, a dosage reduction is unnecessary in the event of mild to moderate impairment of renal function.
In patients with moderate to severe hepatic impairment the half life is prolonged, but when giving the dose every 8 hours, accumulation is rarely seen. Dose reduction is normally not necessary in patients with hepatic impairment.
No special characteristics.
Clinical studies for topical clindamycin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Clinical studies for clindamycin phosphate vaginal cream 2% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Preclinical data reveal no special hazard for humans based on studies of repeat dose toxicity, reproductive toxicity or genotoxicity. Carcinogenicity studies have not been conducted.
In dogs, repeated high oral doses produced ulceration of the mucosa of the stomach and gall bladder.
Fertility studies in rats treated orally with up to 300 mg/kg/day (72-fold the human exposure based on mg/m²) revealed no effects on fertility or mating ability.
Fertility studies in rats treated orally with up to 300 mg/kg/day (31 times the human exposure based on mg/m²) revealed no effects on fertility or mating ability.
In oral embryo foetal development studies in rats and subcutaneous embryo foetal development studies in rats and rabbits, embryo-foetal toxicity was observed at doses that produced maternal toxicity. In rats, maternal death occurred with an exposure ratio of approximately 3000 relative to patient exposure. In rabbits, maternal toxicity, including abortions, occurred at exposure ratio of approximately 400. Embryo-foetal toxicity, including post-implantation loss and decreased viability, occurred in rabbits at an exposure ratio of 1000.
In oral embryo-foetal development studies in rats and subcutaneous embryo-foetal development studies in rats and rabbits, embryo-fetal toxicity was observed at doses that produced maternal toxicity. In rats, maternal death occurred with exposure margins of approximately 400-fold relative to patient exposure. In rabbits, maternal toxicity, including abortions, occurred at exposure margins of 50-fold relative to patient exposure. Embryo-fetal toxicity, including post-implantation loss and decreased viability, occurred in rabbits at exposure margins of 120-fold.
Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential.
Long-term studies in animals to evaluate carcinogenic potential have not been performed with clindamycin.
Genotoxicity tests performed included a rat micronucleus test and an Ames test. Both tests were negative.
Clindamycin was not genotoxic when evaluated in the in vivo rat micronucleus test and the Ames test.
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