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Pharmacodynamic effects: Efficacy is related to the time period over which the agent level is above the minimum inhibitory concentration (MIC) of the pathogen (%T/MIC).
Resistance: Resistance to clindamycin is most often due to mutations at the rRNA antibiotic binding site or methylation of specific nucleotides in the 23S RNA of the 50S ribosomal subunit. These alterations can determine in vitro cross resistance to macrolides and streptogramins B (MLSB phenotype). Resistance is occasionally due to alterations in ribosomal proteins. Resistance to clindamycin may be inducible by macrolides in macrolide-resistant bacterial isolates. Inducible resistance can be demonstrated with a disk test (D-zone test) or in broth. Less frequently encountered resistance mechanisms involve modification of the antibiotic and active efflux. There is complete cross resistance between clindamycin and lincomycin. As with many antibiotics, the incidence of resistance varies with the bacterial species and the geographical area. The incidence of resistance to clindamycin is higher among methicillin-resistant staphylococcal isolates and penicillin-resistant pneumococcal isolates than among organisms susceptible to these agents.
Antimicrobial activity: Clindamycin has been shown to have in vitro activity against most isolates of the following organisms: Aerobic bacteria: Gram-positive bacteria: Staphylococcus aureus (methicillin-susceptible isolates); Coagulase-negative staphylococci (methicillin-susceptible isolates); Streptococcus pneumoniae (penicillin-susceptible isolates); Beta-hemolytic streptococci groups A, B, C, and G; Viridans group streptococci; Corynebacterium spp.
Gram-negative bacteria: Chlamydia trachomatis.
Anaerobic bacteria: Gram-positive bacteria: Actinomyces spp.; Clostridium spp. (except Clostridium difficile); Eggerthella (Eubacterium) spp.; Peptococcus spp.; Peptostreptococcus spp. (Finegoldia magna, Micromonas micros); Propionibacterium acnes.
Gram-negative bacteria: Bacteroides spp.; Fusobacterium spp.; Gardnerella vaginalis; Prevotella spp.
Fungi: Pneumocystis jirovecii.
Protozoans: Toxoplasma gondii; Plasmodium falciparum.
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. 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 Clinical and Laboratory Standards Institute (CLSI) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) for systemically administered antibiotics.
Clinical and Laboratory Standards Institute (CLSI) breakpoints for relevant organisms are listed as follows. (See Table 1.)
Click on icon to see table/diagram/imageA report of "Susceptible" (S) indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" (R) indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the usually achievable concentrations; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard clindamycin powder should provide the MIC ranges in Table 2. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 2 should be achieved. (See Table 2.)
Click on icon to see table/diagram/imageThe European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints are presented as follows. (See Table 3.)
Click on icon to see table/diagram/imageEUCAST QC ranges for MIC and disk zone determinations are in the table as follows. (See Table 4.)
Click on icon to see table/diagram/imagePharmacokinetics: Serum level studies with a 150 mg oral dose of clindamycin hydrochloride in 24 normal adult volunteers showed that clindamycin was rapidly absorbed after oral administration. An average peak serum level of 2.50 mcg/mL was reached in 45 minutes; serum levels averaged 1.51 mcg/mL at 3 hours and 0.70 mcg/mL at 6 hours. Absorption of an oral dose is virtually complete (90%), and the concomitant administration of food does not appreciably modify the serum concentrations; serum levels have been uniform and predictable from person to person and dose to dose. Serum level studies following multiple doses of clindamycin hydrochloride for up to 14 days show no evidence of accumulation or altered metabolism of drug. Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Concentrations of clindamycin in the serum increased linearly with increased dose. Serum levels exceed the MIC (minimum inhibitory concentration) for most indicated organisms for at least six hours following administration of the usually recommended doses. Clindamycin is widely distributed in body fluids and tissues (including bones). In vitro studies in human liver and intestinal microsomes indicated that clindamycin is predominantly oxidized by CYP3A4, with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N-desmethylclindamycin. The average biological half-life is 2.4 hours. Approximately 10% of the bioactivity is excreted in the urine and 3.6% in the feces; the remainder is excreted as bioinactive metabolites. Doses of up to 2 grams of clindamycin per day for 14 days have been well tolerated by healthy volunteers, except that the incidence of gastrointestinal side effects is greater with the higher doses. No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges. Pharmacokinetic studies in elderly volunteers (61-79 years) and younger adults (18-39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4.0 hours (range 3.4 - 5.1 h) in the elderly compared to 3.2 hours (range 2.1 - 4.2 h) in younger adults. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function.
Obese Pediatric Patients Aged 2 to Less than 18 Years and Obese Adults Aged 18 to 20 Years: An analysis of pharmacokinetic data in obese pediatric patients aged 2 to less than 18 years and obese adults aged 18 to 20 years demonstrated that clindamycin clearance and volume of distribution normalized by total body weight are comparable regardless of obesity.
Toxicology: Preclinical Safety Data: Carcinogenesis: Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential.
Mutagenesis: Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.
Impairment of Fertility: Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.1 times the highest recommended adult human dose based on mg/m2) revealed no effects on fertility or mating ability.
In oral embryo fetal development studies in rats and subcutaneous embryo fetal development studies in rats and rabbits, no developmental toxicity was observed except at doses that produced maternal toxicity.
