Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: Pfizer New Zealand Ltd, PO Box 3998, Auckland, New Zealand, Toll Free number: 0800 736 363
Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis. It binds to the 50S ribosomal subunit and affects both ribosome assembly and the translation process. Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin. At usual doses, clindamycin exhibits bacteriostatic activity in vitro.
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 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 methicillinresistant staphylococcal isolates and penicillin-resistant pneumococcal isolates than among organisms susceptible to these agents.
Clindamycin has been shown to have in vitro activity against most isolates of the following organisms:
Gram-positive bacteria:
Staphylococcus aureus (methicillin-susceptible isolates)
Coagulase-negative Staphylococci (methicillin-susceptible isolates)
Streptococcus pneumoniae (penicillin-susceptible isolates)
Streptococci groups A, B, C, and G
Viridans groups Streptococci
Corynebacterium spp.
Atypical bacteria:
Chlamydia trachomatis
Gram-negative bacteria:
Bacteroides spp.
Fusobacterium spp.
Gardnerella vaginalis
Prevotella spp.
Gram-positive bacteria:
Propionibacterium acnes
Actinomyces (Eubacterium) spp.
Eggerthella (Eubacterium) spp.
Peptococcus spp.
Peptostreptococcus spp. (Finegoldia magna, Micromonas micros)
Clostridioides spp. (except C. difficile)
Pneumocystis jirovecii
Toxoplasma gondii
Plasmodium falciparum
Dilution or diffusion techniques – either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. CLSI or EUCAST). Standardised susceptibility testing procedures require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures.
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 below.
Table 1. CLSI Susceptibility Interpretive Criteria for Clindamycin:
| Pathogen | Minimal Inhibitory Concentrations (mcg/mL) | Disk Diffusion (Zone Diameters in mm)a | ||||
|---|---|---|---|---|---|---|
| S | I | R | S | I | R | |
| Staphylococcus spp. | ≤0.5 | 1–2 | ≥4 | ≥21 | 15–20 | ≤14 |
| Streptococcus spp. | ≤0.25 | 0.5 | ≥1 | ≥19 | 16–18 | ≤15 |
| Anaerobic bacteriab | ≤2 | 4 | ≥8 | NA | NA | NA |
NA=not applicable; S=susceptible; I=intermediate; R=resistant.
a Disk content 2 micrograms of clindamycin
b MIC ranges for anaerobes are based on agar dilution methodology.
A 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 high dosage of drug can be used. This category also provides a buffer zone, which 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.
Standardised 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.
Table 2. CLSI Acceptable Quality Control (QC) Ranges for Clindamycin to be Used in Validation of Susceptibility Test Results:
| QC Strain | Minimum Inhibitory Concentration Range (mcg/mL) | Disk Diffusion Range (Zone Diameters in mm) |
|---|---|---|
| Staphylococcus aureus ATCC 29213 | 0.06-0.25 | NA |
| Staphylococcus aureus ATCC 25923 | NA | 24-30 |
| Streptococcus pneumoniae ATCC 49619 | 0.03-0.12 | 19-25 |
| Bacteroides fragilis ATCC 25285 | 0.5-2a | NA |
| Bacteroides thetaiotaomicron ATCC 29741 | 2-8a | NA |
| Eggerthella lenta ATCC 43055 | 0.06-0.25a | NA |
NA=Not applicable.
ATCC is a registered trademark of the American Type Culture Collection
a MIC ranges for anaerobes are based on agar dilution methodology.
The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints are presented below.
Table 3. EUCAST Susceptibility Interpretive Criteria for Clindamycin:
| Organism | MIC breakpoints (mg/L) | Zone diameter breakpoints (mm)a | ||
|---|---|---|---|---|
| S ≤ | R > | S ≥ | R < | |
| Staphylococcus spp. | 0.25 | 0.5 | 22 | 19 |
| Streptococcus Groups A, B, C and G | 0.5 | 0.5 | 17 | 17 |
| Streptococcus pneumoniae | 0.5 | 0.5 | 19 | 19 |
| Viridans group streptococci | 0.5 | 0.5 | 19 | 19 |
| Gram-positive anaerobes | 4 | 4 | NA | NA |
| Gram-negative anaerobes | 4 | 4 | NA | NA |
| Corynebacterium spp. | 0.5 | 0.5 | 20 | 20 |
a Disk content 2 µg of clindamycin
NA=not applicable; S=susceptible; R=resistant
EUCAST QC ranges for MIC and disk zone determinations are in the table below.
Table 4. EUCAST Acceptable Quality Control (QC) Ranges for Clindamycin to be Used in Validation of Susceptibility Test Results:
| QC Strain | Minimum Inhibitory Concentration Range (mcg/mL) | Disk Diffusion Range (Zone Diameters in mm) |
|---|---|---|
| Staphylococcus aureus ATCC 29213 | 0.06-0.25 | 23-29 |
| Streptococcus pneumoniae ATCC 49619 | 0.03-0.125 | 22-28 |
ATCC is a registered trademark of the American Type Culture Collection
Serum level studies with a 150 mg oral dose of clindamycin in 24 normal adult volunteers showed that clindamycin was rapidly absorbed after oral administration. An average peak serum level of 2.50 micrograms/mL was reached in 45 minutes; serum levels averaged 1.51 micrograms/mL at three hours and 0.70 micrograms/mL at six hours. Absorption of an oral dose is virtually complete (90%).
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 DALACIN HCl for up to 14 days show no evidence of accumulation or altered metabolism of drug. Multiple-dose studies in newborns and infants up to 6 months of age show that the drug does not accumulate in the serum and is excreted rapidly.
Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Haemodialysis 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 oxidised 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 faeces; the remainder is excreted as bioinactive metabolites. Clindamycin is mainly eliminated by hepatic metabolism and biliary excretion.
Doses of up to 2 g 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.
An analysis of pharmacokinetic data in obese paediatric patients aged 2 to less than 18 years demonstrated that clindamycin clearance and volume of distribution normalised by total body weight are comparable regardless of obesity.
None stated.
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