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Cleocin IV

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Cleocin I.V.




CLINICAL PHARMACOLOGY

Distribution

Biologically inactive clindamycin phosphate is converted to active clindamycin. By the end of short-term intravenous infusion, peak serum levels of active clindamycin are reached.

After intramuscular injection of clindamycin phosphate, peak levels of active clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Serum level curves may be constructed from IV peak serum levels as given in Table 1 by application of elimination half-lives (see Excretion).

Serum levels of clindamycin can be maintained above the in vitro minimum inhibitory concentrations for most indicated organisms by administration of clindamycin phosphate every 8 to 12 hours in adults and every 6 to 8 hours in pediatric patients, or by continuous intravenous infusion. An equilibrium state is reached by the third dose.

No significant levels of clindamycin are attained in the cerebrospinal fluid even in the presence of inflamed meninges.

Metabolism

In vitro studies in human liver and intestinal microsomes indicated that clindamycin is predominantly metabolized by Cytochrome P450 3A4 (CYP3A4), with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N-desmethylclindamycin.

Excretion

Biologically inactive clindamycin phosphate disappears rapidly from the serum; the average elimination half-life is 6 minutes; however, the serum elimination half-life of active clindamycin is about 3 hours in adults and 2. hours in pediatric patients.

Special Populations

Renal/Hepatic Impairment

The elimination half-life of clindamycin is increased slightly in patients with markedly reduced renal or hepatic function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Dosage schedules need not be modified in the presence of mild or moderate renal or hepatic disease.

Use In Elderly

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 function1.

Serum assays for active clindamycin require an inhibitor to prevent in vitro hydrolysis of clindamycin phosphate.

Table 1. Average Peak and Trough Serum Concentrations of Active Clindamycin After Dosing with Clindamycin Phosphate

Dosage Regimen Peak
mcg/mL
Trough
mcg/mL
Healthy Adult Males (Post equilibrium)
  600 mg IV in 30 min q6h 10.9 2.0
  600 mg IV in 30 min q8h 10.8 1.1
  900 mg IV in 30 min q8h 14.1 1.7
  600 mg IM q12h* 9  
Pediatric Patients (first dose)*
  5-7 mg/kg IV in 1 hour 10  
  5-7 mg/kg IM 8  
  3-5 mg/kg IM 4  
*Data in this group from patients being treated for infection.

Microbiology

Mechanism Of Action

Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the ribosome. Clindamycin is bacteriostatic.

Resistance Resistance to clindamycin is most often caused by modification of specific bases of the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete. Because the binding sites for these antibacterial drugs overlap, cross-resistance is sometimes observed among lincosamides, macrolides and streptogramin B.Macrolide-inducible resistance to clindamycin occurs in some isolates of macrolide-resistant bacteria. Macrolide-resistant isolates of staphylococci and beta-hemolytic streptococci should be screened for induction of clindamycin resistance using the D-zone test.

Antimicrobial Activity

Clindamycin has been shown to be active against most of the isolates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Gram-Positive Bacteria

Staphylococcus aureus (methicillin-susceptible strains)
Streptococcus pneumoniae
(penicillin-susceptible strains)
Streptococcus pyogenes

Anaerobic Bacteria

Clostridium perfringens
Fusobacterium necrophorum

Fusobacterium nucleatum

Peptostreptococcus anaerobius

Prevotella melaninogenica

At least 90% of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clindamycin susceptible MIC breakpoint for organisms of a similar type to those shown in Table 2. However, the efficacy of clindamycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible strains)
Streptococcus agalactiae

Streptococcus anginosus

Streptococcus mitis

Streptococcus oralis

Anaerobic Bacteria

Actinomyces israelii
Clostridium clostridioforme

Eggerthella lenta

Finegoldia (Peptostreptococcus) magna

Micromonas (Peptostreptococcus) micros

Prevotella bivia

Prevotella intermedia

Propionibacterium acnes

Susceptibility Testing Methods

When available, the clinical microbiology laboratory should provide cumulative in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,3 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 2.

Diffusion Techniques

Quantitative methods that require the measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method2,5. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of bacteria to clindamycin. The disk diffusion breakpoints are provided in Table 2.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to clindamycin can be determined by a standardized test method2,4. The MIC values obtained should be interpreted according to the criteria provided in Table 2.

Table 2. Susceptibility Test Interpretive Criteria for Clindamycin

Pathogen Susceptibility Interpretive Criteria
Minimal Inhibitory Concentrations
(MIC in mcg/mL)
Disk Diffusion
(Zone Diameters in mm)
S I R S I R
Staphylococcus spp. ≤0.5 1–2 ≥4 ≥21 15–20 ≤14
Streptococcus pneumoniae and other Streptococcus spp. ≤0.25 0.5 ≥1 ≥19 16–18 ≤15
Anaerobic Bacteria ≤2 4 ≥8 NA NA NA
NA=not applicable

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. 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 antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

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 test2,3,4,5. Standard clindamycin powder should provide the MIC ranges in Table 3. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 2 should be achieved.

Table 3. Acceptable Quality Control Ranges for Clindamycin

QC Strain Acceptable Quality Control Ranges
Minimum Inhibitory Concentration Range
(mcg/mL)
Disk Diffusion Range
(Zone Diameters in mm)
Enterococcus faecalis1
ATCC 29212
4-16 NA
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
0.5-2 NA
Bacteroides thetaiotaomicron
ATCC 29741
2-8 NA
Clostridium difficile2
ATCC 700057
2-8 NA
Eggerthella lenta
ATCC 43055
0.06-0.25 NA
1. Enterococcus faecalis has been included in this table for quality control purposes only.
2. Quality control for C. difficile is performed using the agar dilution method only, all other obligate anaerobes may be tested by either broth microdilution or agar dilution methods.
NA=Not applicable ATCC® is a registered trademark of the American Type Culture Collection

REFERENCES

1. Smith RB, Phillips JP: Evaluation of CLEOCIN HCl and CLEOCIN Phosphate in an Aged Population. Upjohn TR 8147-82-9122-021, December 1982.

2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 26th ed. CLSI supplement M100S. Wayne, PA: Clinical and Laboratory Standards Institute; 2016.

3. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-A10. Wayne, PA: Clinical and Laboratory Standards Institute; 2015.

4. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Eighth Edition. CLSI document M11-A8. Wayne, PA: Clinical and Laboratory Standards Institute; 2012.

5. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -Twelfth Edition. CLSI document M02-A12. Wayne, PA: Clinical and Laboratory Standards Institute; 2015.

Last reviewed on RxList: 5/11/2017
This monograph has been modified to include the generic and brand name in many instances.

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