Clindamycin Injection USP

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 method^2,3 (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 method^2,5.  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 method^2,4.  The MIC values obtained should be interpreted according to the criteria provided in Table 2.

Table 2. Susceptibility Test Interpretive Criteria for Clindamycin

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 test^2,3,4,5.   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

¹Enterococcus faecalis has been included in this table for quality control purposes only.

²Quality 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.

Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well.  When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency.

Clindamycin should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Clindamycin should be prescribed with caution in atopic individuals.

Certain infections may require incision and drainage or other indicated surgical procedures in addition to antibiotic therapy.

The use of clindamycin may result in overgrowth of nonsusceptible organisms - particularly yeasts.  Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation.

Clindamycin should not be injected intravenously undiluted as a bolus, but should be infused over at least 10 to 60 minutes as directed in the DOSAGE AND ADMINISTRATION section.

Clindamycin dosage modification may not be necessary in patients with renal disease.  In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found.  However, it was postulated from studies that when given every eight hours, accumulation should rarely occur.  Therefore, dosage modification in patients with liver disease may not be necessary.  However, periodic liver enzyme determinations should be made when treating patients with severe liver disease.

Prescribing clindamycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Patients should be counseled that antibacterial drugs including clindamycin injection should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When clindamycin injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.  Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by clindamycin injection or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.  Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.  If this occurs, patients should contact their physician as soon as possible.

During prolonged therapy periodic liver and kidney function tests and blood counts should be performed.

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents.  Therefore, it should be used with caution in patients receiving such agents.

Antagonism has been demonstrated between clindamycin and erythromycin in vitro.  Because of possible clinical significance, the two drugs should not be administered concurrently.

Long-term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential.  Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative.

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.

Teratogenic Effects
Pregnancy Category B

In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters, has not been associated with an increased frequency of congenital abnormalities.

Clindamycin should be used during the first trimester of pregnancy only if clearly needed.  There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (2.1 and 1.1 times the highest recommended adult human dose based on mg/m², respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (0.9 and 0.5 times the highest recommended adult human dose based on mg/m², respectively) revealed no evidence of teratogenicity.

Clindamycin contains benzyl alcohol.  Benzyl alcohol can cross the placenta (see WARNINGS). 

Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL at dosages of 150 mg orally to 600 mg intravenously.  Because of the potential for serious adverse reactions

in nursing infants, clindamycin should not be taken by nursing mothers.

When clindamycin is administered to the pediatric population (birth to 16 years) appropriate monitoring of organ system functions is desirable.

This product contains benzyl alcohol as a preservative.  Benzyl alcohol has been associated with a fatal “Gasping Syndrome” in premature infants (see WARNINGS).

Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients.  However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe.  These patients should be carefully monitored for the development of diarrhea.

Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.

Clostridium difficile colitis.

Antibiotic-associated colitis (see WARNINGS), pseudomembranous colitis, abdominal pain, nausea, and vomiting.  The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS).  An unpleasant or metallic taste has been reported after intravenous administration of the higher doses of clindamycin phosphate.

Maculopapular rash and urticaria have been observed during drug therapy.  Generalized mild to moderate morbilliform-like skin rashes are the most frequently reported of all adverse reactions. 
 
Severe skin reactions such as Toxic Epidermal Necrolysis, some with fatal outcome, have been reported (see WARNINGS).  Cases of Acute Generalized Exanthematous Pustulosis (AGEP), erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. Anaphylactic shock, anaphylactic reaction and hypersensitivity have also been reported (see WARNINGS).  

Pruritus, vaginitis, angioedema and rare instances of exfoliative dermatitis have been reported (see Hypersensitivity Reactions).

Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy.

Although no direct relationship of clindamycin to renal damage has been established, renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed.

Transient neutropenia (leukopenia) and eosinophilia have been reported.  Reports of agranulocytosis and thrombocytopenia have been made.  No direct etiologic relationship to concurrent clindamycin therapy could be made in any of the foregoing.

Immune System

Drug reaction with eosinophilia and systemic symptoms (DRESS) cases have been reported.

Injection site irritation, pain, induration and sterile abscess have been reported after intramuscular injection and thrombophlebitis after intravenous infusion.  Reactions can be minimized or avoided by giving deep intramuscular injections and avoiding prolonged use of indwelling intravenous catheters.

Polyarthritis cases have been reported.

Cardiopulmonary arrest and hypotension have been reported following too rapid intravenous administration (see DOSAGE AND ADMINISTRATION).

Parenteral IV Administration

Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis, Peptococcus species and Clostridium species other than Clostridium perfringens): 600 to 1,200 mg/day in 2, 3 or 4 equal doses.

More severe infections, particularly those due to proven or suspected Bacteroides fragilis, Peptococcus species, or Clostridium species other than Clostridium perfringens: 1,200 to 2,700 mg/day in 2, 3 or 4 equal doses.

For more serious infections, these doses may have to be increased. In life-threatening situations due to either aerobes or anaerobes these doses may be increased.  Doses of as much as 4,800 mg daily have been given intravenously to adults (see Dilution for IV Use and IV Infusion Rates).

Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows:

15 to 20 mg/kg/day in 3 to 4 equal doses.  The lower dosage may be adequate for small prematures.

Parenteral IV Administration
20 to 40 mg/kg/day in 3 or 4 equal doses.  The higher doses would be used for more severe infections.  As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m²/day for serious infections and 450 mg/m²/day for more severe infections.

Parenteral therapy may be changed to oral clindamycin flavored granules (clindamycin palmitate hydrochloride) or clindamycin capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician.

In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

Clindamycin Injection, USP must be diluted prior to IV administration.  The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL.  Infusion rates should not exceed 30 mg per minute.  The usual infusion dilutions and rates are as follows:

Administration of more than 1,200 mg in a single 1-hour infusion is not recommended.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of Clindamycin Injection, USP in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically.  No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions.  For current information regarding compatibilities of clindamycin phosphate under specific conditions, please visit www.fresenius-kabi.us or call Fresenius Kabi USA, LLC toll-free at 1-800-551-7176.

Room Temperature: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in  5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.  Also, 18 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, in minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.

Refrigeration: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 32 days at 4°C.

IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

Frozen: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in minibags demonstrated physical and chemical stability for at least eight weeks at -10°C.

Frozen solutions should be thawed at room temperature and not refrozen.