Clindamycin Hydrochloride, Clindamycin Palmitate Hydrochloride, Clindamycin Phosphate
Clindaymcin is a semisynthetic antibiotic that is a derivative of lincomycin.
Spectrum Clindamycin is active against most aerobic gram-positive cocci including staphylococci, Streptococcus pneumoniae, and other streptococci (except Enterococcus faecalis [formerly S. faecalis]).
The drug also is active in vitro against Arcanobacterium haemolyticum (formerly Corynebacterium haemolyticum). Clindamycin is active against some anaerobic and microaerophilic gram-negative and gram-positive organisms including Actinomyces, Bacteroides, Eubacterium, Fusobacterium, Propionibacterium, microaerophilic streptococci, Peptococcus, Peptostreptococcus, and Veillonella.
Clindamycin is active in vitro against Prevotella and Porphyromonas (both formerly classified as Bacteroides); Mobiluncus (motile, anaerobic, curved rods) also are inhibited in vitro by the drug. Clostridium perfringens, C. tetani, Corynebacterium diphtheriae, and Mycoplasma are also inhibited by clindamycin. Some strains of Haemophilus influenzae and Neisseria gonorrhoeae may be inhibited by clindamycin.
Clindamycin is active in vitro and in vivo against Gardnerella vaginalis (formerly Haemophilus vaginalis). Clindamycin has been reported to have some activity against Plasmodium in vitro. Clindamycin is inactive against N. meningitidis, Enterobacteriaceae, fungi, and most strains of C. difficile. In vitro, clindamycin concentrations of 0.04-0. mcg/mL inhibit most susceptible strains of staphylococci, streptococci, pneumococci, Corynebacterium diphtheriae, and Actinomyces. In vitro, the minimum inhibitory concentration (MIC) of clindamycin for most susceptible anaerobic and microaerophilic bacteria is 0.1-4 mcg/mL.
In Vitro Susceptibility Testing
The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to clindamycin, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated.
If results indicate that a clinical isolate has intermediate susceptibility to clindamycin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug concentrations and response rates may be lower than for strains identified as susceptible.
Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated (e.g., urine) or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.
If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to clindamycin, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliably demonstrated in clinical trials.
Disk Susceptibility Tests
When the disk-diffusion procedure is used to test susceptibility to clindamycin, a disk containing 2 mcg should be used. When disk susceptibility testing is performed according to NCCLS standardized procedures, Staphylococcus with growth inhibition zones of 21 mm or greater are susceptible to clindamycin, those with zones of 15-20 mm have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug. When susceptibility of Streptococcus is evaluated according to NCCLS standardized procedures using Mueller-Hinton agar (supplemented with 5% sheep blood), Streptococcus (including S. pneumoniae) with growth inhibition zones of 19 mm or greater are susceptible to clindamycin, those with zones of 16-18 mm have intermediate susceptibility, and those with zones of 15 mm or less are resistant to the drug.
Dilution Susceptibility Tests
When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures, Staphylococcus with MICs of 0.5 mcg/mL or less are susceptible to clindamycin, those with MICs of 1-2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug. When broth dilution susceptibility testing is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (with 2-5% lysed horse blood), Streptococcus (including S. pneumoniae) with MICs of 0.25 mcg/mL or less are susceptible to clindamycin, those with MICs of 0.5 mcg/mL have intermediate susceptibility, and those with MICs of 1 mcg/mL or greater are resistant to the drug.
Resistance
Staphylococcal resistance to clindamycin has been induced in vitro and has been shown to be acquired in a stepwise manner. Natural and acquired resistance to the antibiotic has been demonstrated in vitro and in vivo in strains of staphylococci, streptococci, and B. fragilis. Complete cross-resistance occurs between clindamycin and lincomycin, and there is evidence of partial cross-resistance between clindamycin and erythromycin. In vitro, bacteria resistant to erythromycin and susceptible to clindamycin may exhibit a dissociated type of resistance to clindamycin during susceptibility testing if erythromycin is also present. This phenomenon may be the result of competition between erythromycin and clindamycin for the ribosomal binding site.
Pharmacokinetics
Absorption
Approximately 90% of an oral dose of clindamycin hydrochloride is rapidly absorbed from the GI tract. Prior to absorption, oral clindamycin palmitate hydrochloride is hydrolyzed in the GI tract to active clindamycin. Clindamycin is not inactivated by gastric acidity.
Serum concentrations of clindamycin appear to be predictable, increasing linearly with increased doses. The extent of absorption and peak serum concentrations of clindamycin are not appreciably affected when either clindamycin hydrochloride capsules or clindamycin palmitate hydrochloride oral solution is administered with food, although peak serum concentrations may be delayed.
Following oral administration of a single 150-mg dose of clindamycin hydrochloride to healthy fasting adults, peak serum concentrations of clindamycin average 1.9-3.9 mcg/mL and are attained within 45-60 minutes; serum concentrations of clindamycin average 1.5 mcg/mL at 3 hours and 0.7 mcg/mL at 6 hours. Oral doses of clindamycin palmitate hydrochloride produce serum concentrations of clindamycin similar to those achieved with oral clindamycin hydrochloride. In a study in healthy children, oral administration of clindamycin palmitate hydrochloride 2, 3, or 4 mg/kg every 6 hours produced mean peak serum clindamycin concentrations of 1.24, 2.25, and 2.44 mcg/mL, respectively, 1 hour after the first dose.
After the fifth dose, peak serum concentrations of the drug averaged 2.46, 2.98, and 3.79 mcg/mL, respectively. Following IM or IV administration, clindamycin phosphate is rapidly hydrolyzed in plasma to active clindamycin. Following IM administration of clindamycin phosphate, peak serum concentrations occur within 3 hours in adults and 1 hour in children. In healthy adult males, IM doses of 300 mg of clindamycin phosphate every 8 hours result in average peak serum clindamycin concentrations of 6 mcg/mL. IV doses of 600 mg of clindamycin phosphate infused over 20 minutes every 8 hours in healthy adult males result in average peak serum clindamycin concentrations of 10 mcg/mL. In a study in children with infections, single IV or IM doses of 5-7 mg/kg resulted in average peak serum clindamycin concentrations of 10 or 8 mcg/mL, respectively.
Distribution
Clindamycin is distributed into many body tissues and fluids including saliva, ascites fluid, pleural fluid, synovial fluid, bone, and bile. However, even in the presence of inflamed meninges, only small amounts of the drug diffuse into CSF. The concentration of clindamycin in synovial fluid and bone is reported to be 60-80% of concurrent serum concentrations of the drug; the degree of penetration does not appear to be affected by joint inflammation. Clindamycin readily crosses the placenta, and cord blood concentrations of the drug have been reported to be 46% of concurrent maternal blood concentrations. Clindamycin is distributed into milk. At a concentration of 1 mcg/mL, clindamycin is approximately 93% bound to serum proteins.
Elimination
The serum half-life of clindamycin is 2-3 hours in adults and children with normal renal function. The serum half-life is increased slightly in patients with markedly reduced renal or hepatic function. In neonates, the serum half-life depends on gestational and chronologic age and body weight. The serum half-life of clindamycin reportedly averages 8.7 and 3.6 hours in premature and full-term neonates, respectively, and about 3 hours in infants 4 weeks to 1 year of age; serum half-life was longer in infants weighing less than 3.5 kg than in heavier infants.
Serum concentrations of the drug are not appreciably affected by hemodialysis, peritoneal dialysis, or prolonged administration in patients (including neonates and infants) with normal renal function. Clindamycin is partially metabolized to bioactive and inactive metabolites. The major bioactive metabolites are clindamycin sulfoxide and N-demethyl- clindamycin which are excreted in urine, bile, and feces.
Within 24 hours, approximately 10% of an oral dose of clindamycin is excreted in urine and 3.6% is excreted in feces as active drug and metabolites; the remainder is excreted as inactive metabolites. Probenecid has no effect on clindamycin excretion.
Chemistry and Stability
Chemistry
Clindamycin is a semisynthetic derivative of lincomycin that differs structurally from lincomycin in the substitution of a chlorine atom for the 7-hydroxyl group and the inversion of the involved 7-carbon. Clindamycin is commercially available as the hydrochloride hydrate, the palmitate hydrochloride, and the phosphate ester. Potency of clindamycin hydrochloride, clindamycin palmitate hydrochloride, and clindamycin phosphate is expressed in terms of clindamycin.
Each mg of the hydrochloride hydrate, palmitate hydrochloride, or phosphate has a potency of not less than 800, 540, or 758 mcg of clindamycin, respectively; potency of the phosphate is calculated on the anhydrous basis. The hydrochloride, palmitate hydrochloride, and phosphate occur as a white or practically white crystalline powder, a white to off-white amorphous powder, and a white to off-white hygroscopic crystalline powder, respectively, which may have faint, characteristic odors and are freely soluble in water.
Clindamycin phosphate reportedly has a solubility of about 400 mg/mL in water at 25°C. The pKa of clindamycin is 7.45. Sodium hydroxide and/or hydrochloric acid may have been added during the manufacture of clindamycin phosphate injection to adjust the pH to 5.5-7. When reconstituted as directed, oral solutions of clindamycin palmitate hydrochloride have a pH of 2.5-5.
Commercially available clindamycin phosphate injections containing 300, 600, or 900 mg of clindamycin in 5% dextrose injection, have osmolalities of 296, 322, or 339 mOsm/L kg, respectively, and a pH of 5.5-6.
Stability
Clindamycin hydrochloride capsules and clindamycin palmitate hydrochloride powder for oral solution should be stored at 20-25°C. Following reconstitution with water, clindamycin palmitate hydrochloride oral solution is stable for 2 weeks at room temperature; to avoid thickening, the reconstituted oral solution should not be refrigerated. Clindamycin phosphate in 5% dextrose injections should be stored at room temperature (25°C), and exposure to temperatures warmer than 30°C should be avoided. ADD-Vantage® vials of clindamycin phosphate injection should be stored at a controlled room temperature of 20-25°C. The commercially available injections of clindamycin phosphate in 5% dextrose have an expiration date of 24 months following the date of manufacture.
The commercially available injections of clindamycin phosphate in 5% dextrose (Galaxy®) are provided in plastic containers fabricated from specially formulated multilayered plastic PL 2501. Solutions in contact with the plastic can leach out some of the chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals as well as by tissue culture studies.
At a concentration of 6, 9, and 12 mg of clindamycin per mL, clindamycin phosphate is physically and chemically compatible for at least 16 days at 25°C or at least 32 days when refrigerated at 4°C in glass or polyvinyl chloride (PVC) containers, or for at least 8 weeks when frozen at -10°C in PVC containers of the following IV solutions: 5% dextrose, 0.9% sodium chloride, or lactated Ringer’s. At a concentration of 18 mg of clindamycin per mL, clindamycin phosphate is physically and chemically compatible for at least 16 days at 25°C in PVC containers of 5% dextrose. The drug is also physically and microbiologically compatible for 24 hours at room temperature in IV solutions containing sodium chloride, dextrose, potassium, or vitamin B complex in concentrations used clinically.
However, certain concentrations or admixtures of calcium salts may result in physical incompatibility.Clindamycin phosphate has been reported to be incompatible with various drugs (e.g., aminophylline, ampicillin, barbiturates, magnesium sulfate, phenytoin sodium) but compatible with other drugs including cephalothin sodium (no longer commercially available in the US), gentamicin sulfate, kanamycin sulfate, and penicillin G; however, the compatibility depends on several factors (e.g., concentration of the drugs, specific diluents used, resulting pH, temperature).
Specialized references should be consulted for specific compatibility information. Following dilution of clindamycin phosphate injection from ADD-Vantage® vials, resultant solutions containing 6, 9, or 12 mg of clindamycin per mL of 5% dextrose injection or 0.9% sodium chloride injection are stable for 24 hours at room temperature or 14 days when refrigerated at 5°C.
Preparations
Clindamycin Hydrochloride Oral Capsules 75 mg (of clindamycin) Cleocin HCl®, (with tartrazine) Pfizer 150 mg (of clindamycin) Cleocin HCl®, (with tartrazine) Pfizer 300 mg (of clindamycin) Cleocin HCl®, Pfizer Clindamycin Palmitate Hydrochloride Oral For solution 75 mg (of clindamycin) per 5 Cleocin Pediatric®, (with mL ethylparaben) Pfizer Clindamycin Phosphate Parenteral Injection 150 mg (of clindamycin) per Cleocin Phosphate®, (with mL benzyl alcohol 9.45 mg/mL and edetate disodium 0.5 mg/mL) Pfizer 9 g (150 mg/mL) (of Cleocin Phosphate®, (with clindamycin) pharmacy bulk benzyl alcohol 9.45 mg/mL and package edetate disodium 0.5 mg/mL) Pfizer Clindamycin Phosphate Injection, (with benzyl alcohol 9.45 mg/mL and edetate disodium 0.5 mg/mL) AstraZeneca Elkins-Sinn Hospira Lederle Injection, for IV 150 mg (of clindamycin) per Clindamycin Phosphate ADD-infusion only mL (300 mg) Vantage®, (with benzyl alcohol 9.45 mg/mL and edetate disodium 0.5 mg/mL) Hospira 150 mg (of clindamycin) per Cleocin Phosphate® ADD-mL (600 and 900 mg) Vantage®, (with benzyl alcohol 9.45 mg/mL and edetate disodium 0.5 mg/mL) Pfizer Clindamycin Phosphate ADD-Vantage®, (with benzyl alcohol 9.45 mg/mL and edetate disodium 0.5 mg/mL) Hospira Clindamycin Phosphate in Dextrose Parenteral Injection, for IV 6 mg (of clindamycin) per mL Cleocin Phosphate® IV, infusion (300 mg) in 5% Dextrose (Galaxy® [Baxter]) Pfizer 12 mg (of clindamycin) per Cleocin Phosphate® IV, mL (600 mg) in 5% Dextrose (Galaxy® [Baxter]) Pfizer 18 mg (of clindamycin) per Cleocin Phosphate® IV, mL (900 mg) in 5% Dextrose (Galaxy® [Baxter]) Pfizer