Cleocin (Clindamycin)

Clindamycin is a semisynthetic antibiotic and a derivative of lincomycin. It is active against most aerobic gram-positive cocci, including staphylococci, Streptococcus pneumoniae, and other streptococci (except Enterococcus faecalis, formerly S. faecalis).

Clindamycin is effective in vitro against a range of bacteria, including gram-positive and anaerobic organisms. It works against pathogens such as Arcanobacterium haemolyticum, Actinomyces, Bacteroides, and Fusobacterium. Clindamycin also inhibits Prevotella, Porphyromonas, Mobiluncus, and some strains of Clostridium and Haemophilus influenzae.

It also shows activity against Gardnerella vaginalis and has some effect on Plasmodium in vitro. However, it is ineffective against Neisseria meningitidis, Enterobacteriaceae, fungi, and most strains of Clostridioides difficile (formerly Clostridium difficile). The minimum inhibitory concentration (MIC) for clindamycin typically ranges from 0.04 to 4 mcg/mL for susceptible strains of staphylococci, streptococci, and anaerobic bacteria.

Pharmacokinetics

Clindamycin may be bacteriostatic or bactericidal, depending on the drug concentration at the site of infection and how susceptible the infecting organism is. Clindamycin palmitate hydrochloride and clindamycin phosphate are inactive until they are hydrolysed to free clindamycin; this happens rapidly in vivo. Clindamycin appears to inhibit protein synthesis in susceptible organisms by binding to 50S ribosomal subunits; the main effect is inhibition of peptide bond formation. The site of action appears to be the same as that of erythromycin, chloramphenicol, lincomycin, oleandomycin, and troleandomycin.

Absorption

About 90% of oral clindamycin hydrochloride is rapidly absorbed after being converted to active clindamycin in the GI tract. Serum concentrations rise linearly with dosage and are only minimally affected by food, although peak levels may be delayed. After a 150 mg dose, peak serum levels average 1.9-3.9 mcg/mL within 45-60 minutes.

Clindamycin phosphate is quickly hydrolysed to active clindamycin after IM or IV administration. Peak serum concentrations occur within 3 hours in adults and within 1 hour in children.

Distribution

Clindamycin is widely distributed in body tissues and fluids but penetrates the CSF poorly. Concentrations in synovial fluid and bone are about 60-80% of serum levels. It crosses the placenta and is present in breast milk; approximately 93% is bound to serum proteins.

Elimination

The serum half-life is typically 2-3 hours in adults and children and may be prolonged in patients with renal or hepatic impairment. In neonates, half-life varies by age and weight. Clindamycin is partly metabolised and is excreted mainly in urine and faeces. About 10% of an oral dose appears in urine within 24 hours as active drug and metabolites. Probenecid does not affect its excretion.

Uses

Before choosing clindamycin, an Australian doctor should consider the nature of the infection and whether less toxic alternatives (for example, erythromycin) are suitable.

Clindamycin is used mainly to treat serious infections caused by susceptible gram-positive and anaerobic bacteria. Because of the risk of C. difficile-associated diarrhoea and colitis, its use should be limited to serious infections when other less toxic antibiotics are unavailable. Clindamycin should not be used empirically for infections that are likely to be non-bacterial (for example, some upper respiratory tract infections). When appropriate, the causative organism should be cultured, and clindamycin does not replace the need for surgery when this is indicated. It is ineffective for meningitis because it does not reach adequate concentrations in the CNS.

Clindamycin is also indicated for serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. Its use should be reserved for penicillin-allergic patients or for other patients in whom, in the doctor's judgment, penicillin is inappropriate.

1. Anaerobes: Serious respiratory tract infections such as empyema, anaerobic pneumonitis, and lung abscess; severe skin and soft tissue infections; septicaemia; intra-abdominal infections such as peritonitis and intra-abdominal abscess (typically involving anaerobes that normally live in the GI tract); infections of the female pelvis and genital tract such as endometritis, non-gonococcal tubo-ovarian abscess, pelvic cellulitis, and postsurgical vaginal cuff infection.
2. Streptococci: Serious respiratory tract infections; severe skin and soft tissue infections.
3. Staphylococci: Serious respiratory tract infections; severe skin and soft tissue infections.
4. Pneumococci: Serious respiratory tract infections.

In Australian clinical practice, bacteriological studies should be performed to identify the causative organisms and their susceptibility to clindamycin.

To help reduce the development of drug-resistant bacteria and maintain the effectiveness of Cleocin and other antibacterial medicines, Cleocin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered when selecting or modifying antibacterial therapy.

Administration

Clindamycin hydrochloride and clindamycin palmitate hydrochloride are given orally. Clindamycin phosphate is given by IM injection or by intermittent or continuous IV infusion.

Oral administration

Clindamycin hydrochloride capsules and clindamycin palmitate hydrochloride oral solution may be taken with or without food. To reduce the risk of oesophageal irritation, clindamycin hydrochloride capsules should be taken with a full glass of water.

Clindamycin palmitate hydrochloride oral solution is reconstituted by adding 75 mL of water to the 100 mL bottle. Add most of the water first and shake vigorously, then add the remaining water and shake until the solution is uniform. The resulting solution contains 75 mg of clindamycin per 5 mL.

Parenteral administration

Before IV administration, clindamycin phosphate injection (including injection contained in ADD-Vantage® vials) must be diluted with a compatible IV solution to a concentration not exceeding 18 mg/mL. For intermittent IV infusion, the diluted solution should be infused over at least 10-60 minutes at a rate not exceeding 30 mg/minute; the drug should not be given IV undiluted as a bolus.

The manufacturers suggest that 300 mg or 600 mg doses be diluted in 50 mL of diluent and infused over 10 or 20 minutes, respectively; 900 mg doses be diluted in 50-100 mL and infused over 30 minutes; and 1.2 g doses be diluted in 100 mL and infused over 40 minutes. A maximum of 1.2 g should be given by IV infusion in a single 1-hour period.

As an alternative to intermittent IV infusion, clindamycin may be given by continuous IV infusion after the first dose has been given by rapid IV infusion. Commercially available clindamycin phosphate in 5% dextrose is given by IV infusion. Inspect containers for leaks by firmly squeezing the bag, and visually inspect solutions for particulate matter and discolouration where feasible. Discard the injection if the container seal is not intact, leaks are found, or the solution is not clear. Additives should not be introduced into the injection container.

The injection should not be used in series connections with other plastic containers because this may result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.

Clindamycin phosphate pharmacy bulk packs are not intended for direct IV infusion; doses must be further diluted in a compatible IV infusion solution before administration. The bulk pack is intended for use only in a laminar flow hood. Entry into the vial should be made using a sterile transfer set or other sterile dispensing device; multiple entries with a syringe and needle are not recommended because of the increased risk of microbial and particulate contamination. Record the date and time the bulk pack was opened on the vial.

After entry into a bulk pack vial, the entire contents should be used promptly; any unused portion should be discarded within 24 hours after initial entry. The manufacturer of another clindamycin phosphate bulk pack (Gensia) states that the contents should be used as soon as possible after initial entry, but within 4 hours; if not used immediately, the vial should be stored at room temperature under the laminar flow hood during this period.

Dosage

Dosage is expressed in terms of clindamycin and depends on the severity of infection and the susceptibility of the infecting organism. In serious anaerobic infections, parenteral clindamycin is usually used initially, and oral clindamycin may be substituted when the patient's condition allows; however, in clinically appropriate circumstances, therapy may be started or continued with oral clindamycin. The duration of therapy depends on the type and severity of infection. If clindamycin is used for infections caused by group A beta-haemolytic streptococci, therapy should continue for at least 10 days. At least 6 weeks of therapy may be required for severe infections such as endocarditis or osteomyelitis.

Oral dosage

IM/IV adult dosage

Side effects

Clindamycin is associated with a range of side effects. Gastrointestinal reactions (for example, nausea and vomiting) and the risk of pseudomembranous colitis due to C. difficile overgrowth are among the most serious effects linked to systemic use.

GI effects

GI side effects commonly occur with oral, IM, or IV clindamycin and may be severe enough to require treatment to be stopped. These effects include nausea, vomiting, diarrhoea, abdominal pain, and tenesmus. In addition, flatulence, bloating, anorexia, weight loss, and oesophagitis have occurred. An unpleasant or metallic taste has occasionally occurred following IV administration of high doses. Non-specific colitis and diarrhoea, as well as potentially fatal C. difficile-associated diarrhoea and colitis (antibiotic-associated pseudomembranous colitis), have also occurred.

Diarrhoea and colitis

C. difficile-associated diarrhoea and colitis, especially when triggered by clindamycin, may be marked by severe diarrhoea and abdominal cramping and may include blood or mucus in stools. Symptoms often develop 2-9 days after starting clindamycin but can occur weeks later. In institutions, infection may be spread within the healthcare setting, and asymptomatic carriers may be present.

Diagnosis may involve endoscopic examination to identify pseudomembranes when clinically indicated. Management generally includes stopping the antibiotic responsible and providing supportive care (for example, fluid and electrolyte replacement). In moderate to severe cases, targeted therapy (for example, oral metronidazole or vancomycin) may be used based on clinical judgment and local guidance. Anti-diarrhoeal medicines may worsen the condition and should generally be avoided.

Dermatologic and sensitivity reactions

Generalised mild to moderate morbilliform rash is the most frequently reported adverse reaction to clindamycin. Maculopapular rash, urticaria, pruritus, fever, hypotension, and rarely polyarthritis have also occurred. A few anaphylactoid reactions have been reported. Rarely, erythema multiforme, sometimes resembling Stevens-Johnson syndrome, has occurred.

Local effects

Thrombophlebitis, erythema, and pain and swelling have occurred with IV administration. IM administration has caused pain, induration, sterile abscess, and reversible increases in serum creatine kinase (CK/CPK). Local reactions can be minimised by deep IM injections and by avoiding prolonged use of indwelling IV catheters.

Other adverse effects

Other reported adverse effects include transient increases in serum bilirubin, alkaline phosphatase, and AST (SGOT); transient leukopenia; neutropenia; eosinophilia; thrombocytopenia; and agranulocytosis. Rare cases of cardiopulmonary arrest and hypotension have been reported following overly rapid IV administration. Renal dysfunction (for example, azotaemia, oliguria, and/or proteinuria) has rarely been observed in patients receiving the drug.

Precautions and contraindications

Patients should be monitored for diarrhoea, which may indicate severe colitis. If diarrhoea is clinically significant or persistent, stopping the drug should be considered and alternative treatment evaluated. Older patients with severe illness may have more severe effects and should be closely observed for changes in bowel habit.

Routine tests for liver and renal function and blood cell counts are recommended during prolonged use because of the potential overgrowth of non-susceptible organisms (particularly fungi). If hypersensitivity reactions occur, clindamycin should be stopped immediately and appropriate treatment started.

Cleocin capsules contain tartrazine, which can cause allergic reactions in sensitive individuals. Use caution in patients with a history of GI disease and in those with severe renal or hepatic impairment; serum concentrations may need monitoring. Clindamycin is contraindicated in individuals with hypersensitivity to clindamycin or lincomycin. It is not suitable for CNS infections because it does not distribute adequately into the CNS.

Paediatric precautions

When clindamycin is given to paediatric patients, organ system function should be monitored.

Each mL of clindamycin phosphate injection contains 9.45 mg of benzyl alcohol. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates, particularly when large amounts (about 100-400 mg/kg/day) were administered. In Australia, product information and neonatal prescribing guidance generally note that the presence of small amounts of this preservative in a commercially available injection does not necessarily rule out its use when clinically indicated in neonates.

Geriatric precautions

Clinical studies did not include enough patients aged 65 years and older to determine whether older patients respond differently from younger patients. Clinical experience indicates that C. difficile-associated diarrhoea and colitis may occur more often and be more severe in patients older than 60 years.

Therefore, older patients receiving clindamycin should be carefully monitored in Australia for the development of diarrhoea (for example, changes in bowel frequency). Studies have not shown clinically important differences in oral or parenteral clindamycin pharmacokinetics between younger adults and older patients with normal hepatic function and normal (age-adjusted) renal function.

Pregnancy, fertility, and lactation

Clindamycin safety during pregnancy is not fully established because adequate, well-controlled studies in pregnant women are lacking. Animal studies have not shown significant fetal harm at high doses, but animal findings do not always predict human outcomes. Therefore, clindamycin should be used during pregnancy only when clearly needed.

Clindamycin does not appear to impair fertility or mating ability in rat studies.

Clindamycin is excreted in breast milk, with reported concentrations ranging from 0.7 to 3 mcg/mL after oral or IV administration. Because of the potential for serious adverse reactions in breastfed infants, decisions about breastfeeding should take into account the importance of the drug to the mother.

Resistance

Staphylococcal resistance to clindamycin has been induced in vitro and is acquired stepwise. Natural and acquired resistance has been demonstrated 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 in vitro testing, organisms resistant to erythromycin and susceptible to clindamycin may show inducible resistance to clindamycin when erythromycin is present, likely because of competition for the ribosomal binding site.

Acute toxicity

The manufacturer does not report information to date on human overdosage. Clindamycin is not removed by haemodialysis or peritoneal dialysis.

Drug interactions

Neuromuscular blocking agents

Clindamycin has neuromuscular blocking effects that may increase the action of other medicines in this group (for example, ether, tubocurarine and pancuronium). Use clindamycin with caution in patients taking these medicines, and monitor for prolonged blockage.

Aminoglycosides

Clindamycin has been reported to interfere with the bactericidal activity of aminoglycosides in vitro, and some clinicians recommend that these medicines should not be used at the same time. However, in vivo antagonism has not been shown, and clindamycin has been given with an aminoglycoside with no apparent reduction in activity.