Clindamycin: new look at an old drug

January 2005

Clindamycin, an antibiotic available for use since 1966, is classified as a lincosamide antimicrobial agent. It is chemically similar to lincomycin, which, although commercially available, is not commonly used. For those readers interested in trivia, lincomycin was first isolated from Streptomyces lincolnesis, a microbe found in soil near Lincoln, Neb. Clindamycin may be assuming a more significant role in pediatric infectious disease therapy, as it maintains relatively good activity toward several important pathogens, such as Streptococcus pneumoniae and Staphylococcus aureus. This month’s Pharmacology Consult will review the use of clindamycin, including clinical indications, adverse effects, drug-drug interactions and pharmaceutical factors.

Antimicrobial activity

Clindamycin’s antimicrobial activity includes many gram-positive aerobes, such as many strains of S. pneumoniae (including strains nonsusceptible to penicillin) and other streptococci, although not enterococcus. Clindamycin is also active against S. aureus, including some, but not all, methicillin-resistant strains. Nosocomially acquired S. aureus is more likely to display resistance to clindamycin, as compared with community-acquired S. aureus, which often is sensitive to clindamycin. S. aureus resistant to erythromycin may display resistance to clindamycin as well or quickly develop resistance once exposed to clindamycin. Clindamycin additionally displays activity toward many anaerobic bacteria, including Bacteroides fragilis, Peptostreptococcus, Clostridium perfringens and other anaerobes. Clindamycin is not active toward Clostridium difficile. Most gram-negative aerobes are resistant to clindamycin, and important pediatric pathogens included are Haemophilus influenzae and Moraxella catarrhalis.

Several large, multicenter susceptibility studies (including ones at several pediatric institutions) have been conducted with S. pneumoniae isolates. Doern evaluated 1,531 S. pneumoniae isolates in 1999-2000 and found a nonsusceptibility rate of 9.2% for clindamycin. This compared with 34.2% for penicillin, 24.7% for ceftriaxone, 27.2% for cefdinir (Omnicef, Abbott) and 26.2% for azithromycin (Zithromax, Pfizer). Clindamycin displayed relatively good activity toward penicillin-resistant S. pneumoniae, with a 73.9% susceptibility rate. Of other non-ß-lactam antibiotics evaluated in this study — macrolides, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole – only chloramphenicol (8.3%) had a lower rate of nonsusceptibility. The Alexander Project evaluated antibiotic susceptibilities to more than 8,000 S. pneumoniae isolates cultured from adults worldwide with community-acquired respiratory tract infections in 1998-2000. Rates of resistance displayed included 18.2% for penicillin, 0.6% for ceftriaxone, 21.9% for cefdinir, 24.4% for azithromycin and 13.9% for clindamycin.

Pharmacology of clindamycin

Clindamycin displays activity to the above pathogens by inhibiting protein synthesis via binding to bacterial ribosomes, thus its use in treating streptococcal toxin disease. The macrolide antibiotics (including azithromycin) bind to the same ribosomal site, and thus, these antibiotics should not be used together, as antagonism will occur. Time above pathogen minimum inhibitory concentration (MIC), ie, the time that the concentration of the antibiotic at the site of infection remains above the MIC of the pathogen, is an important determinant of the antibacterial activity of clindamycin.

Relevant pharmacokinetic characteristics of clindamycin include good oral absorption and good tissue distribution, including bile, bone and joint, urine and respiratory tissues. Clindamycin does not distribute well into cerebrospinal fluid, even with inflammation. Clindamycin is highly bound to serum proteins (>90%). Clindamycin is hepatically metabolized to active and inactive metabolites and does not require dose adjustment for renal dysfunction. Dose adjustment may be necessary for significant hepatic dysfunction or concomitant hepatic and renal dysfunction. Clindamycin’s propensity for significant drug-drug interactions is not likely to be a significant concern for most pediatric patients. While clindamycin may interact with a relatively long list of other drugs, many of these interactions involve drugs more commonly used in adults. However, as with any newly prescribed medication, it is wise to assess a patient’s concomitant medications and the likelihood of clinically significant interactions.

Clindamycin is available in many dosage forms, mirroring its numerous clinical uses: including oral capsules, parenteral (IV and intramuscular administration) and topical formulations (gel, lotion, solution for acne and vaginal cream and suppositories). It is also available as a pediatric solution (Cleocin Pediatric, Pharmacia) for oral administration. Unfortunately, the taste of this cherry-flavored solution, which some children may find bitter, may adversely affect adherence. Commercially available flavoring systems available in many community pharmacies, however, offer flavor-enhancing recipes that may improve the solution’s taste and enhance adherence.

Clindamycin pediatric oral solution should not be refrigerated by caregivers, as this increases its viscosity, potentially reducing the ability of the caregiver to accurately measure a dose.

Perhaps the most well known and feared adverse effect of clindamycin is pseudomembranous colitis. Although this may occur after administration of numerous antibiotics (including b-lactam antibiotics), it is perhaps more frequently associated with clindamycin. Incidence rates for clindamycin-induced pseudomembranous colitis are reported as 0.1% to 10%, and it has also been reported following topical administration. This adverse effect results from overgrowth of strains of toxin-producing Clostridium difficile (toxin A and B, an enterotoxin and cytotoxin, respectively). Risk of clindamycin-induced pseudomembranous colitis is not correlated with dose or duration of therapy, and it may occur several weeks after administration.

Clinical uses

Clindamycin’s potential clinical uses are numerous. It is useful for anaerobic infections, including pelvic inflammatory disease, abscesses, abdominal infections and dental infections. It may also be considered for bone or joint infections resulting from anaerobic pathogens or S. aureus. Clindamycin can also be useful in patients with documented type I allergic reactions to ß-lactam antibiotics.

More recently, clindamycin has been recommended for consideration in the treatment of common pediatric infections resulting from S. pneumoniae, such as acute otitis media or sinusitis. Clindamycin (30-40 mg/kg/day in three divided doses) has been recommended in the new AAP clinical practice guideline “Diagnosis and Management of Acute Otitis Media” for children with type I allergies to penicillin who have not adequately responded to an initial trial of antibiotic therapy. It is important that clinicians consider clindamycin’s lack of activity toward H. influenzae and M. catarrhalis when using it for acute otitis media. Thus, when it is used, clinicians should be targeting S. pneumoniae as a likely pathogen for the child. This may occur in a child who has not adequately responded to an antibiotic with good activity toward H. influenzae or M. catarrhalis (including ß-lactamase–producing strains). Because clindamycin may be active toward penicillin-nonsusceptible S. pneumoniae, it can be a useful treatment option. Guidelines on the treatment of sinusitis from the AAP (“Clinical practice guideline: management of sinusitis,” 2001) similarly recommend consideration of clindamycin for children with type I penicillin allergy, when the infecting pathogen is known to be S. pneumoniae. Usually this drug is used when pneumococcus is recovered from middle ear fluid of a child who has failed therapy and the organism is resistant to ß-lactam antibiotics.

Clindamycin may also be considered for mild-to-moderate severity skin/soft-tissue or other infection resulting from S. aureus, including some strains of methicillin-resistant S. aureus (MRSA). Nosocomially acquired MRSA is likely to display multidrug resistance, including to the cephalosporins, aminoglycosides and clindamycin. Vancomycin should be used for infections resulting from this pathogen. Community-acquired MRSA, however, is more likely to be sensitive to clindamycin. While community-acquired MRSA is more likely to result in skin or soft tissue infection, case reports of serious infection have been published. It is important for clinicians to assess the potential for community-acquired MRSA to express inducible resistance to clindamycin. This may occur in strains resistant to erythromycin, expressing a gene (erythromycin resistance methylase gene) that allows resistance to clindamycin to be induced during therapy. Thus, use of clindamycin in a child infected with a community-acquired MRSA known to be resistant to erythromycin and susceptible to clindamycin may result in clinical failure in some instances, as expression of this inducible gene confers resistance to clindamycin during treatment. The presence of this inducible resistance can be evaluated by a microbiology laboratory (“D test”). Trimethoprim-sulfamethoxazole is another oral antibiotic that may be considered for use in mild-to-moderate severe infection from community-acquired MRSA. Vancomycin is recommended for severe MRSA infections (nosocomially or community-acquired). Oxacillin or nafcillin can be added for children suspected of infection due to S. aureus acquired in the community, prior to antibiotic susceptibility determination, as these agents continue to have good activity toward methicillin-susceptible S. aureus.

For more information:

• Kasten MJ. Clindamycin, metronidazole, and chloramphenicol. Mayo Clin Proc. 1999;74:825-833.
• Doern GV. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother. 2001;45:1721-1729.
• Jacobs MR. The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired tract infection to commonly used antimicrobial agents. J Antimicrob Chemother. 2003;52:229-246.
• Subcommittee on Management of Sinusitis and Committee on Quality Improvement, American Academy of Pediatrics. Clinical practice guideline: management of sinusitis. Pediatrics. 2001;108:798-808.
• Subcommittee on Management of Acute Otitis Media, American Academy of Pediatrics. Diagnosis and management of acute otitis media. Pediatrics. 2004;113:1451-1465.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.