Clindamycin: An overview

INTRODUCTION — Clindamycin is a lincosamide antibiotic that has been approved by the US Food and Drug Administration for the treatment of anaerobic, streptococcal, and staphylococcal infections. Its major disadvantage is its propensity to cause antibiotic-associated diarrhea, including Clostridioides difficile colitis. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology".)

There has been increased interest in the use of clindamycin because it achieves high intracellular levels in phagocytic cells, high levels in bone, and appears to be able to reduce toxin production in toxin-elaborating strains of streptococci and staphylococci. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

The spectrum of activity, pharmacology, and adverse effects of clindamycin will be reviewed here. The clinical use of clindamycin is discussed separately in the appropriate topic reviews on specific infections. (See "Anaerobic bacterial infections" and "Complications, diagnosis, and treatment of odontogenic infections" and "Deep neck space infections in adults" and "Ludwig angina" and "Peritonsillar cellulitis and abscess" and "Lung abscess in adults" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections" and "Staphylococcus aureus in children: Overview of treatment of invasive infections".)

MECHANISM OF ACTION — Clindamycin works primarily by binding to the 50s ribosomal subunit of bacteria. This agent disrupts protein synthesis by interfering with the transpeptidation reaction, which thereby inhibits early chain elongation. Chloramphenicol and macrolides such as erythromycin, clarithromycin, and azithromycin also act at the 50s ribosomal subunit and may compete for binding at this site. Clindamycin and the related drug lincomycin are often discussed along with the macrolides but are not chemically related. (See "Azithromycin and clarithromycin", section on 'Mechanism of action and chemical structure'.)

Clindamycin may potentiate the opsonization and phagocytosis of bacteria even at subinhibitory concentrations [1,2]. By disrupting bacterial protein synthesis, clindamycin causes changes in the cell wall surface, which decreases adherence of bacteria to host cells and increases intracellular killing of organisms. The drug also exerts an extended postantibiotic effect against some strains of bacteria, which may be attributed to persistence of the drug at the ribosomal binding site.

Clindamycin is considered a bacteriostatic antibiotic but is bactericidal against some strains of staphylococci, streptococci, and anaerobes such as Bacteroides fragilis. However, killing activity may vary with drug concentration, bacterial species, and inoculum. Bactericidal activity against B. fragilis is inconsistent [3]. Penicillins are more rapidly bactericidal versus Staphylococcus aureus than is clindamycin [4]. However, clindamycin does inhibit production of staphylococcal toxin associated with the toxic shock syndrome [5]. Clindamycin has also been shown to almost completely inhibit alpha toxin expression in S. aureus in contrast with beta-lactams, which strongly induce, and fluoroquinolones, which partially induce, expression [6].

SPECTRUM OF ACTIVITY — Clindamycin generally has in vitro activity against staphylococci, viridans group streptococci, Streptococcus pyogenes, and Streptococcus pneumoniae. It also demonstrates potent activity against anaerobes such as B. fragilis, Clostridium perfringens, Fusobacterium spp, Prevotella melaninogenicus, and Peptostreptococcus spp. However, increasing rates of resistance among B. fragilis have limited its utility against these organisms. (See 'Resistance' below.)

Clindamycin is not typically active against Haemophilus influenzae, enterococci, or Neisseria meningitidis. Mycoplasma pneumoniae and aerobic gram-negative bacilli are usually resistant.

Clindamycin is active in vitro against Toxoplasma gondii, Actinomyces israelii, Nocardia asteroides, and Babesia spp. Clindamycin also has some activity against Plasmodium falciparum and Plasmodium vivax (both chloroquine-susceptible and -resistant strains). Combination therapy with quinine or chloroquine has been tried [7]; clindamycin should not be used alone for the treatment or prevention of malaria. (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children".)

RESISTANCE — There are several mechanisms of bacterial resistance to clindamycin, including modification of the target, inactivation of the drug, or efflux of the drug. Resistance has been conferred by both plasmid- and chromosomally mediated mechanisms, including:

●Plasmid-mediated resistance in S. aureus and B. fragilis, conferred by enzymes that methylate specific adenine residues in the ribosomal-binding site in the 23s ribosomal RNA of the 50s ribosomal subunit [8]. In gram-positive cocci, this mechanism also confers resistance to macrolides. (See "Azithromycin and clarithromycin", section on 'Resistance'.)

●Alteration of a single 50s ribosomal protein of the receptor site, which also confers resistance to macrolides.

●Adenylation conferred by a plasmid-mediated 3-lincomycin 4-clindamycin 0-nucleotidyltransferase that catalyzes the nucleotidylation of the hydroxyl group of position 4 of clindamycin [9]. This mechanism of resistance is most frequently found in staphylococcal isolates, including S. aureus, and impairs bactericidal activity and reduces activity at high inoculum levels. Although adenylation confers high-level resistance to lincomycin, clindamycin resistance may not be detected by routine testing methods. This type of resistance is uncommon and probably not of great clinical importance.

●Gram-negative organisms such as Pseudomonas spp, Enterobacteriaceae, and Acinetobacter spp are intrinsically resistant to clindamycin due to poor permeability of the cellular outer envelope to the drug [10].

Cross-resistance of S. aureus to lincomycin and clindamycin is complete. In addition, bacteria that are erythromycin-resistant may quickly develop resistance when exposed to clindamycin. Strains of S. aureus have also developed resistance to clindamycin during treatment. Other bacteria such as S. pneumoniae, group A Streptococcus, Corynebacterium diphtheriae, B. fragilis, Peptostreptococcus spp, and Cutibacterium (formerly Propionibacterium) acnes have also developed resistance to clindamycin.

Increasing resistance among group B streptococci has also been reported [11-15]. In a report of group B streptococcal isolates obtained as part of routine prenatal screening in Louisiana, clindamycin resistance was present in 33 percent of 544 isolates [16]. In 30 percent of strains, clindamycin resistance was constitutively expressed, and in 70 percent it was inducible. Rates of inducible clindamycin resistance in other studies of group B Streptococcus have been substantially lower [14].

A resistance phenotype identified in erythromycin-susceptible, clindamycin-resistant strains of Streptococcus agalactiae had high minimum inhibitory concentrations (MICs) to clindamycin and lincomycin plus high MICs to dalfopristin, a streptogramin-A antibacterial agent [17]. By contrast, the strains were susceptible to macrolides and quinupristin, a streptogramin B-type antibiotic.

Rates of resistance of the B. fragilis group to clindamycin have increased over time in the United States and Europe. In the United States, the frequency of clindamycin resistance in B. fragilis increased from 3 percent in 1987 to 26 percent from 1997 to 2004 [18,19]. Some centers have reported clindamycin resistance rates of B. fragilis to be as high as 44 percent [20]. (See "Anaerobic bacterial infections", section on 'Antimicrobial resistance'.)

Since rates of antibiotic resistance within Bacteroides may vary with geographic area and local antibiotic use, local susceptibility patterns should be considered in the selection of empiric therapy. Susceptibility testing for anaerobic bacteria is not routinely performed in the clinical laboratory setting, since the techniques are cumbersome and not well-standardized. However, testing may be indicated in certain clinical situations, including brain abscess, endocarditis, osteomyelitis, arthritis, prosthetic device or vascular graft infection, and refractory or recurrent bacteremia [21]. Testing may be particularly useful in the setting of serious infection, persistent infections, potentially resistant pathogens that will be treated medically rather than surgically, or when prolonged therapy is anticipated.

The primary benefit of susceptibility testing is not documentation of susceptibility but rather demonstration of unexpected resistance to an antimicrobial that is normally useful. The clinical relevance of documented bacterial resistance in the setting of mixed anaerobic infections remains unclear. An alternative approach to requesting susceptibility testing upon isolation of a Bacteroides spp is to reserve such testing for a clinical treatment failure or recurrent infection and to send an isolate to a reference laboratory at that time.

C. difficile is often resistant to clindamycin but susceptible to metronidazole and vancomycin. C. perfringens is usually uniformly susceptible, but other clostridial species may be resistant in 15 to 30 percent of cases.

PHARMACOKINETICS — Clindamycin is well absorbed after oral administration and is approximately 90 percent bioavailable. The drug generally distributes well into body tissues but does not achieve significant levels in the cerebrospinal fluid, even during episodes of meningitis. It does penetrate well into bone. Since the drug is actively transported into polymorphonuclear leukocytes and macrophages, it may also achieve excellent penetration into abscesses.

Clindamycin is metabolized in the liver to active and inactive metabolites. One active metabolite, N-demethyl clindamycin, is more active than the parent compound. Clindamycin is excreted in urine and, to a lesser extent, in the bile as metabolites. The half-life in patients with normal renal function is 2.4 hours, but it is extended to approximately six hours in those with renal insufficiency. The half-life of the drug is also extended in patients with hepatic failure. The drug is not appreciably removed by peritoneal dialysis or hemodialysis.

TOXICITY — The most common adverse effects associated with clindamycin are diarrhea and allergic reactions.

Gastrointestinal — Diarrhea has been reported in 2 to 20 percent of those receiving clindamycin. Typically, the diarrhea is mild and self-limited in nature and resolves upon discontinuation of the drug. Clindamycin has been frequently implicated in antibiotic-associated diarrhea due to C. difficile [22,23]. Pseudomembranous colitis caused by overgrowth of C. difficile has been reported in 0.1 to 10 percent of patients receiving clindamycin and can be severe or life threatening. Although this condition has been documented with almost all antibiotics, clindamycin, ampicillin, amoxicillin, and the cephalosporins are most frequently implicated, the last three based upon the frequency of use. In a comparison of clindamycin and ampicillin, pseudomembranes were documented by endoscopy in 2 percent of patients receiving clindamycin and 0.3 percent of patients receiving ampicillin [22]. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology".)

Antibiotic-associated diarrhea can occur during antibiotic therapy or even several weeks after the cessation of therapy. Topical and vaginal preparations of clindamycin have also been implicated in causing this disease, which may be attributable to systemic absorption of the drug [24,25]. Clindamycin should be used with caution among patients with inflammatory bowel disease, since antibiotic-associated diarrhea in this patient population may be particularly intolerable.

Other gastrointestinal side effects have been reported with clindamycin. These include nausea, vomiting, flatulence, metallic taste, anorexia, and esophagitis. Following administration of clindamycin, it is advisable to sit upright for 30 minutes to minimize risk of gastrointestinal discomfort.

Allergic reactions — Maculopapular skin rash has been noted in up to 10 percent of patients receiving clindamycin [26]. Other reactions such as drug fever, eosinophilia, erythema multiforme, drug rash with eosinophilia and systemic symptoms [27], Sweet syndrome, and urticaria have also been reported. Some cases have resembled Stevens-Johnson syndrome. Although rare, cardiopulmonary arrest and hypotension have been reported with rapid intravenous infusions of clindamycin. Delayed-type hypersensitivity reactions including maculopapular exanthema and pruritus have also been reported following skin prick or intradermal testing for clindamycin in some patients [28].

Local reactions — Injection-site pain and swelling have been reported with the use of intravenous and intramuscular clindamycin. Thrombophlebitis may occur with infusions of intravenous clindamycin. Induration and sterile abscess have been reported with intramuscular administration of the drug. Contact dermatitis may be associated with topical forms of clindamycin. In addition, symptomatic vaginitis and vulvar irritation have been reported with intravaginal clindamycin.

Other — Less common adverse reactions reported with the use of clindamycin include elevation of liver transaminases, jaundice, and polyarthritis. Hematopoietic effects such as neutropenia, leukopenia, agranulocytosis, and thrombocytopenic purpura have also been reported. Renal dysfunction associated with the use of clindamycin is rare but may be characterized by oliguria, azotemia, and proteinuria.

DRUG INTERACTIONS — Clindamycin undergoes hepatic metabolism by CYP3A4. Potent inducers of CYP3A4 metabolism (eg, rifampin) can significantly decrease clindamycin serum concentrations [29-31]. Although in one study, a reduction in the rate of clinical cure was not observed when clindamycin was administered with rifampin for the treatment of gram-positive bone and joint infections [31], decreased clindamycin effect is possible if it is combined with strong CYP3A4 inducers (table 1).

Since clindamycin has neuromuscular-blocking properties, it should be used with caution in patients receiving neuromuscular-blocking agents. Since clindamycin, macrolides, and chloramphenicol target the same ribosomal site, these drugs should not be used in combination.

Details about specific interactions may be obtained by using the drug interactions program included within UpToDate.

DOSING AND ADMINISTRATION — Clindamycin is available for oral, parenteral, and topical administration. (See "Clindamycin (systemic): Drug information" and "Clindamycin (topical): Drug information" and "Clindamycin (systemic): Pediatric drug information" and "Clindamycin (topical): Pediatric drug information".)

SPECIAL POPULATIONS

Pregnancy — Animal studies have failed to demonstrate fetal risk with clindamycin therapy, and human data are limited. One study evaluating live births in Quebec suggested an increased rate of major congenital malformations, musculoskeletal and ventricular/atrial septal defects in the first year of life among infants who had maternal clindamycin exposure during the first trimester [32]. This finding was not replicated in a subsequent European case-control study; however, the study identified a possible association of clindamycin with hydrocephalus in an exploratory analysis [33]. Additional well-designed studies are needed to evaluate this risk. Clindamycin does cross the placenta with levels approximating 50 percent of maternal serum levels.

A study evaluating pharmacokinetics of clindamycin in pregnant women reported lower clindamycin concentrations in umbilical cord blood than maternal blood and suggested that maternal concentrations may not exceed the area under the curve to minimum inhibitory concentration target for effective group B Streptococcus prevention for neonates during delivery [34].

In a study of pregnant women with bacterial vaginosis at 15.6 weeks gestation (mean), use of clindamycin (300 mg by mouth twice daily for five days) was associated with fewer miscarriages or preterm deliveries when compared with placebo [35]. In contrast, since intravaginal clindamycin has been associated with an increased risk of preterm birth, clindamycin intravaginal cream should not be used in pregnant women.

Nursing — Clindamycin is excreted in the breast milk, but the American Academy of Pediatrics considers clindamycin administration compatible with breastfeeding. However, some practitioners may still elect to avoid clindamycin therapy in women who are nursing.

Neonates — Clindamycin should generally be avoided in neonates since each milliliter of intravenous clindamycin contains 9.45 mg of benzyl alcohol. Organ system functions should be carefully monitored in infants receiving clindamycin intravenously.

Dialysis — Clindamycin does not appear to be significantly removed by hemodialysis or peritoneal dialysis. Thus, no dosing adjustments are necessary in patients undergoing dialysis. Patients undergoing hemofiltration also do not appear to require clindamycin dose adjustments.

Renal and hepatic dysfunction — No specific dose adjustments are recommended for patients with renal or hepatic dysfunction receiving clindamycin. However, as noted above, the half-life of the drug is prolonged in such patients, which could increase the potential for adverse events. Such patients should be monitored closely, and dose adjustments should be considered if toxicity is suspected.

MONITORING DURING THERAPY — Patients receiving clindamycin should be monitored for hepatic or renal dysfunction and for the occurrence of potential side effects. If diarrhea occurs, the drug should be stopped. Patients experiencing diarrhea during or after receiving antibiotic therapy should be evaluated for the presence of C. difficile and treated accordingly.

SUMMARY

●Overview – Clindamycin is a lincosamide antibiotic that has been approved by the US Food and Drug Administration for the treatment of anaerobic, streptococcal, and staphylococcal infections. Its major disadvantage is its propensity to cause antibiotic-associated diarrhea. (See 'Introduction' above.)

●Mechanism of action

•Clindamycin works primarily by binding to the 50s ribosomal subunit of bacteria. This agent disrupts protein synthesis by interfering with the transpeptidation reaction, which thereby inhibits early chain elongation. (See 'Mechanism of action' above.)

•Clindamycin is considered a bacteriostatic antibiotic but is bactericidal against some strains of staphylococci, streptococci, and anaerobes such as Bacteroides fragilis. However, killing activity may vary with drug concentration, bacterial species, and inoculum. Bactericidal activity against B. fragilis is inconsistent. Penicillins are more rapidly bactericidal versus Staphylococcus aureus than is clindamycin. However, clindamycin does inhibit production of staphylococcal toxin associated with the toxic shock syndrome. Clindamycin has also been shown to almost completely inhibit alpha toxin expression in S. aureus. (See 'Mechanism of action' above.)

●Spectrum of activity – Clindamycin generally has in vitro activity against staphylococci, viridans group streptococci, Streptococcus pyogenes, and Streptococcus pneumoniae. It also demonstrates potent activity against anaerobes such as B. fragilis, Clostridium perfringens, Fusobacterium spp, Prevotella melaninogenicus, and Peptostreptococcus spp. (See 'Spectrum of activity' above.)

●Mechanisms and rates of resistance – There are several mechanisms of bacterial resistance to clindamycin, including modification of the target, inactivation of the drug, or efflux of the drug. Resistance has been conferred by both plasmid- and chromosomally mediated mechanisms. Rates of resistance of the B. fragilis group to clindamycin have increased over time in the United States and Europe. (See 'Resistance' above.)

●Pharmacokinetics – Clindamycin is well absorbed after oral administration and is approximately 90 percent bioavailable. The drug generally distributes well into body tissues but does not achieve significant levels in the cerebrospinal fluid, even during episodes of meningitis. It does penetrate well into bone. Since the drug is actively transported into polymorphonuclear leukocytes and macrophages, it may also achieve excellent penetration into abscesses. (See 'Pharmacokinetics' above.)

●Drug interactions – Since clindamycin has neuromuscular-blocking properties, it should be used with caution in patients receiving neuromuscular-blocking agents. Since clindamycin, macrolides, and chloramphenicol target the same ribosomal site, these drugs should not be used in combination. (See 'Drug interactions' above.)

●Toxicity – The most common adverse effects associated with clindamycin are diarrhea, including Clostridioides difficile colitis, and allergic reactions. (See 'Toxicity' above.)

●Use in special populations

•Clindamycin appears to be safe in pregnant females although clindamycin intravaginal cream should not be used. Although the American Academy of Pediatrics considers clindamycin compatible with breastfeeding, some practitioners may still elect to avoid clindamycin in females who are nursing. Clindamycin use in neonates is generally avoided due to presence of benzyl alcohol in clindamycin formulations. (See 'Pregnancy' above and 'Nursing' above and 'Neonates' above.)

•Although no specific dose adjustments are recommended for patients with renal or hepatic dysfunction, half-life of the drug is prolonged, which could increase the potential for adverse events. (See 'Dialysis' above and 'Renal and hepatic dysfunction' above.)