Clindamycin

Ronda L. Akins, Pharm.D.

Assist. Professor and Vice Chair of Research

Department of Pharmacy Practice

School of Pharmacy

Texas Tech University Health Sciences Center

1300 Coulter

Amarillo, TX 79106

Tel: 806/356-4000 Ext. 303

Fax: 806/356-4018

Pager: 800/692-4522

Email: Ronda.Akins@ttuhsc.edu

Elizabeth Coyle, Pharm.D.

Assistant Professor, Infectious Diseases

University of Houston

College of Pharmacy

1441 Moursund St

Houston, Texas

office: (713)795-8390

pager: (281)267-0133

fax: (713)795-8383

Email: ecoyle@uh.edu

Matthew E. Levison, M.D.

Professor of Medicine and Public Health

Division of Infectious Diseases

Drexel University School of Medicine

Philadelphia, Pennsylvania

Email: matthew.levison@drexel.edu

Jan Verhoef, M.D., Ph.D.

CLASS

               Clindamycin has been in clinical use for almost 35 years; nevertheless, it remains an important antimicrobial agent, highly active against Gram-positive and anaerobic bacteria (118). Clindamycin was introduced as an orally administered agent, intended primarily for the treatment of staphylococcal and streptococcal infections. However, because of its excellent activity against anaerobic bacteria, it soon also became the drug of choice for infections caused by these bacteria. The combination of clindamycin and gentamicin emerged as the standard treatment for mixed aerobic-anaerobic infections (15). Over the years clindamycin has also been considered for some additional indications: acne vulgaris, Pneumocystis and Toxoplasma infections in patients with acquired immunodeficiency syndrome (AIDS), etc.

               The monograph Clindamycin in the Treatment of Human Infections published at the 20th anniversary of the worldwide introduction of clindamycin is a valuable source of information (125).

Chemical Structure and Structure-Activity Relationships

               The parent molecule of clindamycin, lincomycin, was discovered by Mason and coworkers in 1961 (69). Lincomycin produced by a new species of Streptomyces lincolnensis, var. lincolnensis, which was isolated from a soil sample collected in Nebraska (in the vicinity of Lincoln; hence the name). The compound is active in vitro and in vivo against a variety of Gram-positive bacteria and is well-absorbed following oral administration. No cross-resistance was observed in bacteria resistant to other antibiotics known at that time.

               In 1967, lincomycin was approved for use in human infections and a large program was initiated at the Upjohn company to modify the product chemically to enhance its pharmacokinetic characteristics and to improve its antibacterial activity. Halogenation at the C-7 position in the sugar moiety led to production of very active semisynthetic compounds (13, 64, 66); the best example is clindamycin, the 9(S)-chloro-7-deoxylincomycin derivative (Figure 1). It has a broader spectrum of antimicrobial activity, greater potency, and better absorption than lincomycin. Thus, clindamycin was developed for clinical studies. Clindamycin subsequently passes the various phases of clinical research and received approval in countries.

               Clindamycin is worldwide available in several forms:

               ●   Capsules for oral administration (clindamycin hydrocholoride)

               ●   In solution as a prodrug (clindamycin phosphate, developed to reduce pain' on injection, for intramuscular and                                intravenous administration)

               ●  An oral liquid pediatric formulation (clindamycin palmitate)

               ●  A topical solution for the treatment of acne vulgaris (clindamycin phosphate)

ANTIMICROBIAL ACTIVITY

               The National Committee for Clinical Laboratory Standards (NCCLS) published the breakpoints for clindamycin to define susceptible, intermediately susceptible, and resistant microorganisms (77, 78). Susceptible aerobic bacteria have a breakpoint concentration of 0.50 mg/L or less, intermediately susceptible aerobic bacteria have breakpoint concentrations of 1 to 2 mg/L, and minimal inhibitory concentrations (MICs) of 4.mg/L or more indicate resistant aerobic bacteria. Anaerobic bacteria are considered susceptible when the MIC is 4 mg/L or less and resistant when the MIC is 8 mg/L or more.

               Of course, susceptibility to clindamycin can also be determined by disk. The standard disk-diffusion method uses a 2-µg clindamycin disk (79). A 10-ug clindamycin disk was developed for susceptibility testing of anaerobes, using thioglycolate broth containing a disk. Results of this assay correlate closely with those of the NCCLS agar dilution method for clindamycin; however, NCCLS has not approved the broth disk method because of quality control problems (78). The antimicrobial activity of clindamycin is summarized in the various tables, using MIC90 data (125).

Gram-Positive Aerobic Bacteria

               Clindamycin is active against a large variety of Gram-positive aerobic bacteria, such as Gram-positive bacilli, staphylococci (including penicillinase-producing strains), and streptocoocci (Table 1). Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus bovis, and Lancefield group B, C and G streptococci are all susceptible to clindamycin, although an increasing number of centers are isolating some clindamycin resistant group A streptococci together with group A streptococci resistant to erythromycin (12). Penicillin-susceptible viridans streptococci are generally susceptible to clindamycin penicillin-resistant strains of this group, however, may have reduced susceptibility to clindamycin. Some penicillin resistant pneumococci are resistant to clindamycin; both are susceptible (4, 22). Thus, clindamycin can be given empirically when penicillin-resistant pneumococci cannot be ruled out, and laboratory testing is mandatory. Methicillin-susceptible Staphylococcus aureus isolates are susceptible to clindamycin as well. Although clindamycin is active against some strains of nosocomial methicillin-resistant staphylococci, an increasing number of staphylococcal strains resistant to methicillin are also resistant to clindamycin. This limits the use of clindamycin for infections due to these organisms (37). Thus, as is the case with penicillin-resistant pneumococci, clindamycin cannot be used empirically to treat infections possibly due to nosocomial methicillin-resistant S. aureus (MRSA). Clindamycin is usually active against community-acquired MRSA and is considered an appropriate treatment.

               As with S. aureus, most methicillin-resistant strains of coagulase-negative staphylococci are also resistant to clindamycin (5). The urinary tract pathogen Staphylococcus saprohyticus as well as Staphylococcus warneri, Staphylococcus apitis, and Staphylococcus stimulans is usually susceptible to clindamycin (34). However, increased resistance among Gram-positive bacteria against a variety of antibiotics dictates proper in vitro susceptibility testing before agents such as clindamycin are used to treat patients with infections due to these microorganisms.

               Clindamycin has some activity against various other bacteria, including Listeria monocytogenes, Bacillus cereus, Bacillus anthracis and Corynebacterium diphtheriae, but the clinical significance of these in vitro observations is not known. Clindamycin is not active against Enterococcus faecalis, Enterococcus faecium, and Nocardia listeroides.

Gram-Negative Aerobic Bacteria

               Clindamycin has poor activity against almost all species of Gram-negative aerobic bacteria. Only some activity has been observed against some strains of Moraxella catarrhalis (18), Haemophilus influenzae (18), Legionella (51), and Neisseria meningitidis, but the clinical value is limited. Clindamycin does have some in vitro activity against Campylobacter jejuni, Campylobacter fetus, Campylobacter coli, Helicobacter pylori (120), Gardnerella vaginalis, and Neisseria gonorrhoeae. However, very few patients with infections caused by these organisms have been treated with clindamycin.

Anaerobic Bacteria

               Clindamycin has been widely used against infections caused by anaerobic bacteria because of its broad spectrum of activity. It has been considered as one of the drugs of choice in the treatment of infections due to anaerobic Gram-negative bacteria, belonging to the Bacteroides fragilis group including Bacteroides distasonis, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotamicron, and Bacteroides vulgatus. Unfortunately, over the past several years, MICs to clindamycin have significantly increased in many large scale surveys (47,49, 60, 85).In one survey, the percentage of resistance isolates increased from 14% to 29% over an 8 year period (1,2).

               These data underscore the need for continuous monitoring of susceptibility patterns for Bacteroides. Prevotella melaninogenicus, Prevotella bivia, Prevotella disiens, Fusobacterium species, and Veillonella species are highly susceptible. Eikenella is usually resistant (43, 58). The in vitro activity of clindamycin against many important Gram-positive anaerobic species is summarized in Table 2. The compound is highly effective in vitro against most strains of actinomycetes, eubacteria, lactobacilli, propionibacteria, and peptostreptococci. Clostridia are often more resistant to clindamycin than most other anaerobes. The activity of clindamycin against C. difficile, the cause of pseudomembranous colitis, is highly variable: MIC90S range from 4 to more than 256 µg/mL.

               Clindamycin is also active against Chlamydia trachomatis. But Mycoplasma pneumoniae and Ureaplasma are usually resistant (88). At a concentration of about 2 mg/L, clindamycin inhibits 90% of C. trachomatis strains. Often, synergy is observed between an aminoglycoside and clindamycin against Chlamydia (86). Therefore this combination is one of the recommended treatment schedules for patients requiring hospitalization for pelvic inflammatory disease (87).

Protozoa

               During the screening of antibiotics against protozoa such as Plasmodium berghe, an infection in rodents, it was found that clindamycin was also active against protozoa such as Plasmodium, Pneumocystis carinii, and toxoplasma gondii. In in vitro and human studies, clindamycin is active against both chloroquine-resistant: chloroquine-susceptible malaria. Clindamycin exerts its antiprotozoal activity mainly after 48 to 72 hours. Exposure of protozoa to clindamycin for 24 hours leads to only 20 to 25% inhibition, independent of dosage; exposure for 72 hours leads to 75% inhibition. This time-dependent effect of clindamycin observed in vitro may explain the slow clinical response of P. falciparum to clindamycin (92). In vitro, clindamycin has limited activity against Toxoplasma; however, in combination with pyrimethamine for Toxoplasma infections of the central nervous system in AIDS patients.

               In vitro clindamycin alone has a poor activity against P. carinii and is ineffective as either prophylaxis or treatment for P. carinii pneumonia in animals. On the other hand, primaquine alone has a good in vitro activity against P. carinii, but is surprisingly ineffective as prophylaxis or treatment. However, the combination of clindamycin and primaquine is active therapeutically and prophylactically.

MECHANISMS OF ACTION

               Clindamycin and lincomycin inhibit bacterial protein synthesis by their action at the bacterial ribosome. The antibiotics bind preferentially to the 50S ribosomal subunit and inhibit initiation of peptide chain synthesis (93). Clindamycin may inhibit the binding of aminoacyl-tRNA or inhibit the translocation reaction following amino acid binding on the ribosome. Clindamycin acts at the same ribosomal binding site as erythromycin and chloramphenicol; therefore, the binding of anyone of these antibiotics can inhibit the action of the other compounds.

               Although clindamycin is regarded primarily as a bacteriostatic agent (42, 76, 103, 115), the drug has a concentration-dependent bactericidal activity against a variety of organisms, including staphylococci (11, 48, 86), streptococci, anaerobes (55, 89, 112, 124), and H. pylori (44). Clindamycin was bactericidal for B. fragilis in a number of studies (55, 89, 124). The activity of clindamycin is affected by serum or by variation in inoculum size. Clindamycin is more active against Gram-positive aerobic bacteria in alkaline environment than in an acidic environment. However the pH does not affect the activity of clindamycin against anaerobes. Interestingly, clindamycin can inhibit β-lactamase production by Enterobacter and Pseudomonas (81) without inhibiting growth (98).

Postantibiotic Effect

               Bacterial protein synthesis inhibitors, such as clindamycin, exert a pronounced postantibiotic effect (PAE) against susceptible species (19). This is likely due to persistence of the drug at the ribosomal binding site. Clindamycin demonstrates a prolonged postantibiotic effect (2.5-5.5 hours) for a variety of species, including S. aureus, S. pyogenes, and S. pneumoniae (19, 59). Animal studies have confirmed the in vivo expression of a clindamycin postantibiotic effect. In experiments with S. aureus, the protein synthesis inhibitors clindamycin and erythromycin induced postantibiotic effects of 7.1 and 6.8 hours, respectively; the cell wall-active β-lactam antibiotics induced PAEs of only 1.2 to 4.6 hours (117).

MECHANISMS OF RESISTANCE

               Resistance may be due to a chromosomal mutation that results in an altered drug receptor site on the 50S ribosomal protein. A plasmid- or transposon-mediated target modification by methylation of adenine on the 23S ribosomal RNA of the 50S ribosomal subunit may also confer resistance (90, 104). These strains are cross-resistant to all macrolide, lincosamide, and streptogramin B antibiotics (MLSB phenotype). Expression of inducible MLSB resistance may be constitutive or inducible (91). Expression of inducible MLSB resistance differs in staphylococci, streptococci, and enterococci. In staphylococci, 14- and 15-membered macrolides, but not lincosamides or streptogramins, are inducers of the methylase. In streptococci and enterococci, macrolides, lincosamides, and streptogramin B are efficient inducers (33). Strains with inducible resistance can be shown to become resistant to clindamycin when erythromycin is present; in a double-disk induction test, clindamycin distorts the zone of inhibition in the vicinity of erythromycin because of induction of methylase by subinhibitory concentrations of erythromycin. Resistance is not due to reduced drug uptake (108). Rare isolates of staphylococci (104) and some veterinary isolates of streptococci (29) may enzymatically inactivate clindamycin by adenylation. Plasmid-mediated transferable resistance to clindamycin (and erythromycin) was found in B. fragilis in 1991 (46).

PHARMACOKINETICS

Serum Half-Life

               Clindamycin phosphate (900 mg intravenously) produces peak levels of 15 l-µg/mL and trough levels of about 2.0 -µg/mL; clindamycin phosphate (600 mg intravenously) gives levels of about 11.0 and 2.0 µg/mL, respectively (Figure 2). Serum half-life is about 3 hours.

Absorption

               The presence of food can delay absorption, but peak and trough levels are usually not reduced (Figure 3). Both esters, clindamycin palmitate and clindamycin phosphate, are absorbed as the inactive ester and are readily hydrolyzed in blood to active clindamycin. Intramuscular clindamycin phosphate administration, which is relatively painless, results in slightly lower peak serum levels than equivalent doses administered intravenously. A 600 mg oral dose of clindamycin administered every 8 hours is usually bioequivalent to a 450-mg dose given every 6 hours when both regimens are evaluated over a 3-day period.

               In normal newborn infants, 5- to 7-mg/kg doses of clindamycin given intravenously and intramuscularly produce peak serum levels of 8 to 10 µg/mL (52). Premature infants in the first month postpartum display a longer half-life (8.68 hours) following clindamycin administration than full-term infants (3.60 hours) (125).

Tissue Penetration: Clindamycin is rapidly and markedly concentrated inside polymorphonuclear leukocytes, reaching an intracellular concentration about 40 times that in the extracellular environment. Patients with chronic granulomatous disease suffer from recurrent infections with catalase-producing organisms, particularly staphylococci. Phagocytosis occurs in chronic granulomatous disease, but the microorganisms survive inside the leukocytes. Clindamycin significantly reduced the number of viable intracellular staphylococci in normal and patient leukocytes tested in vitro. Controlled clinical trials are needed to translate these laboratory findings into applicable therapy.

Lincosamides penetrate into choledochal bile, cholecystic bile, gallbladder and liver tissue. An intravenous dose of 1.5 g of lincomycin results in the following concentrations: serum 34 µg/mL (at 2 hours); choledochal bile, 215 µg/mL (at 3 hours 15 minutes); cholecystic bile, 28 µg/mL (at 3 hours 36 minutes); gallbladder tissue, 28 µg/g (at 2 hours, 55 minutes); and liver tissue, 15.4 µg/g (at 4 hours). These concentrations exceed the MICs at which 90% of strains of clinical anaerobic strains are inhibited (MIC90).

Distribution

               Clindamycin reaches most tissues. In some instances (e.g. tonsils, sputum, bronchi, lungs, pleura, pleural fluid, liver, gallbladder, appendix, and decubitus ulcer), tissue concentrations may exceed serum levels. Higher tissue concentrations offer an advantage when treating skin, intraabdominal, and lower respiratory tract infections. Clindamycin concentrations in bone reach 60 to 80% of those attained in serum, suggesting the usefulness of clindamycin treatment for some patients with osteomyelitis. Distribution of clindamycin into the cerebrospinal fluid is limited, even when the meninges are inflamed, and clindamycin concentrations in spinal cord blood reach only half the levels found in serum. As a result, clindamycin is of limited use in treating meningitis. The fact that clindamycin penetrates into abscess tissues, first discovered in an animal model, has been successfully applied to treatment of human abscesses. Clindamycin concentrations in breast milk are variable.

Routes of Elimination

               Approximately 95% of administered clindamycin or its esters are either excreted unchanged or metabolized in the liver to a mixture of active and inactive metabolites that are excreted in the feces. Although the half-life of clindamycin is prolonged in patients with moderate-to-severe liver disease, dosage reduction is not considered necessary if the antibiotic is administered every 8 hours. Because the half-life of clindamycin can be prolonged in patients with impaired renal function, some clinicians suggest adjusting dosage on the basis of serum drug levels and creatinine clearance time. Other clinicians, however, do not find such adjustment necessary. During hemodialysis or peritoneal dialysis, clindamycin is not lost in the dialysate, so dose adjustment is probably not necessary (125).

Influence on Host-Parasite Interactions

               At subinhibitory concentrations, clindamycin enhances opsonization and subsequent phagocytosis of S. pyogenes, due to the inhibition of M protein synthesis. Similarly, opsonization of S. aureus is enhanced due to the reduction of protein A synthesis, an important cell wall component of staphylococci that inhibits phagocytosis (Figure 4). Clindamycin also inhibits capsule production by S. aureus (73). In addition, at low concentrations, clindamycin strongly inhibits production of toxic-shock-syndrome toxin and other toxins by S. aureus. The concentration of clindamycin that interfered with toxin production is of the order of 0.001 to 0.01 µg/mL. Similar observations were made with group A streptococci, clostridia. Clindamycin inhibits erythrogenic toxin product by streptococci (106, 24, 25, 68).

               Several bacteria produce a glycocalyx that plays a role in adherence of bacteria to foreign bodies and tissues. Glycocalyx produced by staphylococci, Bacteroides, and streptococci is an important virulence factor and is implicated in the pathogenesis of osteomyelitis, endocarditis, and catheter-related sepsis (23). Clindamycin concentrations below the MIC decrease glycocalyx production and subsequent adherence of bacteria to cells and foreign bodies (116). Clindamycin also reduces fibronectin binding to S. aureus at a concentration as low as 1/32 of the MIC, with maximal reduction at 1/16 of that concentration. This may be relevant in that fibronectin possibly plays a role in bacterial adherence to host cells.

DOSAGE

Normal

Oral Administration: Clindamycin can be administered orally as the hydrated hydrochloride salt (Cleocin HCL) or the palmitate esteric ester (Cleocin Pediatric). Clindamycin hydrochloride is available as a capsule for adults and for children who are able to swallow capsules. The capsules are in the following strengths: 75, 150, and 300 mg. A peak serum level of about 3 µg/mL is achieved 1 to 2 hours after oral administration of a dose of 300 mg in adult, and the peak is doubled by doubling the dose (66). A dosage of 150 to 450 mg every 6 hours is recommended for adults, depending on the severity of infection. Similarly, two dosage ranges are recommended for children: 8 to 16 mg/kg daily or 16 to 20 mg/kg daily, each in three or four divided equal doses depending on the severity of infection. Food does not significantly impair adsorption (87). Higher serum levels are reported after oral administration of clindamycin to patients with Crohn's disease, celiac disease, and jejunal diverticulosis (53).

               Clindamycin palmitate hydrochloride is a water-soluble hydrochloride salt of the ester of clindamycin and palmitic acid. The ester is available as granules to be suspended in water for children and adults who are unable to swallow capsules. Each 5 mL contains the equivalent of 75 mg of clindamycin base. The ester is hydrolyzed in vivo to the active base. Dosage of the ester is similar to that of salt, 8 to 25 mg/kg daily in three or four divided equal doses, and serum levels achieved; similar to those achieved with oral administration of clindamycin hydrochloride (20). In children weighing 10 kg or less, the minimal dose should be 37.3 mg every 8 hours.

Parenteral Administration: The water-soluble ester, clindamycin-2-phosphate (Cleo Phosphate) is used for parenteral administration, as the base is too irritating and poorly soluble at neutral pH. The intramuscular dose of clindamycin is 600 to 2700 mg daily in adults, given in two, three, or four divided equal doses. A dose of 300 mg produces a peak serum level of about 5 µg/mL at 2.5 hours after intramuscular administration. Lower serum levels are attained in diabetic patients after intramuscular administration. A single intramuscular dose of 600 mg or more is not recommended.

               Each milliliter contains the equivalent of 150 mg of clindamycin. For intravenous administration, clindamycin-2- phosphate is diluted, 1 part to 25 parts, and infused over 10 to 40 minutes, depending on the volume. The usual dose is 900 to 2700 mg daily in adults and as much as 4800 mg daily in life-threatening infections in adults, given in two, three, or four divided equal doses. Administration of more than 1200 mg in a single1 hour infusion is not recommended. A 300 mg-dose infused over 30 minutes produces a peak serum level of about 15 µg/mL in an adult.

               Parenteral dosage (intramuscular or intravenous) in neonates (< l month) is 15 to 20 mg/kg daily in three or four divided equal doses, the lower dose being adequate in premature infants. In children over 1 month of age, the dosage is 20 to 40 mg/kg daily in three or four divided equal doses.

Intravaginal Administration: Clindamycin phosphate is used for intravaginal administration in a semisolid white cream (Cleocin Vaginal Cream 2%) that contains 2% of the drug at a concentration equivalent to 20 mg/g of clindamycin. Each applicator full of    5 g of vaginal cream contains approximately 100 mg of clindamycin phosphate. The recommended dose is one applicator full of vaginal cream intravaginally, preferably at bedtime, for 7 consecutive days.

Topical Administration: Clindamycin phosphate is used for topical administration in a solution, lotion, and gel (Cleocin T) at a concentration equivalent to 10 mg/mL of clindamycin. Topical preparations are applied as a thin film twice daily to the affected area of skin.

Renal Failure

               Clindamycin is mainly excreted by nonrenal mechanisms. The dose of clindamycin is not necessarily reduced in patients with renal failure, but in severe renal failure accompanied by severe metabolic aberrations, monitoring of serum levels is recommended during high-dose therapy. Clindamycin is not significantly removed by hemodialysis (30) or peritoneal dialysis (67).

Hepatic Failure

               The rate of elimination of clindamycin is prolonged in severe hepatic disease but is not consistently correlated with any specific liver function abnormality (32, 53, 121). The dose of clindamycin is not necessarily reduced in patients with hepatic failure, but in severe hepatic failure accompanied by severe metabolic aberrations, monitoring of serum levels (if available) is recommended during high-dose therapy.

Obesity

               The effect of obesity on dosing of clindamycin is unknown.

Ascites and Edema

               The effect of ascites or edema on dosing of clindamycin is unknown.

Pregnancy

               Safety of clindamycin for use in pregnancy has not been established. Clindamycin is placed in pregnancy category B; drugs for which adequate, well-controlled studies in pregnant patients have not been done but which have shown no evidence of teratogenicity or fetal toxicity in animal or human studies. Thus, clindamycin should be used during pregnancy only if clearly needed.

Nursing Mothers

               Clindamycin is reported to appear in breast milk in concentrations of 0.7 to 3.8 µg/mL after doses of 150 mg orally to 600 mg intravenously.

ADVERSE EFFECTS

Diarrhea

               Diarrhea occurs in up to 20% of patients receiving clindamycin. In most patients the cause of the diarrhea is unknown, but in up to 20% of patients with clindamycin-associated diarrhea, the stool culture is positive for toxigenic C. difficile and the stool toxin assay is positive. This organism (9, 41) produces inflammation of the colon that spans the spectrum from slight mucosal erythema to pseudomembranous colitis (53, 110). In all patients with pseudomembranous colitis, the stool culture is positive for C. difficile and the stool toxin assay is positive. Diarrhea may be mild to severe and is frequently associated with abdominal cramps, fever, and passage of blood or mucus in the stool. The occurrence of pseudomembranous colitis is unrelated to size of the dose; it occurs after oral, parenteral, or topical administration of clindamycin in 0.01 to 10% of clindamycin-treated patients. Pseudomembranous colitis can occur in association with other antibiotics, but less frequently than with clindamycin. The onset may occur during clindamycin therapy or up to several weeks after stopping. Neutrophilic leukocytosis is common.

               Colitis following oral administration may be three to four times more frequent than following parenteral administration. Older patients with significant accompanying underlying illnesses, patients recuperating from abdominal surgery, and patients with a history of gastrointestinal diseases, particularly colitis, may be able to tolerate diarrhea less well than younger patients or those without underlying gastrointestinal disease.

               Some patients respond spontaneously when clindamycin is stopped, but many patients require specific therapy. Nevertheless, despite specific antimicrobial therapy with oral or intravenous metronidazole or oral vancomycin, diarrhea may persist or relapse in some patients. The disease may be complicated by dehydration, hypoalbuminemia, hypotension, toxic megacolon, and colonic perforation which can be potentially fatal.

               Use clindamycin cautiously in patients with previous gastrointestinal disease, particularly colitis. If mild diarrhea occurs, stopping clindamycin may be all that is necessary. Cholestyramine and colestipol resins, which bind the toxin in vitro, may be given orally. In moderate-to-severe cases, fluids and electrolytes, protein supplementation, and treatment for 7 to 10 days with an antimicrobial agent that has specific activity against C. difficile (e.g. oral or intravenous metronidazole 500 mg every 4 hours, or oral vancomycin, 500-2000 mg/day in three or four divided doses) should be given. If a resin and vancomycin are to be used concurrently, vancomycin should be given either 1 to 2 hours before or 4 hours after the resin. Although usually not advisable, clindamycin may be continued if absolutely necessary, with the addition of oral vancomycin or metronidazole and close observation of the patient. Relapses, which occur in up to 55% of patients, may be treated with repeated courses of the same antibiotic as before or an alternative agent (8). Antiperistaltic agents such as opiates, diphenoxylate with atropine (Lomotil), or loperamide (Imodium) may prolong or worsen the condition (83).

Neuromuscular Blockade

               Rare instances have been reported of enhancement of the action of neuromuscular blocking agents by concomitantly administered clindamycin that results in possible profound and severe respiratory depression (7, 36, 95). Patients who receive these combinations should be closely monitored.

Allergy

               Allergic reactions may result from hypersensitivity to clindamycin or lincomycin in susceptible individuals. Rash is a frequent adverse reaction to clindamycin, reported in up to 10% of treated patients in one study (39). Rarely, more-severe hypersensitivity reactions, such as Stevens-Johnson syndrome, anaphylaxis, polyarthritis, or blood cell abnormalities may occur (62). Clindamycin is contraindicated in individuals with a history of allergy to clindamycin and lincomycin.

               Allergic reactions, including asthma, may occur to yellow dye no. 5 (tartrazine) in the 75- and 150-mg capsules in susceptible individuals. The frequency of tartrazine sensitivity in the general population is low, but it is frequent in patients with preexisting bronchial asthma and aspirin hypersensitivity.

Esophagitis

               Esophageal irritation caused by a capsule swallowed without water lodging in the lower esophagus has been reported (107).

Cardiovascular Reaction

               Rare instances of hypotension and cardiopulmonary arrest have been reported following too-rapid intravenous infusion of clindamycin. The intravenous dose should infuse over 10 to 40 minutes, depending on the size of the dose.

“Gasping Syndrome”

               Clindamycin phosphate sterile solution contains benzyl alcohol as a preservative, which has been associated with potentially fatal "gasping syndrome" in premature infants, according to the package insert. However, since market introduction, no cases of gasping syndrome have been reported to Pharmacia & Upjohn through their worldwide product safety surveillance unit (personal communication).

Symptomatic Cervicitis/Vaginitis

               Symptomatic cervicitis/vaginitis occurs in 16% of patients treated with intravaginal application of clindamycin phosphate 2% vaginal cream. It may be due to local irritation from the 'topical medication or to overgrowth and subsequent infection by antibiotic-resistant Candida albicans, which occurs in 11% of treated patients. Development of symptomatic cervicitis/vaginitis requires discontinuation of clindamycin phosphate use and if clinically appropriate, antimicrobial treatment specific for C. albicans vaginitis.

Condom Breakage

               Clindamycin phosphate 2% vaginal cream contains mineral oil, which may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Clindamycin phosphate 2% vaginal cream should be discontinued at least 72 hours before use of latex condoms or diaphragms.

Skin Irritation

               Skin dryness, erythema, burning, peeling, etc. or contact dermatitis may occur with topical application of clindamycin phosphate solution, gel, or lotion. Overgrowth and subsequent follicular infection with antibiotic-resistant organisms, such as Gram-negative bacilli, may be complicating factors. In addition, the topical solution contains an alcohol base that may be irritating to abraded skin, eyes, or mucous membranes of the mouth. In the event of accidental contact with sensitive surfaces, bathe the surface (e.g., abraded skin, affected eye, or oral mucosa) with copious amounts of cool water.

DRUG INTERACTIONS

Drug/Food

               No significant interaction has been reported (87).

Drug/Drug

               Antagonism has been demonstrated between clindamycin or erythromycin and other macrolide antimicrobial agents (e.g., azithromycin and clarithromycin) and between clindamycin and lincomycin in vitro by competition for the same bacterial binding site. The clinical significance of the in vitro interactions is unknown.

               Concomitant administration of some skeletal muscle relaxants and clindamycin has been reported to result in enhanced neuromuscular blockade. Muscle relaxants include atracrium baclofen, carisoprodol, cyclobenzaprine, dantrolene, diazepam, doxacurium, meprobamate, methocarbamol, metocurine, pancuronium, quazepam, tubocurarine, and vecuronium. Other drugs that may potentiate neuromuscular blockade include the antimicrobial agents, colistin and aminoglycosides (36). Patients who receive these combinations should be closely monitored and may require a reduction in dosage of the neuromuscular blocking agent. The need for respiratory support should be anticipated.

               Concomitant use of anion-exchange resins (e.g., cholestyramine or colestipol) and some antibiotic agents may result in reduced or delayed antibiotic absorption. However, no interaction of colestipol with clindamycin has been found, and interaction of cholestyramine with clindamycin is not documented in the current package insert. In general, it is recommended that if concomitant administration is required, the antibiotic should be given at least 1 hour before or 4 hours after administration of the resin or kaolin/pectin.

               Clindamycin phosphate in solution is incompatible with ampicillin, phenytoin, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

Drug/Laboratory

               Intramuscular clindamycin injections elevate CPK values in most patients, possibly because of muscle irritation from the intramuscular injection (52).

               Clindamycin has been reported to cause transient leukopenia, thrombocytopenia, and eosinophilia; agranulocytosis may occur. Reversible mild elevations in transaminase alkaline phosphatase values occur in some patients (73-Levison), rarely associated with other evidence of hepatic injury such as jaundice (31, 62). Some of these abnormal laboratory results may be false-positive colorimetric reactions. Intramuscular clindamycin injections may elevate SGOT values, possibly because of muscle irritation from the intramuscular injection. During prolonged therapy with clindamycin, periodic liver and kidney function tests and blood counts should be monitored.

CLINICAL INDICATIONS

               Because clindamycin does not diffuse adequately into cerebrospinal fluid, clindamycin should not be used in the treatment of meningitis. Clindamycin has been reported to be no more effective than placebo in treatment of M. pneumoniae pneumonia (101). Because of the risk of clindamycin-associated colitis, use of clindamycin is restricted to serious infection and patients in whom other, less-toxic, alternative antimicrobial therapy is inappropriate. Use clindamycin cautiously in patients with previous gastrointestinal disease, particularly colitis. If mild diarrhea occurs, stopping clindamycin may be all that is necessary.

Actinomycosis

               Actinomyces spp., usually A. israelii, can produce a chronic necrotizing pulmonary infection that follows aspiration of oral flora into the lower respiratory tract and is characterized by fibrosis and fistulae that cross tissue planes from the lung to pleura, bone, and skin. This infection is frequently polymicrobial and involves, in addition to Actinomyces spp., other oral bacteria, including Actinobacillus actinomycetemcomitans. Actinomycosis can be treated effectively with clindamycin. However, although most members of the oral flora that cause necrotizing pneumonia are sensitive to clindamycin, A. actinomycetemcomitans is resistant to this antibiotic. A. actinomycetemcomitans is reported to be susceptible to cephalosporins, fluoroquinolones, tetracycline, and azithromycin. Failure of therapy for necrotizing anaerobic pneumonia with clindamycin was reported in one patient to be likely due to this clindamycin-resistant pathogen (75).

Regimens: The usual parenteral dose is 900 to 2700 mg daily in adults, given in two, three, or four divided equal doses for 4 to 6 weeks, and the oral dose is 150 to 450 mg every 6 hours in adults, depending on the severity of the infection. The total duration of therapy is 6 to 12 months.

Acne

               Clindamycin phosphate as a solution, lotion, or gel for topical administration has been found effective for the treatment of acne (109, 113). Propionibacterium acne, the presumed pathogen is susceptible to clindamycin.

Regimens: Clindamycin phosphate in solution, lotion, and gel for topical administration is applied as a thin film twice daily to the affected area of skin until a clinical response results.

Bacterial Vaginosis

               Patients with bacterial vaginosis usually complain of a vaginal discharge that has a "fishy" ammonia odor or emits such an odor when mixed with 10% KOH solution. The vaginal discharge has few or no WBCs, a pH above 4.5, and many "clue cells" (i.e., epithelial cells coated on the surface with tiny bacilli that stain Gram negative). The presumed pathogens, such as Gardnerella vaginalis or Mobiluncus sp., are susceptible to clindamycin. Clindamycin phosphate vaginal cream 2% has been found effective for the treatment of bacterial vaginosis (3, 72, 99).

Regimens: The dose is one applicator full of clindamycin phosphate vaginal cream 2% intravaginally, preferably at bedtime, for 7 consecutive days. Additionally, oral treatment of 300 mg BID for 7 days may be used as an alternative to vaginal cream or oral metronidazole.

Pneumococcal Disease

               Clindamycin can be used for serious infections caused by clindamycin-susceptible strains of pneumococci ( < 50.5 µg/mL) that involve the respiratory tract, when penicillin is judged to be inappropriate (e.g., the patient has a penicillin allergy).

S. pneumoniae, the most common cause of community-acquired pneumonia, accounts for 30 to 60% of community-acquired bacterial pneumonias. S. pneumoniae had been almost uniformly susceptible to penicillin; however, a few clones of penicillin-resistant pneumococci emerged under the selective pressure) of antibiotic usage. These clones spread throughout the world as a result of human migration and have become established in new areas, again under antibiotic usage over the past several decades (56). Penicillin-resistant strains are more likely to be resistant to antimicrobial agents, such as clindamycin, chloramphenicol, tetracycline, and famethoxazole. Therefore, excessive use of a number of different antimicrobial agents may select for penicillin resistance.

               In both South Africa and Spain, clindamycin resistance has been found to parallel erythromycin resistance. However, strains isolated more recently in the United States are commonly reported to be susceptible to clindamycin (38, 80).

               The clinical significance of drug-resistant S. pneumoniae is now in question as discordant therapy with beta-lactam agents in vitro have proven to be effective (123). Susceptibility to clindamycin among these strains in the United States is confirmed by reliable assays and the prevalence of clindamycin susceptibility remains high, clindamycin is an option for treatment of pneumonia due to these strains. On the other hand, the clinical significance of drug-resistant S. pneumoniae is now in question as discordant therapy with beta-lactam agents in vitro have proven to be effective in several large scale studies worldwide (6, 122, 123).

Regimens: The usual parenteral dose is 900 to 2700 mg daily in adults, given in two, three, or four divided equal doses for 1 to 2 weeks. Oral dosage of 150 to 450 mg every 6 hours is recommended for adults, depending on the severity of infection, for 1 to 2 weeks.

Malaria

               Clindamycin alone has been found effective for the treatment of falciparum malaria (61); however, it is more effective if given in combination with quinine or chloroquine.

Regimens: Clindamycin 5 mg/kg twice daily for 5 days is given in combination with quinine or chloroquine.

Babesiosis

               Clindamycin in combination with quinine has been found effective for the treatment of patients with severe babesia (58, 119).

Regimens: Clindamycin is given in a dosage of 20 mg/kg daily in children or 300 to 600 mg parenterally every 6 hours in adults plus quinine 25 mg/kg daily in children or 650 mg orally every 6 or 8 hours in adults for 7 to 10 days. Quinine is contraindicated in pregnancy.

Toxoplasmosis

               Clindamycin in combination with pyrimethamine has been found effective for the treatment of toxoplasmosis of the central nervous system (27, 65). If serum toxoplasma antibody assay is negative or if single lesions are seen on computed tomography (CT) or magnetic resonance imaging (MRI) scar, a biopsy of the brain lesions should be performed to confirm the diagnosis in patients with AIDS. If multiple enhancing ring lesions are seen on CT or MRI scans, cerebral toxoplasmosis may be treated empirically. If no response is seen in symptoms or scans in 14 days, then biopsy of the brain lesion is required to confirm the diagnosis. Folinic acid is used to reduce the bone marrow depressive effects of pyrimethamine without interfering with its antitoxoplasma effects. Maintenance therapy is required, because the relapse rate in untreated patients exceeds 30%. Intravitreal clindamycin has been effective in anecdotal cases of toxoplasmic retinitis (54). Pyrimethamine is a category C drug (animal studies show toxicity, human studies inadequate, but benefit outweighs risk), but limited studies have shown no teratogenicity in the first trimester of pregnancy.

Regimens: Pyrimethamine 200 g loading dose on day 1, then 50 to 75 mg. once daily plus folinic acid 10 mg orally plus clindamycin 600 to 1200 mg orally or intravenously every 6 hours for 3 to 6 weeks is given. Suppressive therapy must be continued for life in patients with AIDS to prevent relapse: pyrimethamine 50 to 75 mg/day orally plus folinic acid 10 mg/day orally plus clindamycin 300 mg every 6 hours orally.

Pneumocystis carinii Pneumonia

               Community-acquired pneumonia in a population with known, suspected HIV infection is likely due to P. carinii, especially chest radiographs reveal diffuse interstitial infiltrates. The combination of clindamycin and primaquine has proven effective for patients with mild-to-severe disease due to this organism in uncontrolled trials (14). One randomized, double-blind trial that compared intravenous clindamycin plus oral primaquine with intravenous or oral trimethoprim/sulfamethoxazole in patients with P. carinii pneumonia found no difference in clinical response rate or in rate of dose-limiting toxicity between the respective treatment groups (111). Similarly, a recent large multicenter, prospective double-blind, randomized trial of oral trimethoprim/ sulfamethoxazole, dapsone/trimethoprim, and clindamycin/primaquine in mild-to-moderate PCP (pAO2 -paO2:5 45 mm Hg at entry) in 181 patients with HIV infection found no statistically significant difference in clinical response, survival, or dose-limiting toxicity among the three treatment groups (97). Toxicity associated with clindamycin/primaquine therapy has included usually mild rash, neutropenia, methemoglobinemia, fever, serum transaminase elevations, diarrhea, and hemolysis. Because hemolytic anemia may occur with primaquine in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, determination of G6PD is recommended before starting primaquine. Primaquine is contraindicated in pregnancy.

Regimens: For alternate therapy for patients with severe sulfa hypersensitivity, the dose of clindamycin is 450 to 900 mg orally or intravenously every 6 to 8 hours plus primaquine base 15 to 30 mg once daily orally in adults for 3 weeks. Prednisone or prednisolone 40 mg orally or intravenously twice daily for 5 days, then 40 mg orally once daily for 5 days, then 20 mg once daily for 11 days is indicated at the initiation of antipneumocystis therapy if the initial paO2 is 70 mm Hg or below.

Surgical Prophylaxis

               Because of its antimicrobial activity against microflora of the sinuses and oronasopharynx, clindamycin can be used for chemoprophylaxis of clean-contaminated neurosurgery that crosses the sinuses or oronasopharynx or prophylaxis for head and neck surgery that enters the oral cavity.

Regimen: Clindamycin 600 to 900 mg intravenously is given in a single dose.

Prophylaxis for Bacterial Endocarditis

               Because of its antimicrobial activity against periodontal and upper respiratory tract microflora, clindamycin can be used for chemoprophylaxis of endocarditis in penicillin-allergic patients with significant cardiac lesions (prosthetic cardiac valves, previous endocarditis, most congenital cardiac defects, and rheumatic and other acquired valvular dysfunction, including mitral valve prolapse with valvular insufficiency) who are to undergo certain dental procedures that cause gingival or mucosal bleeding, tonsillectomy and adenoidectomy, bronchoscopy with a rigid bronchoscope, sclerotherapy for esophageal varices, or surgical procedures involving the respiratory mucosa (21).

Regimens: Clindamycin 600 mg in adults and 20 mg/kg in children (single dose) is given orally (1 h) or intravenously (30 min) before the procedure (26).

Anaerobic Bacterial Infections

               Clindamycin can be used to treat infection caused by susceptible anaerobic bacteria (MIC < 4 µg/mL), in particular anaerobic Gram-negative bacilli (e.g., B. fragilis, P. melaninogenica, and Fusobacterium nucleatum), Peptostreptococcus sp., Capnocytophagia ochracea, Clostridium perfringens, involving the respiratory tract, skin and soft tissue, bone and joint. Indeed, most anaerobic pathogens are sensitive to clindamycin. Long-considered to be a stalwart in the treatment of intraabdominal infections including peritonitis, abscesses and female pelvic and genital tract infections, the in vitro susceptibility of clindamycin has been steadily increasing such that a notable proportion of clinical isolates in many hospitals are now resistant in vitro. These infections are usually polymicrobial and involve clindamycin-resistant Enterobacteriaceae or enterococci, which require additional specific antimicrobial therapy such as a β-lactam or aminoglycoside antibiotic.

               Clindamycin offers an advantage over β-lactamase-sensitive β-lactams, because of the frequency of anaerobic pathogens (e.g., 100% of B. fragilis and up to 50% of P. melaninogenica) that produce β-lactamase (45, 63). Metronidazole, β-lactamase-resistant β-lactam antibiotics (e.g., cefoxitin, imipenem, or meropenem), or combinations of β-lactam antibiotics with β-lactamase inhibitors (e.g., ampicillin/sulbactam, amoxicillin/clavulanic acid, piperacillin/tazobactam, or ticarcillin/clavulanic acid) can be used with similar efficacy in place of clindamycin for anti-anaerobe activity; indeed all the β-lactam antimicrobial agents can be used alone for polymicrobial anaerobic infection because of the additional activity against an aerobic bacterial component (100, 102, 28). Metronidazole must be combined with another antimicrobial agent with activity against aerobes.

               In a prospective study of bacteremic patients infected with B. fragilis, clinical failures and microbiologic persistence were seen for clindamycin when MICs were found to be 16 μg/ml-256 μg/ml (82). The authors concluded that antimicrobial susceptibility testing in vitro for the Bacteroides species group is now necessary to guide antibiotic therapy.

Regimens: The usual parenteral dose of clindamycin is 900 to 2700 mg/day in adults, given in two, three, or four divided equal doses for 2 to 4 weeks in combination with an antimicrobial agent active against concomitant aerobic pathogens, such as a third-generation cephalosporin (e.g., ceftriaxone), aminoglycoside, or aztreonam. The oral dose of clindamycin recommended for adults is 150 to 450 mg every 6 hours, depending on the severity of infection, for 2 to 4 weeks.

Aerobic Bacterial Infections

               Clindamycin can be used to treat infections caused by susceptible aerobic bacteria (MIC < 0.5 µg of clindamycin/mL), such as streptococci (16, 39) and staphylococci that involve, for example, the respiratory tract, bloodstream, skin and soft tissue, and bone.

Streptococcal Infections

               Several studies have suggested that β-lactamase-producing Bacteroides sp. or S. aureus coexisting with group A streptococci may antagonize the activity of β-lactam antibiotics such as penicillin in the treatment of group A streptococci pharyngitis and result in persistent or relapsing streptococcal infection, whereas clindamycin has been effective in these circumstances (17, 50). Certain strains of group A streptococci are particularly invasive and may produce toxic shock syndrome because of their M protein, streptococcal pyrogenic exotoxins, and perhaps other virulence factors. High-dose penicillin therapy is the treatment of choice, but penicillin is relatively effective in eradicating dense populations of these organisms in tissues, presumably because expression of penicillin-binding proteins in organisms in the stationary phase (the predominant state in maximally dense microbial tissue populations) is lower than that of log-phase organisms. Indeed in the mouse model of streptococcal myositis, survival was better with clindamycin than with penicillin. In addition, clindamycin, an inhibitor of microbial protein synthesis may decrease production of M protein streptococcal pyrogenic exotoxin. For these same reasons, although the clinical benefit of the addition of clindamycin to penicillin therapy is unknown, it is advisable in patients with life-threatening streptococcal disease (96, 105, 106).

Staphylococcal Infections

               Most methicillin-sensitive staphylococci are sensitive to clindamycin, but methicillin-resistant staphylococci are variably clindamycin resistant. Clindamycin has been effective in therapy for S. aureus infection caused by susceptible strains, especially osteomyelitis and septic arthritis (34, 40 94).

               Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is becoming a more frequently encountered pathogen with the incidence of 42-47% reported (35, 84). However, unlike nosocomial-acquired MRSA, most strains remain susceptible to many antibiotics except for β-lactams. Clindamycin and trimethoprim/sulfamethoxazole retains significant activity against these community-acquired isolates with 92 – 100 % and 88.9 – 98 % susceptibility (10, 35). Therefore, clindamycin is often utilized as treatment for patients with CA-MRSA. It is important to note that regional variations of resistance exist for CA-MRSA (114). Thus, therapy should be monitored and appropriately adjusted based on the sensitivity report.

Regimens: Clindamycin 150 to 450 mg orally every 6 h, 600 to 2700 mg intravenously daily in two, three or four divided equal doses is given in adults. Treatment of streptococcal infection should be continued for at least 10 days to prevent subsequent development of acute rheumatic fever.

Anthrax

               Clindamycin does have activity against Bacillus anthracis, with an MIC50 = 0.5µg/mL (74). Although clindamycin is not considered the drug of choice for anthrax infections (ciprofloxacin or tetracycline would be first line), it may be added to the antibiotic regimen due to its proposed ability to decrease bacterial toxins. In the 2001 inhalation anthrax cases, clindamycin was added to the regimens due to its inhibition of toxins in streptococcal disease. This activity was extrapolated to the treatment of inhalation anthrax because of the toxin production associated with high morbidity and mortality associated with inhalation anthrax infections (70).

Regimen: Clindamycin 900 mg given intravenously every 8 hours.

Diptheria

               Clindamycin orally was found to be as effective as a single injection of benzathine penicillin in eradication of C. diptheriae from the nasopharynx or asymptomatic carriers (71).

Regimen: A 7-day course of clindamycin, 150 mg four times daily, is given.

TABLES AND FIGURES

Table 1: I Table 1.  In vitro Activity of Clindamycin Against Gram-Positive Aerobic Bacteria 

Table 2.  In Vitro Activity of Clindamycin Against Gram-Positive Anaerobic Bacteria 

Figure 1. The chemical structure of lincomycin and clindamycin. (From Zambrano D, ed. Clindamycin in the treatment of human infections. Kalamazoo, MI: The Upjohn Company, 1992. With permission).

Figure 2. Average plasma concentrations of clindamycin obtained for six normal adult male volunteers following i.v. administration of 900 mg q. 8 h and 600 mg q. 6 h clindamycin phosphate sterile solution in a crossover study design. (From Zambrano D, ed. Clindamycin in the treatment of human infections.  Kalamazoo, MI: The Upjohn Company, 1992. With permission).

 Figure 3. A. Average plasma concentrations of clindamycin obtained for 13 normal adult male volunteers following i.m.administration of 300 mg clindamycin phosphate sterile solution. B. Average plasma concentrations of clindamycin obtained for 22 normal adult male volunteers following oral administration of 300 mg clindamycin hydrochloride immediate after a meal. (From Zambrano D, ed. Clindamycin in the treatment of human infections. Kalamazoo, MI: The Upjohn Company, 1992. With permission).

 Figure 4.  Subinhibitory concentrations of clindamycin enhances uptake of S. aureus by PMN and decreased protein levels in the cell wall. PrA, protein A.

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