Clindamycin

Absorption

Oral bioavailability is nearly complete, at approximately 90%, and peak serum concentrations (Cmax) of, on average, 2.50 μg/mL are reached at 0.75 hours (Tmax). The AUC following an orally administered dose of 300mg was found to be approximately 11 μg?hr/mL. Systemic exposure from the administration of vaginal suppository formulations is 40-fold to 50-fold lower than that observed following parenteral administration and the Cmax observed following administration of vaginal cream formulations was 0.1% of that observed following parenteral administration.

Toxicity

The oral LD50 in mice and rats is 2540 mg/kg and 2190 mg/kg, respectively.
While no cases of overdose have been reported, symptoms are expected to be consistent with the adverse effect profile of clindamycin and may therefore include abdominal pain, nausea, vomiting, and diarrhea. During clinical trials, one 3-year-old child was given a dose of 100 mg/kg daily for 5 days and showed only mild abdominal pain and diarrhea. Activated charcoal may be of value to remove unabsorbed drug, but hemodialysis and peritoneal dialysis are ineffective. General supportive measures are recommended in cases of clindamycin overdose.

Description

Clindamycin, a derivative of lincomycin, was first isolated from Streptomyces lincolnesis in 1962 and became commercially available in 1966. The name originates from Lincoln, Nebraska, where the organism was first isolated from a soil sample. The parent compound of clindamycin is lincomycin, which is produced by actinomycete, Streptomyces liconelnensis, which belongs to the order of Actinobacteria. It replaced lincomycin use because of its better absorption and clinical spectrum. Lincomycin belongs to the lincosamides, which is a class of antibiotics. The compounds use as antibiotic agents stems from their ability to interfere with the protein synthesis of bacteria. The chemical modification of lincomycin, clindamycin, has proven to be superior to the natural product for clinical applications. Clindamycin is better absorbed from the gastrointestinal tract and food does not interfere with its absorption. It is also eight times more active against aerobic gram-positive cocci, and it has proven activity against gram-positive and gram-negative anaerobic bacteria as well as protozoal organisms like Toxoplasma and Plasmodium species.

Description

Clindamycin is an older antibiotic that is used to treat bacterial infections including pneumonia, strep throat, osteomyelitis, and endocarditis. It was first synthesized in 1966 by Barney J. Magerlein*, Robert D. Birkenmeyer, and Fred Kagan* at Upjohn (Kalamazoo, MI) by chemically modifying lincomycin1, a natural antibiotic. In the next few years, the same authors published additional articles and patents on clindamycin.
Clindamycin works by inhibiting ribosomal translocation in bacteria, reducing their ability to make proteins. It is most effective against aerobic Gram-positive and some anaerobic Gram-negative bacteria. It was approved by the US Food and Drug Administration in 1970.
Over the years, clindamycin has been a useful, versatile drug; but it is not without side effects such as nausea, diarrhea, and rashes. Significantly, it increases the risk of hospital-acquired colitis caused by Clostridium difficile. Although it has some ability to combat methicillin-resistant Staphylococcus aureus (MRSA), many bacteria have developed resistance to it.
Currently, clindamycin is taking on a new use: the development of more effective antibiotics. For an example, see this month’s Molecule of the Future, below.
1. CAS Reg. No. 154-21-2.

Originator

Dalacin-C,Diethelm,Switz.,1968

The Uses of Clindamycin

Clindamycin is a semi-synthetic analogue of lincomycin, prepared by chloride substitution of the exocyclic sugar hydroxy group. This affords a more hydrophobic compound with improved pharmacodynamics. Like other members of the lincosamide family, clindamycin is a broad spectrum antibiotic with activity against anaerobic bacteria and protozoans. Clindamycin acts by binding to the 23S ribosomal subunit, blocking protein synthesis. Clindamycin has been extensively studied with over 8,000 literature citations.

What are the applications of Application

Clindamycin is a lincosamide antibiotic that can bind the bacterial 50S ribosomal subunit, interfering with protein synthesis.

Background

Clindamycin is a semi-synthetic lincosamide antibiotic used in the treatment of a variety of serious infections due to susceptible microorganisms as well as topically for acne vulgaris. It has a relatively narrow spectrum of activity that includes anaerobic bacteria as well as gram-positive cocci and bacilli and gram-negative bacilli. Interestingly, clindamycin appears to carry some activity against protozoans, and has been used off-label in the treatment of toxoplasmosis, malaria, and babesiosis.
Clindamycin is derived from, and has largely replaced, lincomycin, a naturally occurring lincosamide and the eponymous member of this antibiotic class, due to its improved properties over the parent compound. The name lincomycin is derived from Lincoln, Nebraska, where it was first isolated from Streptomyces lincolnensis found in a soil sample.

Indications

In oral and parenteral formulations, clindamycin is indicated for the treatment of serious infections caused by susceptible anaerobic bacteria, as well as susceptible staphylococci, streptococci, and pneumococci. Used topically, it is indicated for the treatment of acne vulgaris and is available in combination with benzoyl peroxide or tretinoin for this purpose, or as a triple combination therapy with benzoyl peroxide and adapalene. Clindamycin is also indicated as a vaginal cream, suppository, or gel for the treatment of bacterial vaginosis in non-pregnant females.
Clindamycin is used for antimicrobial prophylaxis against Viridans group streptococcal infections in susceptible patients undergoing oral, dental, or upper respiratory surgery, and may be used for prophylaxis against bacterial endocarditis in penicillin-allergic patients at high risk of these infections.

Definition

ChEBI: Clindamycin is a carbohydrate-containing antibiotic that is the semisynthetic derivative of lincomycin, a natural antibiotic. The physiologic effect of clindamycin is by means of Decreased Sebaceous Gland Activity, and Neuromuscular Blockade.

Indications

Clindamycin (Cleocin), 300 to 450 mg/day, is an extremely effective agent for acne.

brand name

Cleocin (Pharmacia & Upjohn).

Therapeutic Function

Antibacterial

Biological Activity

Clindamycin is a lincosamide antibiotic. It is active against Gram-positive bacteria, including various strains of S. pneumoniae, S. viridans, S. aureus, and S. epidermidis (MICs = 0.002-0.1, 0.005-0.2, 0.04-1.6, and 0.1-0.2 μg/ml, respectively). Clindamycin is also active against chloroquine-resistant and -sensitive strains of P. falciparum (IC50s = 3.12 and 8.81 nM, respectively). It inhibits bacterial protein synthesis by interacting with the 50S ribosome. Clindamycin increases survival in a mouse model of a secondary S. pneumoniae infection when administered at a dose of 15 mg/kg twice daily for seven days. Formulations containing clindamycin have been used in the treatment of bacterial infections.

Contact allergens

This lincosanide antibiotic is used in topical form for acne, or systemically has been responsible for exanthematous rashes and acute generalized exanthematous pustulosis.

Mechanism of action

Clindamycin inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. The use of clindamycin with macrolides is not recommended since both of them compete for binding sites to the 50S subunit.

Pharmacokinetics

Clindamycin exerts its bacteriostatic effect via inhibition of microbial protein synthesis. Clindamycin has a relatively short Tmax and half-life necessitating administration every six hours to ensure adequate antibiotic concentrations.
Clostridium difficile associated diarrhea (CDAD) has been observed in patients using clindamycin, ranging in severity from mild diarrhea to fatal colitis and occasionally occurring over two months following cessation of antibiotic therapy. Overgrowth of C. difficile resulting from antibiotic use, along with its production of A and B toxins, contributes to morbidity and mortality in these patients. Because of the associated risks, clindamycin should be reserved for serious infections for which the use of less toxic antimicrobial agents are inappropriate.
Clindamycin is active against a number of gram-positive aerobic bacteria, as well as both gram-positive and gram-negative anaerobes. Resistance to clindamycin may develop, and is generally the result of base modification within the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete, and may also occur between clindamycin and macrolide antibiotics (e.g. erythromycin) due to similarities in their binding sites.
As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

Clinical Use

Clindamycin is effective in the treatment of most infections secondary to anaerobes and gram-positive cocci. It can be used for anaerobic pulmonary, intra-abdominal, gynecologic, pelvic, diabetic foot, and decubitus ulcer infections. Another appropriate agent should be added since the majority of these infections are polymicrobial. It can also be used as an alternative agent for patients with severe penicillin allergy. It is also used to treat Clostridium perfringens infection.
Oral preparations of clindamycin and vaginal cream are alternatives to metronidazole for the treatment of bacterial vaginosis. Topical solution is used for treatment of acne vulgaris and rosacea.
Clindamycin is extensively metabolized by the liver and the half-life is prolonged in patients with cirrhosis and hepatitis. Dose reductions are recommended in patients with acute liver disease.

Side Effects

The most commonly observed adverse effect is diarrhea. The reported incidence of C. difficile colitis in patients treated with clindamycin varies from 0.1 to 10%. The syndrome may be fatal. If the patient develops C. difficile colitis, clindamycin should be discontinued and the patient should be treated for C. difficile . Other side effects include rash, nausea, vomiting, diarrhea, flatulence, abdominal distension, anorexia, and transient elevation of liver enzymes. Other less common events, such as fever, neutropenia, thrombocytopenia, and eosinophilia have been reported.

Synthesis

Clindamycin, methyl-[7-chloro-6,7,8-trideoxy-6-trans-(1-methyl-4-propylL-2-pyrrollidin-carboxamido)-1-thio-L-threo-α-D-galacto-octapyranoside] (32.5.2), which is a 7(S)-chloro-7-deoxy derivative of lincomycin, is synthesized by replacing the hydroxyl group of lincomycin (32.5.1) at C7 by treating it with triphenyl phophine in acetonitrile (Raydon reagent), in which a configuration transformation takes place in the given carbo hydrate.

Veterinary Drugs and Treatments

Topical clindamycin is an optional topical treatment for feline acne.
Clindamycin inhibits bacterial protein synthesis by binding to the 50S ribosome; primary activity is against anaerobic and grampositive aerobic bacteria. For more information on the pharmacology of clindamycin, refer to the monograph for systemic use found in the main section.

Drug interactions

Potentially hazardous interactions with other drugs
Ciclosporin: may cause reduced ciclosporin levels.
Erythromycin: antagonism demonstrated in vitro; manufacturers recommend that the two drugs should not be administered concurrently.
Muscle relaxants: enhanced neuromuscular blockade.

Metabolism

Clindamycin undergoes hepatic metabolism mediated primarily by CYP3A4 and, to a lesser extent, CYP3A5. Two inactive metabolites have been identified - an oxidative metabolite, clindamycin sulfoxide, and an N-demethylated metabolite, N-desmethylclindamycin.

Metabolism

Clindamycin undergoes metabolism, presumably in the liver, to the active N-demethyl and sulfoxide metabolites, and also to some inactive metabolites. About 10% of a dose is excreted in the urine as active drug or metabolites and about 4% in the faeces; the remainder is excreted as inactive metabolites. Excretion is slow, and takes place over several days