clindamycin and tetracycline antibiotics Flashcards
synthesis of clindamycin
Clindamycin is synthesized from the naturally occurring antibiotic lincomycin by treatment with chlorine and triphenylphosphine in acetonitrile. The reaction proceeds with inversion of configuration. Lincomycin has antibiotic activity but it is no longer used because of its toxicity.
clindamycin MOA
The mechanism of action of clindamycin is similar to that of the macrolide antibiotics like erythromycin. It inhibits protein synthesis by binding to the bacterial 50S ribosome. It binds to the same site as erythromycin. Antagonism and cross-resistance between clindamycin and erythromycin have been reported.
clincal use of clindamycin
Clindamycin is most effective against:
1) Aerobic Gram-(+) cocci, including some members of the Staphylococcus and Streptococcus genera.
2) Anaerobic Gram-(–) bacilli, including some members of the Bacteroides and Fusobacterium genera.
Clindamycin may be used systemically to treat bone infections with Staphylococcus aureus, or topically to treat severe acne. It is available as a vaginal cream for treatment of bacterial vaginosis.
Clindamycin has replaced penicillin for treatment of lung abscesses and anaerobic lung and pleural space infections. It is also used to treat MRSA.
Clindamycin is administered IV with pyrimethamine and leucovorin to treat AIDS patients with encephalitis caused by Toxoplasma gondii.
Note: The relatively high incidence of pseudomembranous colitis and diarrhea limit the use of clindamycin to infections in which it is clearly the superior agent.
clindamycin dosage forms
Clindamycin preparations for oral administration include capsules and oral suspensions. It is also available for intravenous injection as clindamycin phosphate. Topical foams or solutions contain either clindamycin hydrochloride or clindamycin phosphate.
clindamycin metabolism
Clindamycin is extensively metabolized by cytochrome P450 enzymes in the liver to the sulfoxide and the N-demethylated derivative. The metabolites are pharmacologically inactive**.
clindamycin PKs
Approximately 90% of the administered dose is absorbed from the GI tract. It is widely distributed and penetrates the CNS in high enough concentrations** to be useful in the treatment of cerebral toxoplasmosis in human immunodeficiency virus-infected patients.
Clindamycin and its metabolites are mainly excreted in the urine and bile. The elimination half life is 1.5-5 hours. Accumulation of clindamycin can occur in patients with hepatic failure, and adjustment of the dosage may be required**.
clindamycin AEs
Common adverse reactions include diarrhea, pseudomembranous colitis, nausea, vomiting, abdominal cramps, and rash. Topical application may cause contact dermatitis.
Pseudomembranous colitis is a potentially lethal condition** commonly associated with clindamycin. It may affect up to 2–10% of patients treated with clindamycin. Overgrowth of Clostridium difficile, which is inherently resistant to clindamycin, results in the production of a toxin that causes a range of adverse effects ranging from diarrhea to colitis and toxic megacolon. This should be recognized and treated promptly with metronidazole or vancomycin*.
chemical properties of tetracyclines
chelation, epimerization, dehydration and cleavage in base
chelation of tetracyclines
Chelation. Tetracyclines form stable chelates with polyvalent metal ions such as Ca++, Al+++, Cu++, and Mg++.
The ability of tetracyclines to form insoluble chelates* has a number of consequences:
1) Tetracyclines should not* be administered with foods that are rich in calcium because the insoluble calcium chelates are not absorbed from the GI tract. They should not* be administered with antacids that contain multivalent metals (e.g. TUMS), or with hematinics containing iron.
When concomitant therapy with tetracyclines and multivalent metals cannot be avoided, the metals should be administered 1 hour before* or 2 hours after** the tetracycline.
In spite of the chelation problem, the preferred route of administration is oral, since oral absorption is adequate in the absence of multivalent metal ions in the GI tract.
2) Tetracyclines chelate calcium during formation of teeth, resulting in permanently brown or gray teeth. Consequently, tetracyclines should not be administered to children when they are forming their permanent teeth. The discoloration of the teeth becomes worse with time as a result of a photooxidation reaction
3) The pain on injection* caused by tetracyclines has been attributed to the formation of insoluble calcium complexes. To minimize this, injectable formulations contain EDTA to chelate the calcium, and they are buffered to acidic pH where chelation is suppressed.
Epimerization of tetracyclines
The hydrogen on the amine-bearing carbon atom is acidic, resulting in enolization and epimerization. The epitetracycline product is pharmacologically inactive. This can occur in the solid state (in capsules) as well as in solution. Old tetracycline preparations can loose approximately half of their potencies in this way. Epimerization is slow in the solid state and most rapid in solution at pH 4.
dehydration of tetracyclines
The tertiary, benzylic hydroxyl group at C-6 has an antiperiplanar relationship with the proton at C-5a, so it is “set up” for elimination. Note that the C-12a hydroxyl group is tertiary, but it is not next to an antiperiplanar hydrogen and is also deactivated by being next to a carbonyl group, so it is stable.
Discolored, old tetracycline samples should be thrown out. Not only is 4-epianhydrotetracycline inactive as an antibiotic, it is also toxic to the kidneys and can produce a Fanconi-like syndrome (failure of the reabsorption mechanism in the proximal convoluted tubules) that can be fatal. Therefore, commercial samples of tetracycline are closely monitored for 4- epianhydrotetracycline. Some tetracyclines, such as minocycline and doxycycline, lack a C-6 hydroxyl group and are therefore completely free of this potential for toxicity.
cleavage in base of tetracyclines
Tetracyclines undergo cleavage in base at pH values of 8.5 or above. The lactone product in inactive.
tetracyclines MOA
Tetracyclines bind to the 30S ribosomal subunit and inhibit bacterial protein synthesis by blocking the attachment of the aminoacyl-tRNA to the A site of the ribosome, resulting in termination of peptide chain growth. More precisely, they are inhibitors of the codon-anticodon interaction. The tetracycline binding sites do not overlap with the erythromycin binding site. Tetracyclines can also inhibit protein synthesis in the host, but are less likely to reach the concentration required for toxicity because eukaryotic cells, in contrast to bacteria, do not have a tetracycline uptake mechanism.
Tetracycline binds to the small ribosomal subunit in six different locations. The Tet1 site has highest occupancy and is located near the site where the aminoacyl-t-RNA docks in the A site of the ribosome. The functional significance of each site is not known.
tetracyclines therapeutic use
The tetracyclines are broad-spectrum antibiotics. Their most common use is for treatment of acne. They remain the treatment of choice for infections caused by chlamydia (trachoma, psittacosis, salpingitis, urethritis, and lymphogranuloma venereum), Rickettsia (typhus, Rocky mountain spotted fever), brucellosis, and spirochetal infections (borreliosis, syphilis, and Lyme disease). They are also used to treat anthrax, plague, tularemia, and Legionnaires’ disease.
tetracycline
1) Tetracycline is the classical antibiotic of the tetracycline class. It is produced by fermentation of Streptomyces aureofaciens. It is generic and relatively inexpensive.
2) Food and milk lower oral absorption by about 50%.
demeclocycline
1) Demeclocycline is produced by a genetically altered strain of Streptomyces aureofaciens.
2) It has a secondary hydroxyl group at C-6 instead of the tertiary hydroxyl group. Demeclocycline therefore dehydrates more slowly than tetracycline because the secondary cation intermediate formed from demeclocycline in the dehydration reaction is less stable (higher energy) than the tertiary cation intermediate (lower energy) formed from tetracycline.
3) Food and milk lower oral absorption by about 50%
minocycline
1) Minocycline lacks a C-6 hydroxyl group and therefore does not undergo acid-catalyzed dehydration. It therefore has no potential for 4-epianhydrotetracycline-mediated toxicity.
2) It is synthesized from demeclocycline.
3) Minocycline has 90-100% oral bioavailability.
4) The absorption of minocycline is lowered by about 20% when taken with food or milk.
5) Minocycline has vestibular toxicities** (vertigo, ataxia, nausea) not shared with other tetracyclines.
oxytetracycline
1) Oxytetracycline is produced by fermentation of Streptomyces rimosis.
2) It is the most hydrophilic tetracycline and has been largely replaced by its semisynthetic descendants.
3) It is available with polymyxin B as an opthalmic ointment.
doxycycline
1) Doxycycline is synthesized from oxytetracycline.
2) It lacks a C-6 hydroxyl group and therefore does not undergo acid-catalyzed dehydration. It therefore has no potential for 4-epianhydrotetracycline-mediated toxicity.
3) Because it has no potential for 4-epianhydrotetracycline-mediated toxicity and produces fewer GI symptoms, it is considered to be the tetracycline of choice by many physicians.
4) It has 90-100% oral bioavailability.
5) The absorption of doxycycline is lowered by about 20% when taken with food or milk.
6) It has a half-life (18-22 hours) that permits once a day dosing.
Tigecycline
Tigecycline. A glycylcycline antibiotic derivative of minocycline. Active against a variety of gram-positive and gram-negative bacteria. Parenteral, administered by slow IV infusion.
1) Tigecycline lacks a C-6 hydroxyl group and therefore does not undergo acid-catalyzed dehydration. It therefore has no potential for 4-epianhydrotetracycline-mediated toxicity.
2) It is synthesized from minocycline.
3) It is administered by slow IV infusion. No oral form is available.
4) Hepatotoxicity (rare), pancreatitis, and anaphylactoid reactions may occur.
5) Inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains.
6) Tigecycline is protected from resistance development due to efflux pump induction and also due to ribosomal protection proteins.
Chloramphenicol MOA
Chloramphenicol binds reversibly to the 50S ribosomal subunit at a site that is near the site for erythromycin and clindamycin (competitive binding interactions occur among these drugs). It inhibits the peptidyl transferase activity of the ribosome and thus blocks peptide bond formation between the P site and the A site.
Chloramphenicol therapeutic use
Chloramphenicol sodium succinate is a prodrug for IV or IM administration that is hydrolyzed to chloramphenicol in the liver. Chloromycetin succinate is specifically indicated for bacterial meningitis, typhoid fever, rickettsial infections, intraocular infections and other serious infections where bacteriological evidence or clinical judgment indicates that chloramphenicol is an appropriate antibiotic.
Chloramphenicol is lipid soluble, and it remains relatively unbound to plasma proteins. It penetrates effectively into all tissues of the body, including the brain.
chloramphenicol MOR
Resistance to chloramphenicol results from 1) reduced membrane permeability; 2) mutation of the 50S ribosomal subunit, and 3) elaboration of chloramphenicol acetyltransferase, which acetylates one or both of the hydroxy groups to form metabolites that do not bind to the 50S ribosomal subunit.
Cloramphenicol metabolism
Chloramphenicol is metabolized to its glucuronide in the liver. The glucuronide is pharmacologically inactive and is readily excreted by the kidneys. The reaction involves nucleophilic attack of the less hindered primary alcohol on UDPGA, catalyzed by glucuronyl transferase.
The dose of chloramphenicol must therefore be reduced if hepatic function is impaired. There is no standard dose reduction for chloramphenicol in liver impairment, and the dose should be adjusted according to measured plasma concentrations. Neonates cannot metabolize chloramphenicol and should never receive it.
Chloramphenicol is also metabolized by reduction of the nitro group to an amino. The metabolite is less active than chloramphenicol.