Spectrum of Action--Clinical Uses: Choramphenicol, Tetracyclines, Macrolides, Clindamycin

• Chloramphenicol (Chloromycetin)

• Tetracyclines

• Erythromycin, Clarithromycin (Biaxin), Azithromycin (Zythromax)

• Clindamycin (Cleocin)

Chloramphenicol (Chloromycetin)

• Chloramphenicol is seldom systemically used because of availability of other, better medications and because of its toxicity.

• Clinical uses: serious rickettsial infections (typhus or Rocky Mountain spottend fever) in children under 8 (when tetracyclines are contraindicated)

• Alternative treatment for bacterial meningitis due to a very penicillin-resistant pneumococcal isolate

• Meningococcal infections in patients with significant penicillin hypersensitivity.

• Chloramphenicol may be used for eye infections because of its broad antibacterial spectrum and because of its effective penetration of ocular tissue.

• Adverse Effects

  • GI: nausea vomiting diarrhea (adults);Oral or vaginal candidiasis due to alteration in normal flora

  • Bone marrow suppression: Chloramphenical--dose-related

  • Gray baby syndrome in newborns is due to chloramphenicol accumulation due to ineffective gluruonidation of the drug.

    • Syndrome includes: gray color, shock, hypothermia, flaccidity and vomiting.

Tetracyclines

• Tetracyclines: broad spectrum antibiotics: protein synthesis inhibitors

• Tetracycline bacteriostatic: many gram-positive and gram-negative bacteria including:

  • anaerobes

  • rickettsiae

  • chlamydiae

  • mycoplasma

  • some protozoa (amebas).

• Antibacterial spectrum is similar between tetracyclines although bacteria resistant to tetracyclines may remain sensitive to minocycline

• Resistance: Tetracyclines (Archer,G.L. and Polk, R.E. Treatment and Prophylaxis of Bacterial Infections, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 859.;Chambers, H.F., Chloramphenicol, Tetracyclines, Macrolides, Clindamycin and Streptogramins, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 745.) 

  • Most common mechanism for gram-negative bacterial resistance: insertion of a plasmid-encoded active-efflux pump that translocates tetracycline out of the cell.

  • Mechanisms for gram-positive bacterial resistance may be either through this active efflux mechanism or through changes in its ribosomal target.

  • Three mechanisms for resistance:

    • decreased intracellular concentration by decreased influx or increased efflux

    • decreased tetracycline ribosomal binding

    • enzymic inactivation of tetracycline

• Classification: short-acting (tetracycline (Achromycin), oxytetracycline, chlortetracycline: 1/2 life: 6-12 h) intermediate-acting (demeclocycline (Declomycin), methacycline: 1/2 life 12 h) long-acting (doxycycline (Vibramycin, Doryx), minocycline (Minocin), 1/2 life: 16-18h).

• Clinical Use  A tetracycline is the drug of choice for treating these infections:Mycoplasma pneumoniae, chlamydiae, rickettsia, some spirochetes.

  • Used in combination with other drugs to treat gastric and duodenal ulcer casue by Helicobacter pylori.

  • May be used in a variety of gram-positive and gram-negative bacterial infections in the absence of resistance.

  • No longer recommended for treatment of gonococcal disease due to the emergence of resistant strains.

  • Tetracyclines + aminoglycoside for: plague tularemia and brucellosis. May be used in treatment of protozoal infections: Entamoeba histolytica or Plasmodium falciparum

  • Other uses: acne, bronchitis, Lyme disease leptospirosis some mycobacterial infections (nontuberculous)

• Adverse reactions

  • GI: Nausea, vomiting--most common

  • Bone-Teeth: Tetracyclines bind to calcium incorporated into newly formed bone (young children) leading to discoloration; in the case of incorporation into bone, deformity or growth inhibition may occur.

Erythromycin, Clarithromycin (Biaxin) and Azithromycin (Zythromax)

Macrolides include erythromycin and semisynthetic derivatives clarithromycin and azithromycin

• Mechanisms of Resistance

  • reduced cellular permeability or enhancement of efflux

  • production by Enterobacteriaceae of enzymes that hydrolyze macrolides

  • following chromosomal mutation or by macrolide-inducible or normally present change in ribosomal binding site properties.

  • Methylase production is responsible for most of gram-positive microbe resistance Cross-resistance is complete between erythromycin and clarithromycin and azithromycin.

• Clinical Use  (note: clarithromycin is similar to erythromycin with respect to spectrum of action but has a lower frequency of GI upset)

  • Erythromycin is the drug of choice in treatment corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma)

  • in respiratory, neonatal ocular or genital chlamydia infections community-acquired pneumonia because its broad spectrum of treatment of action allows effective treatment of pneumoncoccus, Mycoplasma and Legionella

  • Erythromycin: penicillin-substitute for patients allergic to penicillin

•  Adverse Reactions

  • Gastrointestinal:

    • anorexia

    • nausea

    • diarrhea

    • vomiting

  • Liver toxicity: may produce cholestatic hepatitis (fever, impaired hepatic function, jaundice)

• Clindamycin Spectrum of Action

  • Streptococci, staphylococci and pneumococci are inhibited by clindamycin; however, in contrast to their susceptability to erythromycin, enterococci and gram-negative aerobic microbes are resistant (due to poor permeability of outer membrane)

  • Bacterioides (and other anaerobes), both gram-positive and gram-negative are mostly susceptable.

• Clindamycin Mechanism of Resistance

  • mutation of the ribosomal binding site

  • Inactivation of clindamycin by methylase

  • Modification of the receptor site by methylase production

• Clinical Indications

  • Primary, important indication for clindamycin: severe anaerobic infections due to Bacterioides and other anaerobes in mixed infections.

  • prophylaxis: Clindamycin (Cleocin) instead of erythromycin for endocarditis prior to dental procedures on patients who have valvular diseas

  • Clindamycin (Cleocin)+ primaquine: effective alternative to trimethoprim-sulfamethoxazole (Bactrim) in treating moderate to moderately-severe Pneumocystis carinii pneumonia in AIDS patients.

  • Clindamycin (Cleocin): useful in treating AIDS-related CNS toxoplasmosis.combination with pyrimethamine (Daraprim).

•  Adverse Reactions

  • Common:

    • rash

    • nausea

    • diarrhea

  • Hepatic dysfunction and neutropenia (occasional)

  • Colitis due to antibiotic selection and growth of toxigenic C. difficile

Chambers, H.F., Chloramphenicol, Tetracyclines, Macrolides, Clindamycin and Streptogramins, in Basic and Clinical Pharmacology,(Katzung, B. G., ed) Appleton-Lange, 1998, p. 749-750.