MACROLIDES, TETRACYCLINES, AND SULFONAMIDES

Paula A. Teichner, Pharm.D.


Goals and Objectives:

By the end of this lecture, the student should be able to:


  1. Describe the mechanism of action for the marcolides, tetracyclines and sulfonamides.

  2. List the spectrum of activity for the macrolides, tetracyclines, and sulfonamides.

  3. List the pharmacokinetic parameters and the major clinical indications for the macrolides, tetracyclines and sulfonamides.

  4. Describe the major adverse effects and drug interactions for the macrolides, tetracyclines and sulfonamides.

  5. Describe the differences between erythromycin and the newer macrolides (advantages and disadvantages).

  6. Devise a rational treatment plan for use of the macrolides, tetracyclines and sulfonamides based on the clinical indication and patient specific characteristics.


Required Reading:

Harrison's Principles of Internal Medicine. 12th Edition. 1991.Chapter 85. Pages 489-492.

MACROLIDES

ERYTHROMYCIN

A. MECHANISM OF ACTION

Generally considered bacteriostatic, however may be bactericidal under certain circumstances.

Inhibits bacterial RNA-dependent protein synthesis. Macrolides bind to the 50S subunit of the 70S ribosome, which causes dissociation of t-RNA from the ribosome inhibits protein synthesis.

B. SPECTRUM OF ACTIVITY

Gram positive aerobes - Active against streptococcus pneumoniae and other streptococci, staphylococci, and corynebacterium diphtheriae.

Gram negative aerobes - Active against Legionella pneumophila, Neisseria gonorrhoeae, Moraxella catarrhalis, Bordetella pertussis. Enterobacteriaceae are resistant.

Anaerobes - Bacteroides fragilis are usually resistant.

Other - Mycoplasma pneumoniae, chlamydia trachomatis/pneumoniae, Treponema pallidum.

C. PHARMACOKINETICS

Absorption - Erythromycin base is subject to destruction by gastric acid and is poorly soluble in water. Newer oral preparations have acid-resistant coating to prevent drug dissolution until drug reaches the small bowel. Generally better absorption in the fasting state. Several different salt forms available to make drug more soluble and acid stable.

Distribution - Penetrates most tissues except the brain and CSF. High concentrations achieved in macrophages and PMNs. Persists in tissue longer than serum.

Metabolism/Excretion - Concentrated by the liver, excreted in bile and feces. Dosage reduction not necessary in patients with renal failure.


D. CLINICAL USES FOR ERYTHROMYCIN
Most common uses:

  1. Community-acquired Pneumonias - where atypical pathogens such as Mycoplasma pneumoniae and Legionella pneumophilia are common.
  2. Chlamydial infections (ie. chlamydia pneumoniae pneumonia or chlamydia trachomatis pelvic infections, especially in pregnancy.)
  3. Bordetella pertussis
Other uses:
  1. Streptococcal infections in patients with PCN allergy
  2. Minor staphylococcal skin infections
  3. Campylobacter gastroenteritis
  4. Syphilis in pregnancy
  5. Prophylaxis of bacterial endocarditis

E. ADVERSE DRUG REACTIONS

1. GI upset - nausea, vomiting, diarrhea

2. Thrombophlebitis - with parenteral administration. Can be decreased by diluting in 250 ml of fluid and slowing the rate of infusion.

3. Hypersensitivity reactions - fever, skin rash, eosinophilia

4. Cholestatic Hepatitis - occurs with estolate preparation, mainly in adults. DO NOT USE ESTOLATE IN ADULTS.

5. Ototoxicity - associated with large doses, especially in the elderly or patients with underlying renal insufficiency.

F. DRUG INTERACTIONS

Erythromycin inhibits cytochrome P450 enzyme system, and can decrease the clearance and increase the toxicity of theophylline, carbamezepine, cyclosporine, terfenadine, triazolam, etc. Erythromycin can also increase the hypoprothrombinemic effect of warfarin. Erythromycin may increase the bioavailability of digoxin which may increase the serum levels and cause toxicity.

G. DRUG PREPARATIONS AND DOSING

Oral - Several oral preparations are available: base, stearate salt, ethylsuccinate ester and estolate form. Available as capsules and film-coated tablets. Dose is 250-500 mg po q6 hours, 333 mg po q8 hours or 500 mg po q12h depending on the severity of illness and the indication.

Parenteral - Available as lactobionate or gluceptate salt. Used for patients with serious infections or patients unable to take oral medications. Dose is 250-1000 mg iv q6h. Must be given as an intravenous infusion. DO NOT give IM secondary to pain upon injection.

CLARITHROMYCIN (Biaxin) AND AZITHROMYCIN (Zithromax)

A. BACKGROUND

Clarithromycin is a 14-member structure (macrolide), similar to erythromycin, while azithromycin is a 15-member lactone ring (azalide). Both drugs were approved for use in 1991. Compared to erythromycin, these agents have better absorption, a longer t1/2, fewer GI side effects, better tissue penetration and a broader spectrum of activity. The disadvantage is the high cost compared to erythromycin.
B. SPECTRUM OF ACTIVITY

Gram positive aerobes - Clarithromycin is 2-4 times more active in vitro than erythromycin against most streptococci and staphylococci. Azithromycin is 2-4 times less active against the gram positives compared to erythromycin.

Gram negative aerobes - Azithromycin has greater activity than both erythromycin and clarithromycin against Moraxella catarrhalis and Hemophilus influenzae. The active metabolite of clarithromycin, 14-hydroxyclarithromycin, is slightly more active against M. catarrhalis and H. influenzae than the parent drug, and the combination of the two provides additive or synergistic activity.

Other - Both azithromycin and clarithromycin are more active than erythromycin against chlamydia spp. and Legionella pneumophilia. Clarithromycin has good activity against Helicobacter pylori. Both clarithromycin and azithromycin are active against Toxoplasma gondii and atypical mycobacteria such as Mycobacterium avium.


C. PHARMACOKINETICS

PHARMACOKINETICSCLARITHROMYCINAZITHROMYCIN
Bioavailability (%) 55%. Take with or without food 37%. Take on empty stomach
Distribution In tissuesExtensively distributed in tissues.
Metabolism In liver, metabolites renally eliminatedMost unmetabolized and excreted in feces
T1/2 (hours) 5-7 hours68 hours. T1/2 in tissue is 2-4 days.
Dosage Adjustment in RF CrCl < 30 ml/minNot required



D. INDICATIONS FOR USE OF CLARITHROMYCIN & AZITHROMYCIN

1. Upper and lower respiratory tract infections (ie. pharyngitis, sinusitis, bronchitis and pneumonia) - to cover pathogens usually seen in these infections such as S. pneumoniae, H. influenzae, M. pneumoniae, M. catarrhalis, etc.
2. Skin infections - uncomplicated
3. Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis (Azithromycin only).
4. Mycobacterium Avium Complex in patients with AIDS - Clarithromycin is approved for treatment, and must be used in combination with at least one other drug. Both clarithromycin and azithromycin are approved for MAC prophylaxis.
5. Helicobacter pylori - Clarithromycin

E. ADVERSE DRUG REACTIONS

1. GI - occur less frequently than with erythromycin. Most common are nausea, diarrhea, abdominal pain and taste disturbance. GI side effects may be more common in patients with HIV.

2. Hepatotoxicity - abnormalities in liver function tests occur uncommonly.

F. DRUG INTERACTIONS

Clarithromycin - may increase levels of theophylline (by ~20%) and carbamezepine. May increase the cardiovascular toxicity of terfenadine and astemizole. May increase serum concentrations of rifabutin.

Azithromycin - does NOT appear to interact with the cytochrome P450 system, thereby allowing other drugs to be metabolized without inhibition. No known drug interaction with theophylline, carbamezepine or terfenadine. ? effect on warfarin. Food decreases the absorption separate from meals.

G. DRUG PREPARATIONS AND DOSING

Clarithromycin

Only availabe po as 250 mg and 500 mg tablets
Dose is 250-500 mg po q12 hours depending on infection being treated.

Azithromycin

Available po as 250 mg capsules, 600 mg tabs and 1 gram oral suspension dose packet. Dose for respiratory tract infections and skin infections is 500 mg x 1 dose (2 capsules), followed by 250 mg po x 4 more days (Total therapy = 5 days). Can be given as a shorter treatment course due to prolonged tissue half-life. For treatment of non-gonococcal urethritis/cervicitis, given as a single 1 gram oral dose.

H. COST
(Cost per treatment course in retail setting)

Erythromycin (500 qid)Clarithromycin (500 bid)Azithromycin (250 qd)
$12.29/10 day course$62.29/10 day course$39.29/5 day course

I. Comparison Between Newer Macrolides and Erythromycin

Advantages of Clarithro and Azithro over Erythromycin

Disadvantages
Increase COST!

DIRITHROMYCIN (Dynabac)

New macrolide with spectrum of activity similar to that of erythromycin. Approved in October 1995 for once-daily dosing (500 mg po qd). Take with food. Available as 250 mg tablets. Not recommended for use in fections where H. influenzae is suspected.

TETRACYCLINES

A. MECHANISM OF ACTION

Tetracyclines are primarily bacteriostatic. They enter the bacteria by diffusion and once inside, bind reversibly to the 30S ribosomal unit >> block addition of amino acids to the growing peptide chain.

B. SPECTRUM OF ACTIVITY

Gram positive aerobes - Many gram (+) cocci are susceptible, but many strains of staphylococci, streptococci, and pneumococci are developing resistance. Therefore, the tetracyclines are NOT the drugs of choice for most gram positive aerobes.

Gram negative aerobes - Pseudomonads and many Enterobacteriaceae are resistant. Urinary concentrations are adequate for community-acquired E. coli infections.

Anaerobes - Increased incidence of Bacteroides fragilis resistance to the tetracyclines. Therefore they are not the drugs of choice for suspected or documented B. fragilis infections.

Other - Active against Mycoplasma pneumoniae, Chlamydia trachomatis, Borellia burgdorferi, and Rickettsiae.


C. CLASSIFICATION


CLASSIFICATIONSERUM T1/2GI ABSORPTION (%)
Short Acting (oxytetracycline, tetracycline)9 hours
8 hours
58
77
Intermediate (demeclocycline) 12 hours66
Long Acting (doxycycline, minocycline)18 hours
16 hours
93
95

D. PHARMACOKINETICS

Absorption occurs primarily in the proximal small bowel. Improved when taken in the fasting state (less important for doxycycline and minocycline). Peak levels 1-3 hours post- dose. Absorption is impaired when taken concurrently with other divalent and trivalent cations such as calcium and magnesium (antacids, milk).

Distribution into the lungs, liver, kidney, sputum. All tetracyclines are concentrated in the liver and excreted into bile. Long-acting TCNs have enhanced lipid solubility better tissue penetration.

Excretion - primarily via the kidneys. T1/2 prolonged in renal failure except for doxycycline. The TCNs are not recommended for use in renal failure (except doxycycline).


E. CLINICAL USES FOR THE TETRACYCLINES

Drugs of Choice For:
1. Rickettsial Infections (Rocky Mountain spotted fever, etc).
2. Sexually Transmitted Diseases (STDs)/ Pelvic Inflammatory Disease (PID) - Chlamydia trachomatis is common pathogen in these infections and tetracycline is drug of choice.
3. Atypical Pneumonias
Caused by organisms such as Mycoplasma pneumoniae and Chlamydia pneumoniae.
4.
Lyme Disease (early) - caused by Borrelia burgdoferi.

Other Common Uses:
1. Brucellosis
2. Helicobacter pylori
3. Acne
4. Traveller's diarrhea


F. ADVERSE EFFECTS

1. Teeth and Bone - May cause a grey-brown discoloration of the teeth (which is permanent) and enamel hypoplasia. Also may cause depression of skeletal bone growth in the human fetus and children. Not for use in pregnant or lactating women or in children under 8 years of age.

2. Hypersensitivity Reactions - urticaria, morbilliform rashes

3. Photosensitivity

4. Gastrointestinal irritation - Nausea, vomiting, diarrhea

5. Esophageal Ulceration - Can be avoided by taking medication with full glass of water and not prior to bed.

6. Renal Dysfunction - Tetracyclines aggravate pre-existing renal failure by inhibiting protein synthesis.

7. Vestibular Toxicity - Consists of tinnitus, dizziness, light-headedness. Occurs only with minocycline. Reversible after d/c of drug.

G. DRUG INTERACTIONS

Food decreases absorption of tetracycline. Calcium, magnesium, aluminum, iron- containing products and milk form complexes with the tetracyclines and decrease absorption>>Separate administation time by 2 hours.

H. DRUG PREPARATIONS AND DOSING


DRUGHOW AVAILABLEUSUAL ADULT DOSE
Tetracycline 250, 500 mg caps/tablets250-500 mg po q6 hours
Doxycycline50, 100 mg caps/tablets
INJ - 100, 200 mg vial
200 mg x 1, 100 mg po/IV q12-24 hours
Minocycline50, 100 mg caps/tablets
INJ - 100 mg vial
200 mg x 1, 100 mg po q12 hours

SULFONAMIDES

A. MECHANISM OF ACTION

The sulfonamides were the first systemic antibacterial drugs used in humans. Sulfonamides are primarily bacteriostatic, and work by interfering with folic acid synthesis. Sulfonamides competitively inhibit incorporation of PABA (para-aminobenzoic acid) into dihydrofolic acid (an intermediate in the process of folate metabolism)>> inhibit formation of folate which is essential for microorganism cell division.

B. SPECTRUM OF ACTIVITY

Gram positive aerobes - Are active against Streptococcus pyogenes.

Gram negative aerobes - E. coli are usually susceptible, especially at concentrations achieved in the urine. Active against some strains of Neisseria meningitidis.

Other - Active against Chlamydia, Toxoplasma and Nocardia species.

C. CLASSIFICATION OF SULFONAMIDES

1. Short Acting (sulfisoxazole, sulfadiazine) - soluble in urine.

2. Intermediate Acting - Sulfamethoxazole (Gantanol)
Less soluble and excreted more slowly than short acting sulfonamides >> provides higher blood levels. Increased chance of crystalluria >> need to ensure good urine output.

3. Long Acting - No longer recommended secondary to hypersensitivity reactions.

D. PHARMACOKINETICS

Rapidly absorbed (short and intermediate acting), well-distributed in body. Drug metabolized in the liver and excreted renally via glomerular filtration and tubular secretion. Dosage reduction necessary in renal failure.

E. CLINICAL USE OF SULFONAMIDES

1. Uncomplicated UTI - problems with increasing resistance.

2. Toxoplasma gondii - sulfadiazine used in combination with pyrimethamine.

3. Nocardia asteroides

F. ADVERSE EFFECTS

1. Hematologic - avoid in patients with glucose 6-phosphate dehydrogenase deficiency >>hemolysis. Can also cause bone marrow suppression >> leucopenia, anemia, or thrombocytopenia.

2. Hypersensitivity reactions - rash, fever, vasculitis, erythema multiforme, Stevens- Johnson syndrome.

3. Kernicterus - Avoid in neonates and during the last trimester of pregnancy. Sulfonamides compete for bilirubin-binding sites and increase levels of unconjugated bilirubin.

G. DRUG INTERACTIONS

Sulfonamides can increase the activity of warfarin need to decrease dose of oral anticoagulants. Hypoglycemic effect of tolbutamide and chlorpropamide may be increased by sulfonamides.


TRIMETHOPRIM

A. MECHANISM OF ACTION

Inhibits the enzyme dihydrofolate reductase, thereby interfering with the conversion of dihydrofolate to tetrahydrofolate, the precursor of folinic acid.

B. SPECTRUM OF ACTIVITY

See TMP/SMX below

C. PHARMACOKINETICS

Well absorbed from the GI tract, widely distributed in tissues, primarily excreted unchanged by the kidneys (60-80%). Serum t1/2 9-11 hours and prolonged in renal failure. Dosage adjustment required in renal failure.

D. CLINICAL USE

1. Uncomplicated UTIs

2. Pneumocystis carinii pneumonia - in combination with dapsone.

E. AVAILABILITY

100, 200 mg tablets.

TRIMETHOPRIM-SULFAMETHOXAZOLE [TMP/SMX], (Bactrim, Septra)

A. BACKGROUND

This compound is also known as co-trimoxazole. This combination inhibits 2 sequential steps of bacterial metabolism (see below). Has 2 theoretical advantages: 1. Decreases chance of developing resistance, and 2. May be synergistic. Available in oral and intravenous formulations. Combination provides ideal blood ratio of 1: 20 for optimal synergy.


B. MECHANISM OF ACTION

Sequential inhibition of synthesis of folic acid inhibit DNA production. Folate production is essential for nearly all microorganisms because they cannot extract exogenous folate from their diet, which is in contrast to mammalian cells.


The combination product TMP/SMX is bactericidal and synergistic against many gram positive and gram negative bacteria.

C. SPECTRUM OF ACTIVITY

Gram Positive Cocci - Active against Staphylococcus aureus (including some MRSA), S. epidermidis, Streptococcus pneumoniae, and viridans streptococci. Not active against enterococci.

Gram Negative Aerobes - Active against most Enterobacteriaceae including E. coli, Enterobacter spp. Hemophilus influenzae, Moraxella catarrhalis, Salmonella and Shigella spp, Xanthomonas maltophilia. Not active against Pseudomonas aeruginosa.

Anaerobes - Not active against anaerobes.

Other - Listeria monocytogenes, Pneumocystis carinii and most Nocardia species.

D. PHARMACOKINETICS

Absorption - Well absorbed from the GI tract.

Distribution - Distributes into most tissues; penetrates CSF (~40% of serum levels), pleural and peritoneal fluids. Achieves high concentrations in the prostatic fluid.
Elimination - Primarily excreted by the kidneys. When CrCl < 30 ml/minute, needs dosage adjustment.

F. CLINICAL USES FOR TMP/SMX (DOSING)

  1. Urinary Tract Infections
    - Acute (1 DS po q12 hours)
    - Recurrent
  2. Pneumocystis carinii pneumonia - treatment and prophylaxis (15 mg/kg/day TMP in doses q6-8 hours. 1 DS po qd or qM,W,F for prophylaxis).
  3. Prostatitis (1 DS po q12 hours)
  4. Acute exacerbations of chronic bronchitis (1 DS po q12 hours)
  5. Sinusitis/Otitis media - good for ampicillin-resistant strains of H. influenzae and M. catarrhalis (1 DS po q12 hours).
  6. Salmonella/Shigella
  7. Nocardia infections (10-15 mg/kg/day TMP)


G. ADVERSE EFFECTS

1. GI - nausea, vomiting, diarrhea

2. Hypersensitivity reactions - rash more common in AIDS patients (ie. in up to 50% of patients).

3. Hematologic - as above.

4. Teratogenesis and Kernicterus - Avoid in pregnant or lactating women, or infants < 2 months of age.

5. Hepatitis - rare.

H. DRUG INTERACTIONS

As mentioned above. TMP/SMX may increase levels of phenytoin, methotrexate. Use cautiously in patients receiving other bone marrow suppressive agents, especially in patients with HIV (ex. AZT).

I. DRUG PREPARATIONS