Antibiotics

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Antibiotics

• Sulfonamides
• Tetracyclines
• Macrolides
• Clindamycin

John W. Gnann Jr., M.D.
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Sulfonamides

• First effective systemic antibodies
• Mechanisms - competitively inhibits modification
  of PABA into folic acid, blocking DNA synthesis.
  Bacteria, unlike humans, cannot utilize preformed
  folate. Bacteriostatic.

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Sulfonamides

• Resistance
• Alterations in the enzymes that metabolize PABA
• Appearance of alternative pathways for folate
  synthesis

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Sulfonamides

• Pharmacokinetics
• Good oral absorption
• Partially acetylated by liver free and
  metabolized drug excreted by glomerular
  filtration
• Dosage reduction required for CrCl lt 30 ml/min.
  Removed by hemodialysis.
• Good CNS penetration

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Sulfonamides

• Spectrum of action
• GPC, GNR - previously broad-spectrum, now
  significant resistance
• Toxoplasma gondii
• Chlamydia trachomatis
• Nocardia asteroides
• Plasmodium falciparum

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Sulfonamides

• Major clinical uses
• UTIs - increasing sulfa resistance among GNR
• Toxoplasmosis (with pyrimethamine)
• Nocardia asteroides
• Topical - burns, conjunctivitis, vaginitis

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Sulfonamides

• Other clinical uses
• Plasmodium falciparum malaria (Fansidar-sulfadoxi
  ne plus pyrimethamine)
• Rheumatic fever prophylaxis (alternative to
  penicillin or erythromycin)
• Meningococcal prophylaxis (alternative to
  rifampin)
• Chlamydia infections (alternative to
  tetracycline)
• Inflammatory bowel disease (Azulfidine -
  sulfasalazine)

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Sulfonamide Toxicity

• GI - nausea, vomiting, diarrhea
• Hypersensitivity
• Rash, fever, anaphylaxis
• Stevens-Johnson syndrome - erythema multiforme
• PAN-like vasculitis
• Renal - crystalluria and obstruction
• Hematologic
• Hemolysis - associated with G6PD deficiency
• Aplastic anemia, leukopenia, thrombocytopenia
• Contraindicated during 3rd RM of pregnancy.
  Increases unconjugated fetal bilirubin
• Potentiates activity of coumadin, methotrexate

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Trimethoprim

• Mechanism - blocks folic acid synthesis by
  competitively inhibiting dihydrofolate reductase.
  True synergism with sulfonamides.
• Pharmacokinetics
• Good oral absorption
• T½ 9-11 hours, permits bid dosing
• Renal clearance by tubular secretion
• Good penetration into CSF, bile, prostate
• In vitro activity - broad spectrum of GPC and
  GNR. Pseudomonas and anaerobes resistant.
• Indications - UTI (Trimpex 100-200 mg po bid)

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Trimethoprim-Sulfamethoxazole (Septra, Bactrim)

• Indications
• Urinary tract infection
• cystitis - treatment, prophylaxis
• pyelonephritis
• prostatitis - acute, chronic
• Gastrointestinal infections (alternative to
  quinolone)
• shigellosis
• salmonella enteric fever
• enteropathogenic E. coli - treatment, prophylaxis

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Trimethoprim-Sulfamethoxazole (Septra, Bactrim)

• Indications (continuation)
• Respiratory tract infections
• otitis media
• bronchitis - acute, chronic
• Pneumocystis carinii pneumonia - treatment,
  prophylaxis--preferred drug
• Nocardia asteroides infections
• Granuloma inguinale (Donovanosis)

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Tetracyclines

• Mechanism of action
• Complex structure - 4 fused rings
• Binds to 30S ribosomal subunit, blocking access
  of tRNA to mRNA, thereby inhibiting bacterial
  protein synthesis
• Bacteriostatic

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Tetracyclines

• Spectrum of action
• GPC, GNR - previously broad-spectrum, now
  significant resistance. Most staph and strep
  resistant.
• Some anaerobic bacteria
• Rickettsia, Ehrlichia, Coxiella
• Borrelia species
• Chlamydia trachomatis
• Brucella species
• Francisella tularensis
• Vibrio cholerae

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Tetracyclines - Pharmacokinetics

• 3 groups, based on duration of action
• Group I T½ 6-8 hr (e.g., oxytetracycline)
• Group II T½ 12-14 hr (e.g., demeclocycline)
• Group III T½ 16-18 hr (e.g., doxycycline)
• Doxycycline is preferred for IV use

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Tetracyclines - Pharmacokinetics

• Absorption of Group I in small bowel impaired by
  food, milk, antacids, iron, etc. Group III
  completely absorbed (95)
• Good tissue levels, except marginal in CSF
• Metabolized in liver, excreted in urine and bile.
  Tetracyclines should not be used in renal
  failure, except doxycycline (biliary and fecal
  excretion).
• Crosses placenta, accumulates in fetal bones and
  teeth. Excreted in breast milk.

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Tetracyclines

• Indications
• Rickettsia, Ehrlichia, Coxiella infections
• Lyme disease, relapsing fever
• Trachoma, LGV, psittacosis, NGU
• Brucellosis, Tularemia (with aminoglycoside)
• Cholera

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Tetracyclines

• Alternative therapy
• Actinomycosis
• Anthrax
• Shigellosis
• Granuloma inguinale
• Syphilis
• Chronic bronchitis
• Acne
• Mycoplasma, Legionella

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Tetracyclines

• Adverse effects/toxicities
• Nausea, vomiting, diarrhea, esophageal ulcers
• Discoloration of teeth in children less than 8
  years old
• Bone growth retardation in infants
• Phototoxic rash (esp. doxycycline)
• Hepatotoxicity - acute fatty liver of pregnancy
• Azotemia - negative nitrogen balance

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Tetracyclines

• Adverse effects/toxicities (continuation)
• Nephrogenic diabetes insipidus (demeclocycline)
• Vertigo, vestibular dysfunction (minocycline)
• Candida superinfection - thrush, vaginitis
• Hypersensitivity - fever, rash, periorbital edema
• Thrombophlebitis with IV
• Pain with IM (not recommended)
• Pseudotumor cerebrii

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Macrolides

• Erythromycin
• Clarithromycin
• Azithromycin

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Macrolides

• Mechanism of action
• Complex macrocyclic lactone ring structures
• Binds to 50S ribosomal subunit, blocking the
  transpeptidation and translocation reactions,
  thereby inhibiting bacterial protein synthesis
• Bacteriostatic

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Erythromycin

• Spectrum of activity
• Primarily aerobic gram-positive cocci
• Legionella and Mycoplasma
• Enteric GNR are all resistant

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Erythromycin

• Pharmacokinetics
• Well absorbed by small bowel
• Most excreted in bile. Dosage adjustment not
  required in renal failure.
• Penetrates well into most tissues except CSF
• Safe antibiotic - serious adverse effects are
  rare. Non-serious adverse effects (esp. NV) are
  common.

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Erythromycin Preparations

• Oral - 20-200 mg every 6 hours
• Erythromycin base (e.g., E-mycin, PCE)
• Erythromycin stearate (e.g., Erythrocin)
• Erythromycin ethylsuccinate (e.g., EES)
• Erythromycin estolate (e.g., Ilosone)

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Erythromycin Preparations

• IV - 500-1000 mg every 6 hours
• Erythromycin gluceptate
• Erythromycin lactobionate
• Topical
• Solution for acne
• Ophthalmologic ointment

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Erythromycin

• Indications
• Mycoplasma pneumonia
• Legionella pneumonia
• Pertussis - prophylaxis
• Chlamydia trachomatis - conjunctivitis and
  pediatric pneumonia
• Stimulate peristalsis

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Erythromycin

• Alternative drug for
• Beta-hemolytic streptococci S. pneumoniae
• S. aureus (minor infection)
• Prophylaxis of rheumatic fever and bacterial
  endocarditis
• Lymphogranuloma venereum chancroid
• Nongonococcal urethritis
• Campylobacter jejuni gastroenteritis
• Diphtheria carrier state

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Erythromycin - Adverse Reactions

• Potentially lethal arrhythmias (prolonged Q-T)
  when combined with some long-acting
  antihistamines (e.g., Seldane)
• GI - cramps, N V, diarrhea very common
• Thrombophlebitis (with VI administration)
• Cholestatic hepatitis (erythromycin estolate)
• Allergic reactions (rash, fever, eosinophilia) -
  rare
• Hearing loss (transient, reversible) - rare
• Drug interactions - can potentiate effects of
  theophylline, coumadin, cyclosporin

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Macrolide Pharmacology

• Erythromycin Clarithromycin Azthromycin
• Absorption 55 37
• with food variable increased decreased
• Elimination T½ 2.0 hr 4.5 hr 55-76 hr
• Active metabolite no yes no
• Elimination hepatic hepatic hepatic
• (renal 5-10) (renal 30-50) (renal 5)

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Macrolide Spectrum of Activity

• Erythromycin Clarithromycin Azthromycin
• S. pneumoniae S S S
• S. pyogenes S S S
• S. aureus V S S
• H. influenzae R S S
• M. catarrhalis R S S
• N. gonorrhoeae R R R
• Enteric GNR R R R
• Chlamydia sp. S S S
• M. pneumoniae S S S
• L. pneumophilia S S S
• C. diptheriae S R R
• L. monocytogenes S S R
• B. pertussis S S S

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Roles for Clarithromycin and Azithromycin

• Compared to erythromycin, they
• Have better activity against fastidious
  gram-negatives
• Cause fewer GI adverse effects
• Are easier to dose
• Are much more expensive
• Primary use is for respiratory tract infections
• Innovative uses
• Treatment of atypical mycobacteria (eg, MAC)
  (clarithromycin)
• MAC prophylaxis (azithromycin)
• Single-dose therapy chancroid or NGU
  (azithromycin)
• Helicobacter pylori (clarithromycin other)

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Clindamycin

• Mechanism of action
• Lincosamide antibiotic - binds to 50S ribosomal
  subunit, blocking transpeptidation reaction,
  thereby inhibiting bacterial protein synthesis
• Primarily bacteriostatic

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Clindamycin

• Spectrum of activity
• Anaerobes - very active against most Bacteroides
  fragilis isolates
• Aerobic gram-positive cocci - good activity
  against streptococci (except enterococcus). Most
  S. aureus (80) are susceptible.
• Aerobic gram-negatives - no activity
• Protozoa - Pneumocystis, Toxoplasma, Babesia,
  Plasmodium sp.

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Clindamycin

• Pharmacokinetics
• Well absorbed after oral dosing
• Well tolerated IM
• Metabolized by liver, excreted in urine (90) and
  stool
• Penetrates well into most tissues except CSF
• Usual dose IV
• 600 mg every 6 hour
• 900 mg every 8 hour

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Clindamycin (Cleocin)

• Indications
• Anaerobic infections likely to involve S.
  fragilis (i.e., intra-abdominal, pelvic).
  Usually combined with aminoglycoside.
• Alternative to penicillin G for C. perfringens
  infections or anaerobic pneumonia
• Alternative drug for S. aureus or strep
  infections
• Protozoal infections - pneumocystis, malaria,
  babesiosis, toxoplasmosis
• Acne - topical therapy

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Clindamycin

• Adverse effects
• Clostridium difficle colitis (pseudomembranous
  colitis antibiotic associated colitis).
  Caused by toxin, occurs in 1-10 of
  clindamycin-treated patients. Potentially
  lethal.
• Diarrhea (non-C. difficle) 20
• Hepatotoxicity - reversible SGOT elevation
• Hypersensitivity reaction - rash (rare)