azithromycin (Zithromax, Zmax, Z-pak, AzaSite)

Introduction

Tradenames: Zithromax, Zmax.

Indications

• bacterial infections due to susceptible organisms, including
  • gastrointestinal infections
    • traveler's diarrhea
    • enterocolitis
    • proctitis
  • acute otitis media
  • upper respiratory tract infections
    • acute sinusitis
  • lower respiratory tract infections
    • pertussis
    • pneumonia
  • eye infections
    • conjunctivitis
  • urogenital infections
    • urethritis
    • pelvic inflammatory disease
    • gonorrhea
    • chancroid
• boutonneuse fever
• toxoplasmosis
• prevention of COPD exacerbations
• prophylaxis for bacterial endocarditis
• empiric treatment of fever of unknown origin
• Mycobacterium avium complex

Contraindications

• long-term use after stem-cell transplantation for hematologic malignancy

pregnancy category = b

safety in lactation = ?

Benefit/risk

• in combination with a beta-lactam antibiotic for community-acquired pneumonia in the elderly
  • number needed to treat to reduce 90 day mortality = 21
  • number need to harm to cause 1 MI = 144

Dosage

• 10 mg/kg up to 500 mg PO on day 1, then 5 mg/kg 250 mg QD for 4 days. (Zithro-pak Z-pak)
• Pharyngitis: 12 mg/kg up to 500 mg PO QD for 5 days
• Chlamydia: 1 g PO single dose
• Mycobacterium avium
  • treatment 600-1200 mg PO/IV QD for 6 weeks
  • prophylaxis: 1200 mg PO weekly
• 500 mg IV QD
• new 3 day regimen
• 2000 mg (Zmax) one-time dose
• Z-pak 500 PO day 1, the 250 mg QD for 4 days

Tabs: 250, 500 mg.

Suspension: 100 & 200 mg/5 mL (15 mL). Extended-release: Zmax: 200 mg (oral suspension)

Ophthalmic: (AzaSite) 1% opthalmic solution

• 1 drop BID for 2 days, then 1 drop QD for next 5 days

Pharmacokinetics

• rapid oral absorption
• food decreases absorption by 40-50%
• tissue distribution:
  • good: skin, lungs, sputum, tonsils, cervix
  • poor CSF penetration
  • leukocytes concentrate azithromycin, resulting in high levels of drug at the site of infection
  • tissue levels exceed serum levels by an order of magnitude
  • elimination from tissues lags behind elimination from blood
• terminal 1/2life is 68 hours
• biliary elimination of unchanged drug; only 6% eliminated in the urine

elimination via liver

Antimicrobial activity

Gram positive

• Streptococcus
  • Streptococcus group A
  • Streptococcus group B
  • Streptococcus group C
  • Streptococcus group G
• Streptococcus pneumonia*
• Staphylococcus aureus (MSSA) (+/-)
• Staphylococcus epidermidis (+/-)

Gram negative

• Neisseria gonorrhoeae (+/-)
• Moraxella catarrhalis
• Haemophilus influenzae
• Legionella
• Haemophilus ducreyi
• Campylobacter

Atypical bacteria

• Chlamydia species (FDA approved for urethritis/cervicitis)
• Chlamydophila pneumoniae
• Mycoplasma pneumonia, Mycoplasma hominis
• Mycobacterium avium

Anaerobes

• Actinomyces
• Bacteroides melaninogenicus
• Clostridium species

* community-acquired resistant pneumococcus has been reported

Adverse effects

• not common (1-10%)
  • diarrhea, nausea/vomiting, abdominal pain, cramping
  • hearing loss with chronic use
• uncommon (< 1%)
  • thrombophlebitis, ventricular arrhythmias, fever, skin rash, eosinophilia, increased aspartate transaminase (AST), & cholestatic jaundice less than erythromycin, ototoxicity (transient deafness), hypertrophic pyloric stenosis
• allergic reactions (rare)
• unlikely among macrolides to cause QT prolongation or interact with other drugs inhibiting or metabolized by cyt P450 3A4
• azithromycin is associated with increased risk for cardiovascular death
  • risk of potentially fatal arrhythmia
    • no increased risk of ventricular arrhythmia;
    • 2-fold risk in ventricular arrhythmia associated with underlying infection, not azithromycin
  • excess cardiovascular mortality is attributable to the infection being treated, not the antibiotic
  • higher risk of arrhythmia & mortality than amoxicillin
  • increased risk of cardiovascular death (RR=1.8) within 5 days of outpatient treatment (relative to amoxicillin)
    • no increased risk 6-10 days after treatment
  • benefits outweigh risks in elderly hospitalized with commmunity-acquired pneumonia
• other
  • 2-fold increased risk of miscarriage

• drug adverse effects of macrolide(s)

Drug interactions

• Al+3 & Mg+2 containing antacids decrease serum levels by 24%
• increased effect/toxicity & or serum levels with:
  • alfentanil, anticoagulants, astemizole, terfenadine, loratadine, bromocryptine, carbamazepine, cyclosporine, digoxin, disopyramide, theophylline, phenytoin, ergotamine, triazolam
• unlikely among macrolides to cause QT prolongation or interact with other drugs inhibiting or metabolized by cyt P450 3A4

• drug interaction(s) anticonvulsants with anti-bacterial agents
• drug interaction(s) of digoxin in combination with macrolides
• drug interaction(s) of statins with macrolide
• drug interaction(s) of antibiotics with warfarin
• drug interaction(s) of theophylline with macrolide
• drug interaction(s) of macrolides with sulfonylureas

Laboratory

• azithromycin in serum/plasma

More general terms

• macrolide (macrolide antibiotic)

More specific terms

• Azithromycin Ophthalmic

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=441190
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3033819
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=55185
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=447043
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2269
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5311011
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=370511