What are the indications, adult and pediatric dosing, contraindications, and alternative therapies for clarithromycin?

Clarithromycin: Indications, Dosing, Contraindications, and Alternatives

Indications

Clarithromycin is FDA-approved for community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, and acute maxillary sinusitis in adults, with additional guideline-supported uses in pertussis and atypical respiratory infections. 1

Respiratory Tract Infections

• Community-acquired pneumonia (CAP) in adults as part of combination therapy with a β-lactam (ceftriaxone, amoxicillin-clavulanate) or as monotherapy only in areas where pneumococcal macrolide resistance is documented <25% 2, 3
• Acute bacterial exacerbation of chronic bronchitis (AECB) in adults 1, 4
• Acute maxillary sinusitis in adults 2, 1
• Pertussis treatment and post-exposure prophylaxis in children >1 month and adults 2, 5

Atypical Pathogen Coverage

• Excellent activity against Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila when used as part of CAP treatment regimens 2, 6, 7
• Mycobacterium avium complex (MAC) infections at 500 mg twice daily with ethambutol 5

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Adult Dosing

Standard Immediate-Release Formulation

• Community-acquired pneumonia (hospitalized): 500 mg IV or orally twice daily for 7–10 days, always combined with a β-lactam (ceftriaxone 1–2 g IV daily) 2, 3
• Pertussis: 500 mg orally twice daily for 7 days (total daily dose 1 g) 2, 5
• Acute bacterial sinusitis: 500 mg orally twice daily for 14 days 2
• AECB: 500 mg orally twice daily for 7 days 4, 8

Extended-Release Formulation

• CAP, AECB, acute maxillary sinusitis: 1000 mg (two 500 mg tablets) orally once daily for 7–14 days 1, 4, 8
• The extended-release formulation is bioequivalent to immediate-release regarding area under the curve but has improved gastrointestinal tolerability 4, 9, 8
• Must be taken with food to optimize absorption 1, 8

Renal Impairment Dosing

• Severe renal impairment (CrCl <30 mL/min): Reduce dose by 50% or double the dosing interval 1
• Moderate renal impairment with concomitant atazanavir or ritonavir: Reduce clarithromycin dose 1
• No adjustment needed for mild-to-moderate hepatic impairment 2, 9

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Pediatric Dosing

Clarithromycin is contraindicated in infants <1 month due to risk of infantile hypertrophic pyloric stenosis (IHPS). 2, 5

Children >1 Month

• Pertussis: 15 mg/kg/day divided into 2 doses (maximum 1 g/day) for 7 days 2, 5
• Respiratory tract infections: 15 mg/kg/day divided into 2 doses for 7–10 days 5
• NTM infections (ages 1 month–11 years): 7.5 mg/kg twice daily (maximum 500 mg per dose) 5

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Contraindications

Absolute Contraindications

• Hypersensitivity to clarithromycin or any macrolide antibiotic 2, 5, 1
• History of cholestatic jaundice or hepatic dysfunction with prior clarithromycin use 1
• Concomitant use with cisapride, pimozide, astemizole, or terfenadine due to risk of fatal cardiac arrhythmias (QT prolongation, torsades de pointes) 2, 1
• Concomitant use with colchicine in patients with renal or hepatic impairment due to risk of colchicine toxicity 1
• Concomitant use with lomitapide, lovastatin, or simvastatin due to risk of rhabdomyolysis 1
• Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine) due to risk of ergot toxicity 1
• Concomitant use with lurasidone 1

Relative Contraindications and Warnings

• Known QT prolongation, ventricular arrhythmias, hypokalemia, hypomagnesemia, or significant bradycardia: Avoid clarithromycin 1
• Concomitant Class IA or III antiarrhythmics: Avoid clarithromycin 1
• Pregnancy (FDA Category C): Animal studies show fetal harm; use only when no alternative exists 2, 5
• Coronary artery disease: Increased risk of all-cause mortality ≥1 year after treatment; balance risk versus benefit 1

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Drug Interactions

Clarithromycin is a potent inhibitor of cytochrome P450 3A4 (CYP3A), leading to numerous clinically significant drug interactions. 2, 1

Major CYP3A Interactions

• Alfentanil, bromocriptine, cyclosporine, carbamazepine, cilostazol, disopyramide, ergot alkaloids, statins (lovastatin, simvastatin), methylprednisolone, quinidine, rifabutin, vinblastine, tacrolimus, triazolo-benzodiazepines (triazolam, alprazolam), and sildenafil 2
• Concomitant use can result in elevated drug concentrations, increasing therapeutic and adverse effects 2

Additional Interactions

• Zidovudine, hexobarbital, phenytoin, valproate, theophylline, digoxin, and oral anticoagulants 2
• Rifampin: Induces CYP450 enzymes and markedly reduces clarithromycin levels; avoid combination or use alternative macrolide 2

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Adverse Effects

Common (Gastrointestinal)

• Epigastric distress, abdominal cramps, nausea, vomiting, diarrhea (6% incidence with extended-release), and dysgeusia (abnormal taste, 7% incidence) 2, 5, 1, 8
• Extended-release formulation has improved GI tolerability compared to immediate-release 4, 8

Serious but Rare

• Hepatotoxicity: Discontinue if signs/symptoms of hepatitis occur 1
• Severe hypersensitivity reactions: Anaphylaxis, skin rashes, drug fever, eosinophilia 2, 5
• QT prolongation and torsades de pointes: Especially in elderly patients or those with cardiac risk factors 1
• Clostridioides difficile-associated diarrhea (CDAD): Evaluate if diarrhea develops 1
• Exacerbation of myasthenia gravis 1

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Alternative Therapies

For Community-Acquired Pneumonia

Outpatient (Previously Healthy Adults)

• First-line: Amoxicillin 1 g orally three times daily for 5–7 days (superior pneumococcal coverage) 2, 3
• Alternative: Doxycycline 100 mg orally twice daily for 5–7 days 2, 3
• Macrolide alternative: Azithromycin 500 mg day 1, then 250 mg daily for days 2–5 (only in areas with <25% macrolide resistance) 2, 3

Outpatient (Comorbidities or Recent Antibiotic Use)

• Combination therapy: Amoxicillin-clavulanate 875/125 mg twice daily PLUS azithromycin or doxycycline 2, 3
• Respiratory fluoroquinolone monotherapy: Levofloxacin 750 mg daily or moxifloxacin 400 mg daily (reserve for β-lactam allergy or contraindications) 2, 3

Hospitalized (Non-ICU)

• Preferred regimen: Ceftriaxone 1–2 g IV daily PLUS azithromycin 500 mg daily 2, 3
• Alternative: Respiratory fluoroquinolone monotherapy (levofloxacin 750 mg IV daily or moxifloxacin 400 mg IV daily) 2, 3

ICU (Severe CAP)

• Mandatory combination therapy: Ceftriaxone 2 g IV daily PLUS azithromycin 500 mg IV daily OR respiratory fluoroquinolone 2, 3

For Pertussis

• First-line alternative: Azithromycin 500 mg day 1, then 250 mg daily for days 2–4 (5-day course) 2, 5
• Second-line alternative: Erythromycin 500 mg four times daily for 14 days (higher GI side effects) 2, 5
• For macrolide-intolerant patients >2 months: Trimethoprim-sulfamethoxazole (TMP-SMZ) 8 mg/kg trimethoprim + 40 mg/kg sulfamethoxazole per day in 2 divided doses for 14 days 2, 5

For Acute Bacterial Sinusitis

• First-line: Amoxicillin-clavulanate (high-dose: 2 g/125 mg twice daily or 90 mg/6.4 mg per kg per day in children) 2
• Alternatives: Respiratory fluoroquinolones (levofloxacin, moxifloxacin), cefpodoxime, cefuroxime, or cefdinir 2

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Critical Clinical Pitfalls

• Never use macrolide monotherapy (including clarithromycin) in hospitalized CAP patients—it provides inadequate coverage for typical bacterial pathogens like S. pneumoniae and leads to treatment failure 2, 3
• Avoid macrolide monotherapy in outpatient CAP when local pneumococcal macrolide resistance exceeds 25% (most U.S. regions have 20–30% resistance) 2, 3
• Do not use clarithromycin in infants <1 month due to IHPS risk 2, 5
• Screen for drug interactions before prescribing—clarithromycin's CYP3A inhibition causes numerous serious interactions 2, 1
• Monitor ECG in patients at risk for QT prolongation (baseline and after 2 weeks) 5, 1
• Obtain blood and sputum cultures before initiating antibiotics in all hospitalized CAP patients to enable pathogen-directed therapy 2, 3