Clarithromycin

Clarithromycin is an Antibiotic agent belonging to Macrolide

Clarithromycin is used in the Treatment of Chronic obstructive pulmonary disease, acute exacerbation, Helicobacter pylori eradication, Mycobacterial (nontuberculous) infection, Otitis media, Pneumonia, community-acquired, Skin/skin structure infection, Streptococcal pharyngitis, group A. It is also used to treat Bartonella spp. infection; Bronchiolitis obliterans, including diffuse panbronchiolitis and symptomatic cryptogenic bronchiolitis obliterans; Endocarditis, prophylaxis; Mycobacterial (nontuberculous, rapidly growing) infection; Pertussis; Q fever (Coxiella burnetii), acute symptomatic.

Clarithromycin is Rapidly and well absorbed from the gastrointestinal tract. Bioavailability: Approx 50%. It is Widely and readily distributed into most body tissues and fluids. Crosses the placenta and enters breast milk. Plasma protein binding: 80%.

Metabolism: Partially metabolised in the liver by CYP3A4 isoenzyme and undergoes extensive first-pass metabolism into 14-hydroxyclarithromycin (active) and get excreted Via urine (approx 20-40% as unchanged drug; 10-15% as metabolites); faeces (5-10% as unchanged drug). Elimination half-life: Immediate-release: 3-7 hours (clarithromycin); 5-9 hours (14-hydroxyclarithromycin).

The Tmax of Clarithromycin was achieved within 2-3 hours (immediate-release); 5-8 hours (modified-release). Cmax was about 0.78 to. 0.94 mg/L

Clarithromycin shows common side effects like Headache, dizziness, Diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Clarithromycin is available in the form of Tablets, and Suspension

Clarithromycin is available in India, Germany, Canada, Italy, USA

Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound. Like other macrolides, it then penetrates bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump.

Clarithromycin is available in the form of Tablets and Suspension .

Oral:

IR tablets and granules for suspension: Administer with or without meals. Administer every 12 hours rather than twice daily to avoid peak and trough variation. Shake suspension well before each use.

ER tablets: Administer with food. Do not break, crush, or chew.

Clarithromycin is used in the Treatment of • Chronic obstructive pulmonary disease, acute exacerbation, Helicobacter pylori eradication, Mycobacterial (nontuberculous) infection, Otitis media, Pneumonia, community-acquired, Skin/skin structure infection, Streptococcal pharyngitis, group A. It is also used to treat Bartonella spp. infection; Bronchiolitis obliterans, including diffuse panbronchiolitis and symptomatic cryptogenic bronchiolitis obliterans; Endocarditis, prophylaxis; Mycobacterial (nontuberculous, rapidly growing) infection; Pertussis; Q fever (Coxiella burnetii), acute symptomatic.

Clarithromycin is a macrolide antibiotic that selectively binds to the 50S ribosomal subunit of susceptible bacteria and prevents the activated amino acids translocation, resulting in inhibition of intracellular protein synthesis

Clarithromycin is approved for use in the following clinical indications

● Chronic obstructive pulmonary disease, acute exacerbation: Treatment of acute bacterial exacerbation of chronic bronchitis in adults due to susceptible Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

● Helicobacter pylori eradication: Eradication of Helicobacter pylori to reduce the risk of duodenal ulcer recurrence as a component of combination therapy (triple therapy) in adults with H. pylori infection and duodenal ulcer disease (active or 5-year history of duodenal ulcer).

● Mycobacterial (nontuberculous) infection: Prophylaxis and treatment of disseminated mycobacterial infections due to Mycobacterium avium complex (MAC) in patients with advanced HIV infection.

● Otitis media: Treatment of acute otitis media in pediatric patients due to susceptible H. influenzae, M. catarrhalis, or S. pneumoniae.

● Pneumonia, community-acquired: Treatment of community-acquired pneumonia due to susceptible Mycoplasma pneumoniae, S. pneumoniae, or Chlamydophila pneumoniae (adult and pediatric patients) and H. influenzae, H. parainfluenzae, or M. catarrhalis (adults).

● Skin/skin structure infection: Treatment of uncomplicated skin/skin structure infection due to susceptible Staphylococcus aureus or Streptococcus pyogenes.

● Streptococcal pharyngitis, group A: Treatment of pharyngitis/tonsillitis due to susceptible S. pyogenes (alternative agent for patients with severe penicillin allergy).

• Although not approved there have been certain off label use documented for Clarithromycin which includes:

Bartonella spp. infection; Bronchiolitis obliterans, including diffuse panbronchiolitis and symptomatic cryptogenic bronchiolitis obliterans; Endocarditis, prophylaxis; Mycobacterial (nontuberculous, rapidly growing) infection; Pertussis; Q fever (Coxiella burnetii), acute symptomatic

Clarithromycin is available in various strengths as 125 mg/5 mL (50 mL, 100 mL); 250 mg/5 mL (50 mL, 100 mL), 250 mg, 500 mg.

Clarithromycin is available in the form of Oral Solution, Suspension solution and Tablets.

• Dosage Adjustment in Kidney Patient

CRRT: Unlikely to be significantly dialyzed (large V_d) (expert opinion):

Oral: Follow dosing recommendations for patients with CrCl <30 mL/minute. Note: In general, use of IV antimicrobial therapy may be preferred in patients receiving CRRT (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be significantly dialyzed (large V_d) (expert opinion):

Oral: Follow dosing recommendations for patients with CrCl <30 mL/minute.Note: In general, use of IV antimicrobial therapy may be preferred in patients receiving PIRRT (expert opinion).

● Dosage Adjustment for Pediatric Patients

Bartonellosis:

Primary treatment (alternative agent): Adolescents, HIV-infected: Immediate release: Oral: 500 mg twice daily for ≥3 months. After completion of therapy, closely monitor for relapse; if relapse occurs, an additional course of treatment followed by long-term suppression is recommended. Note: Should not be used for endocarditis or CNS infections

Endocarditis, prophylaxis before invasive dental or respiratory tract procedures (alternative agent for patients with penicillin allergy): Limited data available:

Note: Recommended only in patients who are at highest risk for infective endocarditis (IE) or adverse outcomes (eg, history of IE, prosthetic heart valves or prosthetic material used to repair valves, unrepaired cyanotic congenital heart disease, repaired congenital heart disease with prosthetic material or device during first 6 months after procedure, repaired congenital heart disease with residual defects at the site or adjacent to site of prosthetic patch or device, heart transplant recipients with cardiac valvulopathy).

Infants, Children, and Adolescents: Immediate release: Oral: 15 mg/kg as a single dose administered 30 to 60 minutes prior to procedure; maximum dose: 500 mg/dose

Helicobacter pylori eradication :

Note: Use as part of an appropriate combination regimen; usual duration of therapy is 14 days.

Weight-directed dosing: Children and Adolescents: Immediate release: Oral: 7.5 to 10 mg/kg/dose twice daily; maximum dose: 500 mg/dose.

Fixed dosing : Children and Adolescents: Immediate release:

15 to <25 kg: Oral: 250 mg twice daily.

25 to <35 kg: Oral: 500 mg in the morning and 250 mg in the evening.

≥35 kg: Oral: 500 mg twice daily.

Lyme disease (Borrelia spp. Infection), erythema migrans (alternative agent):

Note: Current guidelines recommend macrolides (azithromycin) only when first-line agents cannot be used due to lower efficacy.

Infants, Children, and Adolescents: Immediate release: Oral: 7.5 mg/kg twice daily for 14 days; maximum dose: 500 mg/dose

Mycobacterial infection, nontuberculous:

Mycobacterium avium complex infection in patients that are HIV-exposed/-infected:

Infants, Children, and Adolescents: Limited data available in Infants and Children <20 months:

Primary prophylaxis (patients who meet age-specific CD4 count thresholds): Immediate release: Oral: 7.5 mg/kg/dose every 12 hours; maximum dose: 500 mg/dose.

Treatment: Immediate release: Oral: 7.5 to 15 mg/kg/dose every 12 hours as part of an appropriate combination regimen for ≥12 months; maximum dose: 500 mg/dose; follow with chronic maintenance therapy (secondary prophylaxis).

Chronic maintenance therapy (secondary prophylaxis): Immediate release: Oral: 7.5 mg/kg/dose every 12 hours as part of an appropriate combination regimen; maximum dose: 500 mg/dose. May be discontinued once there are no signs/symptoms of M. avium complex disease, and the CD4 count has exceeded age-specific thresholds for ≥6 months in response to stable antiretroviral therapy.

Pulmonary infection in patients with or without cystic fibrosis (eg, M. avium complex, Mycobacterium abscessus): Limited data available: Infants, Children, and Adolescents: Immediate release: Oral: 7.5 mg/kg/dose every 12 hours for ≥12 months after culture conversion; maximum dose: 500 mg/dose

Otitis media, acute (AOM) (alternative agent for patients who cannot tolerate beta-lactam antibiotics):

Note: Not recommended for routine empiric use due to limited efficacy against Streptococcus pneumoniae and Haemophilus influenzae.

Infants ≥6 months and Children: Immediate release: Oral: 7.5 mg/kg/dose every 12 hours; maximum dose: 500 mg/dose (manufacturer’s labeling). For patients with severe or recurrent AOM, tympanic membrane perforation, or who are <2 years of age, treat for 10 days; for patients ≥2 years of age with mild to moderate, nonrecurrent disease without tympanic membrane perforation, shorter durations of 5 to 7 days may be sufficient

Peritonitis (peritoneal dialysis), prophylaxis for patients requiring invasive dental procedures:

Infants, Children, and Adolescents: Immediate release: Oral: 15 mg/kg as a single dose 30 to 60 minutes prior to dental procedure; maximum dose: 500 mg/dose

Pertussis; treatment or postexposure prophylaxis:

Infants, Children, and Adolescents: Immediate release: Oral: 7.5 mg/kg/dose every 12 hours for 7 days; maximum dose: 500 mg/dose

Pneumonia, community-acquired (presumed or proven atypical pneumonia); mild infection or step-down therapy:

Infants >3 months, Children, and Adolescents: Immediate release: Oral: 7.5 mg/kg/dose every 12 hours for 10 days; shorter courses may be appropriate for mild disease; maximum dose: 500 mg/dose

Streptococcus, group A; pharyngitis/tonsillitis (alternative agent for severe penicillin allergy):

Infants ≥6 months, Children, and Adolescents: Immediate release: Oral: 7.5 mg/kg/dose every 12 hours for 10 days; maximum dose: 250 mg/dose

Increased risk of bradycardia with potassium-reducing agents (e.g. loop diuretics). Increased risk of tendon disorder with corticosteroids. Decreased absorption by forming chelates with antacids containing Al, Mg, Fe, sucralfate and multivalent cations. May enhance anticoagulant effects of warfarin.

Potentially Fatal: Increased risk of QT prolongation with class IA (e.g. quinidine) and class III (e.g. amiodarone) antiarryhthmics, terfenadine, cisapride, erythromycin, antipsychotics (e.g. haloperidol), and TCA (e.g. amitriptyline).

Hypersensitivity to clarithromycin, erythromycin, any of the macrolide antibiotics, or any component of the formulation; history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin; concomitant use with cisapride, ergot alkaloids (eg, ergotamine, dihydroergotamine), HMG-CoA reductase inhibitors extensively metabolized by CYP3A4 (eg, lovastatin, simvastatin), lomitapide, or pimozide; concomitant use with colchicine in patients with renal or hepatic impairment.

● Concerns related to adverse effects:

● Altered cardiac conduction: Use has been associated with QT prolongation and infrequent cases of arrhythmias, including torsades de pointes (may be fatal); avoid use in patients with known prolongation of the QT interval, ventricular cardiac arrhythmia (including torsades de pointes), uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, dofetilide, sotalol) antiarrhythmic agents or other drugs known to prolong the QT interval.

● Hepatic effects: Elevated liver function tests and hepatitis (hepatocellular and/or cholestatic with or without jaundice) have been reported; usually reversible after discontinuation of clarithromycin. May lead to hepatic failure or death (rarely), especially in the presence of preexisting diseases and/or concomitant use of medications. Discontinue immediately if symptoms of hepatitis (eg, anorexia, jaundice, abdominal tenderness, pruritus, dark urine) occur.

● Hypersensitivity reactions: Severe acute reactions have been reported, including anaphylaxis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schönlein purpura (IgA vasculitis), and acute generalized exanthematous pustulosis; discontinue therapy and initiate treatment immediately for severe acute hypersensitivity reactions.

● Superinfection: Use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Clarithromycin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

● Clarithromycin and its active metabolite (14-hydroxyclarithromycin) are present in breast milk.

● Data related to the presence of clarithromycin in breast milk is available from 12 breastfeeding women taking oral clarithromycin 250 mg twice daily for puerperal infections. Serial blood and milk samples were obtained at timed intervals. Both clarithromycin and its active metabolite, 14-hydroxyclarithromycin, were present in breast milk. The mean peak clarithromycin milk concentration was 0.85 mg/L ± 0.12 mg/L at 2.2 ± 0.2 hours after the dose; peak 14-hydroxyclarithromycin concentrations were 0.63 mg/L ± 0.08 mg/L at 2.8 ± 0.3 hours after the dose. The half-lives of clarithromycin and 14-hydroxyclarithromycin in breast milk were 4.3 ± 0.3 hours and 9 ± 1.2 hours, respectively

Teratogenic Effects - Pregnancy Category C

Clarithromycin has not been shown to have any teratogenic effects at oral doses as high as 810 mg/kg/day (11 times the recommended maximum human dose based on mg/m² or 50 times based on mg/kg) and 160 mg/kg/day (4 times the recommended maximum human dose based on mg/m² or 10 times based on mg/kg) when administered to pregnant rats and rabbits, respectively. Additional studies in rats with oral doses up to 360 mg/kg/day (5 times the recommended maximum human dose based on mg/m² or 23 times based on mg/kg) demonstrated no adverse effect on late fetal development, labor, delivery, lactation, neonatal viability, or growth of the newborn. Doses equivalent to 50 and 10 times the recommended maximum human dose of Clarithromycin (based on mg/kg) were fetotoxic (i.e., decreased fetal body weight and increased fetal mortality) in rats and rabbits, respectively. Minor skeletal variations were reported in rats receiving doses of 810 mg/kg/day, which is more than 10 times higher than the recommended maximum human dose based on mg/m².

Immediate release: Food delays rate, but not extent of absorption; Extended release: Food increases clarithromycin AUC by ~30% relative to fasting conditions. Management: Administer immediate release products without regard to meals. Administer extended release products with food.

• Common Adverse effects

CNS effects including seizures, increased intracranial pressure, lightheadedness, dizziness, tremor; psychotic reactions (e.g. hallucinations, nervousness, delirium), sensory or sensorimotor peripheral neuropathy, prolonged QT interval, blood glucose disturbances (hypo-/hyperglycemia), phototoxicity, superinfection (prolonged use), bronchospasm.

• Less Common Adverse effects:

CNS effects including seizures, increased intracranial pressure, lightheadedness, dizziness, tremor; psychotic reactions (e.g. hallucinations, nervousness, delirium), sensory or sensorimotor peripheral neuropathy, prolonged QT interval, blood glucose disturbances (hypo-/hyperglycemia), phototoxicity, superinfection (prolonged use), bronchospasm

• Rare Adverse effects

Hepatitis, jaundice. Injury, poisoning and procedural complications: Infusion site reaction (e.g. pain, reddening), phlebitis. Investigations: Increased hepatic enzymes (ALT/AST, alkaline phosphatase, GGT), decreased forced expiratory volume.

May result in significant hypoglycaemia with oral hypoglycaemics (e.g. sulfonylureas, repaglinide, nateglinide) and insulin. Increased risk of haemorrhage and elevated INR and prothrombin time with warfarin. May induce metabolism and decrease efficacy with CYP3A inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital). May reduce the plasma levels with strong CYP450 inducers (e.g. efavirenz, nevirapine, rifabutin, rifapentine). Decreased exposure with etravirine. Increased plasma concentration and exposure with fluconazole. May elevate the serum concentrations of digoxin and CYP450 substrates (e.g. alprazolam, carbamazepine, cilostazol, ciclosporin, methylprednisolone, omeprazole, quetiapine, sildenafil, sirolimus, tacrolimus, vinblastine, theophylline, valproate, tolterodine). May increase the risk of torsades de pointes with quinidine or disopyramide. May decrease the plasma concentrations of zidovudine. Ritonavir significantly inhibits the metabolism of clarithromycin. Concomitant use with atazanavir, itraconazole, saquinavir, or certain Ca channel blockers (e.g. verapamil, amlodipine, diltiazem) may result in bi-directional drug interactions. Increased or prolongation of sedation with triazolam.

Potentially Fatal: Concomitant use with cisapride, pimozide, domperidone, terfenadine, and astemizole may cause QT prolongation or cardiac arrhythmias including ventricular tachycardia or fibrillation, and torsades de pointes. Increased serum concentrations and risk of acute toxicity of ergotamine or dihydroergotamine. Markedly elevated plasma concentrations of oral midazolam. Significantly increased transaminases with lomitapide. Increased risk of myopathy and rhabdomyolysis with lovastatin or simvastatin. Increased serum levels and risk of toxicity of colchicine. May increase serum concentrations of ranolazine; decrease serum concentrations of the active metabolite of ticagrelor.

The common side effects of Clarithromycin include the following Feeling sick (nausea) or being sick (vomiting), stomach ache, wind (flatulence), indigestion, Tooth or tongue discoloration.

Symptoms: Abdominal pain, vomiting, nausea, and diarrhoea.

Management: Supportive treatment. Initiate prompt elimination of unabsorbed drugs.

Pharmacodynamic

Clarithromycin is a macrolide antibiotic whose spectrum of activity includes many gram-positive (Staphylococcus aureus, S. pneumoniae, and S. pyogenes) and gram-negative aerobic bacteria (Haemophilus influenzae, H. parainfluenzae, and Moraxella catarrhalis), many anaerobic bacteria, some mycobacteria, and some other organisms including Mycoplasma, Ureaplasma, Chlamydia, Toxoplasma, and Borrelia. Other aerobic bacteria that clarithromycin has activity against include C. pneumoniae and M. pneumoniae. Clarithromycin has an in-vitro activity that is similar or greater than that of erythromycin against erythromycin-susceptible organisms. Clarithromycin is usually bacteriostatic, but may be bactericidal depending on the organism and the drug concentration.

Pharmacokinetics

• Absorption: Rapidly and well absorbed from the gastrointestinal tract. Bioavailability: Approx 50%. Time to peak plasma concentration: 2-3 hours (immediate-release); 5-8 hours (modified-release).
• Distribution: Widely and readily distributed into most body tissues and fluids. Crosses the placenta and enters breast milk. Plasma protein binding: 80%.
• Metabolism: Partially metabolised in the liver by CYP3A4 isoenzyme and undergoes extensive first-pass metabolism into 14-hydroxyclarithromycin (active).
• Excretion: Via urine (approx 20-40% as unchanged drug; 10-15% as metabolites); faeces (5-10% as unchanged drug). Elimination half-life: Immediate-release: 3-7 hours (clarithromycin); 5-9 hours (14-hydroxyclarithromycin).

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Clarithromycin -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Clarithromycin
• https://europepmc.org/article/med/6988203