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Roxithromycin

Roxithromycin is a semi-synthetic derived from erythromycin, characterized by the molecular formula C41H76N2O15 and a molecular weight of 837.0 g/mol. It is primarily used to treat a variety of susceptible bacterial infections, including those of the (such as and ), urinary tract, and soft tissues. Roxithromycin exerts its antibacterial effect by binding to the 50S subunit of the bacterial , thereby inhibiting protein synthesis and preventing ; it is generally bacteriostatic at low concentrations. The drug is rapidly absorbed following , achieving high tissue penetration including into , with a of approximately 12 hours; it undergoes hepatic metabolism and is about 96% bound to proteins. In terms of , roxithromycin is active against many Gram-positive cocci and bacilli (e.g., ), some Gram-negative cocci and bacilli (e.g., and ), but shows limited activity against most other Gram-negative bacilli and is ineffective against Gram-negative anaerobes. Clinical evaluations, including double-blind trials comparing it to comparators like erythromycin and , have demonstrated success rates of 89–90% in treating lower respiratory tract infections such as and , with overall mild adverse effects primarily involving gastrointestinal symptoms like and . Although not approved for use , roxithromycin is marketed internationally under brand names such as Rulide and is considered a safe option for oral therapy in appropriate indications, with low transfer into but potential for monitoring gastrointestinal effects.

Medical uses and administration

Indications

Roxithromycin is indicated for the treatment of mild to moderately severe infections caused by susceptible , primarily in adults and children. In adults, it is approved for upper respiratory tract infections such as acute , , and ; lower respiratory tract infections including , exacerbations of chronic , and ; skin and soft tissue infections; dental infections; and non-gonococcal urethritis. In children, indications include acute , , and . It is also used for ear, nose, and throat infections such as . The demonstrates activity against a range of pathogens, including like Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus (excluding MRSA); some Gram-negative organisms such as Haemophilus influenzae and Moraxella catarrhalis; and atypical pathogens including Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia trachomatis, Legionella pneumophila, and Ureaplasma urealyticum. Clinical studies have reported high rates for roxithromycin in treating , with overall rates ranging from 78% to 97% in cases of upper and lower , /, , and when compared to other like erythromycin. For skin and soft tissue , including and dental , cure rates of 87-96% have been observed in multicenter trials. In genitourinary , such as chlamydia-associated , bacteriological eradication rates exceed 90% in comparative studies with .

Dosage and administration

Roxithromycin is administered orally, available in tablet or oral formulations, and should be taken on an empty —at least 15 minutes before or more than three hours after a —to optimize , as can reduce . Tablets must be swallowed whole with liquid and not chewed or crushed. For adults and adolescents weighing 40 kg or more, the standard dosage is 150 mg twice daily or 300 mg once daily, typically for 5 to 10 days depending on the infection's severity and clinical response. Treatment duration may extend to 10 days for or up to 20 days for certain non-gonococcal genital infections, with therapy continuing at least two days after symptoms resolve to prevent . For , a reduced regimen of 150 mg twice daily is recommended. In children weighing less than 40 , the dosage is 5 to 8 / per day, divided into two doses, for 5 to 10 days, with a maximum treatment duration of 10 days. For children 40 and over, the adult dosage applies: 150 twice daily. The oral suspension should be shaken well before use and measured with an appropriate device. Therapy should be reassessed if symptoms persist beyond 48 to 72 hours, with consideration to extend duration for infections up to 14 days based on clinical improvement, or discontinue if no response to avoid unnecessary exposure. Dosage adjustments are not typically required for renal impairment in short courses, but hepatic impairment may necessitate reduction to 150 mg once daily in severe cases.

Contraindications and precautions

Contraindications

Roxithromycin is contraindicated in patients with known to the drug, other antibiotics such as erythromycin, or any of its excipients, due to the risk of severe allergic reactions including . Severe hepatic impairment, such as Child-Pugh class C , represents another absolute , given the drug's hepatic and potential for prolonged leading to . Concurrent administration with vasoconstrictive ergot alkaloids like amine or is prohibited owing to the risk of acute and peripheral ischemia. Similarly, coadministration with certain substrates possessing narrow therapeutic indices, including , , , and , is contraindicated because of the potential for life-threatening QT interval prolongation and ventricular arrhythmias such as . Relative contraindications include conditions where roxithromycin should be avoided if possible or used only under close monitoring. Patients with may experience exacerbation of due to the drug's potential neuromuscular blocking effects, similar to other . Individuals with pre-existing prolonged or risk factors for , such as electrolyte imbalances or concomitant use of other QT-prolonging agents, require careful evaluation, as roxithromycin can further extend the . reactions may exhibit cross-reactivity among , including erythromycin, , and , necessitating avoidance in patients with allergies to any member of this class.

Use in special populations

Roxithromycin's safety and efficacy have been established in pediatric patients, including infants and children as young as 2 months old, for treating and infections, with weight-based dosing recommended at 5 to 8 mg/kg/day divided into two doses for a maximum of 10 days. In children weighing more than 40 kg, the adult dose of 150 mg twice daily may be used, while lower weights require adjusted formulations such as oral suspension to ensure accurate administration. Compared to erythromycin, roxithromycin is associated with a lower incidence of gastrointestinal side effects in children, contributing to better tolerability during treatment. In elderly patients, no major dosage adjustments are typically required for roxithromycin, with the standard regimen of 150 mg twice daily or 300 mg once daily maintained for short courses. However, monitoring for declines in hepatic or renal function is advised due to age-related physiological changes that may prolong the drug's to approximately 27 hours. Elderly individuals are at increased risk of drug interactions due to , particularly with anticoagulants like , where roxithromycin can potentiate effects and elevate international normalized ratio levels, necessitating close monitoring. During pregnancy, roxithromycin is classified as category B1, indicating limited data but no evidence of increased risk to the in at therapeutic doses, though embryotoxicity occurred at high exposures exceeding 180 mg/kg/day in rats; use is recommended only if benefits outweigh potential risks. Limited human data suggest it is generally considered safe, but consultation with a healthcare provider is essential. In , roxithromycin is minimally excreted into at low levels unlikely to cause adverse effects in , though monitoring for gastrointestinal upset in the breastfed is advised, and discontinuation of may be considered if necessary. For patients with renal , no dosage adjustment is needed in mild to moderate cases ( clearance >30 mL/min), as the drug undergoes limited renal excretion, but caution is warranted in severe ( clearance <30 mL/min or <10 mL/min in some guidelines) due to prolonged up to 18 hours and reduced clearance, potentially requiring half the usual dose to avoid accumulation. In hepatic , dosage reduction to half (e.g., 150 mg once daily) or interval extension is recommended for moderate to severe cases, such as with or , where may extend to 25 hours; liver enzymes should be monitored closely, and use is contraindicated in severe hepatic dysfunction.

Adverse effects

Common adverse effects

Roxithromycin is generally well tolerated, with an overall incidence of adverse events ranging from 4% to 10% across clinical trials, depending on the dosing regimen such as 150 twice daily or 300 once daily. The most frequent adverse effects are gastrointestinal in nature, occurring in 3-7% of patients and manifesting as (5-10%), (3-5%), (2-4%), and (1-3%). These effects arise partly from the drug's influence on gastrointestinal and are notably less common than with erythromycin, reflecting roxithromycin's enhanced tolerability profile. Additional common adverse effects include (approximately 2%), taste disturbances (1-2%), and (1%), all of which are typically mild. Most adverse events are self-limiting and resolve without intervention; symptomatic management, such as the use of antidiarrheals for gastrointestinal symptoms, is usually sufficient, with treatment discontinuation required in only 1-2% of cases.

Serious adverse effects

Roxithromycin, like other antibiotics, is associated with rare but potentially life-threatening adverse effects that require immediate medical attention. These serious reactions occur infrequently, typically in less than 1% of patients, and are more likely in individuals with predisposing factors such as pre-existing cardiac conditions, hepatic impairment, or history. Cardiovascular effects include prolongation and , which have been documented in isolated case reports, particularly among patients with underlying heart disease or imbalances; the incidence is estimated at less than 0.1%. These arrhythmias can lead to sudden cardiac events, though large cohort studies have not shown an overall increased risk of cardiac death with roxithromycin compared to non-macrolide alternatives. Hepatic reactions, such as cholestatic and significant elevations in liver (affecting 0.1-0.5% of users), are reversible upon drug discontinuation but can occasionally progress to severe injury, including or, in rare pediatric cases, fulminant hepatic failure. Elderly patients may be at higher risk for these elevations. of liver is recommended in at-risk individuals, with prompt cessation if symptoms like or emerge. Severe allergic reactions encompass , , and cutaneous syndromes such as Stevens-Johnson syndrome or , occurring very rarely (less than 0.01%). These events can manifest as , , or widespread skin detachment and necessitate immediate discontinuation and supportive care. Other serious effects include difficile-associated pseudomembranous , reported in less than 0.1% of cases and potentially ranging from mild to life-threatening with pseudomembrane formation; roxithromycin should be halted if suspected. Additionally, roxithromycin can exacerbate symptoms, worsening in affected patients, who require close clinical monitoring. Post-marketing surveillance has identified additional case reports of ventricular arrhythmias and , underscoring the need for vigilance and reporting of unexpected events to systems. Patients with risk factors from special populations, such as the elderly or those on interacting drugs, may face heightened severity.

Drug interactions

Pharmacokinetic interactions

Roxithromycin, a , acts as both a and a weak inhibitor of 3A4 (), potentially altering the of co-administered drugs that are substrates, leading to increased plasma concentrations and risk of toxicity. It also inhibits (P-gp), an efflux transporter, which can affect the absorption and elimination of certain substrates. A notable pharmacokinetic interaction occurs with , where roxithromycin inhibits its metabolism, resulting in elevated international normalized ratio (INR) levels and heightened . In a series of 30 reported cases, INR values rose rapidly after initiating roxithromycin, ranging from 3.6 to 16.7 (mean 7.6) compared to pre-treatment levels of 1.4 to 3.7 (mean 2.5), with elevations often detectable within 3 days and four instances of serious hemorrhage. Clinical monitoring of INR is recommended within 3 days of starting roxithromycin in patients on , with potential need for dose adjustments. Roxithromycin inhibits P-gp-mediated efflux of , increasing its serum concentrations and potentially causing , as evidenced by case reports of shortly after roxithromycin initiation in elderly patients. Monitoring of levels and possible dose reduction are advised during concurrent use. In contrast, pharmacokinetic studies show minimal to no interaction with or . Roxithromycin has little effect on theophylline pharmacokinetics, with no clinically relevant changes in plasma levels observed in controlled studies, allowing safe co-administration without dose adjustments. Similarly, no alteration in carbamazepine pharmacokinetics occurs with roxithromycin, despite theoretical involvement. As a substrate, roxithromycin's own metabolism can be accelerated by inducers like rifampin, potentially reducing its plasma levels and efficacy, necessitating dose adjustments or alternative antibiotics. No pharmacokinetic interaction is evident with oral contraceptives, as roxithromycin does not alter ethinyl or progestin levels, preserving contraceptive efficacy. Additionally, co-administration with antacids or H2-receptor blockers like does not affect roxithromycin absorption or bioavailability.

Pharmacodynamic interactions

Roxithromycin, as a , can exhibit pharmacodynamic interactions by additively prolonging the when co-administered with other drugs that affect cardiac repolarization, thereby increasing the risk of ventricular arrhythmias such as . This risk is heightened with agents like , , , , and class IA (e.g., quinidine, ) or class III (e.g., amiodarone, ) antiarrhythmic drugs, particularly in patients with predisposing factors such as imbalances, , or congenital . Roxithromycin may potentiate the effects of non-depolarizing neuromuscular blocking agents during surgical procedures, leading to enhanced muscle relaxation and prolonged recovery from blockade, although such interactions are rare and more commonly associated with other like erythromycin. Additionally, it can exacerbate symptoms in patients with by interfering with neuromuscular transmission. Due to competitive binding at the 50S ribosomal subunit, roxithromycin antagonizes the antibacterial activity of other agents targeting the same site, such as clindamycin and , potentially reducing overall efficacy in treating bacterial infections. Close monitoring of INR is recommended during concomitant use of roxithromycin with oral coumarin anticoagulants like .

Pharmacology

Mechanism of action

Roxithromycin, a semisynthetic , exerts its primary antibacterial effect through reversible binding to the 50S subunit of the bacterial , specifically targeting domain V of the 23S rRNA. This interaction occurs near the entrance of the nascent peptide exit tunnel, where the drug sterically hinders the progression of the elongating polypeptide chain. By binding in this manner, roxithromycin inhibits the translocation step of protein synthesis, preventing the movement of peptidyl-tRNA from the A-site to the on the and thereby blocking the elongation of bacterial proteins essential for growth and survival. The antibiotic's activity is concentration-dependent: at therapeutic plasma levels typically achieved in clinical use (around 5–10 /L), roxithromycin acts as a by halting protein synthesis and inhibiting bacterial replication. However, at higher concentrations, it exhibits bactericidal effects against certain Gram-positive pathogens, such as streptococci, by more profoundly disrupting ribosomal function and leading to bacterial . This dual activity profile contributes to its efficacy in treating infections caused by susceptible organisms. Roxithromycin's spectrum of activity correlates with its molecular interactions and bacterial physiology; it shows particularly high potency against , where inherent weaknesses in systems allow sustained intracellular drug levels to maintain ribosomal inhibition. In contrast, its moderate effectiveness against atypical intracellular pathogens, including , , and species, stems from the drug's favorable enabling accumulation within host cells and , where these organisms reside. Bacterial resistance to roxithromycin primarily arises via two key mechanisms: active efflux of the drug from the cell, often mediated by the mef gene encoding efflux pumps that reduce intracellular concentrations below inhibitory thresholds, and target site modification through N6-dimethylation of adenine residues in domain V of 23S rRNA by enzymes encoded by erm genes, which diminishes the drug's binding affinity to the . These resistance pathways are widespread among Gram-positive cocci and can compromise therapeutic outcomes.

Pharmacokinetics

Roxithromycin is rapidly absorbed from the following , with peak plasma concentrations achieved within 1 to 2 hours after a dose. The absolute is approximately 50%, and is delayed but not significantly reduced by food intake. For a 150 mg dose, the mean peak plasma concentration (C_max) is about 6.6 mg/L in young adults, increasing to 10.7 mg/L for a 300 mg dose; steady-state concentrations are reached within 2 to 4 days with repeated dosing. The drug exhibits extensive distribution into tissues, achieving concentrations 2 to 30 times higher than in in sites such as the lungs, tonsils, , and , which supports its against respiratory and infections via intracellular accumulation in . It has a large , reflecting wide tissue penetration. is high at 92% to 96%, primarily to alpha-1-acid , with binding decreasing at higher concentrations due to saturation. Roxithromycin undergoes limited hepatic metabolism, primarily via , producing inactive metabolites such as descladinose roxithromycin and minor N-demethylated forms, with no active metabolites contributing to its antibacterial activity. concentrations of metabolites are about half those of the parent drug. Elimination occurs mainly through biliary and fecal routes, with approximately 53% of the dose excreted unchanged in feces and only 7% to 10% in ; pulmonary accounts for about 13%. The elimination is around 12 hours in healthy adults, extending to 18 to 27 hours in patients with renal or hepatic impairment or in the elderly, though no dose adjustment is typically required for mild cases. Steady-state is achieved in 2 to 3 days, and are generally linear over the therapeutic dose range of 150 to 300 mg, despite some evidence of saturable absorption at higher doses.

Chemistry and formulations

Chemical structure and properties

Roxithromycin is a semi-synthetic 14-membered derived from erythromycin A. Its molecular formula is C₄₁H₇₆N₂O₁₅, and the molecular weight is 837.0 g/mol. The core structure consists of a large macrocyclic ring attached to two deoxy sugars: desosamine at and cladinose at C3. Key modifications distinguish it from erythromycin, including the replacement of the C9 with a (2-methoxyethoxy)methyloxime moiety. These structural changes improve acid , preventing in the gastric , and reduce gastrointestinal side effects such as irritation compared to erythromycin. Roxithromycin exists as a white to off-white crystalline powder. It is poorly soluble in , with a solubility of approximately 0.019 mg/mL at 25°C, and this is pH-dependent, increasing under ic conditions while the modifications enhance overall against . The compound remains stable at neutral . The synthesis of roxithromycin begins with erythromycin A and involves the formation of a 9- intermediate by reaction with , followed by selective O-alkylation of the using 2-methoxyethoxymethyl chloride in the presence of a to attach the .

Available formulations

Roxithromycin is primarily available in oral formulations, including film-coated tablets in strengths of 150 mg and 300 mg, which are the most common commercial forms for adult use. An oral at a concentration of 50 mg/5 mL is also available, particularly for pediatric administration, often prepared from or as a ready-to-use liquid. These formulations are designed for ease of swallowing and , with the suspension allowing for weight-based dosing in children. The medication is widely available as a generic since the original patents expired in the early , following its development and initial approval in the . Key manufacturers include (successor to the original developer Hoechst Marion Roussel, marketing under brands like Rulide) and various generic producers such as , Pharmaceuticals, and Lupin. Storage recommendations for roxithromycin formulations specify (below 25°C), protection from moisture and light to maintain stability. The typical shelf-life is 2 to 3 years from the date of manufacture, depending on the specific product and packaging. No standard injectable or other non-oral forms are commercially available, and historical suspensions beyond the current oral variant have not been widely documented as discontinued.

History

Development

Roxithromycin was developed in the late 1970s by the French pharmaceutical company as a semisynthetic derivative of , specifically designed to address the parent compound's acid instability in gastric juice and associated gastrointestinal intolerance, which led to variable oral absorption and poor tolerability. The research focused on modifying the core to improve stability while retaining antibacterial activity against Gram-positive pathogens. A key innovation came with the 1980 patent filing (US 4,349,545, published in 1982) by inventors Solange Gouin d'Ambrieres, André Lutz, and Jean-Claude Gasc, which described novel erythromycin A derivatives featuring an at the 9-position, including the (9S)- with a 2-methoxyethoxymethyl , enhancing acid stability, oral (up to 85% in rats), and tissue penetration compared to erythromycin's less than 10%. These modifications resulted in longer half-lives and superior , allowing once- or twice-daily dosing. Preclinical studies in the early 1980s, including in vitro broth dilution tests against 275 clinical isolates and in vivo models of infection in mice and rats, demonstrated roxithromycin's (coded RU 28965) antibacterial spectrum similar to erythromycin but with markedly superior potency—up to sixfold greater in protecting against experimental infections by respiratory pathogens such as Streptococcus pneumoniae and Haemophilus influenzae, attributed to enhanced lung tissue concentrations. In vitro, minimal inhibitory concentrations (MICs) were generally comparable or slightly higher than erythromycin's against Gram-positive cocci, but roxithromycin excelled against certain anaerobes like Bacteroides fragilis. Early 1980s clinical trials, including seven developmental studies sponsored by Roussel Uclaf, evaluated roxithromycin in adults with upper infections, showing satisfactory clinical response rates of approximately 87% (per protocol analysis) against H. influenzae and other pathogens. Comparative studies in patients with lower infections have demonstrated that roxithromycin is comparable to erythromycin in efficacy but with fewer gastrointestinal side effects and lower withdrawal rates (2% vs. 7% for erythromycin in pooled comparators). These trials highlighted reduced adverse events, primarily mild and transient, supporting roxithromycin's profile for better patient compliance.

Regulatory approval

Roxithromycin was patented in 1980 by the French pharmaceutical company Roussel Uclaf and first approved for oral use in in 1987. The drug has been authorized through national procedures in member states by the (), with ongoing periodic safety update reports confirming its status as a nationally authorized medicinal product. It is also approved by the () in , where multiple formulations such as Roxithromycin have been registered since at least 2006. Roxithromycin is available in over 100 countries worldwide but has not received approval from the U.S. () for marketing in the United States. The original brand name is Rulid, marketed by Roussel Uclaf (now part of ), with generics such as Roxil and Surlid available in various markets. Availability varies by region; it is typically prescription-only in and . Following patent expiration around 2000, generic versions entered markets globally, increasing accessibility. Post-approval , coordinated by the , monitors rare adverse effects, including potential cardiac risks, though large cohort studies have found no significant increase in cardiac death associated with roxithromycin use. No major withdrawals or restrictions have occurred, but ongoing surveillance tracks resistance patterns in bacterial pathogens.