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Spiramycin
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| Routes of administration | oral |
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| E number | E710 (antibiotics) |
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| ECHA InfoCard | 100.029.476 |
| Chemical and physical data | |
| Formula | C43H74N2O14 |
| Molar mass | 843.065 g·mol−1 |
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| Melting point | 134 to 137 °C (273 to 279 °F) |
| Solubility in water | Insoluble in water; Very soluble in acetonitrile and methanol; Almost completely(>99.5) in ethanol. mg/mL (20 °C) |
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Spiramycin is a macrolide antibiotic and antiparasitic. It is used to treat toxoplasmosis and various other infections of soft tissues.
Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2] Spiramycin has been used in Europe since the year 2000 under the trade name "Rovamycine", produced by Rhone-Poulenc Rorer, Sanofi and Famar Lyon, France and Eczacıbaşı İlaç, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.[citation needed] Spiramycin has been studied as a virulence inhibitor in Pseudomonas aeruginosa.[3]
Medical uses
[edit]Available forms
[edit]It is available for parenteral and oral administration.[citation needed] Another treatment option (typically used after 16w gestation) are a combination of pyrimethamine and sulfadiazine (given with leucovorin).[2]
Pharmacology
[edit]Pharmacodynamics
[edit]The antibiotic action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium species. Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general.
Chemistry
[edit]History
[edit]It was isolated in 1954 as a product of Streptomyces ambofaciens by PINNERT-SINDICO.[4][5] As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice.
References
[edit]- ^ "Spiramycin advanced consumer information". Drugs.com.
- ^ a b "Toxoplasmosis". MayoClinic.com.
- ^ Calcagnile M, Jeguirim I, Tredici SM, Damiano F, Alifano P (March 2023). "Spiramycin Disarms Pseudomonas aeruginosa without Inhibiting Growth". Antibiotics. 12 (3): 499. doi:10.3390/antibiotics12030499. PMC 10044227. PMID 36978366.
- ^ a b "Spiramycin". www.toku-e.com. Retrieved 2019-02-28.
- ^ a b Parker CT, Garrity GM (18 August 2022). Parker CT, Mannor K, Garrity GM (eds.). Streptomyces ambofaciens Pinnert-Sindico 1954 (Approved Lists 1980) emend. Nouioui et al. 2018. Name Abstract (Report). NamesforLife, LLC. doi:10.1601/nm.6849.
Spiramycin
View on Grokipediafrom Grokipedia
Medical uses
Human indications
Spiramycin is primarily indicated for the treatment of acute toxoplasmosis in pregnant women to prevent the transmission of Toxoplasma gondii to the fetus, particularly when infection is diagnosed in the first or early second trimester, ideally before 18 weeks of gestation.[4] It is recommended to initiate therapy as soon as possible following maternal seroconversion to maximize efficacy in reducing vertical transmission, and it is most effective if started within 8 weeks of seroconversion.[3][4] As an alternative to the combination of pyrimethamine and sulfadiazine plus leucovorin for maternal toxoplasmosis, spiramycin is often preferred in the initial phase of treatment due to its lower risk of fetal teratogenicity while providing good placental penetration.[3] Clinical studies have demonstrated that spiramycin reduces the risk of congenital toxoplasmosis transmission by approximately 60% compared to untreated cases.[3][5] In addition to its antiparasitic role, spiramycin is used to treat various bacterial infections caused by susceptible Gram-positive organisms, including skin and soft tissue infections such as cellulitis and infected wounds, as well as dental infections like those involving oral streptococci.[6][7] It is also effective against respiratory tract infections, including tonsillitis, pharyngitis, and pneumonia due to pathogens like Streptococcus pyogenes and other macrolide-sensitive bacteria.[8][6] Spiramycin has a limited role in managing infections caused by atypical bacteria, such as Legionella pneumophila or Chlamydia species, where it shows in vitro activity comparable to erythromycin but is generally considered a secondary option.[9][10]Veterinary uses
Spiramycin is widely employed in veterinary medicine to treat and prevent respiratory tract infections in livestock, targeting pathogens such as Mycoplasma species, Pasteurella multocida, and various Gram-positive bacteria. In pigs, it is particularly effective against enzootic pneumonia caused by Mycoplasma hyopneumoniae, a common issue in intensive farming systems, where it is administered as a feed additive to reduce clinical signs, lung lesions, and associated growth retardation. Spiramycin is administered as a feed additive at levels of 12.5 to 50 g per ton to treat and prevent enzootic pneumonia in pigs, with studies showing improved growth and feed efficiency.[11][12] In cattle, spiramycin addresses respiratory infections, including those involving Mycoplasma and Pasteurella, as well as soft tissue conditions like foot rot, mastitis, and arthritis. It is typically given via intramuscular injection at a dose of approximately 30 mg/kg body weight (equivalent to 100,000 IU/kg), which has shown high efficacy in resolving acute bovine respiratory disease, with clinical improvement observed within 24-48 hours and reduced lesion scores in affected lungs. For foot rot in ruminants, spiramycin penetrates inflamed tissues effectively, aiding in the control of secondary bacterial invaders when used at 20-30 mg/kg daily for 3-5 days. Poultry benefit from spiramycin in managing chronic respiratory disease due to Mycoplasma gallisepticum and Mycoplasma synoviae, with recommended oral doses around 15-16 mg/kg body weight.[13][14][12][15] Beyond livestock, spiramycin plays a role in companion animal medicine, especially for infections resistant to beta-lactams or other common antibiotics, such as staphylococcal skin infections and periodontal diseases in dogs and cats. It is frequently combined with metronidazole in oral formulations at 75,000 IU/kg spiramycin daily, demonstrating significant reduction in dental biofilm formation and resolution of oral infections within 7-10 days.[16][17] Regulatory approvals for spiramycin in veterinary practice are established in the European Union, where it is authorized for use in pigs, cattle, and poultry under strict maximum residue limits (e.g., 200 µg/kg in muscle, 600 µg/kg in liver). Withdrawal periods vary by species and route: 35 days for meat in pigs, 52 days for meat in cattle, and 15 days for poultry meat, ensuring food safety while allowing therapeutic application. These guidelines, informed by pharmacokinetic data, confirm that residues fall below detectable limits post-withdrawal, supporting its continued role in sustainable animal health management.[18][19][20]Administration and safety
Dosage forms and administration
Spiramycin is formulated in various dosage forms to accommodate different administration routes and patient needs, including oral capsules (typically 250 mg and 500 mg strengths), tablets, and suspensions for both adults and children.[6] Oral administration is preferred for most infections, with the typical adult dose ranging from 1.5 to 4 g daily in divided doses—such as 500 mg to 1 g three times daily (1.5-3 g total) or 1 to 2 g twice daily (2-4 g total)—for durations of 5 to 10 days, depending on severity.[21] For children weighing at least 20 kg, the recommended dose is 25 mg/kg twice daily or 17 mg/kg three times daily, adjusted by body weight and administered via suspension if needed for ease.[22] Parenteral formulations include intravenous injections, often in 500 mg vials, reserved for severe infections where oral intake is not feasible, with dosing at 1 to 2 g every 8 hours.[21] Rectal suppositories, available in strengths such as 750 mg, provide an alternative for patients unable to tolerate oral or intravenous routes, particularly in pregnancy; the typical regimen is 2 to 3 suppositories daily.[22] In pregnant women diagnosed with acute toxoplasmosis, spiramycin is administered orally at 3 g daily in divided doses from diagnosis until term or until amniocentesis results confirm fetal status. No major dose reductions are required for renal or hepatic impairment due to its primary biliary excretion pathway, though monitoring is advised in severe cases.[6] Treatment durations generally span 7 to 14 days for most bacterial infections but extend until delivery for toxoplasmosis prophylaxis in pregnancy.[4]Adverse effects and contraindications
Spiramycin is generally well-tolerated, but common adverse effects primarily involve the gastrointestinal system, including nausea, vomiting, diarrhea, and abdominal pain.[23][22] Transient skin reactions such as rash or urticaria have also been reported, typically resolving upon discontinuation.[1] Serious adverse effects are uncommon but can include cholestatic hepatitis, characterized by elevated liver enzymes, abdominal pain, nausea, and jaundice, with an incidence of less than 1% based on post-marketing data.[6][1] Hematologic effects such as leukopenia and thrombocytopenia may occur rarely, while cardiac risks involve QTc prolongation that can lead to arrhythmias, particularly in patients with predisposing factors.[1][24] For parenteral administration, additional effects include paresthesia and local injection-site reactions such as pain or inflammation.[7][22] Spiramycin is contraindicated in patients with known hypersensitivity to macrolide antibiotics due to the risk of cross-reactivity and severe allergic reactions.[25][26] It should be used with caution or avoided in individuals with severe hepatic impairment or a history of cholestatic jaundice, as it may exacerbate liver dysfunction; liver function monitoring is recommended during prolonged therapy.[22][27] Macrolides like spiramycin can worsen myasthenia gravis, so it is generally avoided in patients with this condition.[1] Use in neonates requires caution due to risks such as QT prolongation and is generally avoided unless treating congenital toxoplasmosis.[28]Pharmacology
Pharmacodynamics
Spiramycin is a macrolide antibiotic that exerts its antibacterial effects by binding to the 50S subunit of the bacterial ribosome, where it inhibits the peptidyl transferase activity and blocks protein synthesis through interference with translocation.[6] This binding occurs with a 1:1 stoichiometry and stimulates the dissociation of peptidyl-tRNA from the ribosome, rendering the drug primarily bacteriostatic against susceptible pathogens.[6] The mechanism is analogous to that of other macrolides, targeting the large ribosomal subunit to halt bacterial growth without directly affecting eukaryotic ribosomes.[1] The antibacterial spectrum of spiramycin includes high activity against Gram-positive cocci such as Streptococcus pyogenes and Staphylococcus species, as well as some Gram-negative cocci like Neisseria spp., atypical bacteria including Legionella pneumophila and Mycoplasma pneumoniae, and certain intracellular pathogens.[6] In vitro minimum inhibitory concentrations (MICs) for S. pyogenes typically range from 0.5 to 2 µg/mL, demonstrating potent inhibition at achievable tissue levels.[29] It shows moderate activity against anaerobes like Clostridium perfringens (MIC 2–8 µg/mL) but limited efficacy against Enterobacteriaceae and Pseudomonas spp.[30] Spiramycin exhibits no cross-resistance with beta-lactam antibiotics due to distinct mechanisms of action, though partial cross-resistance occurs with other macrolides via shared ribosomal targets.[31] In its antiparasitic role, spiramycin accumulates preferentially in host tissues and placental sites, achieving concentrations 5- to 40-fold higher than in serum, which enhances efficacy against intracellular parasites like Toxoplasma gondii.[1] Against T. gondii, it inhibits replication by targeting the bacterial-like 50S ribosomal subunit in the parasite's apicoplast organelle, disrupting plastid translation and protein synthesis essential for parasite survival. Resistance to spiramycin primarily arises through erm genes, which encode 23S rRNA methylases that modify the ribosomal binding site, though rates remain lower than for 14-membered macrolides like erythromycin due to reduced inducibility.[32] This ribosomal protection mechanism predominates in clinical isolates, with mutations in apicoplast rRNA also conferring resistance in T. gondii.Pharmacokinetics
Spiramycin exhibits incomplete oral absorption, with an absolute bioavailability of approximately 30-40%. Following a single oral dose of 1 g, peak plasma concentrations (Cmax) range from 0.4 to 1.4 µg/mL, achieved at 2-3 hours (Tmax); for doses of 1-2 g, Cmax values typically fall between 0.5 and 2 µg/mL.[33][6][34] The drug demonstrates extensive distribution throughout the body, characterized by a large volume of distribution exceeding 300 L, indicative of substantial tissue penetration. Spiramycin achieves high concentrations in tissues such as bone, muscle, respiratory tract, saliva, alveolar macrophages (10-20 times serum levels), bile, and the placenta, facilitating fetal exposure. Plasma protein binding is low, ranging from 10-25%.[33][6][7] Metabolism of spiramycin occurs primarily in the liver and is limited compared to other macrolides, with no significant active metabolites identified; the parent drug predominates in systemic circulation.[33][35] Elimination is predominantly via the biliary route, accounting for 60-80% of the dose through fecal excretion, while renal clearance is minimal at less than 10-20% of the administered dose. The terminal elimination half-life is 5-8 hours.[33][6][35] In special populations, spiramycin shows good transplacental transfer, resulting in fetal concentrations of 10-90% of maternal levels and thus increased fetal exposure, particularly relevant for its use in preventing congenital toxoplasmosis. No dosage adjustment is required in mild renal impairment due to the low renal excretion.[36][37][3] Food intake reduces spiramycin absorption by approximately 20-50%, though it may be administered with meals to mitigate gastrointestinal upset.[38][39]Chemistry
Chemical structure
Spiramycin is a macrolide antibiotic featuring a 16-membered macrolactone ring aglycone known as platenolide, to which three deoxysugars are attached: the amino sugar forosamine at the C-9 position and the disaccharide consisting of the amino sugar mycaminose at C-5 and the neutral sugar mycarose linked to mycaminose at its 4'' position.[40] The compound occurs naturally as a mixture of three primary components—I, II, and III—that differ in the degree of acylation at the C-3 hydroxyl group of the macrolactone ring, with spiramycin I bearing a free hydroxyl, spiramycin II an acetyl group, and spiramycin III a propionyl group. These structural variations contribute to subtle differences in polarity and stability among the components, with spiramycin I constituting the major form (typically 70-85% of the mixture in commercial preparations).[7] The molecular formula of spiramycin I, the predominant component, is , corresponding to a molar mass of 843.065 g/mol. Its systematic IUPAC name is (4R,5S,6S,7R,9R,10R,11E,13E,16R)-6-{[(2S,3R,4R,5S,6R)-5-{[(2S,4R,5S,6S)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-4-hydroxy-5-methoxy-10-{[(2R,5S,6R)-5-(dimethylamino)-6-methyloxan-2-yl]oxy}-9,16-dimethyl-2-oxo-1-oxacyclohexadeca-11,13-dien-7-ylacetaldehyde. As a solid, spiramycin presents as a white to off-white crystalline powder with a melting point ranging from 134 to 137 °C. It exhibits poor solubility in water (less than 1 mg/mL at 20 °C) but is freely soluble in organic solvents including methanol (approximately 50 mg/mL) and ethanol (approximately 25 mg/mL). Regarding stability, spiramycin is susceptible to hydrolysis under acidic conditions (pH < 4), which cleaves the glycosidic bonds, but remains stable across neutral to mildly alkaline pH (4–10).Biosynthesis and production
Spiramycin is naturally produced through the fermentation of Streptomyces ambofaciens, a soil-dwelling actinomycete bacterium first isolated from samples in northern France.[41][1] This organism synthesizes spiramycin as a secondary metabolite during its stationary growth phase in aerobic conditions, utilizing a complex biosynthetic machinery encoded by a dedicated gene cluster.[42][43] The biosynthesis of spiramycin begins with the assembly of its macrolactone aglycone, platenolide, by a modular type I polyketide synthase (PKS) system. This PKS incorporates one propionyl-CoA as the starter unit and ten methylmalonyl-CoA extender units to form the 16-membered lactone ring through iterative decarboxylative condensations and β-keto processing steps, including reductions and dehydrations that introduce specific stereochemistry and double bonds.[43][40] Subsequent post-PKS modifications involve glycosylation: the aglycone is first glycosylated at C-5 with mycaminose (a 3-dimethylamino-3,4,6-trideoxyhexose) derived from TDP-activated precursors, followed by attachment of L-mycarose at 4'' of mycaminose and forosamine (a dimethylamino sugar) at C-9 of the aglycone.[40] These glycosylation steps are catalyzed by specific glycosyltransferases within the srm gene cluster, ensuring the final tri-glycosylated structure.[44] Regulatory genes such as srm22 and srm40 coordinate the expression of the biosynthetic operons, responding to environmental cues like nutrient availability.[45] Industrial production of spiramycin relies on large-scale aerobic submerged fermentation of optimized S. ambofaciens strains in bioreactors, typically using carbon sources like glucose or glycerol and nitrogen sources such as ammonium salts, with pH control around 7 and temperatures of 28–30°C.[46] Fermentation durations range from 5–7 days, achieving yields of approximately 5–7 g/L under optimized conditions, though early processes yielded less than 1 g/L.[47][48] Post-fermentation, the antibiotic is recovered from the broth via solvent extraction (e.g., using butanol or ethyl acetate), followed by purification through ion-exchange chromatography, adsorption resins, and final crystallization to obtain the active powder.[49] The commercial product is a mixture primarily composed of spiramycin I (70–80%), with spiramycin II (acetylated at C-3 of the aglycone) and spiramycin III (propionylated at C-3 of the aglycone), reflecting natural biosynthetic variations (ratios may vary by strain and purification, with some preparations enriching spiramycin I to over 85%).[45][7] Production challenges include low initial yields and genetic instability in S. ambofaciens, leading to efforts since the 1990s to enhance output through classical mutagenesis and genetic engineering. Mutants selected for morphological stability and oil tolerance have increased yields by up to 9–50% via improved precursor flux or reduced catabolite repression.[48][50] Genetic modifications, such as overexpression of regulatory genes or pathway enzymes within the srm cluster (fully sequenced by 2007), have further optimized fermentation efficiency without relying on semisynthetic derivatives, maintaining focus on the natural isolate.[43][42]History and society
Discovery and development
Spiramycin was isolated in 1954 by a team of French microbiologists at Rhône-Poulenc laboratories, including Suzanne Pinnert-Sindico, Léon Ninet, Jacques Preud'Homme, and Claude Cosar, from a strain of the soil bacterium Streptomyces ambofaciens obtained from samples collected in France. Initially referred to as "provamycin" among other provisional names, the compound was characterized as a novel macrolide antibiotic through early biochemical analyses.[51] In the late 1950s, the structure of spiramycin was elucidated using degradation studies, revealing a 16-membered macrocyclic lactone ring with attached sugar moieties, distinguishing it from the then-dominant 14-membered macrolides like erythromycin. Preclinical development from 1955 to 1959 involved extensive in vitro and animal testing, which demonstrated strong bacteriostatic activity against Gram-positive pathogens such as staphylococci and streptococci; notably, spiramycin showed superior tissue penetration and efficacy in mouse models of infection compared to erythromycin. The first clinical trials of an oral formulation began in 1955, targeting respiratory tract infections, with promising results in treating conditions caused by susceptible Gram-positive bacteria.[52] A key milestone was the filing of a French patent in 1956 by Rhône-Poulenc for the production process, which facilitated scale-up efforts.[49] By the early 1960s, studies recognized spiramycin's antiparasitic potential, particularly against Toxoplasma gondii in animal models, expanding its therapeutic scope beyond antibacterial applications. Early development faced challenges with low fermentation yields from the native S. ambofaciens strain, often below 1 g/L, which limited initial production; these were addressed through strain selection and medium optimization in the 1960s, boosting yields to commercially viable levels.[53]Commercial availability and regulation
Spiramycin is commercially available under the brand name Rovamycine, primarily produced by Sanofi, with generic formulations such as Spiramycine marketed in Europe. Other trade names include Rovamycin Forte and Toxocare in various regions. For veterinary applications, it is sold as Suanovil and Captalin, often in formulations for livestock treatment.[54] In November 2024, Sanofi announced a collaboration with a Chinese fermentation specialist to optimize spiramycin production processes.[55] The drug has been approved for human use in the European Union since the 1960s, as well as in Canada, Mexico, and Australia, where it is accessible through standard prescription or special access schemes for indications like toxoplasmosis.[56] In Australia, it falls under the Therapeutic Goods Administration's Special Access Scheme Category A, requiring case-by-case approval for use.[57] However, spiramycin is not approved by the U.S. Food and Drug Administration for general use and remains investigational, available only through compassionate use programs for conditions such as toxoplasmosis in pregnancy.[56] In the veterinary sector, spiramycin is widely available as feed additives and injectable formulations for livestock in the EU and Asia, targeting infections in cattle, pigs, and poultry.[18] The European Medicines Agency conducted referrals in the 2010s, including for Suanovil/Captalin products, to harmonize residue limits and ensure food safety compliance across member states.[54] Production of spiramycin is concentrated in Europe, with key manufacturers like Sanofi and Famar Lyon in France, alongside significant output from China, where multiple API suppliers such as Wuxi Fortune Pharma and Lihua Pharma operate.[58] The global market for spiramycin is projected to grow at a compound annual growth rate of 5-7% through 2033, driven by rising demand amid increasing antibiotic resistance challenges.[59][60] Regulatory oversight classifies spiramycin as a WHO-recommended antimicrobial for toxoplasmosis treatment, particularly in pregnant women to prevent congenital transmission, and it is included in AWaRe classification for monitoring purposes.[61] It holds a pregnancy category B or C designation in various jurisdictions, indicating no evidence of risk in animal studies but limited human data, supporting its use when benefits outweigh potential risks.[24] Post-2020, regulatory bodies like the EMA have emphasized enhanced surveillance for macrolide resistance, including spiramycin, as part of broader antimicrobial stewardship efforts in both human and veterinary medicine.[62] Access to spiramycin remains limited in low- and middle-income countries due to supply chain constraints and prioritization of essential medicines, despite its utility in resource-limited settings for bacterial infections.[63] In veterinary regulation, the EU imposed a complete ban on its use as a growth promoter in animal feed since 2006, shifting applications to therapeutic purposes only to mitigate resistance risks.[64]References
- https://wikem.org/wiki/Spiramycin