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Macrolide

Macrolides are a class of antibiotics characterized by a large macrocyclic lactone ring structure, typically derived from natural sources such as the bacterium Saccharopolyspora erythraea (formerly Streptomyces erythreus), and are primarily used to treat bacterial infections by inhibiting protein synthesis.^[1]^[2] The first macrolide, erythromycin, was discovered in 1952 and isolated from Saccharopolyspora erythraea (formerly Streptomyces erythreus), marking a significant advancement in antimicrobial therapy as an alternative for patients allergic to penicillin.^[1] Common modern examples include azithromycin, clarithromycin, and erythromycin, which are effective against a range of gram-positive bacteria (such as streptococci and pneumococci), some gram-negative bacteria (like Haemophilus influenzae), and atypical pathogens causing respiratory infections.^[3]^[2] These antibiotics exert their bacteriostatic effects by binding to the 50S subunit of the bacterial ribosome in the nascent peptide exit tunnel, thereby preventing the elongation of the polypeptide chain during translation.^[1]^[2]^[4] At higher concentrations, they can become bactericidal, particularly against certain susceptible organisms.^[1] Beyond their antimicrobial action, macrolides demonstrate anti-inflammatory and immunomodulatory properties, which contribute to their utility in conditions like chronic obstructive pulmonary disease (COPD) exacerbations and diffuse panbronchiolitis.^[1] Clinically, macrolides are indicated for a variety of infections, including community-acquired pneumonia, streptococcal pharyngitis, otitis media in children, skin and soft tissue infections, and sexually transmitted infections such as chlamydia.^[1]^[3] They are also components of combination therapies, such as clarithromycin with proton pump inhibitors and amoxicillin for Helicobacter pylori eradication in peptic ulcer disease.^[3]^[1] Pharmacokinetically, they exhibit variable oral absorption influenced by food, good tissue penetration (except into cerebrospinal fluid), and primarily biliary excretion, allowing for dosing regimens that range from short courses (e.g., single-dose azithromycin) to extended therapy.^[2] Despite their broad utility, macrolide use is tempered by considerations of resistance, which has increased globally due to mechanisms like ribosomal methylation and efflux pumps, as well as potential adverse effects including gastrointestinal upset, QT interval prolongation leading to arrhythmias, and drug interactions via CYP3A4 inhibition.^[1]^[3] Newer derivatives and research into semisynthetic macrolides continue to address these challenges, underscoring their ongoing relevance in infectious disease management.^[1]

Definition and Structure

Chemical Composition

Macrolides constitute a subclass of polyketides characterized by a large macrocyclic lactone ring, typically comprising 12 to 30 atoms, with 14- to 16-membered rings being most common in therapeutically relevant compounds.^[5]^[6] This ring forms a cyclic ester through the intramolecular esterification of a hydroxyl group and a carboxylic acid, serving as the foundational scaffold of the molecule.^[7] The core aglycone portion of the macrolide consists of this lactone ring, often adorned with a variety of substituents including hydroxyl, methyl, and carbonyl groups that modulate its overall conformation and properties.^[6] A hallmark feature of many macrolides is the attachment of one or more deoxy sugars to the aglycone via glycosidic bonds, which enhance the molecule's polarity and solubility.^[5] Common deoxy sugars include amino sugars that contribute to the basic character of the compound, with linkages typically occurring at specific positions on the ring to stabilize the structure.^[6] Variations in ring size—such as 14-, 15-, or 16-membered configurations—and the nature and position of these substituents profoundly affect the chemical stability, lipophilicity, and solubility of macrolides, influencing their suitability for pharmaceutical applications.^[7] For example, larger rings may confer greater flexibility, while additional hydrophobic substituents can increase membrane permeability.^[6] In nature, macrolides are biosynthesized by actinomycetes, particularly Streptomyces species, as secondary metabolites using modular polyketide synthase (PKS) enzyme complexes.^[8] These PKS systems assemble the polyketide chain from acyl-CoA precursors, cyclizing it to form the lactone ring without requiring extensive post-synthetic modifications in the basic scaffold.^[5] Regarding physicochemical properties, macrolides are generally lipophilic due to their large hydrophobic core, facilitating distribution into tissues, though this is balanced by polar sugar moieties that improve aqueous solubility.^[9] However, they exhibit notable acid lability, particularly in the gastric environment, which can lead to degradation of the lactone ring and necessitate formulation approaches like enteric coatings to ensure stability during oral administration.^[10]

Classification

Macrolides are primarily classified based on the size of their macrocyclic lactone ring, which typically ranges from 12 to 16 members, though larger variants exist in natural products. The 14-membered ring macrolides, exemplified by the erythromycin group, form the most clinically prominent subclass and include natural compounds like erythromycin as well as semi-synthetic derivatives such as clarithromycin and roxithromycin.^[11]^[12] The 15-membered ring macrolides, known as azalides, feature a nitrogen atom inserted into the lactone ring for enhanced stability and spectrum; azithromycin serves as the representative example.^[13] In contrast, 16-membered ring macrolides, such as those in the tylosin group, include tylosin, josamycin, and spiramycin, which are predominantly utilized in veterinary applications due to their broader activity against Gram-positive bacteria and some protozoa.^[14] Within these structural classes, subtypes arise from targeted chemical modifications to address limitations like resistance or instability. Ketolides, derived from 14-membered macrolides, feature a keto group at the C-3 position in place of the L-cladinose sugar, enabling tighter ribosomal binding and efficacy against macrolide-resistant pathogens; telithromycin is a key example.^[15] Fluoroketolides extend this by incorporating fluorine substitutions at the C-2 position, to further boost potency, tissue penetration, and resistance evasion, as seen in solithromycin.^[16] Beyond antibacterial variants, non-antibiotic macrolides encompass compounds with distinct therapeutic roles, such as the immunosuppressants tacrolimus and sirolimus, which are larger-ring (23- and 31-membered, respectively) lactones that inhibit calcineurin or mTOR pathways rather than bacterial protein synthesis.^[17]^[18] Functionally, macrolides divide into antibacterial agents, which inhibit prokaryotic translation by binding the 50S ribosomal subunit, and non-antibacterial types that exhibit antifungal, antiparasitic, or immunomodulatory effects, often as natural toxins or derivatives.^[1]^[19] Many clinically used macrolides are semi-synthetic, derived from natural precursors produced by actinomycetes; modifications like 6-O-methylation in clarithromycin or 15-membered ring expansion in azithromycin mitigate acid instability inherent to the parent erythromycin, improving oral bioavailability and gastrointestinal tolerability.^[20]^[21] Macrolides originate as secondary metabolites from soil bacteria, primarily Streptomyces species, biosynthesized via modular polyketide synthase enzymes that assemble the lactone ring and attach sugars.^[22] Evolutionary divergence has yielded diverse classes, with genome mining techniques—such as bioinformatics analysis of biosynthetic gene clusters—uncovering novel variants from previously silent pathways in bacterial genomes, accelerating the discovery of structurally unique macrolides.^[23]^[24]

History

Discovery and Isolation

The discovery of macrolides emerged in the post-World War II era, when rising penicillin resistance among bacterial pathogens, particularly staphylococci, prompted pharmaceutical companies to launch extensive soil screening programs for new antimicrobial agents from microorganisms. These efforts, led by organizations like Eli Lilly and Company, involved systematic collection and fermentation of soil samples from diverse global locations to identify novel bioactive compounds produced by actinomycetes such as Streptomyces species. This surge in research, part of the broader "Golden Age of Antibiotics" from the 1940s to 1960s, aimed to address clinical needs unmet by existing therapies like penicillin and streptomycin.^[25] The first macrolide antibiotic, pikromycin, was isolated in 1950 from the soil bacterium Streptomyces venezuelae by German chemists Heinrich Brockmann and Walter Henkel during routine screening for antibacterial substances. Pikromycin, a 14-membered ring compound with a bitter taste (from which its name derives, via the Greek pikros), demonstrated activity against Gram-positive bacteria and marked the initial recognition of this structural class, though its full biosynthetic pathway as a polyketide was later elucidated. Shortly thereafter, methymycin, a related 12-membered macrolide, was identified from the same Streptomyces strain, further establishing the polyketide origins of these natural products through fermentation and extraction processes. These early isolations relied on basic techniques like acid-base extraction from culture broths and chromatographic purification to obtain pure compounds for bioassays.^[26]^[27] In 1952, erythromycin became the first clinically viable macrolide when it was isolated by James M. McGuire and colleagues at Eli Lilly from a strain of Streptomyces erythreus (now classified as Saccharopolyspora erythraea) found in soil samples collected from Iloilo on Panay Island in the Philippines. The isolation process involved fermenting the bacterium in nutrient media, followed by filtration to remove mycelial solids, solvent extraction (typically with organic solvents like chloroform or ethyl acetate under adjusted pH conditions), and purification via recrystallization or chromatography to yield the crystalline base. Initial characterization revealed erythromycin as a bacteriostatic agent primarily effective against Gram-positive bacteria, including staphylococci resistant to penicillin, with in vitro minimum inhibitory concentrations demonstrating inhibition of protein synthesis in susceptible strains.^[28]^[29] The term "macrolide" was coined in 1957 by organic chemist Robert B. Woodward to describe this emerging class of antibiotics characterized by their large macrocyclic lactone rings (typically 12-16 members) attached to sugar moieties. Early studies, including those on pikromycin and erythromycin, confirmed their shared polyketide biosynthetic pathways in Streptomyces, with in vitro assays highlighting potent activity against staphylococci and other Gram-positive pathogens, setting the stage for further exploration of natural macrolides.^[30]60219-5/fulltext)

Development of Derivatives

The development of macrolide derivatives began with modifications to the natural erythromycins isolated from Saccharopolyspora erythraea, where erythromycin A emerged as the primary active component alongside minor variants B, C, and D produced during fermentation.^[31] These early natural forms laid the foundation for semi-synthetic improvements aimed at enhancing pharmaceutical properties. In the 1960s, to address poor oral bioavailability due to gastric acid instability, ester salts such as erythromycin estolate (introduced around 1961) and erythromycin ethylsuccinate (developed shortly thereafter) were created; these prodrug forms are absorbed intact in the intestine before hydrolysis by plasma esterases releases the active drug, significantly improving absorption compared to the base form.^[32]^[33] The 1980s marked a surge in structural innovations to overcome limitations like short half-life and acid lability. Azithromycin, the first azalide, was synthesized in 1980 by inserting a methyl-substituted nitrogen into the 14-membered lactone ring of erythromycin, expanding it to a 15-membered ring and extending its plasma half-life to over 68 hours for once-daily dosing.^[13] Similarly, clarithromycin was developed in 1980 through selective 6-O-methylation of erythromycin A, which sterically shields the molecule from acid degradation while broadening its spectrum against Helicobacter pylori and other pathogens.^[36] These modifications represented key semi-synthetic advances, with the U.S. Food and Drug Administration (FDA) approving erythromycin in 1952 as the class pioneer and azithromycin in 1991. The ketolide era in the early 2000s targeted rising macrolide resistance by further altering the erythromycin scaffold, replacing the cladinose sugar at C-3 with a ketone group for enhanced ribosomal binding. Telithromycin, the first approved ketolide, received European Union authorization in 2001 and U.S. FDA approval in 2004 specifically to combat resistant respiratory pathogens like Streptococcus pneumoniae.^[39]^[40] However, post-marketing surveillance revealed severe hepatotoxicity risks, leading to its withdrawal from several markets, including restrictions in the U.S. in 2007 and restrictions and safety warnings in the European Union in 2007, with full withdrawal of marketing authorisation in 2019 due to liver injury cases.^[41]^[42]^[43] Recent advances through 2025 have focused on fluoroketolides and biosynthetic engineering to restore efficacy against multidrug-resistant strains, including methicillin-resistant Staphylococcus aureus (MRSA). Fluoroketolides like solithromycin, featuring a fluorine at the C-2 position for improved potency and reduced resistance induction, advanced to phase 3 trials by 2016 and remain in development for community-acquired pneumonia with activity against macrolide-resistant bacteria.^[16]^[44] Concurrently, combinatorial biosynthesis and genome mining of polyketide synthase (PKS) gene clusters have enabled the engineering of novel macrolide scaffolds; for instance, 2023–2025 studies have utilized metagenomic approaches to identify and modify actinomycete PKS pathways, yielding anti-MRSA variants with altered aglycone structures for better ribosomal affinity and evasion of efflux pumps.^[45]^[46] These efforts build on earlier regulatory shifts, such as the European Union's 1999 ban on tylosin as a veterinary growth promoter—effective from July 1, 1999, alongside spiramycin, bacitracin, and virginiamycin—to curb resistance emergence while preserving therapeutic uses in animal health.^[47]

Pharmacology

Pharmacokinetics

Macrolide antibiotics exhibit variable oral absorption depending on their chemical stability in gastric acid. Erythromycin, a prototypical 14-membered macrolide, has low bioavailability of approximately 25-30% due to degradation in the acidic stomach environment, which can be mitigated by enteric-coated formulations or administration with food for certain esters like erythromycin estolate.^[9]^[48] In contrast, structurally modified derivatives such as clarithromycin (55% bioavailability) and azithromycin (37-38% bioavailability) demonstrate greater acid stability, enhancing absorption and allowing for less frequent dosing.^[9]^[49] Food generally has minimal impact on the absorption of these newer macrolides, though high-fat meals may slightly delay azithromycin peak concentrations.^[49] Following absorption, macrolides display extensive distribution throughout the body, characterized by a high volume of distribution often exceeding 1 L/kg, reflecting their lipophilic nature.^[50] They accumulate preferentially in tissues such as the lungs, prostate, spleen, and liver, achieving concentrations up to 50 times those in plasma, facilitated by uptake into phagocytic cells via macrolide-binding proteins and efflux transporters.^[9] Azithromycin exemplifies this with a volume of distribution of 23-31 L/kg and intracellular accumulation in macrophages exceeding 800 times serum levels.^[9] However, penetration into cerebrospinal fluid is limited, typically reaching only 2-13% of plasma concentrations, restricting their utility in central nervous system infections.^[9]^[51] Metabolism of macrolides primarily occurs in the liver via the cytochrome P450 3A4 (CYP3A4) enzyme system, with variations among compounds. Erythromycin undergoes extensive first-pass metabolism, with about 80% demethylated to inactive metabolites, and it potently inhibits CYP3A4 while also inducing it at higher doses.^[9] Clarithromycin is similarly metabolized by CYP3A4 to active (14-hydroxyclarithromycin) and inactive metabolites.^[9] Azithromycin, however, experiences minimal hepatic metabolism as a weak CYP3A4 substrate, contributing to its prolonged presence in tissues.^[9] Excretion of macrolides is predominantly fecal via biliary routes, accounting for 50-80% of the dose, with enterohepatic recirculation common.^[52] Urinary elimination is minor, typically less than 10-20% unchanged drug.^[9] Elimination half-lives vary widely: erythromycin has a short half-life of about 1.5-2 hours, necessitating multiple daily doses, while clarithromycin's is around 3-4 hours, and azithromycin's extended half-life of 68 hours supports once-daily or short-course regimens.^[50]^[53] In special populations, pharmacokinetics of macrolides can differ significantly. Hepatic impairment reduces clearance, particularly for extensively metabolized agents like erythromycin and clarithromycin, often requiring dose adjustments in severe cases to avoid accumulation.^[54] Pediatric dosing is typically weight-based, with similar bioavailability to adults but potentially higher clearance in young children, necessitating adjusted regimens for efficacy.^[55] In veterinary applications, particularly in ruminants like cattle, absorption is delayed and less predictable due to rumen fermentation, resulting in prolonged half-lives (e.g., 65 hours for tulathromycin), which influences dosing intervals compared to monogastric species or humans.^[56]

Pharmacodynamics

Macrolides exhibit time-dependent antibacterial activity, with efficacy primarily driven by the area under the concentration-time curve over the minimum inhibitory concentration (AUC/MIC) ratio, where values exceeding 25-30 are associated with optimal bacterial killing against susceptible pathogens.^[57] This pharmacodynamic profile supports their bacteriostatic effects at standard therapeutic concentrations, though bactericidal activity can emerge in a concentration-dependent manner at higher doses.^[1] Additionally, macrolides demonstrate a notable post-antibiotic effect (PAE), persisting for 2-4 hours against streptococci following exposure to concentrations 10 times the MIC, which extends suppression of bacterial regrowth beyond the dosing interval.^[58] Their spectrum of activity includes strong efficacy against atypical pathogens such as Legionella pneumophila, facilitated by extensive intracellular accumulation in host cells, allowing sustained exposure to intracellular bacteria.^[1] In contrast to beta-lactams, macrolides achieve superior penetration into lung tissues, with epithelial lining fluid-to-plasma ratios often exceeding 1, enhancing their pharmacodynamic impact in respiratory infections.^[59] Synergistic interactions have also been observed when combined with rifampin, particularly against Legionella species, where the combination yields enhanced bactericidal effects in macrophage models.^[60] Beyond antibacterial effects, macrolides exert dose-dependent immunomodulatory pharmacodynamics, reducing proinflammatory cytokine production—such as interleukin-8 and tumor necrosis factor-alpha—at sub-MIC levels, thereby mitigating host inflammatory responses without eradicating the pathogen.^[61] Resistance mechanisms, including ribosomal methylation that elevates MICs, adversely shift pharmacodynamic targets; for instance, susceptible strains require AUC/MIC ratios of 25-30, but resistant isolates demand values over 100 to achieve comparable efficacy and prevent further resistance selection.^[62] Pharmacokinetic/pharmacodynamic (PK/PD) modeling integrates these indices to optimize dosing regimens, accounting for elevated MICs by predicting exposure thresholds that maintain therapeutic windows in resistant scenarios.^[63]

Mechanism of Action

Antibacterial Activity

Macrolide antibiotics primarily inhibit bacterial protein synthesis by targeting the 50S subunit of the bacterial ribosome.^[64] They bind at the peptidyl transferase center (PTC) within the nascent peptide exit tunnel (NPET), forming hydrogen bonds and van der Waals interactions with residues in the 23S rRNA.^[64] The desosamine sugar moiety plays a critical role in this binding, interacting specifically with adenines A2058 and A2059, which positions the macrolide to occlude the tunnel entrance.^[64] This binding sterically blocks the exit tunnel, preventing the progression of nascent polypeptides and halting translation elongation, particularly at motifs like Nas/Nas sequences in the nascent chain.^[64] The result is a predominantly bacteriostatic effect, suppressing growth in susceptible bacteria by disrupting protein production without directly killing the cells.^[64] For example, erythromycin, a prototypical 14-membered macrolide, exemplifies this inhibition mode.^[64] Macrolides demonstrate activity against Gram-positive cocci such as Streptococcus species (e.g., S. pneumoniae and S. pyogenes) and non-methicillin-resistant Staphylococcus aureus, as well as atypical pathogens like Mycoplasma pneumoniae.^[1] Their spectrum is limited against most Gram-negative bacteria due to poor outer membrane penetration and active efflux mechanisms that expel the drugs from the cell.^[1] Azithromycin, with its expanded spectrum among macrolides, retains efficacy against these targets but shares the same limitations.^[1] Structure-activity relationships highlight that ring size influences binding affinity, with 14-membered macrolides exhibiting the strongest interactions at the ribosomal site compared to 15- or 16-membered variants. The sugar moieties, including desosamine at the C5 position and cladinose at C3, are essential for stabilizing PTC contacts and overall antibacterial potency.^[64] In certain bacteria, such as staphylococci, inducible expression of genes encoding the MLS_B phenotype can reduce macrolide efficacy under specific conditions.

Immunomodulatory Effects

Macrolides exhibit immunomodulatory effects independent of their antibacterial activity, primarily through suppression of pro-inflammatory pathways in host cells. These effects include inhibition of the nuclear factor kappa B (NF-κB) pathway, which reduces the transcription of inflammatory genes, leading to decreased production of cytokines such as interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α).^[65]^[66] Additionally, macrolides modulate neutrophil function by inhibiting chemotaxis and promoting apoptosis, thereby attenuating excessive inflammatory responses in tissues like the airways.^[67]^[68] A seminal example of these effects is observed in diffuse panbronchiolitis (DPB), a chronic inflammatory lung disease prevalent in East Asia during the 1980s. Low-dose erythromycin therapy, initiated in Japan, dramatically improved patient survival rates—from less than 40% at five years to over 90%—by enhancing mucus clearance and reducing airway inflammation, rather than through direct antimicrobial action.^[69]^[70] This treatment decreased neutrophil infiltration in bronchoalveolar lavage fluid and shifted the immune balance toward anti-inflammatory Th2 responses.^[71]^[72] Beyond DPB, macrolides demonstrate anti-inflammatory benefits in cystic fibrosis (CF) exacerbations, where azithromycin reduces pulmonary inflammation and slows lung function decline.^[73] In chronic obstructive pulmonary disease (COPD), long-term azithromycin therapy has been shown in randomized trials to decrease exacerbation frequency by up to 27%, attributed to lowered inflammatory mediator production.^[74] Similarly, in severe asthma, azithromycin maintenance reduces exacerbation rates, particularly in non-eosinophilic phenotypes, through modulation of airway inflammation.^[75]^[76] These immunomodulatory actions are dose-dependent, occurring effectively at sub-minimum inhibitory concentrations (sub-MIC) that spare much of the antibacterial potency while targeting host inflammation.^[77] However, recent studies highlight a double-edged impact: long-term low-dose macrolide use disrupts gut microbiota diversity, depleting keystone species and potentially altering metabolic and immune regulation, which may contribute to adverse outcomes like increased infection risk.^[78]^[77] Non-antibiotic macrolides, such as rapamycin, extend these principles through distinct mechanisms like inhibition of the mammalian target of rapamycin (mTOR) pathway, which suppresses T-cell proliferation and promotes immunosuppression in transplant settings.^[79]^[80]

Clinical Uses

Treatment of Infections

Macrolides are commonly employed in the treatment of respiratory tract infections, serving as first-line therapy for community-acquired pneumonia (CAP) in outpatient adults without comorbidities or risk factors for drug-resistant pathogens, where azithromycin is administered as 500 mg on day 1 followed by 250 mg daily on days 2 through 5.^[81] They are also recommended for postexposure prophylaxis against pertussis (whooping cough), with azithromycin preferred at 500 mg on day 1 and 250 mg daily on days 2 through 5 for adults and adolescents.^[82] In hospitalized patients with non-severe CAP, guidelines recommend empiric monotherapy with a beta-lactam (such as ceftriaxone) or a respiratory fluoroquinolone; addition of a macrolide (azithromycin) is conditional on suspicion of atypical pathogens and low local macrolide resistance, per 2025 ATS guidelines. The 2025 ATS guidelines also recommend shorter courses of antibiotics (minimum 3 days, often <5 days) for clinically stable patients to minimize resistance.^[83] For skin and soft tissue infections, erythromycin is utilized orally for moderate acne vulgaris, particularly in pregnant patients or those with contraindications to tetracyclines, at doses of 500 mg twice daily for 4 to 6 weeks in combination with topical therapies.^[84] Macrolides, such as erythromycin or azithromycin, serve as alternatives for streptococcal skin infections like impetigo or cellulitis in penicillin-allergic individuals, with azithromycin dosed at 500 mg on day 1 followed by 250 mg daily for 4 days.^[85] In infections caused by atypical pathogens, macrolides are the cornerstone of therapy; for legionellosis (Legionnaires' disease), azithromycin is recommended at 500 mg daily for 3 days in mild cases or longer in severe presentations, often preferred over erythromycin due to better tolerability.^[86] For uncomplicated genital infections due to Chlamydia trachomatis, a single 1 g oral dose of azithromycin remains an alternative regimen, though doxycycline is now preferred by CDC guidelines for its superior efficacy against rectal infections.^[87] In pediatric populations, macrolides like azithromycin are indicated as alternatives for acute otitis media in children with penicillin allergy, administered at 10 mg/kg on day 1 followed by 5 mg/kg daily for days 2 through 5, when high-dose amoxicillin (80-90 mg/kg/day) cannot be used.^[88] Veterinary applications include the use of tylosin for treating swine dysentery caused by Brachyspira hyodysenteriae, typically administered in feed at 40-100 g per ton for 21 days or via injection at 8.8 mg/lb body weight daily.^[89] However, regulatory restrictions limit non-therapeutic use; the European Union banned macrolides such as tylosin as growth promoters in animal feed effective January 1, 2006, to curb antibiotic resistance.^[90] Current guidelines, including ATS recommendations from 2025, emphasize macrolides for CAP in macrolide-susceptible cases, particularly outpatients and those with atypical coverage needs, while advising against monotherapy in regions with high pneumococcal resistance.^[91]

Non-Infectious Applications

Macrolides, particularly azithromycin, have been explored for their immunomodulatory properties in managing chronic inflammatory conditions beyond bacterial infections. These effects, which include suppression of pro-inflammatory cytokines and neutrophil activity, contribute to reduced inflammation in respiratory diseases.^[92] In non-cystic fibrosis (non-CF) bronchiectasis, long-term azithromycin therapy has demonstrated efficacy in preventing exacerbations through anti-inflammatory mechanisms. The EMBRACE trial, a randomized, double-blind, placebo-controlled study involving 141 patients, showed that azithromycin (500 mg three times weekly for 6 months) reduced the rate of exacerbations by 40% compared to placebo, with improvements in quality of life and no significant increase in adverse events.^[93] Similarly, in cystic fibrosis, meta-analyses from the 2020s confirm azithromycin's anti-inflammatory benefits, including improved forced expiratory volume in 1 second (FEV1) and reduced pulmonary exacerbations in pediatric patients, attributed to modulation of innate immune responses rather than antibacterial action alone.^[92] A 2025 systematic review and meta-analysis of 18 studies further supported these findings, noting significant reductions in exacerbation frequency and enhancements in lung function across 2,877 patients.^[94] Erythromycin serves as a prokinetic agent in gastrointestinal disorders such as gastroparesis, primarily due to its agonism of motilin receptors, which stimulates gastric motility independently of antimicrobial effects. Clinical reviews indicate that intravenous or oral erythromycin accelerates gastric emptying in diabetic and idiopathic gastroparesis patients, with doses as low as 200 mg providing symptomatic relief for up to several weeks before tachyphylaxis develops.^[95] This motilin-mimetic action enhances the migrating motor complex, offering a targeted approach for delayed gastric emptying without relying on its antibacterial properties.^[96] Experimental studies suggest potential immunomodulatory roles for macrolides in autoimmune conditions like rheumatoid arthritis, though clinical translation remains limited. In collagen-induced arthritis mouse models, azithromycin reduced joint inflammation and disease severity by inhibiting the unfolded protein response pathway involving glucose-regulated protein 78 (GRP78), highlighting a non-antibiotic mechanism for immune regulation.^[97] A 2025 review of antibiotics in rheumatologic diseases corroborated these preclinical findings, noting decreased inflammatory markers in experimental settings but emphasizing the need for human trials.^[98] While polyene macrolides such as amphotericin B and its analogs are employed as antifungals due to their disruption of fungal cell membranes, they represent a structurally distinct subclass from the 14- to 16-membered lactone ring antibacterial macrolides like erythromycin, with mechanisms centered on ergosterol binding rather than ribosomal inhibition.^[99] Emerging applications include low-dose macrolides for inflammation associated with COVID-19 sequelae, though evidence is preliminary and limited to small cohorts. Case reports from 2023-2024 describe favorable responses in post-COVID neuropsychiatric symptoms with azithromycin, potentially linked to its anti-inflammatory effects on persistent cytokine elevation.^[100] In veterinary medicine, macrolides exhibit anti-inflammatory benefits in equine respiratory disease, aiding in the management of conditions like recurrent airway obstruction through immunomodulation that reduces neutrophil influx and mucus production.^[101] Despite these benefits, macrolides are not first-line for non-infectious applications due to risks of promoting bacterial resistance and disrupting gut microbiota diversity. Long-term use, such as azithromycin, has been associated with increased macrolide-resistant pathogens in the oropharynx and gut, potentially exacerbating dysbiosis and long-term microbial imbalances.^[102] Studies further indicate that macrolide exposure reduces bacterial alpha-diversity and selects for resistant strains, limiting their suitability for prolonged therapy in non-bacterial contexts.^[103]

Examples

14- and 15-Membered Macrolides

The 14- and 15-membered macrolides represent a subclass of macrolide antibiotics characterized by their lactone ring size, which influences their pharmacokinetic properties, spectrum of activity, and clinical applications. These agents primarily inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit, offering coverage against Gram-positive bacteria, some Gram-negatives, and atypical pathogens. They are distinguished from larger-ring macrolides by improved tissue penetration and reduced gastrointestinal side effects in second-generation derivatives.^[11]^[104] Erythromycin, the prototype 14-membered macrolide, was introduced in the 1950s and serves as a benchmark for the class due to its broad-spectrum activity against respiratory pathogens. It is administered intravenously or orally for serious infections, including streptococcal endocarditis in penicillin-allergic patients, where it achieves bactericidal synergy with other agents. A unique feature of erythromycin is its agonism of motilin receptors, which stimulates gastrointestinal motility and can lead to side effects like nausea and cramping, though low doses are explored for prokinetic therapy in gastroparesis.^[105]^[106]^[107] Clarithromycin, a second-generation 14-membered macrolide, addresses erythromycin's limitations through structural modifications that enhance acid stability and bioavailability, resulting in superior gastrointestinal tolerance. It is commonly used in dual or triple therapy regimens for Helicobacter pylori eradication, achieving cure rates exceeding 80% when combined with proton pump inhibitors and amoxicillin in susceptible strains. Roxithromycin, another 14-membered derivative, offers similar pharmacokinetics with good tissue distribution and is employed regionally for respiratory tract infections, though its global use is limited compared to clarithromycin. Dirithromycin, also 14-membered, was developed for once-daily dosing but has been discontinued in several markets due to suboptimal efficacy profiles in clinical trials.^[11]^[108]^[104] The 15-membered macrolides, often termed azalides, include azithromycin, which features a nitrogen insertion in the ring for extended half-life (approximately 68 hours) and exceptional lung tissue accumulation. This enables short-course regimens like the Z-Pak (500 mg on day 1 followed by 250 mg daily for 4 days), providing broad coverage against atypical pathogens such as Mycoplasma pneumoniae and Chlamydia pneumoniae in community-acquired pneumonia. Azithromycin also exhibits anti-biofilm activity, inhibiting formation and disrupting established biofilms in pathogens like Pseudomonas aeruginosa and Klebsiella pneumoniae at subinhibitory concentrations, which enhances its utility in chronic infections such as cystic fibrosis exacerbations.^[49]^[109]^[104] Fidaxomicin, a narrow-spectrum 18-membered macrolide, targets Clostridium difficile with minimal disruption to gut microbiota, reducing recurrence rates compared to vancomycin (approximately 15% vs. 25% at 4 weeks post-treatment). It received FDA approval in 2011 for adult Clostridium difficile-associated diarrhea, administered as 200 mg tablets twice daily for 10 days.^[110]^[111] Among recent developments, solithromycin, a fluoroketolide derived from 14-membered structures, has undergone phase 3 trials for community-acquired pneumonia, demonstrating non-inferiority to moxifloxacin with clinical success rates around 79%. It shows enhanced activity against Gram-negative pathogens like Haemophilus influenzae through dual ribosomal binding sites, though regulatory approval remains pending as of 2025 due to hepatic safety concerns observed in trials.^[112]^[113]

16-Membered Macrolides

16-Membered macrolides represent a subclass of macrolide antibiotics characterized by a larger lactone ring structure compared to their 14- and 15-membered counterparts, often featuring complex glycosylation patterns that influence their pharmacological properties. These compounds are produced by actinomycetes such as Streptomyces and Micromonospora species and exhibit a broader spectrum of activity, including enhanced efficacy against certain Gram-negative bacteria due to additional sugar moieties attached to the aglycone core.^[114]^[115] Tylosin, a prototypical 16-membered macrolide derived from Streptomyces fradiae, is primarily employed in veterinary medicine for the treatment and prevention of necrotic enteritis in poultry caused by Clostridium perfringens. Administered orally in feed at doses ranging from 50 to 200 mg/kg, it promotes growth and reduces bacterial load in the intestinal tract, leading to improved weight gain and feed efficiency in broiler chickens.^[116]^[116] In Europe, josamycin serves as a human therapeutic option, particularly for skin and soft tissue infections caused by Gram-positive pathogens like Staphylococcus and Streptococcus species, where it is prescribed as a second-line agent in cases of penicillin allergy.^[117]^[118] Spiramycin, another 16-membered macrolide, is utilized for its anti-parasitic properties, notably in the management of Toxoplasma gondii infection during pregnancy to mitigate vertical transmission to the fetus. Recommended by health authorities for initiation within 8 weeks of maternal seroconversion when infection occurs before 18 weeks gestation, it reduces the risk of congenital toxoplasmosis without crossing the placenta significantly, thereby protecting the developing fetus.^[119]^[119] In Asian markets, midecamycin is commonly applied for respiratory tract infections, including those caused by Mycoplasma pneumoniae and other atypical pathogens, offering an alternative in regions with high macrolide resistance prevalence.^[120] Structurally, these macrolides often incorporate disaccharides such as mycaminose-mycarose at the C-5 position and additional sugars like mycinose at C-23, which contribute to their stability and modest improvement in Gram-negative coverage over smaller-ring macrolides, though activity remains predominantly against Gram-positives.^[114] Their less frequent adoption in human medicine stems from pronounced gastrointestinal side effects, including nausea, vomiting, and diarrhea, which occur more readily than with alternative antibiotics.^[1] A notable non-antibiotic derivative is tylactone, the aglycone core of tylosin lacking the sugar attachments, which serves as a biosynthetic intermediate and has been explored for semi-synthetic modifications in antibiotic development.^[121] Recent assessments indicate limited innovation in 16-membered macrolides, with emphasis shifting toward antimicrobial stewardship in animal agriculture to curb resistance emergence, particularly in veterinary applications like poultry production. Reports from 2023 to 2025 highlight rising macrolide resistance in bovine respiratory pathogens such as Mannheimia haemolytica, underscoring the need for judicious use to preserve efficacy in both animal and human health contexts.^[122]^[123]

Non-Antibiotic Macrolides

Non-antibiotic macrolides encompass a diverse group of compounds derived from polyketide synthases, featuring large lactone rings but lacking the ribosomal-binding domains characteristic of antibacterial macrolides. These molecules exhibit a range of therapeutic and toxic activities, targeting eukaryotic processes such as ion channels, enzymes, and cellular signaling pathways. Their structural versatility has enabled applications in immunosuppression, antifungal therapy, antiparasitic treatment, and emerging biomedical research, often with mechanisms distinct from prokaryotic protein synthesis inhibition. Among the most prominent non-antibiotic macrolides are immunosuppressants like tacrolimus (FK506) and sirolimus (rapamycin). Tacrolimus, a 23-membered macrolide isolated from Streptomyces tsukubaensis, functions as a calcineurin inhibitor by forming a complex with FK-binding protein 12 (FKBP12), which suppresses T-cell activation and cytokine production, thereby preventing organ transplant rejection in liver, kidney, heart, and lung procedures.^[124]^[125] Sirolimus, a 31-membered macrolide from Streptomyces hygroscopicus, binds to FKBP12 to inhibit the mammalian target of rapamycin (mTOR) kinase, disrupting cell proliferation and angiogenesis; it is used in renal transplant immunosuppression, cancer therapy for renal cell carcinoma, and as a coating on coronary stents to prevent restenosis.^[126]^[127] Antifungal polyene macrolides, such as amphotericin B and nystatin, exert their effects by interacting with fungal membrane sterols. Amphotericin B, a 38-membered heptene macrolide produced by Streptomyces nodosus, binds selectively to ergosterol in fungal cell membranes, forming ion-permeable pores that lead to leakage of cellular contents and cell death; it is a cornerstone for treating severe systemic mycoses like candidiasis and aspergillosis, though its clinical use is limited by nephrotoxicity, managed through lipid formulations that reduce renal accumulation.^[128]^[129]^[130] Nystatin, a 38-membered tetraene macrolide from Streptomyces noursei, shares a similar ergosterol-binding mechanism but is primarily employed topically due to poor systemic absorption, effectively treating superficial candidal infections such as oral thrush and cutaneous dermatophytoses with minimal resistance development.^[131]^[132] Macrolide-like antiparasitics include avermectins, a family of 16-membered macrocyclic lactones from Streptomyces avermitilis that serve as precursors to ivermectin. These compounds potentiate chloride conductance by binding to glutamate-gated chloride channels (GluClRs) and, to a lesser extent, GABA-gated channels in invertebrate nerve and muscle cells, causing hyperpolarization, paralysis, and death of parasites; ivermectin, a semi-synthetic derivative, is the standard treatment for onchocerciasis (river blindness), dramatically reducing microfilarial loads in endemic regions.^[133]^[134]^[135] Naturally occurring toxic macrolides, such as bafilomycin and concanamycin, target vacuolar H+-ATPases (V-ATPases) essential for eukaryotic acidification processes. Bafilomycin A1, a 16-membered macrolide from Streptomyces species, inhibits V-ATPase by binding to its Vo subunit, disrupting lysosomal function, autophagy, and endosomal trafficking, which has shown potential in preclinical anticancer studies by inducing apoptosis and inhibiting tumor metastasis in models of breast and colon cancer.^[136]^[137] Concanamycin A, structurally analogous to bafilomycin and isolated from Streptomyces diastatochromogenes, similarly blocks V-ATPase activity at picomolar concentrations, exhibiting comparable effects on cellular acidification and emerging as a tool for investigating acidification-dependent pathologies, including potential anticancer applications through impaired nutrient uptake in tumor cells.^[138]^[139] Recent advances in genome mining of microbial biosynthetic gene clusters have uncovered novel non-antibiotic macrolides with anti-inflammatory and anticancer properties. Between 2023 and 2025, efforts targeting polyketide synthase pathways in actinomycetes have identified macrolide variants that modulate NF-κB signaling for inflammation control in autoimmune models. For instance, EM982, a novel 12-membered ring non-antibiotic macrolide identified in 2024, suppresses TNF-α production by inhibiting NF-κB activity.^[140]^[141]^[142]

Resistance

Bacterial Resistance Mechanisms

Bacteria have evolved several molecular mechanisms to resist macrolide antibiotics, primarily by altering the ribosomal target site, expelling the drug from the cell, enzymatically inactivating it, or protecting the ribosome from drug binding. These mechanisms target the macrolides' inhibition of protein synthesis at the 50S ribosomal subunit's peptidyl transferase center, where the drugs bind to the nascent peptide exit tunnel near domain V of 23S rRNA.^[143] One predominant mechanism is ribosomal modification, mediated by Erm (erythromycin ribosome methylation) methyltransferases, which add one or two methyl groups to the adenine at position 2058 (A2058) in 23S rRNA. This dimethylation sterically hinders macrolide binding and confers the MLS_B phenotype, characterized by cross-resistance to macrolides, lincosamides, and type B streptogramins. Common examples include Erm(B) in streptococci and Erm(C) in staphylococci. Additionally, point mutations in 23S rRNA, such as A2058G or A2059G, or in ribosomal proteins L4 and L22 (e.g., L4 G71R mutation), can reduce affinity for macrolides without methylation.^[143]^[7] Efflux pumps represent another key resistance strategy, actively exporting macrolides from the bacterial cytoplasm. In Gram-positive bacteria, the mef(A) gene encodes a major facilitator superfamily pump that confers low-level resistance (M phenotype) to 14- and 15-membered macrolides like erythromycin and azithromycin, predominantly in streptococci and pneumococci. In Gram-negative bacteria, the intrinsic AcrAB-TolC multidrug efflux system contributes to macrolide impermeability, limiting the drugs' spectrum against Enterobacteriaceae. ABC transporters like Msr(A) can also facilitate efflux alongside other functions.^[143]^[7] Enzymatic inactivation of macrolides occurs through modification of the antibiotic molecule itself. Macrolide 2'-phosphotransferases (Mph), such as Mph(A) and Mph(B), phosphorylate the hydroxyl group at the 2' position of the desosamine sugar, preventing ribosomal binding; Mph(A) expression is often inducible, while Mph(B) is constitutive. Esterases like Ere(A) and Ere(B) hydrolyze the macrolide lactone ring, inactivating drugs such as erythromycin and clarithromycin, and are more common in Gram-negative pathogens like Enterobacteriaceae. Glycosyltransferases (Mgt), such as those encoded by oleD in Streptomyces, add glucose to the macrolide, further contributing to inactivation in producer strains.^[143]^[7] Target protection is a rarer mechanism involving proteins that bind to the ribosome and dissociate bound macrolides, restoring translation. ABC-F family proteins like Msr(D) and Msr(E) achieve this by inducing conformational changes in the ribosome, ejecting the antibiotic from its binding site; these are notable in streptococci and contribute to resistance in clinical isolates. Such proteins mimic the action of tetracycline resistance determinants like Tet(M) but are less widespread for macrolides.^[7]^[144] The genetic basis of these resistance mechanisms often involves mobile genetic elements that facilitate horizontal transfer. Erm genes are frequently located on plasmids or transposons, such as Tn1207.1 carrying erm(B), enabling rapid dissemination among bacteria. Expression can be inducible, as in many Erm variants where translation attenuation regulates methylase production in response to subinhibitory macrolide levels, or constitutive due to mutations like leader peptide deletions. Efflux and inactivation genes, including mef(A)-msr(A) operons and mph/ere, are similarly plasmid-borne, promoting co-resistance and complicating treatment.^[143]^[7]

Clinical and Epidemiological Aspects

Macrolide resistance in Streptococcus pneumoniae exhibits significant regional variation, with rates exceeding 80% reported in parts of Asia, such as 92% in China, 89.1% in Taiwan, and 80.3% in Korea as of studies from 2018–2022.^[145] In the United States, macrolide resistance among S. pneumoniae isolates from clinical settings averages around 40% as of 2020–2023 data, though it can reach higher levels in specific populations like those with community-acquired pneumonia.^[146] For Streptococcus pyogenes, the primary cause of bacterial pharyngitis, macrolide resistance rates are generally lower but remain a concern, ranging from 3% to 9% in the United States and up to 40% in some European countries such as Spain and Turkey as of 2024.^[147]^[148] The spread of macrolide resistance occurs primarily through community-acquired transmission facilitated by horizontal gene transfer of resistance determinants, such as erm genes encoding ribosomal methylation.^[149] In hospital settings, outbreaks have been documented, particularly among methicillin-resistant Staphylococcus aureus (MRSA) strains carrying erm-mediated resistance, which can disseminate via patient-to-patient contact and contaminated environments.^[150] These transmission dynamics underscore the role of both ambulatory and nosocomial pathways in amplifying resistance prevalence. Key risk factors for the emergence and dissemination of macrolide resistance include the overuse of antibiotics in agriculture, where sales of medically important antimicrobials for food-producing animals represent a significant portion of total use (estimated at around 70% based on historical data).^[151] Additionally, global antibiotic consumption has risen by 16.3% from 2016 to 2023, reaching 34.3 billion defined daily doses across 67 reporting countries, with macrolides contributing to this trend through increased human and veterinary applications.^[152] Monitoring of macrolide resistance relies on standardized guidelines from the Clinical and Laboratory Standards Institute (CLSI), which define azithromycin resistance in S. pneumoniae at a minimum inhibitory concentration (MIC) of ≥2 μg/mL, guiding susceptibility testing in clinical laboratories.^[153] Antimicrobial stewardship programs play a crucial role in surveillance and mitigation, implementing strategies like prospective audit and feedback to reduce unnecessary macrolide prescriptions and track resistance trends in real-time.^[154] Looking ahead, studies from 2023 to 2025, such as a 2024 investigation into modified azithromycin analogs, have explored novel macrolide derivatives to circumvent resistance mechanisms and restore susceptibility against macrolide-resistant pathogens.^[155] Recent WHO surveillance as of 2024 indicates continued high resistance in Asia and variable trends in Europe. This resistance has tangible clinical consequences, including elevated treatment failure rates in community-acquired pneumonia, where macrolide monotherapy fails in up to 26% of high-risk cases involving resistant S. pneumoniae strains, necessitating alternative therapies and prolonging hospital stays.^[156]

Safety Profile

Adverse Effects

Macrolides are associated with a range of adverse effects, the most frequent of which are gastrointestinal disturbances occurring in approximately 20-30% of patients. These include nausea, vomiting, abdominal pain, and diarrhea, primarily attributed to the drugs' prokinetic effects via motilin receptor agonism, particularly with erythromycin.^[1]^[157] Additionally, these agents disrupt the gut microbiota, leading to reduced bacterial diversity and an elevated risk of Clostridioides difficile-associated diarrhea, as evidenced by 2025 reviews and studies showing persistent alpha diversity loss post-treatment in certain populations.^[103]^[158] Cardiac toxicities, notably QT interval prolongation, represent a significant concern with macrolides such as clarithromycin and azithromycin, where the risk is dose-dependent and can lead to torsades de pointes. The U.S. Food and Drug Administration issued warnings in 2013 for azithromycin based on observational data linking it to cardiovascular events, highlighting risks in patients with congenital long QT syndrome or other QT-prolonging conditions.^[159]^[160] Hepatic effects are less common but can include cholestatic hepatitis, particularly with erythromycin estolate, manifesting as idiosyncratic reactions with jaundice, pruritus, and elevated liver enzymes in susceptible individuals. This form of hepatotoxicity is rare, estimated at 3.6 cases per 100,000 users, and occurs more frequently with the estolate ester than with other formulations like azithromycin, which carries minimal hepatic risk.^[161]^[1] Allergic reactions to macrolides occur infrequently, with hypersensitivity rates estimated at 0.4% to 3%, typically presenting as maculopapular rash or urticaria, while severe manifestations like anaphylaxis or hypersensitivity syndromes are infrequent but can involve IgE-mediated mechanisms leading to angioedema or bronchospasm.^[162]^[163]^[164] Other notable adverse effects include ototoxicity, primarily reversible sensorineural hearing loss observed with high-dose intravenous administration, as reported in case series of patients receiving erythromycin or azithromycin infusions. Myopathy is a rare complication, occasionally progressing to rhabdomyolysis, particularly in vulnerable populations. Long-term low-dose macrolide use has been linked to sustained reductions in gut microbiota alpha diversity, per 2025 research highlighting age-specific vulnerabilities in microbial recovery.^[165]^[166]^[167]^[168] In special populations, current FDA labeling provides narrative risk summaries rather than letter categories. Erythromycin and azithromycin are generally considered compatible with pregnancy based on available data, though some studies suggest increased risks of miscarriage and birth defects; clarithromycin is avoided due to evidence of teratogenicity. A 2025 review updates safety data, noting increased risks of spontaneous abortion with early pregnancy exposure to macrolides and recommending alternatives when possible, especially for clarithromycin.^[169]^[170]^[171] They should be avoided in patients with myasthenia gravis, as they can exacerbate muscle weakness through neuromuscular blockade.^[172]

Drug Interactions

Macrolide antibiotics, particularly erythromycin and clarithromycin, act as potent inhibitors of the cytochrome P450 3A4 (CYP3A4) enzyme, which can significantly elevate plasma concentrations of co-administered drugs metabolized via this pathway, leading to enhanced therapeutic effects or toxicity.^[1] This inhibition occurs through formation of inactive CYP3A4-iron-metabolite complexes by nitrosoalkane metabolites of the macrolides.^[173] For instance, erythromycin and clarithromycin increase exposure to statins like simvastatin (up to 6.2-fold AUC increase with erythromycin) and atorvastatin, raising the risk of rhabdomyolysis due to myotoxicity.^[173] Similarly, these macrolides potentiate the anticoagulant effects of warfarin by elevating its levels, resulting in international normalized ratio (INR) increases (e.g., up to 16.8 with clarithromycin), which heightens bleeding risk.^[173] Theophylline, another CYP3A4 substrate, experiences elevated concentrations (e.g., 20% increase in AUC with clarithromycin), potentially causing nausea, vomiting, or seizures.^[173] Erythromycin exhibits autoinduction of its own metabolism, where repeated dosing enhances hepatic biotransformation into inhibitory metabolites, potentially altering its pharmacokinetics over time.^[173] In contrast, azithromycin demonstrates minimal CYP3A4 interaction, showing no significant changes in the pharmacokinetics of substrates like theophylline or midazolam, making it a preferable option in polypharmacy scenarios.^[173]^[174] Macrolides can exacerbate QT interval prolongation when combined with other agents that affect cardiac repolarization, such as the antiarrhythmic amiodarone or the antifungal fluconazole, synergistically increasing the risk of torsades de pointes and ventricular arrhythmias.^[175] This pharmacodynamic interaction stems from additive blockade of the hERG potassium channel.^[1] Additional interactions include heightened colchicine toxicity with clarithromycin or erythromycin, particularly in patients with renal impairment, where CYP3A4 inhibition leads to colchicine accumulation and risks of neuromyopathy or fatal outcomes (odds ratio for death up to 18.1).^[176] Erythromycin also inhibits P-glycoprotein (P-gp), an efflux transporter, resulting in increased digoxin bioavailability and serum levels (up to 2-fold), which may precipitate digoxin toxicity manifesting as arrhythmias or gastrointestinal symptoms.^[177]^[178] To mitigate these risks, clinical management involves avoiding or adjusting concomitant therapy; for example, clarithromycin is contraindicated with simvastatin, and if unavoidable, simvastatin should be suspended during macrolide treatment, with resumption only after completion.^[179] For warfarin, frequent INR monitoring and dose reductions are essential.^[180] When macrolides are prescribed with QT-prolonging drugs, baseline and serial electrocardiogram (ECG) monitoring for QTc prolongation (e.g., >500 ms) is recommended to detect early arrhythmogenic potential.^[181] Recent pharmacovigilance analyses from 2023 have reinforced concerns from the COVID-19 era, indicating that azithromycin combined with hydroxychloroquine elevates risks of QT prolongation, ventricular arrhythmias, and sudden cardiac events, with reporting odds ratios exceeding 2 for serious outcomes.^[182]^[183]

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