ATC code J01

ATC code J01 designates "Antibacterials for systemic use" within the Anatomical Therapeutic Chemical (ATC) classification system, an internationally standardized method for classifying drugs based on their therapeutic, pharmacological, and chemical properties.^[1] This code falls under the broader anatomical main group J, which encompasses antiinfectives for systemic use, and specifically includes all antibacterial agents administered systemically—such as via oral, intravenous, or intramuscular routes—excluding antimycobacterials that are classified separately in J04.^[2] The classification prioritizes the primary therapeutic use of these drugs in treating bacterial infections of moderate severity.^[1] The ATC system organizes J01 into second-level therapeutic subgroups based on the drugs' mechanisms of action and chemical structures, enabling precise categorization for pharmacoepidemiological analysis.^[3] Key subgroups include J01A (tetracyclines), J01B (amphenicols), J01C (beta-lactam antibacterials, penicillins), J01D (other beta-lactam antibacterials, such as cephalosporins grouped by generations), J01E (sulfonamides and trimethoprim), J01F (macrolides, lincosamides, and streptogramins), J01G (aminoglycoside antibacterials), J01M (quinolone antibacterials), J01R (combinations of antibacterials from different third-level groups), and J01X (other antibacterials not fitting elsewhere).^[1] Combinations involving sulfonamides and trimethoprim are an exception, placed in J01EE rather than J01R.^[1] Inhaled antiinfectives are classified in J01 because preparations for inhalation cannot be separated from preparations for injection, though topical antiinfectives fall under other ATC groups like D (dermatologicals) or S (sensory organs).^[1] Defined Daily Doses (DDDs) are assigned to J01 drugs to standardize consumption measurements, typically reflecting average maintenance doses for infections of moderate severity over treatment durations exceeding one week, or average daily doses for shorter courses.^[1] Maintained by the WHO Collaborating Centre for Drug Statistics Methodology at the Norwegian Institute of Public Health, the ATC system—including J01—supports global drug utilization research, policy-making, and comparisons of antibacterial prescribing patterns to monitor resistance and optimize antimicrobial stewardship.^[3] Updates to the classification, such as those in the 2025 index, ensure it reflects evolving pharmacological knowledge and new therapeutic agents.^[3]

Introduction

Definition and Scope

The Anatomical Therapeutic Chemical (ATC) classification system, maintained by the WHO Collaborating Centre for Drug Statistics Methodology at the Norwegian Institute of Public Health, designates J01 as the code for antibacterials for systemic use within the broader category of antiinfectives for systemic use (J).^[2] This group specifically addresses antibacterials administered systemically to combat bacterial infections, organized hierarchically by therapeutic, pharmacological, and chemical subgroups at the second through fourth levels, with individual active substances at the fifth level.^[4] The scope of J01 encompasses all antibacterials intended for systemic delivery, including oral, intravenous, and intramuscular routes, primarily for treating moderate to severe bacterial infections based on mode of action and chemistry.^[1][4] It includes approximately 200 active substances as of 2025, with the classification updated annually to incorporate new drugs and reflect evolving therapeutic needs.^[3] However, J01 excludes topical antibacterials (classified under D for dermatologicals or S for sensory organs), antimycotics (J02), antivirals (J05), and antimycobacterials (J04).^[4] In distinction from other groups within the J category, J01 is limited to antibacterials targeting bacteria exclusively, whereas antiprotozoals and antihelminthics for parasites or protozoa fall under P01.^[4] This focused delineation ensures precise categorization for pharmacoepidemiological monitoring and drug utilization studies.^[2]

Nomenclature and Hierarchy

The Anatomical Therapeutic Chemical (ATC) classification system organizes drugs into a hierarchical structure comprising five levels, enabling standardized international comparison of drug utilization. At the first level, drugs are grouped by anatomical main group, denoted by a single letter; for antibacterials for systemic use, this is J (antiinfectives for systemic use). The second level specifies the therapeutic subgroup, represented by a two-letter code, such as J01 for antibacterials for systemic use, which excludes antimycobacterials classified under J04. The third level identifies the pharmacological subgroup with a three-letter code, for example, J01A for tetracyclines or J01C for beta-lactam antibacterials, penicillins. The fourth level denotes the chemical subgroup using a four-letter code, such as J01AA for tetracyclines or J01CA for penicillins with extended spectrum. Finally, the fifth level assigns a specific ATC code to individual active substances or combinations, indicated by a seven-character alphanumeric code like J01AA02 for doxycycline or J01CR02 for amoxicillin and beta-lactamase inhibitor.^[5][6] The ATC system is maintained and updated annually by the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC) in Oslo, Norway, under the oversight of the WHO International Working Group for Drug Statistics Methodology, which convenes twice yearly to review and approve revisions. These updates incorporate new substances, reclassifications based on emerging pharmacological data, and adjustments to reflect changes in clinical practice, with the revised ATC index and Defined Daily Doses (DDDs) published each January for implementation throughout the year. For instance, the 2025 guidelines introduced refinements to classification principles for certain combination products across various groups, ensuring alignment with therapeutic advancements.^[7][4] Fixed-dose combinations within the ATC system, particularly relevant to J01, are denoted at the fifth level using specific numeric suffixes such as "20" or "30" when multiple active ingredients belong to the same fourth-level subgroup. For example, in J01E (sulfonamides and trimethoprim), combinations of two or more sulfonamides are assigned codes like J01EB20, based on the half-life of the longest-acting component. In J01CR (combinations of penicillins, including beta-lactamase inhibitors), however, combinations of two or more penicillins typically use the "50" suffix (e.g., J01CR50), while other J01 subgroups may employ "20" or "30" for analogous fixed combinations to maintain hierarchical consistency. This notation facilitates precise tracking of polypharmacy in antibacterial use without duplicating single-substance codes.^[6][4] A parallel classification exists for veterinary medicines under the ATCvet system, prefixed with "Q" to distinguish animal-use formulations; thus, antibacterials for systemic use in animals are grouped as QJ01, mirroring the structure of human J01 but with variations in approved substances due to species-specific pharmacokinetics, regulatory approvals, and restricted use of certain agents like chloramphenicol in food-producing animals. These differences ensure that veterinary classifications account for unique therapeutic needs while aligning with human ATC principles for cross-sector antimicrobial surveillance.^[6]

J01A Tetracyclines

J01AA Tetracyclines

Tetracyclines classified under J01AA are a group of broad-spectrum bacteriostatic antibiotics that inhibit bacterial protein synthesis by reversibly binding to the 30S ribosomal subunit, preventing the association of aminoacyl-tRNA with the ribosome and thereby blocking amino acid addition to nascent peptide chains.^[8] This action results in the suppression of protein synthesis essential for bacterial growth and replication.^[9] They exhibit activity against a wide range of Gram-positive and Gram-negative bacteria, as well as atypical pathogens such as Chlamydia, Mycoplasma, and Rickettsia, but demonstrate limited efficacy against Pseudomonas species due to inherent resistance mechanisms in these organisms.^[8][9] Key agents in this subclass include doxycycline (J01AA02), a lipophilic tetracycline with a prolonged half-life of approximately 16-22 hours, enabling once- or twice-daily dosing and good tissue penetration.^[10] Minocycline (J01AA08) is notable for its enhanced ability to cross the blood-brain barrier, achieving cerebrospinal fluid concentrations up to 45% of plasma levels, which supports its use in central nervous system infections.^[11] Tigecycline (J01AA12), a glycylcycline derivative, was developed to overcome multidrug resistance (MDR) by binding more tightly to the ribosome and evading common efflux pumps, providing coverage against MDR Gram-negative bacteria, anaerobes, and some Gram-positives.^[12] More recent additions include omadacycline (J01AA15), approved in 2018 as an aminomethylcycline with both intravenous and oral formulations, indicated for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia due to its favorable pharmacokinetics and activity against resistant strains.^[13] Eravacycline (J01AA13), also approved in 2018, is a fully synthetic fluorocycline designed for intravenous use in complicated intra-abdominal infections, offering potency against MDR Enterobacteriaceae and anaerobes through enhanced ribosomal binding.^[14] Resistance to tetracyclines primarily arises from energy-dependent efflux pumps encoded by tet genes, such as tet(A) and tet(B), which actively export the antibiotic from bacterial cells, reducing intracellular concentrations.^[15] Ribosomal protection proteins and enzymatic inactivation also contribute, but efflux remains the dominant mechanism in Gram-negative bacteria. As of 2025, surveillance data indicate rising tetracycline resistance rates in Enterobacteriaceae, with tet gene prevalence exceeding 50% in some clinical isolates from hospital settings, driven by selective pressure from widespread use and horizontal gene transfer via plasmids.^[16][17] Clinically, J01AA tetracyclines are employed for infections such as acne vulgaris (via anti-inflammatory and antibacterial effects on Propionibacterium acnes), Lyme disease (early-stage erythema migrans caused by Borrelia burgdorferi), and rickettsial diseases like Rocky Mountain spotted fever.^[18] They are contraindicated in pregnancy due to risks of fetal bone growth inhibition and tooth discoloration, as tetracyclines readily cross the placenta and bind to calcium in developing fetal tissues.^[19]

QJ01AA Tetracyclines (Veterinary)

QJ01AA encompasses tetracyclines formulated specifically for veterinary use in systemic antibacterial treatment of animals, including livestock, poultry, and aquaculture species. These agents inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit, offering broad-spectrum activity against gram-positive and gram-negative bacteria, as well as atypical pathogens. Key drugs under this code include chlortetracycline combinations (QJ01AA53), which are primarily employed for respiratory infections in cattle, and oxytetracycline combinations (QJ01AA56), which see widespread application in various livestock for treating bacterial enteritis, pneumonia, and other infections.^[20][21][22] Veterinary tetracyclines feature adaptations such as long-acting injectable formulations, which sustain therapeutic plasma levels for 3-5 days after a single dose, facilitating easier administration in large farm animals like cattle and swine. These injectables, often oil-based, are designed for intramuscular use to achieve prolonged efficacy against respiratory and systemic infections. The antimicrobial spectrum mirrors that of human tetracyclines but is tailored to address zoonotic pathogens prevalent in veterinary contexts, such as Brucella species, which cause brucellosis in ruminants and pose transmission risks to humans.^{[23][24][25][26]} In cattle, chlortetracycline combinations are used for the control of bacterial pneumonia associated with shipping fever complex, caused by Pasteurella spp., with feed additives providing 350 mg per head daily for up to 28 days to maintain weight gains during outbreaks. For poultry, oxytetracycline combinations treat mycoplasma infections, including chronic respiratory disease from Mycoplasma gallisepticum and infectious synovitis from Mycoplasma synoviae, administered via water at 200-400 mg/kg for 7-14 days. These applications emphasize prevention and early intervention in herd health management.^{[27][28][29][30]} Regulatory frameworks in the EU and USA mandate strict withdrawal periods for tetracyclines to minimize residues in food products, with EU guidelines under Regulation (EU) 37/2010 setting maximum residue limits (MRLs) at 100 µg/kg for muscle and 200 µg/kg for liver in cattle, requiring 28-35 day meat withdrawal for oxytetracycline injectables. In the USA, FDA tolerances align similarly, with 7-day withdrawal for chlortetracycline in beef cattle feed to prevent violative residues in milk or meat. As of 2025, updates to EU and global monitoring programs, including EFSA's baseline surveys and WHO's GLASS report, emphasize enhanced surveillance of tetracycline resistance in aquaculture, where overuse has driven prevalence rates up to 20-30% in bacterial isolates from farmed fish.^{[31][32][33][34][35]}

J01B Amphenicols

J01BA Amphenicols

Amphenicols in the ATC code J01BA are a class of broad-spectrum bacteriostatic antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking peptidyl transferase activity.^[36][37] This mechanism disrupts peptide bond formation, affecting a wide range of Gram-positive, Gram-negative, and anaerobic bacteria, as well as some intracellular pathogens like Rickettsia and Chlamydia.^[37][38] The primary drug in this subclass is chloramphenicol (J01BA01), available in intravenous and oral formulations, which is reserved for treating severe infections such as bacterial meningitis and typhoid fever when safer alternatives are unavailable or ineffective.^[36][37] Thiamphenicol (J01BA02), a semisynthetic derivative, shares a similar spectrum but is noted for its reduced risk of severe bone marrow toxicity compared to chloramphenicol. Other agents include thiamphenicol acetylcysteinate glycinate for inhalation (J01BA52).^[39][40][41] Due to significant adverse effects, amphenicols are used cautiously and primarily for life-threatening infections. Chloramphenicol carries a risk of idiosyncratic aplastic anemia, estimated at approximately 1 in 25,000 to 40,000 exposures, which can be fatal and requires regular monitoring of complete blood counts.^[37][42] In neonates, particularly preterm infants, it can cause gray baby syndrome, characterized by abdominal distension, cyanosis, hypotension, and potential cardiovascular collapse due to immature hepatic glucuronidation, necessitating plasma level monitoring (target 15-25 mg/L) and avoidance in this population unless essential.^[37][36] Their use has declined over recent decades, largely supplanted by less toxic alternatives like third-generation cephalosporins for meningitis, though they remain relevant in resource-limited settings for severe cases.^[43] Resistance to amphenicols is uncommon but mediated primarily by chloramphenicol acetyltransferase enzymes encoded by cat genes, which inactivate the drug through acetylation.^[38][44]

QJ01BA Amphenicols (Veterinary)

QJ01BA encompasses amphenicols used in veterinary medicine, primarily florfenicol (QJ01BA90), a broad-spectrum bacteriostatic antibiotic effective against gram-positive and gram-negative bacteria, as well as some anaerobes.^[45] This class also includes amphenicol combinations (QJ01BA99), which may incorporate florfenicol or thiamphenicol with other agents to enhance efficacy against mixed infections in animals.^[46] Florfenicol is the predominant agent in this subgroup due to its widespread approval for systemic use in livestock and aquaculture.^[47] Florfenicol offers significant advantages over chloramphenicol, the prototypical amphenicol restricted in veterinary applications, primarily because its chemical modification—replacing the nitro group with a methylsulfonyl group—eliminates the risk of inducing aplastic anemia in treated animals or residue consumers.^[48] Additionally, florfenicol demonstrates superior in vitro activity against many bovine pathogens and improved pharmacokinetics in ruminants, achieving higher plasma concentrations and better tissue penetration compared to chloramphenicol.^[47] These properties make it suitable for food-producing animals, where human safety from residues is paramount.^[49] In cattle, florfenicol is indicated for treating bovine respiratory disease (BRD), particularly infections caused by Mannheimia haemolytica, a key etiologic agent in shipping fever and pneumonic pasteurellosis.^[50] Administered via intramuscular or subcutaneous injection, it rapidly reduces clinical signs and bacterial load in affected herds.^[51] To ensure food safety, 2025 regulatory guidelines, such as those from the U.S. FDA and EU EMA, enforce strict withdrawal periods—typically 28–44 days for slaughter in cattle—and maximum residue limits that vary by jurisdiction. In the U.S. (FDA), the tolerance for the marker residue florfenicol amine is 3.7 mg/kg in muscle (with no tolerance established for milk, as use is prohibited in lactating dairy cattle 20 months or older). In the EU (EMA), the MRL for the sum of florfenicol and its metabolites (measured as florfenicol-amine) is 200 μg/kg in muscle, 3000 μg/kg in liver, and 300 μg/kg in kidney (with no MRL for milk in cattle, as use is not permitted in animals producing milk for human consumption).^[52][53] Antimicrobial resistance to florfenicol is an emerging concern, particularly in aquaculture settings where overuse in finfish farming has led to resistant strains of Vibrio and Photobacterium species.^[54] Monitoring programs, including the EU's European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) and national initiatives like the U.S. National Antimicrobial Resistance Monitoring System (NARMS), track resistance trends and promote prudent use to mitigate spread.^[55][56] These efforts emphasize integrated surveillance to preserve florfenicol's utility in veterinary practice.^[57]

J01C Beta-lactam antibacterials, penicillins

J01CA Penicillins with extended spectrum

Penicillins with extended spectrum, classified under ATC code J01CA, encompass beta-lactam antibiotics that demonstrate enhanced antibacterial activity against Gram-negative rods compared to earlier penicillins, such as those targeting Enterobacteriaceae, while retaining efficacy against many Gram-positive organisms.^[58] These agents are primarily used in human medicine for systemic infections requiring broader coverage beyond narrow-spectrum penicillins.^[58] The mechanism of action for J01CA penicillins involves the beta-lactam ring, which covalently binds to penicillin-binding proteins (PBPs) essential for bacterial cell wall synthesis, thereby inhibiting peptidoglycan cross-linking and leading to cell lysis, particularly in actively dividing bacteria.^[59] This extended spectrum arises from structural modifications, like amino substitutions on the penicillin core, that improve penetration and stability against Gram-negative outer membranes, allowing activity against pathogens such as Escherichia coli and Klebsiella species.^[60] Representative drugs in this category include ampicillin (J01CA01), the first-generation extended-spectrum penicillin introduced in the 1960s, which is effective against susceptible Gram-positive cocci and some Gram-negative bacilli, often administered intravenously for serious infections like meningitis or sepsis.^[61] Amoxicillin (J01CA04), an oral analog of ampicillin with superior gastrointestinal absorption, is commonly prescribed for community-acquired infections such as urinary tract infections (UTIs) and respiratory tract infections due to Streptococcus pneumoniae or Haemophilus influenzae. Piperacillin (J01CA12), a ureidopenicillin with broader coverage including Pseudomonas aeruginosa, is reserved for severe hospital-acquired infections and is typically given intravenously in high doses for polymicrobial conditions.^[62] Combinations within this spectrum, such as ampicillin with sulbactam (classified under J01CR01), pair the penicillin with a beta-lactamase inhibitor to restore activity against enzyme-producing strains, enhancing utility in mixed infections where resistance is suspected.^[63] Resistance to J01CA penicillins primarily stems from beta-lactamase enzymes produced by bacteria, which hydrolyze the beta-lactam ring; extended-spectrum beta-lactamases (ESBLs) pose a particular challenge by conferring resistance to these agents and other beta-lactams.^[64] As of 2025, global surveillance data indicate a rising prevalence of ESBL-producing Enterobacterales, with CDC reports highlighting increased infections in healthcare and community settings, complicating treatment and necessitating alternative therapies like carbapenems.^[65] WHO assessments from the same year underscore this trend as a critical threat, with ESBL rates exceeding 50% in some regions for common pathogens like E. coli.^[66] Therapeutic applications of J01CA penicillins include management of intra-abdominal infections, where agents like piperacillin provide coverage for enteric Gram-negative and anaerobic bacteria in conditions such as appendicitis or peritonitis.^[67] They are also employed for endocarditis prophylaxis in at-risk patients undergoing dental or invasive procedures, with a single dose of amoxicillin or ampicillin recommended to prevent viridans group streptococcal infection.^[68]

J01CE Beta-lactamase-sensitive penicillins

Beta-lactamase-sensitive penicillins, classified under ATC code J01CE, are natural penicillins that are susceptible to hydrolysis by beta-lactamase enzymes produced by certain bacteria. These antibiotics exert their bactericidal effect by binding to penicillin-binding proteins, such as DD-transpeptidase, thereby inhibiting the cross-linking of peptidoglycan in the bacterial cell wall, which leads to osmotic lysis of susceptible Gram-positive organisms. Unlike beta-lactamase-resistant counterparts, their beta-lactam ring is readily cleaved by beta-lactamases, rendering them ineffective against beta-lactamase-producing strains.^[60][69] The primary agents in this group include benzylpenicillin (J01CE01), administered intravenously for severe infections such as streptococcal and pneumococcal diseases, including meningitis and endocarditis. Phenoxymethylpenicillin (J01CE02), an oral formulation, is commonly used for milder infections like streptococcal pharyngitis and scarlet fever. Other examples include propicillin (J01CE03) and clometocillin (J01CE04), though less frequently prescribed.^[70][60][71] Special formulations enhance duration of action through depot injections: procaine benzylpenicillin (J01CE08) provides intermediate release for intramuscular use in conditions like early syphilis, while benzathine benzylpenicillin (J01CE09) offers prolonged release, up to several weeks, for prophylaxis against rheumatic fever and treatment of syphilis and diphtheria. These salts reduce dosing frequency but maintain the same sensitivity to beta-lactamases.^[72][73][70] Therapeutically, J01CE agents are indicated for infections caused by non-beta-lactamase-producing Gram-positive bacteria, including Streptococcus pyogenes, Streptococcus pneumoniae, and Treponema pallidum in syphilis, as well as Corynebacterium diphtheriae in diphtheria. They are limited to susceptible strains due to widespread resistance, particularly penicillinase-mediated in Staphylococcus aureus, where beta-lactamase hydrolyzes the antibiotic, necessitating alternatives for such infections. Over 90% of Staphylococcus aureus isolates produce beta-lactamase, contributing to high resistance rates and limiting the use of penicillin for staphylococcal infections.^{[60][69][72][74]} Hypersensitivity reactions pose a significant risk; approximately 10% of patients report a penicillin allergy, though confirmed IgE-mediated immediate allergies occur in less than 1% of cases, manifesting as anaphylaxis, urticaria, or angioedema shortly after administration. Cross-reactivity with other beta-lactams is possible in confirmed cases, requiring careful history and testing before use.^[75]

J01CF Beta-lactamase-resistant penicillins

Beta-lactamase-resistant penicillins, also referred to as anti-staphylococcal penicillins, constitute a subclass within the ATC code J01CF, specifically targeting infections caused by beta-lactamase-producing strains of Staphylococcus aureus. These agents were developed to overcome the enzymatic hydrolysis of the beta-lactam ring by staphylococcal penicillinase, a narrow-spectrum beta-lactamase prevalent in staphylococci. Unlike standard penicillins, which are rapidly inactivated by this enzyme, beta-lactamase-resistant variants maintain their bactericidal activity by binding to penicillin-binding proteins (PBPs) and inhibiting peptidoglycan cross-linking in the bacterial cell wall.^[76][77] The primary mechanism of resistance to beta-lactamase in these penicillins involves steric hindrance, where bulky substituents—such as isoxazole or aminophenyl groups at the 6-position of the beta-lactam ring—create a spatial clash with the narrow active site of class A beta-lactamases like staphylococcal penicillinase. This prevents effective acylation and hydrolysis of the beta-lactam ring, allowing the antibiotic to persist and exert its effect against penicillinase-producing staphylococci. Key examples include flucloxacillin (J01CF05), which is administered orally or intravenously for treating skin and soft tissue infections, and methicillin (J01CF03), a historical agent introduced in the early 1960s that served as a precursor to the recognition of methicillin-resistant S. aureus (MRSA) due to rapid emergence of resistance shortly after its development.^[78][79][80] These penicillins are particularly indicated for serious Gram-positive infections such as osteomyelitis and septic arthritis, where methicillin-susceptible S. aureus (MSSA) is the predominant pathogen, often requiring prolonged intravenous therapy followed by oral switch. Flucloxacillin, for instance, achieves adequate bone and soft tissue concentrations suitable for staphylococcal osteomyelitis management. However, they offer poor coverage against Gram-negative bacteria due to limited permeability across their outer membranes and lack of activity against Gram-negative beta-lactamases.^[81][60][82] Resistance to beta-lactamase-resistant penicillins in staphylococci primarily manifests as MRSA, mediated by the mecA gene, which encodes an altered PBP2a with low affinity for beta-lactams, enabling bypass of normal PBP inhibition and continued cell wall synthesis. This genetic element, carried on the staphylococcal cassette chromosome mec (SCCmec), confers high-level resistance and has become a global concern. In 2025, MRSA remains a significant pathogen in hospital settings, with hospital-onset bacteremia rates showing a 16% decline from 2022 levels but still contributing to substantial morbidity, often exceeding 30% of S. aureus isolates in high-burden facilities.^[83][84][85] Adverse effects of these agents include acute interstitial nephritis, an immune-mediated hypersensitivity reaction characterized by renal inflammation, eosinophilia, and potential progression to acute kidney injury, particularly associated with methicillin and flucloxacillin use. This complication typically occurs 7-10 days after initiation and may require discontinuation of the drug and supportive care, with higher risks during prolonged therapy.^[86][87][88]

J01CG Beta-lactamase inhibitors

Beta-lactamase inhibitors are pharmacological agents classified under ATC code J01CG within the Anatomical Therapeutic Chemical (ATC) classification system, designed to counteract bacterial enzymes that degrade beta-lactam antibiotics. These inhibitors lack significant standalone antibacterial activity but are essential adjuncts that protect partner beta-lactam drugs from hydrolysis, thereby restoring or extending their therapeutic spectrum against resistant pathogens.^[77] The primary mechanism of action for most J01CG agents involves suicide inhibition of class A, C, and some class D serine beta-lactamases. These inhibitors structurally mimic beta-lactam substrates, binding covalently to the serine residue in the enzyme's active site to form an initial acyl-enzyme intermediate. This complex undergoes rearrangement, leading to irreversible inactivation through ring opening and fragmentation, preventing the enzyme from hydrolyzing the accompanying antibiotic. For instance, clavulanic acid exemplifies this process by forming a trans-enamine intermediate that stabilizes the inactivated state.^[89][77] Key representatives in this subclass include sulbactam (J01CG01) and tazobactam (J01CG02). Other inhibitors like clavulanic acid (used in combinations such as J01CR02), avibactam (J01DD52 with ceftazidime), and vaborbactam (J01DH52 with meropenem) extend this class's scope. Sulbactam, a semisynthetic penicillanic acid sulfone, is commonly paired with ampicillin to treat infections such as intra-abdominal and skin/soft tissue infections caused by beta-lactamase-producing Enterobacteriaceae and anaerobes; its defined daily dose (DDD) is 1 g parenterally, based on a 1:2 ratio with ampicillin. Tazobactam, a triazolyl penicillanic acid sulfone, enhances piperacillin's efficacy against similar pathogens, including Pseudomonas aeruginosa, and is indicated for complicated urinary tract infections and pneumonia; no separate DDD is assigned due to its exclusive use in fixed combinations. Clavulanic acid, derived from Streptomyces clavuligerus, is frequently combined with amoxicillin for respiratory tract and skin infections. Avibactam, a novel diazabicyclooctane, inhibits a broader range of serine beta-lactamases, including KPC carbapenemases, and is used with ceftazidime for multidrug-resistant gram-negative infections. Vaborbactam, another diazabicyclooctane, targets KPC enzymes and pairs with meropenem for complicated urinary tract and intra-abdominal infections.^[77][90][91] By blocking beta-lactamase production, these inhibitors extend the antibacterial spectrum of beta-lactams to include resistant strains such as extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and some AmpC producers, enabling effective treatment of polymicrobial or mixed infections in hospitalized patients. They are particularly valuable in empirical therapy for severe infections where resistance prevalence is high, improving clinical outcomes without promoting further resistance when used judiciously. However, they exhibit no intrinsic activity against non-beta-lactamase-mediated resistance mechanisms.^[89][77] Limitations of J01CG inhibitors include their ineffectiveness against metallo-beta-lactamases (class B), which rely on zinc-dependent hydrolysis and do not form covalent intermediates with these agents. Additionally, some inhibitors like clavulanic acid can induce expression of beta-lactamases in certain bacteria, potentially reducing efficacy. As of 2025, ongoing developments address these gaps with novel inhibitors such as relebactam (classified under J01DH), which enhances carbapenem activity against KPC-producing pathogens and has been approved for complicated infections.^[89][77][92]

J01CR Combinations of penicillins, including beta-lactamase inhibitors

The J01CR subgroup encompasses fixed-dose combinations of penicillins with beta-lactamase inhibitors, designed to counteract bacterial enzymes that degrade the beta-lactam ring, thereby expanding the antibacterial spectrum against resistant pathogens. These formulations pair a penicillin antibiotic, such as amoxicillin or piperacillin, with an inhibitor like clavulanic acid, sulbactam, or tazobactam, enabling treatment of infections caused by beta-lactamase-producing strains of Gram-positive, Gram-negative, and anaerobic bacteria. The synergy arises because the inhibitor binds irreversibly to serine beta-lactamases, preventing hydrolysis of the penicillin while the penicillin itself targets cell wall synthesis.^[93][77] Prominent examples include amoxicillin-clavulanate (J01CR02), an oral agent primarily used for community-acquired infections such as acute otitis media, sinusitis, lower respiratory tract infections, skin and soft tissue infections, and uncomplicated urinary tract infections, with a typical dosing ratio of 7:1 (amoxicillin:clavulanate). Another key product is piperacillin-tazobactam (J01CR05), administered intravenously for severe hospital settings, including hospital-acquired pneumonia, complicated intra-abdominal infections, and sepsis, often at an 8:1 ratio (piperacillin:tazobactam). These combinations are also indicated for complicated urinary tract infections and diabetic foot infections, where polymicrobial involvement necessitates broad coverage. Dosing ratios, such as 2:1 for ampicillin-sulbactam (J01CR01), are standardized to balance efficacy and inhibitor saturation without excess toxicity.^[93][94][95] As of 2025, updated protocols emphasize extended infusions for piperacillin-tazobactam, typically over 3-4 hours, to achieve optimal pharmacodynamic targets (e.g., 50-70% free time above MIC) in critically ill patients with augmented renal clearance or severe infections, improving clinical cure rates and reducing mortality compared to standard 30-minute boluses. Resistance challenges include AmpC beta-lactamases, which hydrolyze penicillins and are poorly inhibited by these agents, and certain extended-spectrum beta-lactamases (ESBLs) that may evade inhibition in high-expression strains, necessitating susceptibility testing. Common adverse effects involve gastrointestinal disturbances, with diarrhea occurring in up to 20% of cases, attributed to clavulanate's disruption of gut microbiota; this risk is lower with sulbactam or tazobactam pairings.^{[96][97][98][93]} The J01CR50 subcategory covers pure combinations of two or more penicillins without beta-lactamase inhibitors, such as ampicillin with dicloxacillin or oxacillin, used rarely for targeted polymicrobial infections like endocarditis or osteomyelitis where synergistic penicillin effects are desired without added inhibitor burden. These lack the extended spectrum against beta-lactamase producers, limiting their role compared to inhibitor-inclusive formulations.^[99][100]

J01D Other beta-lactam antibacterials

J01DB First-generation cephalosporins

First-generation cephalosporins are a subclass of beta-lactam antibiotics classified under ATC code J01DB, characterized by their primary activity against Gram-positive bacteria. These agents inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), which are essential enzymes involved in the final stages of peptidoglycan cross-linking during cell wall formation, leading to bacterial cell lysis and death.^[101] This mechanism is analogous to that of penicillins, but first-generation cephalosporins exhibit a lower cross-reactivity rate with penicillin allergies, estimated at approximately 2% in patients with confirmed IgE-mediated penicillin hypersensitivity.^[102] The antimicrobial spectrum of first-generation cephalosporins is predominantly effective against Gram-positive cocci, including streptococci such as Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus, as well as some Gram-negative organisms like Escherichia coli and Proteus mirabilis.^[101] They demonstrate limited activity against anaerobes and more resistant Gram-negative pathogens, such as Pseudomonas aeruginosa, which distinguishes them from later generations that expand coverage to include broader Gram-negative and anaerobic spectra. Available formulations include both oral options, like cefalexin, and intravenous preparations, such as cefazolin, allowing flexibility in administration routes.^[103] Key examples within this subclass include cefalexin (J01DB01), an oral agent commonly used for community-acquired infections, and cefazolin (J01DB04), a parenteral drug recognized on the WHO Model List of Essential Medicines for its role in preventing surgical infections. These drugs typically have short serum half-lives—around 1-2 hours for cefalexin and approximately 2 hours for cefazolin—necessitating frequent dosing intervals of every 6-8 hours to maintain therapeutic levels.^[104] Clinically, first-generation cephalosporins are indicated for perioperative prophylaxis in surgical procedures to reduce the risk of postoperative infections, treatment of uncomplicated urinary tract infections, and management of skin and soft tissue infections caused by susceptible Gram-positive pathogens.^[101] For instance, cefazolin is a standard choice for surgical prophylaxis due to its efficacy against common skin flora, while cefalexin is frequently prescribed for outpatient treatment of mild respiratory or skin infections.^[102] Resistance to first-generation cephalosporins primarily arises from bacterial production of beta-lactamase enzymes, which hydrolyze the beta-lactam ring and render the drugs inactive, particularly limiting their utility against beta-lactamase-producing Gram-negative bacteria.^[101] AmpC beta-lactamases, often chromosomally mediated in Enterobacteriaceae, are especially effective against these agents, contributing to reduced Gram-negative efficacy in clinical settings.^[105]

J01DC Second-generation cephalosporins

Second-generation cephalosporins, classified under ATC code J01DC, represent an advancement over first-generation agents by offering improved activity against certain Gram-negative bacteria while retaining moderate efficacy against Gram-positive organisms. These antibiotics exhibit enhanced coverage against pathogens such as Haemophilus influenzae and Moraxella catarrhalis, as well as variable activity against anaerobes, particularly in the case of cephamycins which target Bacteroides fragilis. Unlike first-generation cephalosporins, which are primarily effective against Gram-positive cocci, second-generation agents address some limitations in Gram-negative spectrum through structural modifications that confer greater beta-lactamase stability.^[101][106] Within J01DC, two main subtypes exist: true second-generation cephalosporins, such as cefuroxime (J01DC02) and cefprozil, and cephamycins, including cefoxitin (J01DC01) and cefotetan. Cephamycins are distinguished by a 7-alpha-methoxy group in their structure, which provides resistance to extended-spectrum beta-lactamases and superior anaerobic coverage compared to non-cephamycin second-generation cephalosporins, though they generally show reduced activity against staphylococci. Cefuroxime, available in both oral and intravenous formulations, is commonly used for community-acquired respiratory infections, including bronchitis, sinusitis, and otitis media, due to its efficacy against beta-lactamase-producing strains of H. influenzae and M. catarrhalis. Cefoxitin, administered intravenously, is particularly indicated for surgical prophylaxis in intra-abdominal and gynecologic procedures, leveraging its broad coverage of mixed aerobic and anaerobic flora in gastrointestinal infections.^{[102][107][108][109]} Clinical applications of J01DC agents include treatment of acute otitis media in children, where oral formulations like cefuroxime axetil are preferred for their activity against common respiratory pathogens, and perioperative prophylaxis for intra-abdominal surgery to prevent polymicrobial infections. As of 2025, M. catarrhalis isolates remain largely susceptible to parenteral second-generation cephalosporins such as cefuroxime, with sensitivity rates exceeding 90% in most regions, though oral agents like cefaclor and cefprozil show higher resistance in some high-risk populations. Adverse effects mirror those of first-generation cephalosporins, including hypersensitivity reactions and gastrointestinal upset, but second-generation agents carry an elevated risk of Clostridioides difficile infection due to their broader spectrum disrupting gut microbiota, with odds ratios of 2-3 times higher compared to narrower antibiotics.^{[110][111][112][113][114]}

J01DD Third-generation cephalosporins

Third-generation cephalosporins represent a class of beta-lactam antibiotics characterized by enhanced activity against Gram-negative bacteria compared to earlier generations, while retaining variable efficacy against some Gram-positive organisms. These agents feature a modified cephem nucleus that improves penetration into bacterial cells and resistance to beta-lactamases produced by Enterobacteriaceae, making them suitable for treating serious infections caused by these pathogens. However, their spectrum is generally poor against Gram-positive bacteria such as Staphylococcus aureus and Enterococcus species, and most lack reliable activity against anaerobes or atypical pathogens.^[115] The antimicrobial spectrum of third-generation cephalosporins is particularly excellent against Enterobacteriaceae, including Escherichia coli, Klebsiella pneumoniae, and Proteus species, due to their stability against common chromosomal and plasmid-mediated beta-lactamases. Ceftazidime stands out for its additional activity against Pseudomonas aeruginosa, addressing a key limitation of other agents in this class. This targeted Gram-negative focus positions them as frontline options for hospital-acquired infections, though they offer only modest coverage of Gram-positive cocci like Streptococcus pneumoniae.^[115][116] Key drugs in this subclass include ceftriaxone (J01DD04), which is administered once daily and is a preferred agent for bacterial meningitis due to its favorable pharmacokinetics and cerebrospinal fluid penetration. Ceftazidime (J01DD02) is specifically valued for pseudomonal infections, such as in neutropenic patients or ventilator-associated pneumonia. These agents are commonly used for sepsis, intra-abdominal infections, and uncomplicated gonorrhea, often in combination with other antibiotics like azithromycin for the latter. However, ceftriaxone carries a risk of precipitating neonatal jaundice when used in newborns due to competition with bilirubin for albumin binding sites, necessitating caution in pediatric populations.^{[115][116][117]} Combinations of third-generation cephalosporins with beta-lactamase inhibitors expand their utility against resistant strains. For instance, ceftazidime with avibactam (J01DD52) restores activity against carbapenem-resistant Enterobacteriaceae (CRE) by inhibiting class A, C, and some class D beta-lactamases, enabling treatment of complicated urinary tract infections and intra-abdominal infections caused by multidrug-resistant Gram-negative bacteria. This combination has become essential in settings with high CRE prevalence, guided by susceptibility testing.^[118][115] Resistance to third-generation cephalosporins is primarily driven by extended-spectrum beta-lactamases (ESBLs) and carbapenemases in Enterobacteriaceae, with mechanisms including enzymatic hydrolysis and porin mutations reducing drug influx. The WHO Global Antibiotic Resistance Surveillance Report 2025 indicates that resistance to these agents in bloodstream infections exceeds 20% across Asia, with regional estimates for South-East Asia reaching approximately 60% for E. coli and K. pneumoniae in urinary tract infections, underscoring the need for stewardship programs and alternative therapies in endemic areas.^[35][115]

J01DE Fourth-generation cephalosporins

Fourth-generation cephalosporins represent a class of broad-spectrum beta-lactam antibiotics characterized by enhanced stability against many beta-lactamases produced by gram-negative bacteria, allowing effective treatment of infections caused by resistant pathogens.^[101] These agents maintain activity against a wide range of gram-positive organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and Streptococcus pneumoniae, while providing robust coverage of gram-negative bacteria such as Enterobacteriaceae, Neisseria spp., Haemophilus influenzae, and Pseudomonas aeruginosa.^[101] Unlike third-generation cephalosporins, which prioritize gram-negative activity, fourth-generation variants offer a more balanced profile with improved penetration into bacterial outer membranes due to their zwitterionic structure.^[119] The primary drugs in this subclass include cefepime (ATC code J01DE01) and cefpirome (ATC code J01DE02). Cefepime is widely used for empiric therapy in hospitalized patients with febrile neutropenia, pneumonia, complicated urinary tract infections, skin and soft tissue infections, and intra-abdominal infections, often in combination with other agents like metronidazole for polymicrobial cases.^[120] Cefpirome, available primarily outside the United States, shares a similar broad-spectrum profile and is indicated for systemic infections involving gram-positive and gram-negative pathogens, including those with beta-lactamase production.^[121] Both drugs are administered intravenously and are particularly valuable in hospital settings for managing severe or multidrug-resistant infections.^[122] Clinical applications focus on hospital-acquired infections, where these cephalosporins help address pathogens like P. aeruginosa and beta-lactamase-producing Enterobacteriaceae.^[101] However, high doses, especially in patients with renal impairment, carry a risk of neurotoxicity, manifesting as encephalopathy, seizures, or myoclonus.^[120] An emerging combination, cefepime-taniborbactam (ATC code J01DE51), pairs cefepime with a novel beta-lactamase inhibitor to target multidrug-resistant gram-negative infections, including those caused by metallo-beta-lactamase producers, and is under evaluation for complicated urinary tract infections in 2025.^[123] Resistance to fourth-generation cephalosporins remains relatively limited compared to earlier generations, owing to their zwitterionic configuration, which facilitates rapid diffusion through porin channels and confers stability against inducible chromosomal beta-lactamases.^[119] Nonetheless, mechanisms such as extended-spectrum beta-lactamase production or alterations in penicillin-binding proteins can confer resistance in certain strains.^[101]

J01DF Monobactams

Monobactams represent a class of narrow-spectrum beta-lactam antibiotics specifically active against aerobic Gram-negative bacteria, distinguished by their unique chemical architecture within the broader category of other beta-lactam antibacterials under ATC code J01DF. Unlike bicyclic beta-lactams such as penicillins or cephalosporins, monobactams feature a monocyclic beta-lactam ring, which confers resistance to hydrolysis by many beta-lactamases and minimizes immunological cross-reactivity. This structural simplicity allows their use in patients with hypersensitivity to other beta-lactams, as the absence of shared side chains with penicillins results in no significant cross-allergy risk.^[124][125] The mechanism of action for monobactams involves high-affinity binding to penicillin-binding protein 3 (PBP3) on the inner membrane of Gram-negative bacteria, inhibiting the transpeptidation step in peptidoglycan cross-linking during cell wall synthesis. This binding disrupts septum formation, leading to bactericidal effects through autolytic enzyme activation and subsequent cell lysis, with activity confined to aerobic Gram-negative pathogens due to poor penetration into Gram-positive cell walls and lack of efficacy against anaerobes. Monobactams are not hydrolyzed by metallo-beta-lactamases (MBLs), preserving their utility against certain resistant strains.^{[126][127][128]} The primary monobactam in clinical use is aztreonam (ATC code J01DF01), available in intravenous, intramuscular, and inhaled formulations; the inhaled version, such as lysine salt, is indicated for management of Pseudomonas aeruginosa in cystic fibrosis patients aged 7 years and older, suppressing bacterial burden in the lungs. Carumonam (ATC code J01DF02), an N-sulfonated monobactam, offers similar Gram-negative coverage but has limited availability and is primarily used in select regions for parenteral treatment of urinary tract and respiratory infections. A notable combination is aztreonam with avibactam (ATC code J01DF51, branded as Emblaveo), where avibactam inhibits serine-based beta-lactamases, restoring aztreonam's efficacy against MBL-producing Enterobacterales and other multidrug-resistant Gram-negatives in complicated intra-abdominal, urinary tract, or hospital-acquired pneumonia infections.^{[129][130][131][132][133][134]} Monobactams like aztreonam are particularly valuable for treating aerobic Gram-negative infections, including those caused by Pseudomonas aeruginosa, Escherichia coli, and Klebsiella species, in settings such as sepsis, pneumonia, or intra-abdominal infections, especially when penicillin allergy precludes broader beta-lactam options. Their safety profile supports use in penicillin-allergic patients without cross-reactivity concerns, and aztreonam is classified as pregnancy category B, indicating no evidence of fetal risk in animal studies and suitability when clinically necessary. In contrast to carbapenems, monobactams lack coverage against anaerobes or Gram-positives, emphasizing their role in targeted Gram-negative therapy.^{[135][136][137][138]}

J01DH Carbapenems

Carbapenems are a class of broad-spectrum beta-lactam antibiotics classified under ATC code J01DH, reserved for treating severe infections caused by multidrug-resistant bacteria. They are characterized by their stability against many beta-lactamases produced by Gram-negative bacteria, making them a cornerstone in managing complicated intra-abdominal infections, hospital-acquired pneumonia, and sepsis. The group includes both single agents and combinations designed to enhance efficacy or mitigate metabolism, with defined daily doses (DDDs) established by the WHO Collaborating Centre for Drug Statistics Methodology.^[139] The antibacterial spectrum of carbapenems encompasses most aerobic and anaerobic Gram-positive and Gram-negative bacteria, including extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales and Pseudomonas aeruginosa, but excludes methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecium, and Stenotrophomonas maltophilia. This broad coverage stems from their ability to bind multiple penicillin-binding proteins (PBPs) essential for bacterial cell wall synthesis, leading to cell lysis. Key examples include imipenem combined with cilastatin (J01DH51), which provides renal protection against dehydropeptidase-I (DHP-I) hydrolysis of imipenem, meropenem (J01DH02) favored for central nervous system infections due to better cerebrospinal fluid penetration, and meropenem-vaborbactam (J01DH52), approved in 2017 specifically for carbapenem-resistant Enterobacterales (CRE) infections like complicated urinary tract infections by inhibiting class A and C beta-lactamases. Other agents in this subclass, such as ertapenem (J01DH03) and doripenem (J01DH04), offer similar profiles but with variations in anaerobic activity or dosing for outpatient use.^{[140][141][142][143]} Clinically, carbapenems are indicated for life-threatening infections such as severe sepsis and ESBL-producing bacterial infections, where narrower-spectrum alternatives fail, often administered intravenously in hospital settings. Their mechanism involves acylation of PBPs, disrupting peptidoglycan cross-linking, with inherent resistance to hydrolysis by most serine-based beta-lactamases except metallo-beta-lactamases. However, resistance via carbapenemase enzymes like Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-beta-lactamase (NDM) poses a global threat, driven by plasmid-mediated spread in Gram-negative pathogens. Imipenem carries a higher risk of seizures compared to other carbapenems, with meta-analyses reporting an absolute risk up to 3% in vulnerable patients, necessitating dose adjustments in those with renal impairment or seizure history. As of 2025, antimicrobial stewardship programs emphasize judicious use, de-escalation protocols, and infection control to preserve efficacy against CRE, as outlined in European Centre for Disease Prevention and Control guidelines.^{[140][144][145][146]}

J01DI Other cephalosporins and penems

J01DI includes advanced cephalosporins designed to overcome specific resistance mechanisms in Gram-positive and Gram-negative bacteria, as well as penems that offer broad-spectrum oral activity. These agents are classified here due to their novel structural modifications, distinguishing them from earlier cephalosporin generations. They target multidrug-resistant (MDR) pathogens where standard beta-lactams, including carbapenems, may fail due to hydrolysis by extended-spectrum beta-lactamases (ESBLs) or efflux.^[147] Ceftaroline fosamil (J01DI02), a fifth-generation cephalosporin prodrug, exerts bactericidal activity by binding to multiple penicillin-binding proteins (PBPs), notably PBP2a in methicillin-resistant Staphylococcus aureus (MRSA), disrupting cell wall synthesis. It is indicated for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults, with efficacy demonstrated in phase 3 trials showing non-inferiority to vancomycin plus aztreonam for ABSSSI (success rates ~92%) and ceftriaxone for CABP (~84%). Resistance remains rare, primarily involving PBP mutations or efflux, with MIC90 values ≤1 mg/L for MRSA isolates; however, it lacks activity against ESBL-producing Enterobacterales. Approved by the FDA in 2010, ceftaroline provides an alternative to vancomycin for MRSA infections without the nephrotoxicity risks.^[148] Ceftolozane-tazobactam (J01DI54), a combination of a novel cephalosporin with a beta-lactamase inhibitor, enhances stability against AmpC and some ESBLs while tazobactam protects against hydrolysis by plasmid-mediated enzymes. Ceftolozane binds preferentially to PBP3 in Pseudomonas aeruginosa and Gram-negative PBPs, inhibiting peptidoglycan cross-linking. It is approved for complicated urinary tract infections (cUTI), including pyelonephritis, and complicated intra-abdominal infections (cIAI) in adults with limited treatment options, particularly for MDR P. aeruginosa (success rates 95-97% in trials). Resistance mechanisms include porin loss (e.g., OprD) and upregulated efflux pumps (MexAB-OprM), though rates remain low (<5% in surveillance); it is ineffective against metallo-beta-lactamases or KPC carbapenemases. Introduced in 2014, this agent addresses gaps in treating resistant Gram-negative infections.^[149][150] Cefiderocol (J01DI04), a siderophore-conjugated cephalosporin, exploits bacterial iron acquisition systems for intracellular entry via active transport through outer membrane receptors like CirA and FepA. Once inside, it binds PBPs to inhibit cell wall synthesis, maintaining activity against >90% of MDR Gram-negatives, including carbapenem-resistant Acinetobacter baumannii, P. aeruginosa, and Enterobacterales. Indications include cUTI (including pyelonephritis) and hospital-acquired/ventilator-associated pneumonia (HAP/VAP) in adults with few alternatives, with clinical success rates of 70-80% in resistant cases per APEKS trials. Resistance is infrequent but can arise from mutations in siderophore receptors or beta-lactamases capable of hydrolysis (e.g., PER-type); efflux contributes in A. baumannii, though overall susceptibility exceeds 90% in global surveillance. Approved in 2019, cefiderocol represents a breakthrough for iron-dependent uptake in resistant pathogens.^[151][152] Ceftobiprole medocaril (J01DI01), another fifth-generation cephalosporin prodrug, binds avidly to PBP2a in MRSA and PBP2x/2b in penicillin-nonsusceptible Streptococcus pneumoniae, alongside broad Gram-negative coverage via PBP3. It is indicated for S. aureus bacteremia (SAB), including right-sided endocarditis, ABSSSI, and CABP in adults, as well as CABP in pediatric patients ≥3 months; phase 3 data show 69.8% success for SAB versus 68.7% for daptomycin plus aztreonam. Resistance potential is low due to its dual PBP affinity, but staphylococcal mutations or acquired beta-lactamases (e.g., class D OXA) can confer reduced susceptibility; it is inactive against ESBLs or carbapenemases. FDA approval in 2024 expanded its role in MRSA bacteremia, with EU authorization since 2020 for pneumonia and skin infections.^[153][154] Faropenem (J01DI03), an oral penem, inhibits cell wall synthesis by binding PBPs across Gram-positive, Gram-negative, and anaerobic bacteria, with inherent resistance to beta-lactamases including ESBLs and AmpC due to its trans-1-methyl-2-pyrrolidine-3-ylthio side chain. Primarily used for respiratory tract infections (RTI), skin/soft tissue infections, and urogenital infections in regions like Asia, it shows MIC90 ≤1 mg/L for common respiratory pathogens like S. pneumoniae and H. influenzae. Resistance is limited but may promote cross-resistance to carbapenems via selection of beta-lactamase producers; clinical data indicate efficacy comparable to amoxicillin-clavulanate for RTI (cure rates ~85%). Available since the early 2000s in Japan and India, faropenem offers convenient oral therapy for community infections.^[155][156]

J01E Sulfonamides and trimethoprim

J01EA Trimethoprim and derivatives

Trimethoprim and its derivatives belong to the subclass J01EA within the Anatomical Therapeutic Chemical (ATC) classification system for antibacterials, specifically targeting folate synthesis in bacteria to treat infections such as urinary tract infections (UTIs) and certain respiratory conditions.^[157] These agents are primarily bacteriostatic, exerting their effects by selectively inhibiting bacterial enzymes involved in nucleotide synthesis, which disrupts microbial growth without broadly affecting human cellular processes.^[158] The primary mechanism of action for trimethoprim (J01EA01) involves competitive inhibition of dihydrofolate reductase (DHFR), the enzyme responsible for reducing dihydrofolate to tetrahydrofolate, an essential cofactor in the synthesis of purines and thymidylate for DNA replication.^[159] This inhibition is more potent against bacterial DHFR than the human enzyme due to structural differences in the binding site, allowing for a therapeutic window that minimizes host toxicity.^[160] Iclaprim (J01EA03), a diaminopyrimidine derivative structurally related to trimethoprim, similarly targets DHFR but exhibits enhanced activity against resistant strains and is formulated for intravenous administration, development of which was discontinued following the FDA's rejection in 2019, with no approval granted as of 2025.^{[161][162][163]} The antibacterial spectrum of trimethoprim encompasses many Gram-negative Enterobacteriaceae, including Escherichia coli, Klebsiella species, Proteus species, and Enterobacter species, which are common UTI pathogens, as well as some Gram-positive organisms like Staphylococcus saprophyticus.^[164] It demonstrates moderate activity against certain Staphylococcus aureus strains but lacks efficacy against Pseudomonas aeruginosa and other non-fermenters due to intrinsic resistance mechanisms.^[165] Trimethoprim alone is often used orally for uncomplicated UTIs, while derivatives like iclaprim are explored for hospital-acquired infections where broader or resistant coverage is needed.^[164] Resistance to trimethoprim primarily arises through plasmid-mediated production of variant DHFR enzymes that evade inhibition, such as type I dihydrofolate reductases encoded by mobile genetic elements like the dfrA1 gene, facilitating horizontal transfer among bacteria.^[166] In UTIs, resistance prevalence among E. coli isolates has reached approximately 25-28% globally as of 2025, driven by overuse and selective pressure, with higher rates in certain regions exceeding 30%.^[167][168] Clinically, trimethoprim is employed for acute and prophylactic treatment of UTIs, particularly in outpatient settings, and for long-term prevention in recurrent cases.^[165] In immunocompromised patients, it serves as a component in prophylaxis regimens against opportunistic infections, often combined with sulfonamides for enhanced efficacy, though monotherapy is used when combinations are contraindicated.^[165] A notable adverse effect is hyperkalemia, resulting from trimethoprim's inhibition of epithelial sodium channels in the distal nephron, mimicking potassium-sparing diuretics, which poses risks especially in patients with renal impairment or those on concurrent renin-angiotensin-aldosterone system inhibitors.^[169] Monitoring serum potassium is recommended during therapy, particularly at higher doses or in vulnerable populations.^[170]

J01EB Short-acting sulfonamides

Short-acting sulfonamides represent a subgroup of sulfonamide antibiotics classified under ATC code J01EB, characterized by a biological half-life of approximately 7 hours or less, enabling rapid elimination primarily through renal excretion.^[171] These agents were among the first synthetic antibacterials introduced in the 1930s, revolutionizing treatment for bacterial infections before the advent of beta-lactams, though their clinical role has diminished due to widespread resistance.^[172] Representative examples include sulfaisodimidine (J01EB01), sulfamethizole (J01EB02), sulfadimidine (J01EB03), sulfapyridine (J01EB04), and sulfafurazole (J01EB05).^[173] The mechanism of action for short-acting sulfonamides involves competitive inhibition of dihydropteroate synthase (DHPS), a bacterial enzyme essential for incorporating para-aminobenzoic acid (PABA) into the synthesis of folic acid, thereby disrupting tetrahydrofolate production required for bacterial DNA and protein synthesis.^[174] This bacteriostatic effect targets folate-dependent pathogens, particularly Gram-positive and Gram-negative bacteria susceptible to folate pathway disruption.^[175] Pharmacokinetically, these drugs are well-absorbed following oral administration, achieving peak plasma concentrations within 2-4 hours, with wide tissue distribution including high levels in urine due to renal clearance via glomerular filtration and active tubular secretion.^[176] Their short serum half-life, typically 4-7 hours in patients with normal renal function, supports dosing every 6-8 hours for short treatment courses, contrasting with longer-acting variants that allow less frequent administration for sustained therapy.^[177] Excretion is predominantly unchanged in urine (70-90%), concentrating the drug in the urinary tract and enhancing efficacy against localized infections.^[178] Therapeutically, short-acting sulfonamides have been employed for acute, uncomplicated urinary tract infections (UTIs), such as cystitis caused by susceptible Enterobacteriaceae, leveraging their rapid urinary excretion for targeted action.^[179] Historically, they treated chancroid, nocardiosis, and other systemic infections like streptococcal pharyngitis, but current use is limited to regions with low resistance or as alternatives in sulfa-tolerant patients.^[177] For instance, sulfamethizole is indicated for short-term management of uncomplicated UTIs, while sulfadimidine has seen application in bacterial enteritis, though primarily in veterinary contexts today.^[180][181] Resistance to short-acting sulfonamides is prevalent, arising from chromosomal mutations in the folP gene encoding DHPS, which reduce drug binding affinity, or plasmid-mediated acquisition of sul genes conferring alternative DHPS enzymes.^[182] Cross-resistance exists across all sulfonamides, rendering the class ineffective against many common pathogens like Escherichia coli in community settings.^[178] Additionally, risks include crystalluria from insoluble drug precipitates in acidic urine, mitigated by alkalinization and hydration.^[183] These factors have largely supplanted their role in favor of narrower-spectrum agents.

J01EC Intermediate-acting sulfonamides

Intermediate-acting sulfonamides, classified under ATC code J01EC, are bacteriostatic antibiotics that inhibit bacterial folate synthesis by competitively antagonizing para-aminobenzoic acid (PABA) binding to dihydropteroate synthase (DHPS). This group includes drugs with a biological half-life of approximately 11-12 hours, allowing for less frequent dosing compared to short-acting sulfonamides (half-life <7 hours) while providing sustained plasma levels suitable for treating moderate-duration infections.^[184][185] These agents exhibit favorable tissue penetration, including into cerebrospinal fluid and other sites, which supports their use in systemic and localized infections beyond those requiring rapid clearance.^[186] Key examples include sulfamethoxazole (J01EC01) and sulfadiazine (J01EC02). Sulfamethoxazole, with a serum half-life of about 10 hours, serves as a component in co-trimoxazole (sulfamethoxazole-trimethoprim) but can be used alone for urinary tract infections and as prophylaxis in certain immunocompromised states; it achieves good distribution into skin and soft tissues, making it relevant for burn wound infections when combined with other agents.^[187][188] Sulfadiazine, featuring a half-life of 7-17 hours (mean 10 hours), is primarily employed in combination with pyrimethamine for treating toxoplasmosis in patients with acquired immunodeficiency syndrome or congenital infections, leveraging its excellent cerebrospinal fluid penetration.^[189][190] Additionally, sulfadiazine is indicated for rheumatic fever prophylaxis at doses of 500 mg to 1 g daily, reducing recurrence risk in susceptible individuals.^[191] Resistance to intermediate-acting sulfonamides mirrors that of other sulfonamides, primarily arising from plasmid-mediated acquisition of sul genes (e.g., sul1, sul2) that encode variant DHPS enzymes insensitive to the drugs, leading to widespread clinical resistance in gram-negative bacteria like Enterobacteriaceae.^[192][178] These agents can induce folate deficiency by inhibiting host and microbial folate pathways, particularly in patients with malnutrition or malabsorption; supplementation with folinic acid (not folic acid, to avoid antagonizing the antimicrobial effect) is recommended during therapy, especially in toxoplasmosis treatment or prolonged use.^[178] Adverse effects include hypersensitivity reactions, with sulfonamides associated with severe cutaneous reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), occurring in approximately 1-3 cases per 100,000 users.^[193] These reactions show genetic predisposition linked to specific HLA alleles, including HLA-A*11:01 in Japanese populations and HLA-B12 or HLA-DR7 in others, highlighting the role of immune-mediated mechanisms in sulfonamide-induced SJS/TEN.^[194][195]

J01ED Long-acting sulfonamides

Long-acting sulfonamides, classified under ATC code J01ED, are a subgroup of sulfonamide antibacterials characterized by a biological half-life of approximately 35 hours or more, allowing for infrequent dosing such as single daily or weekly administration to improve patient compliance.^[196] These agents achieve prolonged therapeutic levels through structural modifications that enhance lipid solubility and slow renal excretion, reducing the frequency of administration compared to short- or intermediate-acting sulfonamides.^[174] The defined daily doses (DDDs) for these drugs are typically lower than those for shorter-acting sulfonamides due to their extended duration of effect.^[196] Key examples in this category include sulfadimethoxine (J01ED01), sulfalene (J01ED02), and sulfamethoxypyridazine (J01ED05), among others such as sulfametoxydiazine (J01ED04) and sulfaperin (J01ED06).^[197] Sulfadimethoxine, with a plasma half-life ranging from 27 to 36 hours depending on acetylation status, was historically used in humans for treating respiratory, urinary tract, and soft tissue infections, though it is now primarily employed in veterinary medicine in many regions; it remains approved for human use in countries like Russia for bacterial infections in adults and children.^[198][199] Sulfalene, featuring a half-life exceeding 30 hours, has been indicated for chronic bronchitis, urinary tract infections, and certain protozoal infections, enabling once-daily dosing.^[200] These drugs inhibit bacterial dihydropteroate synthase, disrupting folic acid synthesis essential for bacterial growth.^[201] Historically, long-acting sulfonamides like sulfamethoxypyridazine and sulfadimethoxine were explored for leprosy treatment due to their sustained antibacterial activity against Mycobacterium leprae, with clinical trials in the 1960s demonstrating bacteriostatic effects and improvement in lepromatous cases when administered weekly.^[202][203] However, their use has largely been supplanted by multi-drug regimens including dapsone and rifampicin. Resistance to long-acting sulfonamides is widespread, primarily mediated by plasmid-encoded dihydropteroate synthase variants that confer cross-resistance across the sulfonamide class, exacerbated by historical overuse and poor compliance with infrequent dosing regimens leading to subtherapeutic levels.^[204] By 2025, these agents have been discontinued or severely restricted in many regions, including the United States where no long-acting sulfonamides are commercially available for human use, due to high resistance rates and the availability of more effective alternatives.^[205] Their prolonged half-lives increase the risk of accumulation and toxicity, including crystalluria, hypersensitivity reactions, and hemolytic anemia in susceptible individuals, necessitating careful monitoring and hydration to prevent renal complications.^[174][206]

J01EE Combinations of sulfonamides and trimethoprim, including derivatives

The ATC group J01EE encompasses combinations of sulfonamides and trimethoprim, including derivatives, classified as antibacterials for systemic use that target folate synthesis in bacteria.^[207] These fixed-dose combinations exploit synergistic interactions to enhance antibacterial efficacy against a range of gram-positive and gram-negative pathogens, particularly in infections where monotherapy may be insufficient.^[165] The mechanism of action involves sequential blockade of the bacterial folic acid biosynthesis pathway, rendering the combination bactericidal. Sulfonamides, such as sulfamethoxazole, competitively inhibit dihydropteroate synthase (DHPS), preventing the incorporation of para-aminobenzoic acid (PABA) into dihydropteroic acid, an essential precursor to dihydrofolic acid.^[165] Trimethoprim then inhibits dihydrofolate reductase (DHFR), blocking the reduction of dihydrofolic acid to tetrahydrofolic acid, which is crucial for nucleic acid synthesis in bacteria.^[165] This dual inhibition creates a synergistic effect, as the accumulation of dihydrofolic acid amplifies trimethoprim's action, and the combination demonstrates mutual potentiation at clinically relevant concentrations.^[208] Unlike in humans, who obtain folate exogenously, bacteria must synthesize it de novo, making this pathway selectively vulnerable.^[165] The primary drug in this group is sulfamethoxazole and trimethoprim (J01EE01), typically formulated in a 5:1 ratio (sulfamethoxazole:trimethoprim, e.g., 800 mg:160 mg per dose) for systemic administration.^[165] Other combinations include sulfadiazine and trimethoprim (J01EE02), sulfametrole and trimethoprim (J01EE03), and sulfamoxole and trimethoprim (J01EE04), though these are less commonly used outside specific regional or historical contexts.^[209] Clinical applications focus on infections such as urinary tract infections (UTIs), where single-strength doses (400 mg:80 mg twice daily) are standard; Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients, requiring high-dose regimens (15-20 mg/kg/day of the trimethoprim component in divided doses); and traveler's diarrhea, treated with 160 mg trimethoprim twice daily for 3 days.^[165] It also serves as prophylaxis for PCP in HIV patients and for certain toxoplasmosis cases.^[165] However, emerging resistance, particularly in Stenotrophomonas maltophilia, has been documented through mutations in efflux regulators like SmeRv, with rates varying from 7.5% to 14% in recent surveillance, prompting consideration of alternatives like minocycline in severe cases.^[210][211] Derivatives within J01EE primarily involve structural analogs of sulfonamides paired with trimethoprim, but their use remains limited compared to the dominant sulfamethoxazole combination, with no major novel derivatives introduced recently.^[209] Adverse effects include common gastrointestinal disturbances (nausea, vomiting) and allergic reactions (rash, urticaria) in up to 3-5% of patients.^[212] Serious risks encompass severe cutaneous adverse reactions like Stevens-Johnson syndrome or toxic epidermal necrolysis (incidence approximately 1-3 cases per 100,000 users), kernicterus in neonates due to sulfonamide-induced bilirubin displacement from albumin, and trimethoprim-associated hyperkalemia via amiloride-like effects on renal potassium excretion.^[165][212] Contraindications include G6PD deficiency and use near term in pregnancy to avoid kernicterus.^[165]

QJ01EQ Sulfonamides (Veterinary)

QJ01EQ encompasses sulfonamides classified for veterinary use, distinct from human ATC groupings due to the irrelevance of human half-life subdivisions in animal applications. These broad-spectrum antibacterials inhibit folic acid synthesis in bacteria and some protozoa, making them suitable for systemic treatment in livestock and poultry. Unlike human formulations, veterinary sulfonamides under this code are grouped together regardless of duration of action, focusing on efficacy against susceptible gram-positive and gram-negative pathogens.^{[213][214][215]} Key examples include sulfadimethoxine, a long-acting sulfonamide used in cattle, swine, and poultry for its rapid absorption and extended duration; sulfamethazine, an intermediate-acting agent commonly administered via water or feed; and sulfadiazine, effective against a range of infections. These drugs are formulated for oral, injectable, or in-feed delivery to treat conditions such as bacterial pneumonia, foot rot, and soft tissue infections in livestock. In poultry, they target respiratory and enteric diseases, while in swine, they address colibacillosis and other bacterial enteritis. For instance, sulfadimethoxine is indicated for coccidiosis outbreaks in turkeys and fowl cholera, often at dosages of 50-55 mg/kg initially followed by maintenance doses.^{[216][217][218]} Regulatory oversight ensures safe use in food-producing animals, with the FDA approving specific sulfonamides like sulfadimethoxine for labeled indications and establishing tolerance levels and withdrawal periods—typically 7-14 days for meat and 60 hours for milk in dairy cattle—to prevent residues. The USDA's Food Safety and Inspection Service conducts residue monitoring through the National Residue Program, testing slaughter animals for violative levels, with sulfonamides among prioritized compounds due to potential human exposure risks. In the EU, sulfonamides fall under Category D ("Prudence") per EMA guidelines, prohibiting their use for growth promotion or yield increase since the 2006 ban on antimicrobial growth promoters, reinforced by Regulation (EU) 2019/6; as of 2025, updated surveillance emphasizes prudent use to curb resistance, with no new specific bans but stricter prescription requirements for veterinarians.^[219][220] Antimicrobial resistance to sulfonamides is widespread in veterinary pathogens, driven by historical overuse, leading to concerns over zoonotic transfer of resistant strains like sulfonamide-resistant Salmonella and E. coli from animal sources to humans via food chains or direct contact. Studies highlight that residues and resistant bacteria in manure can disseminate into the environment, facilitating horizontal gene transfer and posing public health risks, particularly in regions with intensive livestock production. Prudent use protocols, including susceptibility testing and avoiding monotherapy, are recommended to mitigate these issues.^{[221][222][223]}

QJ01EW Combinations of sulfonamides and trimethoprim (Veterinary)

QJ01EW encompasses veterinary medicinal products that combine sulfonamides with trimethoprim or its derivatives, classified under the Anatomical Therapeutic Chemical (ATC) veterinary system for antibacterial agents targeting bacterial infections in animals. These combinations exploit synergistic sequential blockade of folate synthesis in bacteria, where sulfonamides inhibit dihydropteroate synthase and trimethoprim blocks dihydrofolate reductase, enhancing efficacy against a broad spectrum of gram-positive and gram-negative pathogens.^[215][224] Key products in this category include trimethoprim-sulfadiazine (QJ01EW10), trimethoprim-sulfamethoxazole (QJ01EW01), trimethoprim-sulfadoxine (QJ01EW13), and ormetoprim-sulfadimethoxine (QJ01EW11), available as analogs to human co-trimoxazole but formulated for animal administration. These are commonly used for respiratory tract infections in calves caused by Mannheimia haemolytica or Histophilus somni, urinary tract infections in dogs due to Escherichia coli or Proteus spp., and enteric infections in foals from susceptible E. coli strains.^{[215][225][226]} Formulations are adapted for veterinary use, including oral suspensions, tablets, and injectable solutions to accommodate species-specific dosing and absorption needs; for instance, dogs and cats receive 15–30 mg/kg of the combination every 12 hours orally, while horses may require intravenous administration at 5 mg/kg every 12 hours for acute cases. Dosing intervals of 12–24 hours align with the trimethoprim plasma half-life exceeding 12 hours in most species, ensuring therapeutic levels while minimizing toxicity risks like crystalluria or keratoconjunctivitis sicca in dogs.^[215][221] Withdrawal times for these combinations typically range from 7 to 14 days for meat in cattle and horses, with milk discard periods of 72 hours in non-prohibited uses, though extralabel applications in lactating dairy cattle are restricted to prevent residues. These periods are established based on residue depletion studies to comply with maximum residue limits set by regulatory bodies like the FDA and EMA.^[215][227] Resistance to QJ01EW combinations mirrors patterns in human medicine, driven by chromosomal mutations and plasmid-mediated efflux pumps or integrons, with prevalence exceeding 50% in E. coli isolates from livestock in recent surveillance. Farm-based monitoring programs, such as the European ESVAC and global efforts in 2024–2025, track usage and resistance to promote prudent antimicrobial stewardship in veterinary practice.^{[215][228][55]}

J01F Macrolides, lincosamides and streptogramins

J01FA Macrolides

Macrolides, classified under ATC code J01FA, represent a subclass of antibiotics within the broader J01F group of macrolides, lincosamides, and streptogramins, primarily used for systemic treatment of bacterial infections by inhibiting protein synthesis.^[229] These agents are characterized by their large lactone ring structure, typically 14- or 15-membered, and are valued for their activity against gram-positive bacteria and atypical pathogens, though their use has evolved due to increasing resistance patterns.^[230] Introduced with erythromycin in the 1950s, macrolides have become a cornerstone for treating respiratory and sexually transmitted infections, with newer derivatives offering improved pharmacokinetics.^[231] The mechanism of action for macrolides involves reversible binding to the 50S subunit of the bacterial ribosome at the peptidyl transferase center, specifically domain V of 23S rRNA, which inhibits the translocation step of protein elongation and prevents nascent peptide chain progression.^[230] This binding partially occludes the nascent peptide exit tunnel, leading to premature dissociation of peptidyl-tRNA and halting protein synthesis, resulting in a predominantly bacteriostatic effect, though bactericidal activity can occur at higher concentrations against susceptible organisms.^[231] Unlike bactericidal beta-lactams, this ribosomal targeting spares host cell protein synthesis due to structural differences in eukaryotic ribosomes.^[232] Macrolides exhibit a targeted spectrum of activity, with strong efficacy against gram-positive cocci such as Streptococcus pneumoniae and Streptococcus pyogenes, as well as atypical bacteria including Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia trachomatis.^[233] They show moderate activity against some anaerobes but limited coverage of gram-negative pathogens like Haemophilus influenzae, where penetration and intrinsic resistance reduce effectiveness.^[230] This profile makes them suitable for community-acquired infections but less ideal for polymicrobial or enteric gram-negative cases.^[234] Prominent drugs in this subclass include erythromycin (J01FA01), the prototypical macrolide discovered in 1952 and historically used for respiratory infections despite gastrointestinal side effects; azithromycin (J01FA10), a 15-membered ring azalide with an extended half-life of approximately 68 hours, enabling convenient 3-day dosing regimens such as 500 mg daily for uncomplicated infections; and clarithromycin (J01FA09), a 14-membered ring derivative with enhanced acid stability and tissue penetration, often employed in dual or triple therapy for Helicobacter pylori eradication.^{[235][236][237]} Other agents like roxithromycin (J01FA06) and spiramycin (J01FA02) provide alternatives in specific regions, but azithromycin and clarithromycin dominate modern prescriptions due to their tolerability and broad tissue distribution.^[238] Clinically, macrolides are indicated for community-acquired pneumonia caused by atypical pathogens, streptococcal pharyngitis, and chlamydial infections such as uncomplicated genital Chlamydia trachomatis, where azithromycin's single-dose or short-course options improve adherence.^[230] They are also used in H. pylori regimens combining clarithromycin with proton pump inhibitors and amoxicillin, achieving eradication rates above 80% in susceptible strains.^[236] Regarding adjunctive use in COVID-19, azithromycin has been explored for its potential anti-inflammatory effects in mild-to-moderate cases, with some evidence suggesting reduced symptom duration by about 4 days, though benefits remain debated due to inconsistent trial outcomes and risks of promoting resistance.^[239][240] Resistance to macrolides primarily arises through the MLS_B phenotype, mediated by erm genes encoding ribosomal methylases that modify the 23S rRNA binding site, conferring inducible or constitutive resistance to macrolides, lincosamides, and streptogramin B antibiotics; this cross-resistance extends to lincosamides via shared ribosomal targets.^[241] Efflux pumps like mef(A) contribute to low-level macrolide-specific resistance, while high-level resistance often involves erm(B) in S. pneumoniae.^[242] Prevalence of macrolide resistance in pneumococci exceeds 40% in many regions, with rates reaching 50% in nasopharyngeal carriage and up to 70% in invasive pneumococcal disease isolates, driven by widespread empirical use and horizontal gene transfer.^[243][244] This escalating resistance has prompted guidelines to reserve macrolides for confirmed susceptible infections or as alternatives to beta-lactams in penicillin-allergic patients.^[245]

J01FF Lincosamides

Lincosamides represent a subclass of antibiotics within the ATC code J01FF, primarily targeting Gram-positive aerobic and anaerobic bacteria by inhibiting bacterial protein synthesis. This group includes clindamycin (J01FF01) and lincomycin (J01FF02), with defined daily doses (DDDs) of 1.2 g orally and 1.8 g parenterally for clindamycin, and 1.8 g for both routes for lincomycin, reflecting differences in absorption and indications such as intestinal versus systemic infections.^[246] These agents are particularly valued for their efficacy against susceptible strains in polymicrobial infections where anaerobes are involved, though their use is guided by susceptibility testing due to rising resistance patterns.^[247] The mechanism of action for lincosamides involves reversible binding to the 50S subunit of the bacterial ribosome, specifically interacting with the 23S rRNA peptidyl transferase center to block peptide bond formation and elongation during translation. This inhibition is generally bacteriostatic against most susceptible organisms but can become bactericidal at higher concentrations, particularly against certain streptococci. Structurally analogous to tRNA, lincosamides like clindamycin and lincomycin exhibit a spectrum similar to macrolides, with notable activity against Staphylococcus aureus, Streptococcus species, and anaerobes such as Bacteroides fragilis. Cross-resistance with macrolides occurs due to overlapping ribosomal binding sites, necessitating combined susceptibility testing in clinical practice.^{[247][248][249]} Clinically, clindamycin is the predominant lincosamide, administered orally or intravenously for serious infections including skin and soft tissue infections, aspiration pneumonia, intra-abdominal abscesses, bacterial vaginosis, and dental infections caused by anaerobes or methicillin-susceptible staphylococci. It is also FDA-approved for bone and joint infections, septicemia, and gynecological infections, with off-label applications in toxoplasmosis and malaria prophylaxis. Lincomycin, less frequently used due to higher rates of gastrointestinal intolerance, is reserved for similar serious infections in penicillin-allergic patients, such as streptococcal or staphylococcal bacteremia. Both drugs penetrate well into bone, bile, and abscesses, making them suitable for polymicrobial or deep-seated infections.^[247][248] Resistance to lincosamides primarily arises from erm gene-mediated methylation of adenine 2058 in 23S rRNA, conferring high-level resistance and cross-protection against macrolides and streptogramin B; additional mechanisms include ribosomal mutations, efflux pumps, and enzymatic inactivation via nucleotidyltransferases or acetyltransferases. Inducible resistance, detectable by the D-zone test in staphylococci and streptococci, limits empirical use, especially in community-acquired methicillin-resistant S. aureus (CA-MRSA) settings.^{[247][248][249]} Adverse effects of lincosamides are predominantly gastrointestinal, with clindamycin carrying a high risk of Clostridioides difficile-associated diarrhea and pseudomembranous colitis due to disruption of normal gut flora and toxin production by hypervirulent strains. This risk is amplified in hospitalized patients or those with prior antibiotic exposure, with incidence rates historically linked to clindamycin use in outbreaks. Other effects include nausea, vomiting, and rare hypersensitivity reactions like Stevens-Johnson syndrome; parenteral formulations may cause injection-site pain or, in neonates, gasping syndrome from benzyl alcohol preservatives. Monitoring for colitis is essential, with discontinuation advised upon symptom onset.^{[247][250][251]}

J01FG Streptogramins

Streptogramins are a class of antibiotics classified under ATC code J01FG, consisting of semisynthetic derivatives of natural compounds produced by Streptomyces pristinaespiralis. They are used primarily as combination therapies targeting resistant Gram-positive bacteria, with the two main agents being pristinamycin (J01FG01), an oral formulation available in some European markets, and quinupristin/dalfopristin (J01FG02, trade name Synercid), an intravenous combination approved for severe infections.^[252][253] These agents function through synergistic inhibition of bacterial protein synthesis at the 50S ribosomal subunit, where group A streptogramins (e.g., quinupristin) bind to the peptidyl transferase center and induce a conformational change that enhances binding of group B streptogramins (e.g., dalfopristin), leading to irreversible blockade and bactericidal activity.^[254][255] The antimicrobial spectrum of streptogramins is selective for Gram-positive organisms, demonstrating potent activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), Streptococcus pneumoniae, and other streptococci, as well as some anaerobes like Clostridium species, with minimum inhibitory concentrations (MICs) typically ≤2 mg/L for susceptible strains.^[256][257] However, they exhibit poor activity against Enterobacteriaceae and other Gram-negative bacteria due to limited penetration through the outer membrane.^[258] Clinically, quinupristin/dalfopristin is indicated for complicated skin and skin structure infections caused by susceptible Staphylococcus aureus or Streptococcus pyogenes, and for bacteremia associated with VRE in adults, administered intravenously at 7.5 mg/kg every 8-12 hours.^[259] Pristinamycin is reserved for less severe infections like respiratory tract or skin infections in regions where it is approved.^[260] Resistance to streptogramins remains relatively rare in clinical isolates but can arise through efflux pumps, enzymatic inactivation (e.g., via vat genes encoding acetyltransferases that modify group A components), or ribosomal mutations, particularly in Enterococcus faecium strains from animal sources.^[261][262] Common adverse effects include infusion-site reactions and hepatotoxicity, manifested as elevated conjugated bilirubin (in up to 3.1% of patients) and transaminases, necessitating monitoring of liver function during therapy.^[263] Quinupristin/dalfopristin was discontinued in the United States in 2022 due to manufacturing issues and lack of demand, with no generic alternatives available, though alternatives like glycopeptides may be considered for VRE infections.^[264]

J01G Aminoglycoside antibacterials

J01GA Streptomycins

The Streptomycins subgroup (ATC code J01GA) comprises aminoglycoside antibacterials, with streptomycin (J01GA01) as the primary agent used for severe infections requiring parenteral administration, typically intramuscularly.^[265] Introduced in the mid-20th century, these drugs target bacterial protein synthesis and are now mainly reserved for niche applications due to resistance patterns and toxicity concerns.^[266] Streptomycin acts bactericidally by binding to the 16S rRNA of the 30S ribosomal subunit, inducing miscoding errors during translation and blocking initiation of protein synthesis.^[266] This mechanism is concentration-dependent, with efficacy limited to aerobic bacteria that possess an active electron transport chain necessary for drug uptake.^[266] The agent shows activity against Mycobacterium tuberculosis and select Gram-negative pathogens like Yersinia pestis and Francisella tularensis, while displaying synergy with beta-lactam antibiotics against susceptible strains.^[266] Clinically, streptomycin serves as an adjunct in multidrug regimens for tuberculosis, particularly as a second-line option for multidrug-resistant (MDR-TB) cases when susceptibility testing confirms effectiveness, often combined with drugs like isoniazid and rifampin.^[267][268] It is recommended for treating plague, providing rapid bactericidal activity, though alternatives like gentamicin are often preferred due to better availability and lower toxicity risks.^[269] For tularemia, it has historical use but is no longer first-line as of 2025, with gentamicin preferred.^[270] Adverse effects of streptomycins, especially ototoxicity leading to irreversible hearing loss or vestibular damage and nephrotoxicity causing acute renal impairment, necessitate close monitoring of serum levels and renal function during therapy.^[266] Resistance develops primarily through point mutations in the rpsL gene, which encodes ribosomal protein S12 and alters the binding site, rendering the drug ineffective; such mutations are common in M. tuberculosis isolates.^[271] Unlike newer aminoglycosides in J01GB, streptomycins' narrow spectrum and toxicity profile limit their routine use.^[266]

J01GB Other aminoglycosides

The aminoglycosides classified under ATC code J01GB, excluding streptomycins, exert their bactericidal effects by binding irreversibly to the 30S subunit of the bacterial ribosome, inhibiting protein synthesis and inducing mRNA misreading, which leads to the production of defective proteins and bacterial cell death.^[272] This mechanism is concentration-dependent and results in a prolonged post-antibiotic effect, particularly against aerobic Gram-negative bacteria, enabling once-daily dosing regimens that optimize peak concentrations while minimizing toxicity.^[272] Unlike streptomycins primarily used for tuberculosis, these agents focus on broader Gram-negative coverage in severe infections.^[273] These drugs exhibit a spectrum of activity primarily against aerobic Gram-negative pathogens, such as Pseudomonas aeruginosa, Escherichia coli, and Klebsiella species, with limited efficacy against anaerobes or facultative Gram-positives unless combined with beta-lactams for synergistic enhancement of cell wall permeability and uptake.^[272] Key representatives include gentamicin (J01GB03), which is commonly employed in synergistic therapy for infective endocarditis alongside beta-lactams to improve outcomes in enterococcal and streptococcal cases; amikacin (J01GB06), valued for its activity against multidrug-resistant (MDR) Gram-negative bacilli like Acinetobacter baumannii and extended-spectrum beta-lactamase producers; and plazomicin (J01GB14), a newer engineered aminoglycoside approved by the FDA in 2018 for complicated urinary tract infections (cUTIs), including pyelonephritis, caused by carbapenem-resistant Enterobacterales (CRE).^{[274][275][276]} Clinical applications of J01GB aminoglycosides include treatment of neonatal sepsis, where agents like gentamicin and amikacin are standard empiric choices due to their efficacy against common Gram-negative pathogens in early-onset infections, often combined with ampicillin.^[277] They are also indicated for intra-abdominal infections, such as peritonitis or abscesses, particularly in polymicrobial settings requiring broad aerobic Gram-negative coverage.^[272] As of 2025, updated guidelines emphasize once-daily dosing protocols—typically 5-7 mg/kg for gentamicin or tobramycin based on lean body weight—to enhance efficacy, reduce hospital stay, and limit nephrotoxicity and ototoxicity through lower cumulative exposure.^[278] Resistance to these aminoglycosides primarily arises from plasmid-mediated aminoglycoside-modifying enzymes, including acetyltransferases (AAC) that add acetyl groups to the antibiotic and phosphotransferases (APH) that phosphorylate it, rendering the drug unable to bind the ribosome effectively; these mechanisms are prevalent in MDR Gram-negative isolates.^[279] Nephrotoxicity, involving proximal tubular damage, and ototoxicity, affecting cochlear and vestibular function, remain major concerns but are mitigated by once-daily dosing, which leverages the post-antibiotic effect and allows renal recovery between doses, with monitoring of serum levels and renal function essential for safe use.^[280][272]

J01M Quinolone antibacterials

J01MA Fluoroquinolones

Fluoroquinolones, classified under ATC code J01MA, are a subclass of quinolone antibacterials characterized by the presence of a fluorine atom at the C6 position of the quinolone ring, enhancing their potency and spectrum compared to non-fluorinated precursors in J01MB. These agents exert bactericidal effects by inhibiting bacterial DNA gyrase (a type II topoisomerase that introduces negative supercoils into DNA) and topoisomerase IV (which decatenates daughter chromosomes during replication), stabilizing the DNA-enzyme cleavage complex and leading to double-strand DNA breaks that trigger cell death.^{[281][282][283]} Fluoroquinolones are categorized into generations based on their antimicrobial spectrum and clinical applications, with older agents like ciprofloxacin primarily targeting gram-negative bacteria for urinary tract infections (UTIs), while respiratory fluoroquinolones such as levofloxacin and moxifloxacin offer broader coverage including gram-positive pathogens, atypicals, and anaerobes for lower respiratory infections. Key examples include ciprofloxacin (J01MA02), effective against Pseudomonas aeruginosa due to its strong gram-negative activity; levofloxacin (J01MA12), an L-isomer of ofloxacin optimized for respiratory tract infections like community-acquired pneumonia; and moxifloxacin (J01MA14), which provides enhanced anaerobic coverage suitable for complicated intra-abdominal infections and pneumonia. Defined daily doses (DDDs) for most in this group are based on treatment of respiratory tract infections, except for agents like ciprofloxacin where UTI dosing informs the standard.^{[284][285][286][287][288][289]} These drugs are indicated for serious infections such as community-acquired pneumonia, complicated UTIs, and chronic bacterial prostatitis, where broad-spectrum coverage is needed, but their use is restricted to cases without alternative therapies due to risks. In 2016, the FDA strengthened black-box warnings for all fluoroquinolones regarding disabling and potentially irreversible adverse effects, including tendon rupture (highest risk in patients over 60, those with renal impairment, or on corticosteroids), aortic aneurysm/dissection, peripheral neuropathy, and central nervous system effects like seizures; these warnings remain in effect as of 2025, contributing to declining prescription trends amid efforts to preserve efficacy. Additionally, fluoroquinolones carry a risk of Clostridioides difficile-associated diarrhea, second only to clindamycin among antibiotics, prompting guidelines to avoid them for uncomplicated infections.^{[290][291][292][293][294][295]} Resistance to fluoroquinolones has escalated globally, primarily through chromosomal mutations in the quinolone resistance-determining regions (QRDRs) of gyrA (e.g., Thr83Ile) and parC (e.g., Ser87Leu) genes, reducing drug binding affinity and enabling high-level resistance, particularly in Pseudomonas aeruginosa where efflux pumps and additional mutations compound the issue. By 2025, resistance rates in P. aeruginosa exceed 30-50% in many hospital settings, driven by prior overuse, leading to stewardship programs that limit fluoroquinolone prescriptions to curb further spread. Plasmid-mediated mechanisms, though less common in this group, also contribute in gram-negative pathogens.^{[296][297][298][299]}

J01MB Other quinolones

J01MB encompasses non-fluoroquinolone quinolones, primarily first-generation agents like nalidixic acid, which are classified under the Anatomical Therapeutic Chemical (ATC) system for their antibacterial properties against gram-negative bacteria. These drugs inhibit bacterial DNA gyrase, an enzyme essential for DNA replication and supercoiling, thereby blocking bacterial cell division and leading to cell death. Unlike later fluoroquinolones, agents in this group exhibit a narrower spectrum of activity, mainly targeting Enterobacteriaceae such as Escherichia coli, Proteus, Klebsiella, and Enterobacter species, with limited efficacy against Pseudomonas and gram-positive organisms.^{[300][301][281]} Nalidixic acid (J01MB02) is the prototypical and most commonly used drug in this subcategory, administered orally at a defined daily dose (DDD) of 4 g for the treatment of acute urinary tract infections (UTIs). Developed in the 1960s, it was historically significant for managing uncomplicated UTIs caused by susceptible gram-negative pathogens, particularly in pediatric patients over 3 months of age where dosing is typically 55 mg/kg/day divided into four doses. Its use in children is considered safer than fluoroquinolones due to the absence of arthropathy or growth impairment observed in studies involving short-term treatment. However, its clinical application has diminished over time due to emerging resistance and the availability of more potent alternatives. Other agents like rosoxacin (J01MB01, DDD 0.3 g for gonorrhea) and piromidic acid (J01MB03, DDD 2 g) share similar profiles but are less commonly employed.^{[300][301][302]} Resistance to J01MB quinolones, particularly nalidixic acid, arises primarily through chromosomal mutations in the DNA gyrase subunit (gyrA gene) or efflux pump overexpression, resulting in treatment failure rates of 2-14% during therapy and higher prevalence in community settings. This chromosomal resistance is not plasmid-mediated, but its rapid emergence—often within days of treatment—has limited the drugs' utility to short courses for lower urinary tract infections, exacerbated by poor systemic absorption that confines activity to the urinary tract. Nalidixic acid resistance also serves as a marker for low-level fluoroquinolone resistance in pathogens like Salmonella.^{[301][303][304]} Adverse effects of J01MB quinolones are generally mild, with gastrointestinal disturbances such as nausea, vomiting, diarrhea, and abdominal pain being the most frequent, occurring in up to 10-20% of patients. Central nervous system effects like dizziness, headache, and drowsiness may arise, alongside rare photosensitivity reactions. In contrast to fluoroquinolones, these agents pose a lower risk of musculoskeletal toxicity, making them preferable for pediatric UTI management, though overdose can lead to convulsions or metabolic acidosis, and caution is advised in patients with G6PD deficiency due to hemolytic anemia risk.^{[301][305][302][306]}

QJ01MQ Quinoxalines (Veterinary)

Quinoxalines, classified under the ATC veterinary code QJ01MQ, represent a group of synthetic antimicrobial agents primarily utilized in swine husbandry for their dual roles in bacterial control and growth promotion. The class is dominated by carbadox, a quinoxaline-1,4-dioxide derivative, along with olaquindox (QJ01MQ01), another key quinoxaline-1,4-dioxide used similarly in swine for antibacterial and growth-promoting effects but banned in the EU since 1998.^[307] These compounds are bioreductive prodrugs that activate under anaerobic conditions prevalent in bacterial environments, distinguishing them from broader quinolone antibacterials used in human medicine.^[308][309] The mechanism of action for quinoxalines like carbadox involves DNA intercalation, where the molecule inserts between DNA base pairs, causing strand breaks and mutations that inhibit bacterial replication, particularly in Gram-positive and obligate intracellular pathogens. This genotoxic effect extends to growth promotion by altering the swine gut microbiome, reducing pathogenic load, and potentially influencing nutrient absorption, though the exact metabolic pathways remain under study. In practice, carbadox is incorporated into swine feeds at concentrations of 50-55 mg/kg to treat and prevent proliferative enteropathy (also known as ileitis) caused by Lawsonia intracellularis, as well as bacterial enteritis and post-weaning colibacillosis. Clinical trials have shown it reduces mortality and improves feed efficiency in affected herds by up to 10-15% during outbreaks. However, residues of carbadox and its primary metabolite, desoxycarbadox, persist in tissues, with the latter classified as genotoxic and carcinogenic based on rodent studies, prompting stringent monitoring to ensure levels below 0.1 mg/kg in muscle and liver.^{[310][308][311][312][313]} Regulatory frameworks reflect heightened safety concerns over these residues. The European Union banned carbadox in 1999 for use in food-producing animals due to its carcinogenic potential, a decision upheld across member states and influencing similar prohibitions in Canada (2004) and Australia. In the United States, carbadox was previously approved under 21 CFR 558 for therapeutic applications in swine, mandating a 42-day pre-slaughter withdrawal and barring use in pregnant sows to minimize residue risks. However, in November 2023, the FDA revoked the approved method for detecting residues and proposed to withdraw approval of all NADAs for carbadox due to its inadequacy in monitoring the carcinogenic metabolite desoxycarbadox. As of 2025, the proposal remains pending amid ongoing litigation and advocacy for full withdrawal.^{[311][314][315][316]} As bans proliferate, alternatives to quinoxalines are gaining traction in swine production to address proliferative enteropathy and growth needs without genotoxicity risks. Emerging options include probiotics (e.g., Lactobacillus strains) and postbiotics that modulate gut flora, organic acids like formic and propionic for pH-mediated pathogen control, and phytobiotics such as essential oils from oregano or thyme, which have demonstrated comparable reductions in ileitis lesions in challenge studies. Vaccines targeting Lawsonia intracellularis, like Enterisol Ileitis, offer preventive efficacy with herd-level protection rates exceeding 80%, while functional fatty acids provide supportive antimicrobial effects. These substitutes prioritize microbiome stewardship, though their adoption varies by region due to efficacy variability in field conditions.^[317][318]

J01R Combinations of antibacterials

J01RA Combinations of antibacterials

The J01RA subcategory encompasses fixed-dose combinations of two or more systemic antibacterials from distinct chemical subgroups, designed to provide synergistic or broadened spectrum activity against bacterial pathogens. These formulations target scenarios where monotherapy may be insufficient, such as polymicrobial infections involving mixed aerobic and anaerobic bacteria, by leveraging complementary mechanisms of action to enhance efficacy and reduce the likelihood of resistance emergence during treatment.^[319] Representative examples include cefuroxime combined with metronidazole (J01RA03), which pairs a second-generation cephalosporin with a nitroimidazole to cover both gram-positive/negative aerobes and anaerobes, commonly used in intra-abdominal or gynecological infections. Another is spiramycin with metronidazole (J01RA04), a macrolide-nitroimidazole duo effective against susceptible respiratory and gastrointestinal pathogens. Levofloxacin and ornidazole (J01RA05), though ornidazole has dual antibacterial and antiprotozoal properties, exemplifies quinolone-imidazole pairings for mixed infections. For severe conditions like infective endocarditis, beta-lactam-aminoglycoside regimens (e.g., penicillin or ceftriaxone with gentamicin) are often co-administered—though not always as fixed combinations—to achieve bactericidal synergy against enterococci or staphylococci, as supported by experimental and clinical data (2015 AHA guideline).^{[320][321][322]} These combinations are primarily indicated for empirical therapy in high-risk settings like sepsis or complicated intra-abdominal infections, where rapid broad coverage is needed pending culture results; however, antimicrobial stewardship principles emphasize de-escalation to targeted monotherapy once susceptibilities are known to minimize unnecessary exposure. In endocarditis protocols, such pairings shorten treatment duration and improve outcomes in uncomplicated cases, but alternatives like dual beta-lactams are increasingly preferred to avoid aminoglycoside nephrotoxicity.^{[323][321][324]} Despite benefits, widespread use of these combinations accelerates resistance selection, particularly in multidrug-resistant environments, prompting antimicrobial stewardship programs to restrict them to documented polymicrobial or synergistic needs. IDSA and CDC guidelines from 2024 advocate prospective audit and feedback to curb overuse.^[325][323]

QJ01RV Combinations of antibacterials and other substances (Veterinary)

QJ01RV encompasses veterinary medicinal products that combine systemic antibacterials with non-antibacterial substances, such as corticosteroids, to address bacterial infections accompanied by inflammation or other adjunctive needs. These combinations are classified under the ATCvet system to distinguish them from pure antibacterial mixtures, emphasizing their role in enhancing therapeutic outcomes beyond antimicrobial action alone. The primary subgroup, QJ01RV01, includes formulations pairing antibacterials with corticosteroids to mitigate inflammatory responses in conditions like mastitis and endotoxemia.^[326] Representative examples include penicillin combined with polymyxin and a corticosteroid, or penicillin paired with an aminoglycoside and a corticosteroid, often formulated for intramammary or systemic administration in ruminants. In cattle mastitis treatment, combinations such as cefapirin with prednisolone demonstrate synergistic effects, reducing udder swelling and improving clinical resolution compared to antibiotic monotherapy. These products target gram-positive and gram-negative pathogens while addressing concurrent inflammation, with specific formulations approved for conditions like bovine coliform mastitis.^[327][328] Such combinations are primarily used to reduce inflammation in respiratory diseases and mastitis in food-producing animals, where bacterial infection triggers severe tissue damage. For instance, in bovine respiratory disease, the anti-inflammatory component helps alleviate pyrexia and lung lesions more rapidly when added to antibiotic therapy. In mastitis, they support faster recovery by enhancing the blood-milk barrier integrity and decreasing sensitivity, though usage must comply with food safety residue rules to prevent milk contamination. Overall, these products improve outcomes in endotoxemia by decreasing prostaglandin and thromboxane production, key mediators of septic shock, leading to prolonged survival and reduced fluid requirements.^{[329][330][331]} In the European Union, these combinations are regulated under Regulation (EU) 2019/6 on veterinary medicinal products, which imposes strict limits on antimicrobial use to curb resistance, including mandatory withdrawal periods for steroid-containing formulations to ensure residue levels below maximum residue limits (MRLs) in food products. Guidelines emphasize judicious prescribing, prohibiting routine prophylactic use and requiring veterinary oversight for any combination therapy. For example, the MRL for dexamethasone is set at 0.5 µg/kg in muscle and 2 µg/kg in other tissues. As of the 2025 ATCvet index, no changes have been made to QJ01RV classifications. These rules align with broader efforts to monitor antimicrobial consumption via systems like ESVAC, ensuring combinations are reserved for cases where inflammation significantly impacts efficacy.^{[332][220][333]}

J01X Other antibacterials

J01XA Glycopeptide antibacterials

Glycopeptide antibacterials, classified under ATC code J01XA, are a subclass of antibiotics primarily used against Gram-positive bacterial infections, particularly those caused by multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA).^[334] These agents are large, rigid glycopeptide molecules that target the bacterial cell wall, making them essential for treating severe infections where beta-lactam antibiotics are ineffective.^[335] Vancomycin, the prototypical drug in this class (J01XA01), has been a cornerstone therapy since the 1950s, while teicoplanin (J01XA02) offers advantages in dosing due to its longer half-life.^[336] Newer derivatives like telavancin (J01XA03), dalbavancin (J01XA04, approved 2014), and oritavancin (J01XA05, approved 2014) incorporate structural modifications to enhance potency against resistant pathogens; dalbavancin and oritavancin enable once-weekly or single-dose regimens for acute bacterial skin and skin structure infections (ABSSSI).^{[337][338][339]} The primary mechanism of action for glycopeptide antibacterials involves binding to the D-alanyl-D-alanine (D-Ala-D-Ala) terminus of peptidoglycan precursors in the bacterial cell wall, thereby inhibiting transpeptidation and transglycosylation steps essential for cell wall synthesis.^[335] This interference prevents cross-linking of peptidoglycan chains, leading to weakened cell walls and eventual bacterial lysis, with bactericidal activity predominantly against Gram-positive organisms due to their thick peptidoglycan layer.^[340] Both vancomycin and teicoplanin exert their effects through this shared pathway, though teicoplanin demonstrates improved binding affinity in some strains, contributing to its prolonged serum levels (half-life of approximately 45-70 hours compared to vancomycin's 4-6 hours).^[341] These antibiotics are poorly absorbed orally, necessitating intravenous administration for systemic infections, except in cases of gastrointestinal involvement.^[342] Key therapeutic uses of glycopeptides center on serious Gram-positive infections. Vancomycin is indicated intravenously for MRSA bacteremia, endocarditis, skin and soft tissue infections, and bone/joint infections, with guidelines recommending therapeutic drug monitoring (TDM) to maintain trough levels of 15-20 mg/L for severe cases like endocarditis to optimize efficacy and minimize toxicity.^[343] Orally, vancomycin treats Clostridium difficile-associated colitis by achieving high luminal concentrations without systemic absorption.^[344] Teicoplanin serves similar indications, often as an alternative for patients intolerant to vancomycin, with once-daily dosing due to its pharmacokinetics.^[341] Telavancin, a semisynthetic lipoglycopeptide, is approved for complicated skin and skin structure infections and hospital-acquired pneumonia caused by MRSA, offering dual activity by not only inhibiting cell wall synthesis but also disrupting bacterial membrane integrity via its lipidated side chain.^[337] Resistance to glycopeptides poses significant challenges, primarily in enterococci and staphylococci. Vancomycin-resistant enterococci (VRE) arise from acquired gene clusters such as vanA and vanB, which reprogram cell wall synthesis to produce D-Ala-D-lactate or D-Ala-D-Ser precursors with reduced binding affinity for the antibiotics, conferring high-level resistance (MIC >256 mg/L for vanA).^[345] The vanA cluster, often plasmid-mediated, induces resistance to both vancomycin and teicoplanin, while vanB typically spares teicoplanin.^[346] In staphylococci, heterogeneous vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) emerge through thickened cell walls and mutations altering peptidoglycan metabolism, without van genes, leading to treatment failures in MRSA infections.^[347] As of 2025, efforts to address resistance and improve administration include expanded oral formulations of vancomycin. Recent approvals, such as the ready-to-infuse Tyzavan, enhance stability and convenience for intravenous use, while stability studies support extending the beyond-use date of compounded oral solutions to 90 days under refrigeration, facilitating outpatient management of C. difficile infections.^[348] These developments, alongside ongoing research into lipoglycopeptide variants, aim to sustain the utility of J01XA agents against evolving Gram-positive threats.^[349]

J01XB Polymyxins

Polymyxins are a class of polypeptide antibiotics classified under ATC code J01XB, reserved for systemic treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria, where other antibacterials are ineffective.^[350] They act primarily on the bacterial outer membrane and are considered last-resort options due to their narrow spectrum and toxicity profile, targeting pathogens such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae resistant to carbapenems.^[351] The mechanism of action of polymyxins involves cationic polypeptides that bind electrostatically to the negatively charged lipopolysaccharide (LPS) components of the Gram-negative bacterial outer membrane, displacing divalent cations like Mg²⁺ and Ca²⁺.^[352] This interaction disrupts membrane integrity, leading to increased permeability, leakage of cellular contents, and ultimately bactericidal effects through cell lysis.^[353] Polymyxins exhibit rapid bactericidal activity against susceptible strains but have limited efficacy against Gram-positive bacteria or anaerobes due to their outer membrane specificity.^[354] The primary drugs in this group are colistin (polymyxin E, J01XB01) and polymyxin B (J01XB02). Colistin is administered intravenously or by inhalation for severe infections like carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Enterobacteriaceae (CRE), particularly in ventilator-associated pneumonia and bloodstream infections.^[355] Polymyxin B is used intravenously for systemic infections, intrathecally for meningitis caused by susceptible Gram-negative bacilli, and topically for ocular or skin infections involving Pseudomonas aeruginosa.^[356] Both are derived from soil bacteria (Bacillus polymyxa) and share structural similarities, though polymyxin B is preferred for central nervous system infections due to better cerebrospinal fluid penetration.^[353] Polymyxins are indicated for complicated urinary tract infections (UTIs), ventilator-associated pneumonia, and sepsis due to MDR Gram-negative pathogens, often in critically ill patients.^[357] In 2025, combination therapies incorporating colistin with meropenem have shown synergistic effects against CRAB, reducing clinical failure rates and bacterial load in preclinical and clinical studies, particularly for isolates with heterogeneous resistance.^[358] Similarly, colistin-meropenem regimens have demonstrated improved outcomes in carbapenem-resistant infections compared to monotherapy, with ongoing trials confirming their role in high-mortality settings.^[359] Toxicity remains a major limitation, with nephrotoxicity occurring in up to 50% of patients due to accumulation in renal tubular cells, causing acute kidney injury, and neurotoxicity manifesting as paresthesia or neuromuscular blockade at high doses.^[360] Dosing is weight-based, typically 9-12 million international units (MIU) per day for colistin divided every 8-12 hours using ideal body weight to minimize renal risk, with adjustments for renal function.^[361] Resistance to polymyxins has escalated since 2015, driven by plasmid-mediated mcr genes (e.g., mcr-1 to mcr-10), which encode lipid A phosphoethanolamine transferases that modify LPS to reduce polymyxin binding affinity.^[362] This transferable resistance, first reported in China in 2015, has spread globally via animal agriculture and human infections, contributing to a colistin resistance crisis that threatens the utility of these agents by 2025, with prevalence in MDR Escherichia coli and Klebsiella pneumoniae exceeding 10% in some regions.^[363]

J01XC Steroid antibacterials

The J01XC subgroup within the Anatomical Therapeutic Chemical (ATC) classification system encompasses steroid antibacterials, a narrow class primarily represented by fusidic acid, which is assigned the code J01XC01.^[364] These agents are characterized by their steroidal structure and targeted action against bacterial protein synthesis, distinguishing them from broader antibacterial categories. Fusidic acid, derived from the fungus Fusidium coccineum, is the sole clinically significant member of this group and is employed mainly for infections caused by Gram-positive bacteria, particularly Staphylococcus species.^[365] Fusidic acid exerts its bacteriostatic effect by binding to the elongation factor G (EF-G) in its GDP-bound form on the bacterial ribosome, thereby inhibiting the translocation step during protein synthesis and preventing the progression of the ribosomal complex along messenger RNA.^[365] This mechanism specifically disrupts the 50S ribosomal subunit and the interaction with transfer RNA, rendering it highly effective against Gram-positive organisms like Staphylococcus aureus but ineffective against most Gram-negative bacteria due to poor penetration of their outer membrane.^[364] Clinically, fusidic acid is administered topically in creams or ointments for localized skin infections such as impetigo, where it achieves high concentrations at the site of infection, or systemically via oral sodium fusidate tablets or intravenous formulations for more severe cases.^[366] Oral bioavailability of the sodium fusidate salt is approximately 91%, allowing effective systemic absorption, though it is often used as an adjunct to other antibiotics in conditions like osteomyelitis to enhance penetration into bone tissue and combat staphylococcal infections.^[366][365] Resistance to fusidic acid primarily arises from mutations in the fusA gene, which encodes EF-G, leading to amino acid substitutions (such as L461K) that reduce drug binding affinity and confer high-level resistance, particularly in Staphylococcus aureus isolates.^[367] Additional resistance mechanisms include the plasmid-mediated fusB gene, which encodes a protection protein that stabilizes EF-G and promotes drug dissociation from the ribosome, typically resulting in lower-level resistance.^[368] These resistance determinants have contributed to its restricted systemic use in many regions, favoring topical applications to minimize selective pressure and preserve efficacy against susceptible strains.^[369] Adverse effects of fusidic acid are generally mild, but systemic administration can lead to hepatotoxicity, manifested as reversible elevations in liver enzymes and, in rare cases, jaundice or more severe liver injury, particularly with prolonged use or in patients with pre-existing liver conditions.^[370] Hematologic complications, such as leukopenia or thrombocytopenia, have also been reported alongside hepatotoxic events, though these occur infrequently and resolve upon discontinuation.^[371] Monitoring of liver function is recommended during oral or intravenous therapy to mitigate these risks.^[372]

J01XD Imidazole derivatives

Imidazole derivatives in the ATC code J01XD are a subclass of nitroimidazole antibacterials primarily effective against anaerobic bacteria and certain protozoa, acting through the generation of toxic metabolites under low-oxygen conditions.^[373] These agents are prodrugs that require reductive activation of their nitro group by ferredoxin-like proteins in anaerobic cells, leading to the formation of reactive intermediates such as nitroso radicals and hydroxyamino derivatives. These intermediates damage bacterial DNA by causing strand breaks and inhibiting nucleic acid synthesis, resulting in cell death; the mechanism is selective for anaerobes because the reduction process is oxygen-sensitive and does not occur efficiently in aerobic environments.^{[374][375][376]} The primary drugs in this group include metronidazole (J01XD01), available in oral and intravenous formulations, and tinidazole (J01XD02), which has a longer half-life allowing for once-daily dosing. Metronidazole is widely used for treating infections caused by obligate anaerobes, such as intra-abdominal abscesses, bacterial vaginosis, and Clostridium difficile-associated diarrhea, often administered intravenously in severe cases at doses of 500 mg every 8 hours.^{[377][374][378]} Tinidazole shares a similar spectrum but is preferred for its extended duration of action, typically dosed at 2 g once daily for anaerobic infections. Both drugs are also components of combination regimens for Helicobacter pylori eradication, combined with a proton pump inhibitor and other antibiotics like clarithromycin, to address gastric ulcers associated with anaerobic components of the infection.^[379][380] Concomitant use with alcohol is contraindicated due to the risk of a disulfiram-like reaction, characterized by flushing, nausea, and tachycardia, stemming from potential inhibition of aldehyde dehydrogenase.^[381] Although classified under antibacterials in J01XD, these derivatives exhibit significant activity against protozoal pathogens like Giardia lamblia, where metronidazole is a first-line treatment at 250 mg three times daily for 5-7 days, reflecting their dual utility despite the ATC focus on bacterial indications. Resistance to metronidazole is emerging among Bacteroides species, with rates reaching up to 12.5% in some clinical isolates, often mediated by nim genes that inactivate the drug via nitroimidazole reduction enzymes. This trend has prompted consideration of intravenous alternatives, such as vancomycin for Clostridium difficile infections, particularly in 2025 guidelines emphasizing susceptibility testing for Bacteroides infections to guide therapy.^{[378][382][383][384]}

J01XE Nitrofuran derivatives

Nitrofuran derivatives, classified under ATC code J01XE, represent a group of synthetic antibacterials primarily employed for treating urinary tract infections (UTIs) due to their selective concentration in urine. These agents exert bactericidal effects through activation by bacterial nitroreductases, leading to redox cycling that generates reactive oxygen species (ROS), which damage bacterial DNA, proteins, and lipids.^{[385][386][387]} This mechanism disrupts essential cellular processes, including DNA synthesis and protein function, without relying on common resistance pathways like efflux pumps or enzymatic inactivation.^[388] The primary drug in this subclass is nitrofurantoin (J01XE01), available as oral macrocrystals or monohydrate/macrocrystals formulations, which achieve high urinary concentrations while minimizing systemic exposure. It is indicated for acute uncomplicated cystitis caused by susceptible gram-negative and gram-positive bacteria, such as Escherichia coli and Enterococcus species, with typical dosing of 100 mg twice daily for 5-7 days.^{[388][389][390]} Nitrofurantoin is contraindicated in pyelonephritis or upper UTI due to inadequate tissue penetration and low serum levels, which limit its efficacy beyond the bladder.^{[389][391][392]} Furazidin (J01XE03), another nitrofuran derivative, shares a similar profile and is used for uncomplicated lower UTIs, often at doses of 50-100 mg three to four times daily for 5-7 days, targeting pathogens like E. coli.^{[393][394][395]} Like nitrofurantoin, it relies on urinary excretion for activity and is not suitable for systemic infections. Resistance to nitrofurans remains rare, with prevalence in uropathogenic E. coli typically below 5%, attributed to the requirement for multiple chromosomal mutations in bacterial nitroreductases for inactivation, as the drug's activation occurs primarily within the host urinary environment rather than systemically.^[396][397] This low resistance profile positions nitrofurans as a preferred option for UTIs caused by extended-spectrum beta-lactamase (ESBL)-producing strains, where susceptibility rates exceed 95% in many regions.^[398] By 2025, amid rising ESBL prevalence, nitrofurantoin has seen renewed adoption for outpatient ESBL-UTIs, with clinical failure rates around 22% in retrospective cohorts but overall effectiveness in over 75% of cases, particularly against ESBL-E. coli.^{[399][400][401]} Adverse effects of nitrofuran derivatives are generally mild but include gastrointestinal upset and headache with short-term use. Chronic administration of nitrofurantoin (>6 months) carries a risk of pulmonary toxicity, manifesting as acute pneumonitis or progressive fibrosis, necessitating prompt discontinuation upon respiratory symptoms.^[390][402] Hemolytic anemia is a serious concern in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, where the drug's oxidative stress exacerbates red blood cell breakdown; screening is recommended, and use is contraindicated in severe cases.^{[403][404][405]}

QJ01XQ Pleuromutilins (Veterinary)

Pleuromutilins represent a class of antibiotics exclusively classified under the veterinary ATC code QJ01XQ for systemic use in animals, primarily targeting Gram-positive bacteria and mycoplasmas in livestock such as pigs and poultry.^[406] These agents, derived from the natural compound pleuromutilin produced by the fungus Pleurotus mutilus, are semisynthetic derivatives designed for bacteriostatic activity against pathogens causing respiratory and enteric infections. Key examples include tiamulin (QJ01XQ01) and valnemulin, which have been approved for use in food-producing animals across Europe and other regions since the late 1970s and 1990s, respectively.^[407][408] Unlike their human counterpart lefamulin (classified in J01XX), veterinary pleuromutilins focus on animal-specific applications without systemic human use.^[409] The mechanism of action for pleuromutilins involves binding to the peptidyl transferase center (PTC) of the 50S ribosomal subunit in bacteria, thereby inhibiting protein synthesis by preventing peptide bond formation during translation. This interaction occurs at the A-site of the ribosome, overlapping with the binding sites of other antibiotics like chloramphenicol and clindamycin, but with a unique tricyclic core that confers specificity for Gram-positive organisms and mycoplasmas such as Mycoplasma hyopneumoniae and Brachyspira hyodysenteriae.^[410][411] Tiamulin, for instance, exhibits high potency against swine pathogens, achieving therapeutic concentrations in lung tissue following oral administration in feed or water, while valnemulin demonstrates similar efficacy with enhanced bioavailability in pigs and poultry.^[412][413] In veterinary practice, tiamulin is primarily indicated for treating swine dysentery (Brachyspira hyodysenteriae), enzootic pneumonia (Mycoplasma hyopneumoniae), and ileitis in pigs, often administered via medicated feed at doses of 10-20 mg/kg body weight for 3-5 days. Valnemulin targets similar conditions in pigs, including proliferative enteropathy and spirochaetal colitis, and is also used in poultry for chronic respiratory disease caused by Mycoplasma gallisepticum, with oral premixes providing effective control in broiler and layer flocks. Topical formulations of pleuromutilins, such as tiamulin sprays, are employed for localized skin infections in pigs, reducing bacterial load without systemic exposure. These uses are supported by European Medicines Agency approvals, emphasizing their role in controlling outbreaks in intensive farming systems.^{[414][415][413]} Resistance to pleuromutilins remains rare in veterinary settings, attributed to their low propensity for cross-resistance with other ribosomal inhibitors and the absence of widespread plasmid-mediated mechanisms; primary resistance arises from rare chromosomal mutations in the 23S rRNA, such as those mediated by the cfr methylase enzyme, with prevalence below 1% in monitored European pig and poultry isolates as of 2023. Safety profiles are favorable, with no detectable residues in milk or eggs exceeding maximum residue limits (e.g., 0.05 mg/kg for tiamulin in poultry products) when withdrawal periods are observed, ensuring compliance with food safety standards set by the European Food Safety Authority. Hypersensitivity reactions in handlers are possible but uncommon, and concurrent use with ionophores like salinomycin must be avoided due to toxic interactions.^{[416][417][418]}

J01XX Other antibacterials

The J01XX subgroup within the Anatomical Therapeutic Chemical (ATC) classification system encompasses antibacterials for systemic use that do not fit into other defined categories, primarily targeting resistant Gram-positive bacterial infections through diverse mechanisms of action.^[419] These agents include older compounds like fosfomycin for urinary tract infections and newer synthetic drugs developed to address multidrug-resistant pathogens, such as oxazolidinones and lipopeptides. Their introduction has provided alternatives when standard therapies like beta-lactams or glycopeptides fail, though they are reserved for specific indications due to potential toxicities and emerging resistance. Fosfomycin (J01XX01), a phosphonic acid derivative discovered in the late 1960s, inhibits bacterial cell wall synthesis by blocking the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), which catalyzes the first committed step in peptidoglycan formation. It is primarily indicated for uncomplicated urinary tract infections (UTIs) in women, administered as a single 3 g oral dose of fosfomycin tromethamine, achieving high urinary concentrations with low systemic exposure. This formulation is also used for post-exposure prophylaxis (PEP) in certain UTI scenarios, such as after sexual activity or instrumentation, due to its broad-spectrum activity against Enterobacteriaceae including multidrug-resistant strains. Resistance to fosfomycin arises mainly from chromosomal mutations in murA or transport genes like glpT, but plasmid-mediated mechanisms are increasingly reported in clinical isolates. Linezolid (J01XX08), the first oxazolidinone approved in 2000, exerts its bacteriostatic effect by binding to the P site of the 50S ribosomal subunit, inhibiting the formation of the 70S initiation complex and blocking protein synthesis initiation in Gram-positive bacteria. It is approved for treating serious infections such as nosocomial and community-acquired pneumonia, complicated skin and soft tissue infections, and bacteremia caused by vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Oral and intravenous formulations allow for step-down therapy, with typical dosing at 600 mg every 12 hours. Resistance, often mediated by the cfr gene encoding 23S rRNA methyltransferase, reduces binding affinity and has been documented in clinical settings, particularly with prolonged use. Tedizolid (J01XX11), a next-generation oxazolidinone approved in 2014, shares a similar mechanism but demonstrates improved potency and reduced myelosuppression compared to linezolid, with once-daily 200 mg dosing for acute bacterial skin and skin structure infections due to MRSA or Streptococcus species. Daptomycin (J01XX09), a cyclic lipopeptide derived from Streptomyces roseosporus and approved in 2003, disrupts bacterial cell membrane function by inserting calcium-dependent multilayers into the membrane, leading to rapid depolarization, potassium efflux, and cell death, primarily against Gram-positive organisms. It is indicated for complicated skin and skin structure infections at 4 mg/kg IV daily and Staphylococcus aureus bloodstream infections (bacteremia) at 6 mg/kg IV daily, including right-sided endocarditis. Efficacy is maintained against vancomycin-intermediate S. aureus strains, but non-inferiority trials show comparable outcomes to standard therapies in resistant cases. A key adverse effect is dose-dependent myopathy, manifesting as elevated creatine kinase levels, necessitating weekly monitoring and statin avoidance. Resistance develops via mutations in mprF or yycG, altering membrane composition and reducing insertion. Lefamulin (J01XX12), a semi-synthetic pleuromutilin approved in 2019, inhibits bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit, preventing peptide bond formation and showing activity against Gram-positive and atypical pathogens. It is specifically indicated for adults with community-acquired bacterial pneumonia (CABP) caused by Streptococcus pneumoniae, MRSA, or Haemophilus influenzae, with 150 mg IV every 12 hours or 600 mg oral every 12 hours for 5-7 days. Phase 3 trials demonstrated non-inferiority to moxifloxacin in early clinical response rates, around 87%, supporting its role in reducing fluoroquinolone use. Resistance is rare but involves ribosomal mutations, with ongoing surveillance needed for emerging strains.