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Methicillin

Methicillin is a narrow-spectrum, semisynthetic β-lactam antibiotic belonging to the penicillin class, specifically designed as the first penicillinase-resistant agent to treat infections caused by penicillin-resistant Staphylococcus aureus. Developed by researchers at Beecham Research Laboratories in the late 1950s, it was introduced clinically in 1960 under the code name BRL 1241 and marketed as Celbenin or Staphcillin.92042-0/fulltext) Its chemical structure is derived from 6-aminopenicillanic acid (6-APA) acylated with 2,6-dimethoxybenzoyl chloride, rendering it stable against hydrolysis by staphylococcal β-lactamases.^[1] Methicillin exerts its bactericidal effect by binding to penicillin-binding proteins (PBPs), thereby inhibiting peptidoglycan cross-linking in the bacterial cell wall during active replication, primarily targeting gram-positive cocci such as staphylococci and streptococci.92042-0/fulltext) Administered intravenously or intramuscularly due to poor oral absorption, methicillin was initially used to treat serious infections including skin and soft tissue infections, osteomyelitis, endocarditis, pneumonia, and sepsis caused by penicillinase-producing staphylococci.^[2] However, its clinical utility was short-lived; resistance emerged rapidly, with the first cases of methicillin-resistant Staphylococcus aureus (MRSA) reported in 1961 in the United Kingdom, mediated by the acquisition of the mecA gene encoding the low-affinity PBP2a protein. By the 1970s, widespread MRSA prevalence and the development of safer alternatives like oxacillin and nafcillin diminished its role.^[3] Additionally, methicillin was associated with a high incidence of acute interstitial nephritis, an immune-mediated hypersensitivity reaction occurring in up to 17% of patients after 10 or more days of therapy, characterized by fever, rash, eosinophilia, and renal dysfunction.^[4] This toxicity, often resolving upon discontinuation but occasionally leading to permanent renal impairment, prompted its withdrawal from the market in the United States in the 1970s and its replacement by less nephrotoxic agents globally.^[2] Today, methicillin is no longer used clinically for human infections but remains a benchmark in laboratory testing for β-lactam resistance in staphylococci, where oxacillin is often substituted as a surrogate.^[5]

Medical uses

Therapeutic indications

Methicillin was primarily employed as a parenteral antibiotic, administered via intravenous or intramuscular routes, for treating serious infections caused by penicillin-resistant staphylococci, particularly beta-lactamase-producing strains of Staphylococcus aureus.^[6] It served as a key option in hospital settings for severe gram-positive infections during the mid-20th century, prior to the widespread emergence of resistance that limited its utility.^[7] Specific therapeutic indications included bacteremia (septicemia), endocarditis, osteomyelitis (bone and joint infections), pneumonia, and skin and soft tissue infections attributable to susceptible S. aureus.^[6] These applications targeted invasive or systemic staphylococcal diseases where narrower-spectrum beta-lactam alternatives were ineffective.^[8] Typical adult dosage regimens involved 1-2 grams administered intravenously every 4-6 hours, with adjustments made for renal impairment to prevent accumulation.^[6] For life-threatening infections, higher total daily doses up to 12 grams could be used in divided administrations.^[9] Methicillin is no longer produced or recommended for clinical use due to high rates of resistance and adverse effects, with preferred alternatives including oxacillin or nafcillin for susceptible strains and vancomycin for resistant cases.^[8]

Spectrum of activity

Methicillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class, exhibiting primary activity against gram-positive bacteria due to its targeted inhibition of cell wall synthesis in these organisms.^[8] Its spectrum is limited by a bulky side chain that restricts penetration into gram-negative bacterial outer membranes, rendering it ineffective against gram-negative bacteria, anaerobes, and most enterococci.^[10] Key susceptible organisms include methicillin-susceptible strains of Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Streptococcus pyogenes, and Streptococcus pneumoniae.^[8] In vitro, methicillin demonstrates bactericidal effects against these pathogens, with minimum inhibitory concentrations (MICs) for susceptible staphylococci typically ≤2 μg/mL (CLSI susceptible breakpoint ≤2 μg/mL), indicating the concentrations required to inhibit visible growth.^[11] Resistance to methicillin primarily arises through the acquisition of the mecA gene, which encodes penicillin-binding protein 2a (PBP2a), a low-affinity variant that allows continued cell wall peptidoglycan cross-linking even in the presence of the antibiotic, resulting in methicillin-resistant Staphylococcus aureus (MRSA).^[12] Additionally, methicillin's structure confers inherent resistance to staphylococcal beta-lactamases, as the bulky 2,6-dimethoxyphenyl side chain sterically hinders enzymatic hydrolysis of the beta-lactam ring.^[13] This dual protection initially expanded its utility against beta-lactamase-producing staphylococci, though widespread mecA-mediated resistance has since limited its clinical application.^[14]

Pharmacology

Mechanism of action

Methicillin is a beta-lactam antibiotic that exerts its bactericidal effect by binding to penicillin-binding proteins (PBPs), which are essential enzymes involved in the final stages of bacterial cell wall synthesis.^[15] These PBPs, particularly in staphylococci, include PBP1, PBP2, and PBP3, to which methicillin shows specific affinity, thereby inhibiting the cross-linking of peptidoglycan strands in the cell wall.^[16] This disruption weakens the structural integrity of the cell wall, leading to osmotic instability, autolysis, and ultimately bacterial death.^[15] A key feature of methicillin's efficacy against staphylococcal infections is its resistance to hydrolysis by beta-lactamases, enzymes produced by many resistant strains that typically degrade beta-lactam antibiotics. This stability arises from steric hindrance provided by the 2,6-dimethoxyphenyl side chain, which prevents the enzyme from effectively accessing and cleaving the beta-lactam ring.^[17] As a result, methicillin maintains its activity against beta-lactamase-producing staphylococci by preserving its ability to interact with PBPs.^[18] The antibacterial action of methicillin is time-dependent, characterized by slow, concentration-independent killing where efficacy is primarily determined by the duration that free drug concentrations remain above the minimum inhibitory concentration (MIC). Optimal bactericidal effects are achieved when this time above MIC constitutes 40-70% of the dosing interval, emphasizing the importance of frequent or prolonged dosing to sustain inhibition of cell wall synthesis.^[19] At the molecular level, methicillin's beta-lactam ring mimics the D-alanyl-D-alanine substrate of PBPs, allowing the antibiotic's carbonyl group to be attacked by the active-site serine residue of the enzyme. This nucleophilic attack opens the strained beta-lactam ring, forming a stable covalent acyl-enzyme complex that irreversibly inactivates the transpeptidase activity of the PBP, halting peptidoglycan cross-linking.^[20] The process can be represented as:

\text{PBP-Ser-OH} + \text{Methicillin} \rightarrow \text{PBP-Ser-O-C(O)-R} + \text{opened ring products}

where the acylation prevents the PBP from catalyzing the normal transpeptidation reaction essential for cell wall integrity.^[21]

Pharmacokinetics

Methicillin is administered exclusively via parenteral routes, either intravenously or intramuscularly, owing to its poor oral bioavailability of less than 10%; the drug is largely destroyed by gastric acid and exhibits negligible absorption from the gastrointestinal tract. Following intramuscular administration of a 1 g dose, peak plasma concentrations exceeding 10 µg/mL are achieved within 30 minutes to 1 hour. The drug distributes widely throughout body fluids and tissues, including the lungs, kidneys, liver, and bone, facilitating its use in systemic infections. Plasma protein binding is moderate, ranging from 30% to 40%. Penetration into the cerebrospinal fluid is limited under normal conditions but improves when the meninges are inflamed. Methicillin undergoes partial hepatic metabolism, with approximately 20% to 40% of the dose hydrolyzed to inactive penicilloic acid derivatives.^[8] Elimination occurs primarily via the renal route, with about two-thirds of an intramuscular dose excreted unchanged in the urine within 4 hours through a combination of glomerular filtration and active tubular secretion. The plasma half-life in adults with normal renal function is 25 to 60 minutes; this is markedly prolonged in renal impairment, reaching 4 to 6 hours in anuric patients. Due to its time-dependent antibacterial activity, frequent dosing is required to maintain therapeutic levels, but adjustments are essential in renal failure to prevent accumulation—for instance, reducing to 1 g every 12 hours when creatinine clearance is below 10 mL/min.

Adverse effects

Acute interstitial nephritis

Acute interstitial nephritis (AIN) is the most prominent renal adverse effect linked to methicillin, a penicillin-class antibiotic, with an incidence reported as high as 17% in patients receiving the drug for at least 10 days, exceeding rates observed with other penicillins such as nafcillin or ampicillin.^[22]^[23] This hypersensitivity-mediated condition typically manifests 7-10 days after initiating therapy, though onset can extend to 14 days in some cases.^[24]^[25] The pathophysiology involves a type IV delayed hypersensitivity reaction, primarily T-cell mediated, leading to inflammation in the renal interstitium and tubular damage.^[26] Methicillin specifically triggers granular deposition of immune complexes along the tubular basement membrane, potentially involving anti-tubular basement membrane antibodies that contribute to acute kidney injury (AKI).^[22] This process often accompanies broader hypersensitivity features, such as systemic allergic responses.^[26] Clinically, patients present with fever (in up to 80% of cases), rash, and peripheral eosinophilia forming the classic triad, alongside oliguria, rising serum creatinine levels indicating AKI, and potential progression to renal failure if untreated.^[26]^[22] Urinalysis commonly reveals pyuria, hematuria, white blood cell casts, and eosinophiluria, supporting the inflammatory etiology.^[27]^[28] Diagnosis relies on clinical suspicion in the context of recent methicillin exposure, elevated creatinine, and supportive laboratory findings, with renal biopsy providing definitive confirmation through demonstration of interstitial infiltrates dominated by lymphocytes, monocytes, and eosinophils, often with tubulitis.^[26]^[22] The procedure is particularly indicated in atypical or severe presentations to rule out alternative causes of AKI.^[26] Management centers on immediate discontinuation of methicillin, which is crucial for reversibility, supplemented by supportive measures such as fluid management and dialysis if AKI is severe.^[26] Corticosteroids, typically prednisone at 1 mg/kg daily, are recommended for persistent renal dysfunction beyond 5-7 days or in cases with significant inflammation, accelerating recovery.^[22]^[26] While many patients recover renal function, approximately 50% develop chronic kidney disease due to residual interstitial fibrosis.^[29]

Hypersensitivity reactions

Hypersensitivity reactions to methicillin primarily involve immune-mediated responses, with IgE-mediated type I reactions being the most common form. These reactions occur in approximately 1-10% of patients with a reported history of penicillin allergy, though the true incidence of confirmed hypersensitivity is lower, often around 1-2% upon testing.^[30]^[31] Common manifestations include urticaria, angioedema, and, rarely, anaphylaxis, which has an incidence of 0.015-0.04% among exposed patients. Serum sickness-like reactions, classified as type III hypersensitivity, may also occur, potentially overlapping with other immune-mediated effects such as acute interstitial nephritis. Anaphylaxis, though infrequent, can be life-threatening and typically presents within minutes to hours of administration.^[32]^[33]^[34] Key risk factors include prior exposure to penicillins or other beta-lactams, which increases the likelihood of sensitization, and a personal history of atopy or asthma, which may heighten the severity of reactions. Cross-reactivity with other beta-lactams, such as cephalosporins, is reported in up to 10% of cases based on historical data, though recent studies indicate rates closer to 2% or less, depending on side-chain similarities.^[35]^[36]^[37] Prevention begins with a thorough baseline assessment of allergy history prior to methicillin administration to identify at-risk patients. Skin testing for penicillin allergy is recommended to confirm hypersensitivity and guide safe use; positive results may necessitate alternative therapies. For patients requiring methicillin despite confirmed allergy, desensitization protocols can be employed to temporarily induce tolerance, starting with dilute doses and escalating gradually under supervision. In cases of anaphylaxis, immediate management includes intramuscular epinephrine, followed by supportive care such as antihistamines and corticosteroids.^[31]^[38]^[39]

Medicinal chemistry

Chemical structure

Methicillin has the systematic IUPAC name (2S,5R,6R)-6-[(2,6-dimethoxybenzoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid.^[8] Its molecular formula is C_{17}H_{20}N_{2}O_{6}S, and the molar mass is 380.42 g/mol.^[40] The molecule features a bicyclic core structure typical of penicillins, consisting of a four-membered \beta-lactam ring fused to a five-membered thiazolidine ring.^[8] This 4-thia-1-azabicyclo[3.2.0]heptane system includes geminal methyl groups at the 3-position and a carboxylic acid at the 2-position, with the \beta-lactam carbonyl at the 7-position providing the key reactive amide functionality.^[40] At the 6-amino position of the core, methicillin bears a 2,6-dimethoxybenzoyl side chain, characterized by a benzene ring substituted with methoxy groups at the ortho positions relative to the amide linkage.^[8] This bulky side chain imparts steric protection to the \beta-lactam ring, rendering it resistant to hydrolysis by many \beta-lactamases.^[17] The overall structure can be visualized as the penicillin nucleus with the extended aromatic side chain protruding from the amide nitrogen, emphasizing the fusion of the strained \beta-lactam and the sterically demanding acyl group.^[40]

Physicochemical properties

Methicillin appears as a white to off-white crystalline powder.^[6] It exhibits limited solubility in water, approximately 10 mg/mL at 25°C in phosphate-buffered saline (pH 7.2), rendering it sparingly soluble under neutral conditions, while showing greater solubility in ethanol (around 40 mg/mL) and methanol.^[41]^[42] The pKa value for its carboxylic acid group is 2.77, influencing its ionization and solubility profile in aqueous media.^[6] Methicillin demonstrates acid lability, degrading rapidly in gastric pH environments (below pH 5), which necessitates parenteral administration to avoid oral instability. It remains stable at neutral pH (5-8) but undergoes hydrolysis under alkaline conditions, with the beta-lactam ring susceptible to nucleophilic attack. In solution, reconstituted methicillin sodium (500 mg/mL) maintains potency for 24 hours at room temperature, up to 4 days at 2-8°C, or 4 weeks at -20°C, though it loses activity in certain saline or dextrose infusions.^[6]^[43] The octanol-water partition coefficient (logP) of methicillin is approximately 1.22, reflecting moderate lipophilicity that balances its hydrophilic and hydrophobic characteristics.^[6] This property, partly influenced by the dimethoxy groups in its structure, contributes to its membrane permeability considerations. As a parenteral agent, methicillin is formulated and supplied as its sodium salt for intravenous use, typically in ampules containing 1, 4, or 6 g, with added excipients such as buffers to ensure isotonicity and stability during administration.^[6]^[44]

History

Development

Methicillin was developed in 1959 by George N. Rolinson and colleagues, including F. R. Batchelor, J. H. C. Nayler, and S. Stevens, at Beecham Research Laboratories in Brockham Park, Surrey, UK.91642-1/fulltext)^[45] The effort was driven by the urgent need to counter the rising incidence of penicillin-resistant Staphylococcus aureus strains, which produced β-lactamase (penicillinase) that hydrolyzed the β-lactam ring of penicillin G, rendering it ineffective against hospital-acquired infections.91642-1/fulltext)^[46] Researchers focused on structural modifications to enhance β-lactamase stability while preserving the core antibacterial mechanism of inhibiting cell wall synthesis in Gram-positive bacteria. The initial synthesis involved a semisynthetic approach, starting with 6-aminopenicillanic acid (6-APA) isolated from penicillin G fermentations, followed by acylation at the 6-amino position with the 2,6-dimethoxybenzoyl group to yield the stable derivative (initially coded BRL 1241).^[47]^[6] This side chain innovation provided steric hindrance that prevented β-lactamase access to the β-lactam ring, allowing methicillin to remain active against penicillinase-producing staphylococci.91642-1/fulltext) Preclinical testing conducted by 1960 confirmed the compound's potency, showing bactericidal activity against hundreds of penicillin-resistant S. aureus strains in vitro and protective efficacy in mouse models of staphylococcal infection.91642-1/fulltext) Beecham filed a patent for the semisynthetic penicillins, including methicillin, in 1959 (GB 873049), which was granted in 1961.^[48] The name "methicillin" was adopted to highlight the two methoxy groups on the phenyl ring of the side chain.^[46]

Introduction and decline

Methicillin, a semisynthetic penicillin antibiotic, was first marketed in 1960 by Beecham Research Laboratories (now part of GlaxoSmithKline) under the brand name Celbenin in the United Kingdom and as Staphcillin in the United States, primarily for hospital-based intravenous treatment of staphylococcal infections resistant to earlier penicillins.^[46]^[49] During the 1960s and 1970s, it became a first-line therapy for serious Staphylococcus aureus infections in clinical settings, rapidly gaining adoption due to its resistance to staphylococcal penicillinase.^[7] However, resistance emerged swiftly; the first methicillin-resistant S. aureus (MRSA) isolates were reported in 1961 by Patricia Jevons in the UK, leading to the coining of the "MRSA" terminology and highlighting the drug's vulnerability to bacterial adaptation.^[50] By the early 1960s, limitations in methicillin's profile prompted the development of alternatives within the isoxazolyl penicillin class. Oxacillin was introduced in 1962, followed by flucloxacillin in 1970, offering superior oral bioavailability and reduced nephrotoxicity compared to methicillin, which required intravenous administration and carried a higher risk of acute interstitial nephritis.^[51] These improvements made the newer agents preferable for both hospital and outpatient management of staphylococcal infections, gradually supplanting methicillin in clinical practice.^[52] Methicillin's decline accelerated in the 1980s as MRSA prevalence surged in hospitals, with resistance rates reaching 20-50% in many regions, rendering the drug ineffective against a growing proportion of S. aureus isolates.^[53] By the late 20th century, widespread adoption of alternatives and the dominance of MRSA led to its obsolescence; production ceased in the 2000s amid declining demand and safety concerns.^[54] Despite its discontinuation, the term "methicillin-resistant" endures in MRSA nomenclature and diagnostic testing, even though the drug is no longer manufactured or used clinically as of 2025.^[55]

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