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Methicillin sodium salt (also known as Meticillin sodium) is a β-lactam antibiotic of the penicillin class. It acts by inhibiting penicillin-binding proteins that are involved in the synthesis of peptidoglycan. Compared to other penicillins that face antimicrobial resistance due to β-lactamase, it is less active, can be administered only parenterally, and has a higher frequency of interstitial nephritis, an otherwise-rare adverse effect of penicillins. However, selection of methicillin depended on the outcome of susceptibility testing of the sampled infection, and since it is no longer produced, it is also not routinely tested for any more. It also served a purpose in the laboratory to determine the antibiotic sensitivity of Staphylococcus aureus to other penicillins facing β-lactam resistance; this role has now been passed on to other penicillins, namely cloxacillin, as well as genetic testing for the presence of mecA gene by PCR.
| Targets |
β-lactam
Bacterial penicillin-binding proteins (as a penicillinase-resistant penicillin). The minimal inhibitory concentration (MIC) of methicillin against the test strain of Enterococcus used in this study was 25 μg/ml. [1] |
|---|---|
| ln Vitro |
Methicillin sodium salt (100 μg/mL; 18 h) incubates intracellularly for 18 hours before killing S. aureus[1].
The MIC of methicillin for the test enterococcal strain was 25 μg/ml as determined by standard broth dilution technique. [1] In time-kill synergy studies performed in dextrose-phosphate broth, methicillin at a concentration of 15 μg/ml (a clinically achievable level) combined with gentamicin (5 μg/ml) showed synergistic killing against the test enterococcal strain, defined as a ≥100-fold increase in killing after 24 hours compared to the most effective single agent and a ≥1000-fold decrease from the initial inoculum. [1] |
| ln Vivo |
Methicillin sodium salt (42.5 and 85 mg/kg) against enterococcus in leukocytes, administered intramuscularly four times a day for 21 days or until the cells die naturally[1].
Mice infected with methicillin sodium salt (400 mg/kg; intraperitoneally once) fare better than the comparison group[2]. Mice with infection cannot die if methicillin sodium salt (400 mg/kg; i.h. once) is administered[2]. In a rabbit model of experimental enterococcal endocarditis, treatment with methicillin (42.5 mg/kg per dose, intramuscularly, four times daily) combined with gentamicin (3.5 mg/kg per dose) resulted in only 1 out of 6 rabbits (16.6%) surviving 21 days of therapy with sterile cardiac valves at autopsy. [1] When the dose of methicillin was increased to 85 mg/kg per dose (equivalent to 24 g/day in a 70-kg human) in combination with the same gentamicin regimen, 4 out of 10 rabbits (40%) survived 21 days with sterile valves. The total proportion of animals (including those dying before day 21) with sterile valves was 6 out of 10 (60%). However, the improvement over the lower dose was not statistically significant. [1] The study concluded that the combination of methicillin and gentamicin was not effective in vivo for treating enterococcal endocarditis in this model, despite demonstrating in vitro synergy. [1] |
| Cell Assay |
Cell Line: Leukocytes
Concentration: 100 μg/mL Incubation Time: 18 hours Result: demonstrated superior results in an aerobic environment and successfully eradicated S. aureus at a 3.13 μg/mL bactericidal concentration. |
| Animal Protocol |
Animal Model: White New Zealand rabbits, weighing 2.0 to 3.0 kg[1]
Dosage: 42.5 and 85 mg/kg Administration: Intramuscular injection; 42.5 and 85 mg/kg four times daily; for 21 days or till spontaneous death Result: Inhibited enterococcus at 24 hours with a half-live of 1.1 h, but showed no statistical significance to rabbits. Experimental enterococcal aortic valve endocarditis was induced in white New Zealand rabbits (2.0–3.0 kg) by insertion of a polyethylene catheter into the left ventricle, followed by intravenous injection of 10⁵–10⁶ enterococcal organisms 24 hours later. [1] Treatment commenced 24 hours after bacterial injection. Methicillin was administered intramuscularly four times daily (at 9 a.m., 1 p.m., 5 p.m., and 11 p.m.) at two dose levels: 42.5 mg/kg per dose (equivalent to 12 g/day in a 70-kg human) and 85 mg/kg per dose (equivalent to 24 g/day in a 70-kg human). [1] Gentamicin was co-administered intramuscularly at a dose of 3.5 mg/kg, also four times daily. [1] Therapy duration was 21 days. Animals were autopsied after spontaneous death or at the end of therapy; cardiac vegetations were removed, homogenized, and cultured to determine sterilization. [1] |
| ADME/Pharmacokinetics |
In rabbits, the estimated serum half-life after intramuscular injection of methicillin (at a dose of 42.5 mg/kg) was 1.1 hours. [1] The mean peak serum concentration of methicillin at a dose of 42.5 mg/kg exceeded its minimum inhibitory concentration (MIC, 25 μg/ml) against the test bacteria by more than 1.2 times. At a dose of 85 mg/kg, the ratio of peak serum concentration to MIC increased to 3.2. [1] Serum antibiotic concentrations were determined using Bacillus globigii as the test strain by agar diffusion method. [1]
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| Toxicity/Toxicokinetics |
To assess potential drug toxicity, four uninfected rabbits underwent the same surgery and were then treated with a high dose of methicillin (85 mg/kg each time) in combination with gentamicin for 21 days. All four rabbits survived to the end of the treatment period, and autopsies showed sterile valves, indicating that the drug combination did not cause acute lethal toxicity under experimental conditions. [1]
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| References | |
| Additional Infomation |
Methicillin sodium is an organic sodium salt containing a methicillin (1-) group. Methicillin sodium is the sodium salt form of methicillin, a semi-synthetic β-lactam penicillin antibiotic with anti-β-lactamase activity. Methicillin sodium has a bactericidal effect; it binds to specific penicillin-binding proteins on the surface of bacteria, inhibiting transpeptidase and thus preventing cross-linking of peptidoglycan. This leads to the destruction of the bacterial cell wall, ultimately resulting in bacterial lysis. Methicillin sodium is effective against β-lactamase-producing Staphylococcus. Methicillin sodium is one of the few penicillins that are resistant to penicillinase but sensitive to penicillin-binding proteins. It is easily inactivated by gastric acid and is therefore usually administered by injection. Methicillin is a semi-synthetic penicillin that is anti-penicillinase. [1] This study evaluated the potential of combination therapy of methicillin and gentamicin as an alternative to penicillin G for the initial treatment of suspected enterococcal endocarditis. [1]
Although in vitro experiments showed that methicillin and gentamicin had a synergistic effect on the test enterococci, the combined use of methicillin and gentamicin was not effective in a rabbit endocarditis model and was considered inferior to the combined use of penicillin G and gentamicin. [1] |
| Molecular Formula |
C17H19N2O6S-.NA+
|
|---|---|
| Molecular Weight |
402.39736
|
| Exact Mass |
402.086
|
| CAS # |
132-92-3
|
| Related CAS # |
Methicillin;61-32-5;Methicillin sodium hydrate;7246-14-2
|
| PubChem CID |
23667627
|
| Appearance |
White to off-white solid powder
|
| Boiling Point |
640ºC at 760 mmHg
|
| Melting Point |
196-197℃
|
| Flash Point |
340.9ºC
|
| Vapour Pressure |
2.94E-17mmHg at 25°C
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
27
|
| Complexity |
606
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)C3=C(C=CC=C3OC)OC)C(=O)[O-])C.[Na+]
|
| InChi Key |
MGFZNWDWOKASQZ-UMLIZJHQSA-M
|
| InChi Code |
InChI=1S/C17H20N2O6S.Na/c1-17(2)12(16(22)23)19-14(21)11(15(19)26-17)18-13(20)10-8(24-3)6-5-7-9(10)25-4;/h5-7,11-12,15H,1-4H3,(H,18,20)(H,22,23);/q;+1/p-1/t11-,12+,15-;/m1./s1
|
| Chemical Name |
sodium;(2S,5R,6R)-6-[(2,6-dimethoxybenzoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
|
| Synonyms |
Methicillin sodium salt
|
| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~125 mg/mL (~310.64 mM )
H2O : ~100 mg/mL (~248.51 mM ) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.08 mg/mL (5.17 mM) Solubility in Formulation 5: 100 mg/mL (248.51 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4851 mL | 12.4254 mL | 24.8509 mL | |
| 5 mM | 0.4970 mL | 2.4851 mL | 4.9702 mL | |
| 10 mM | 0.2485 mL | 1.2425 mL | 2.4851 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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