Polymyxins

Sample preparation Sandwich cream or ointment between two layers of 200 mesh sUica gel, extract with carbon dioxide MeOH 95 5 at 300 atmospheres at 55 at 2 mL/min for 75 min (restrictor 300°), sonicate the SFE tube, frits, emd silica gel with MeOH 100 mM HCl 25 75 containing 0.1% Tween 80 for 15 min, filter (0.2 pm), ipject an aliquot of the filtrate. (SFE removes the hydrocarbon base of the cream or ointment leaving behind the insoluble polymyxin.) 

Mobile phase MeCN buffer 21.5 78.5 (Buffer was 100 mM KH2PO4 containing 0.1% tri-fluoroacetic acid.) 

Taylor, L.T. Anal3iical inverse supercritical fluid extraction of polar pharmaceutical compounds from cream and ointment matrices. J.Pharm.BiomedAnal., 1994,12, 1227-1232 

Mobile phase Gradient. A was 0.15% trifluoroacetic acid in water. B was 0.15% trifluo-roacetic acid in MeCN. A B from 100 0 to 50 50 over 25 min. 

Danner, R.L. Joiner, K.A. Rubin, M. Patterson, W.H. Johnson, N. Ayers, K.M. Parrillo, J.E. Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide. AntimicrobAgents Chem-other, 1989, 33, 1428-1434 

Chemical Name Complex antibiotic see structural formula Common Name — 

O-X L-Y 1 L-DAB— L-DAII DAB = a ,7-dianninobutvric acid R alkanoyl X,Y,Z = amino acids 

Trade Name Manufacturer Country Year Introduced 

Bacterium Bacilluspolymyxa Nutrient medium Corn meal 

As described in U.S. Patent 2,595,605, in a pilot plant tank 225 liters of a medium containing the following ingredients was prepared 2% ammonium sulfate, 0.2% potassium di- 

001% ferrous sulfate heptahydrate, 0.5% yeast extract, 1% dextrose, 1% calcium carbonate and 3% corn meal. The fermentation medium was adjusted to pH 7.3 to 7.4. It was then sterilized for 30 minutes at 110°C. After sterilization the pH was about 7. To the medium was added 225 ml of mineral oil. 

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Most polymyxin B sold for human use in the United States is in dermatological, otic, and ophthalmic preparations that usually contain one or more other spectmm extending antibacterials such as bacitracin, neomycin sulfate [1404-04-2], C23H4gNg023, linear gramicidin, oxytetracycline [79-57-2],... 

Some polymyxins are sold for second-line systemic therapy. Polymyxin B sulfate and colistimethate sodium can be used for intravenous, intramuscular, or intrathecal administration, especially for Pseudomonas aerupinosa mP QXiosis, but also for most other gram-negative organisms, such as those resistant to first-line antibiotics. Nephrotoxicity and various neurotoxicities are common in parenteral, but not in topical, use. Resistance to polymyxins develops slowly, involves mutation and, at least in some bacteria, adaptation, a poorly understood type of resistance that is rapidly lost on transfer to a medium free of polymyxin. Resistance can involve changes in the proteins, the lipopolysaccharides, and lipids of the outer membrane of the cell (52). Polymyxin and colistin show complete cross-resistance. 

Bacitracin given parenteraHy is sufftciendy nephrotoxic that it is rarely used in human medicine for other than topical indications (80). Thus safe and effective use, especially as the zinc salt, is limited almost completely to ointments, sprays, and solutions for skin and ophthalmic use in concentrations of 250 to 1000 units per milliliter. Bacitracin is only rarely skin sensitizing. As in the case of polymyxin, bacitracin is usually combined with other antibiotics to enlarge its spectmm of activity, or with corticoids or analgesics to reUeve pain or itching. 

Although tyrothricia is too toxic for parenteral therapy, it was formerly sold in the United States as oral lo2enges. Modem tyrothricin formulations are composed of 70—80% tyrocidines and 30—20% linear gramicidins. Tyrocidines are not as active as linear gramicidins and are too toxic for any therapeutic use by themselves. The bactericidal linear gramicidins are used in the United States solely as an ophthalmic solution in combination with polymyxin B sulfate and neomycin sulfate. The linear gramicidin is used in this aqueous product as a substitute for bacitracin, which lacks stabiUty under such conditions. 

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