402 



DESCRIPTIONS OF ANTIBIOTICS 



to 9.2 to give precipitation of vancomycin on or 

 with the Zn(0HJ2 formed. Vancomycin removed 

 by conversion to the vvater-sohible oxalate, the 

 zinc oxalate being in.soluble. Treated as in I (9). 

 III. Adsorbed on low cross-linked J)o\vex 50 (H"*" 

 and Na"*" forms) from broth-filtrates. Eluted with 

 30 per cent acetone containing 1 per cent triethyl- 

 amine. Eluates concentrated and acidified to pH 

 3.2. Hydrochloride treated as in I (9). 



Chemical and physical properties: Complex con- 

 taining two components. Free base: Amphoteric 

 substance containing organic chlorine. Colorless 

 rosettes. Very soluble in water, dimethyl sulfox 

 ide, dimethylacetamide, and other polar, water- 

 miscible solvents. Moderately soluble in aqueous 

 methanol. Insoluble in organic solvents, other 

 than those above. Forms salts with orange II, 

 methyl orange, and p-(p'-hydroxyphenyl)azoben- 

 zene-sulfonic acid. Precipitated from an aqueous 

 solution with phosphomolybdic or phosphotung 

 Stic acids and heavy metals. Ammonium sulfate 

 and sodium chloride precipitate it from acidic 

 solutions. Forms solvates. Titration data given 

 in reference 9. C = 54.91%; H = 5.85%; N = 

 8.66%,; CI = 4.27%; carbohydrate = 10 to 17%. 

 No S or P (1, 8, 9). Sulfate: Crystalline state lost 

 on drying. Very soluble in 50 per cent methanol 

 containing 10 per cent urea. Insoluble in methanol. 

 Ultraviolet absorption spectrum maxima at 278 

 (Ell, 38.7) (in acid) or 300 m^ (£^JJm 41.3) (in 

 alkali). Hydrochloride: White amorphous sub- 

 stance. Soluble in water; moderately solul^le in 

 aqueous methanol and jjlienol; insolul)le in other 

 organic solvents. Ultraviolet absorption spectrum 

 maximum at 280 to 282 niyu (in acid), shifting to 

 303 to 305 m/x (in alkali). Infrared spectrum given 

 in reference 1 and data in reference 8. Positive 

 biuret, xanthoproteic, Molisch, Seliwanoff, an- 

 throne (carbohydrate), and Folin-Ciocalteau (phe- 

 nol) tests. Negative ninhydrin, Barfoed, glucose 

 oxidase coupled dye oxidation (for glucose), Saka- 

 guchi, Elson-Morgan, Fehling, Benedict, orcinol, 

 HCl, Tollen phloroglucinol, Tollen naphthoresor- 

 cinol, Liebermann, and Ehrlich (aldehyde) tests. 

 Green-Vjrown color with FeCls test. Paper chroma- 

 tographic V)ehavior given in reference 8. Isoelectric 

 point about pH 5.0. Most stable at pH 3 to 5 and 

 at low temperatures. Not destroyed by a variety 

 of enzymes (1, 8, 9). Contains carboxyl, amino, and 

 phenolic groups. Molecular weight, 3300. Hydroly- 

 sis with acid or alkali gives two ninhydrin-positive 

 substances: one, aspartic acid, the other unknown, 

 which gives an immediate atypical brown color 

 with ninhydrin, slowly changing to blue. Partial 

 hydrolysis with dilute acid gives glucose (9). 



Hiolngical activity: Active on gram-positive bac- 

 teria, mycobacteria, and some spirochetes. 

 Slightly- active on certain gram-negative bacteria. 

 Not active on fungi (1). Bactericidal, acting only 

 on multiplying bacteria (2). Less active on a 

 weight basis than erythromycin and penicillin (8). 

 Activity unaffected by pH. Resistance develops 

 slowly. No cross-resistance with erythromycin, 

 spiramycin, antibiotic E 129, or novobiocin (4). 

 Active in vivo against Staph, aureus, Streptococcus 

 pyogenes, D. pneumoniae type I, and Borrelia 

 novyi infections in mice treated parenterally (1). 

 No effect (mice) on Toxoplasma gondii, herpes 

 simplex, or vaccinia viruses (5). Biological activity 

 of the second, minor component of the complex is 

 not known (9). 



Toxicity: LDsn (mice) 489 to 700 mg per kg in- 

 travenously, 1734 mg per kg intraperitoneally, 5 

 gm per kg subcutaneously, with sloughing and 

 necrosis, and 5 gm per kg orally. LDoo (rats) 319 

 mg per kg intravenously, 221 mg per kg intraperi- 

 toneally. LDoo (guinea pigs) 737 mg per kg intra- 

 peritoneally. Repeated intravenous doses cause 

 thrombosis and edema in monkeys (0, 8). Highest 

 concentration permitting epithelial cell migration 

 in tissue culture is 8.1 mg per ml (11). 



Utilization: Antibiotic-resistant staphylococcal 

 or streptococcal infections (10). Clinical trials 

 indicate that use of the drug would be limited by 

 side effects such as irritation of tissues, drug-in- 

 duced fever, and possible renal irritation (7). 



References: 



1. McCormick, ]\I. H. et al . Antil)iotics Ann. 



60(i-611, 1955-1956. 



2. Ziegler, D. W. e/ ai. Antibiotics Ann. 612- 



618, 1955-1956. 



3. Pittenger, R. C. and Brigham, R. B. Anti- 



biotics & Chemotherapy 6: 642-647, 1956. 



4. Garrod, L. P. and Waterworth, P. M. Brit. 



Med. J. 2: 61-65, 1956. 



5. Geraci, J. E. et al. Proc. Staff ^Meetings 



Mayo Clinic 31: 564-582, 1956. 



6. Anderson, R. C. et al. Antibiotics Aim. 



75-81, 1956-1957. 



7. Kirby,W.M.:\I. andDivelbiss, C.L. Anti- 



biotics Ann. 1956-1957, pp. 107-117. 



8. Nishimura, H. ct al. Shionogi Kenkyusho 



Nempo 7: 465-471, 1957. 



9. Higgins, H. M. et al. Antibiotics Ann. 



1957-1958, pp. 906-914. 



10. Kirby, W. M. M. et al. Antibiotics Ann. 



1958-1959, pp. 580-586. 



11. Lawrence, J. C. Brit. J. Pharmacol. 14: 



168-173, 1959. 



