CIBA-GEIGY,,

MEYER-BRUNOT, H. G.

STUFLESSER, H.

THEOBALD, W.

WALKER, N.

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188 CorrespondenceMicrobiological assessment of the concentrationof cephacetrile in plasma and cancellousbone of femoral headsSir,We have been interested in the ability of theantibiotic, cephacetrile, in therapeutic con-centrations, to enter bone tissue. Cephacetrilewas administered in a dose of 0-5 g i.v.initially followed by constant infusion of0-5 g/h for 4 to 18 h. The material used forour study consisted of the excised femoralheads from 15 patients who wese fittedwith artificial hip-joints due to coxarthrosis.We are of course conscious of the negativeselection of this material, since it is well knownthat coxarthrosis is accompanied by deficientcirculation of the blood in the bone tissue.Nevertheless, following intravenous cephace-trile infusion lasting several hours, until thesteady state was achieved, we have been ableto demonstrate that cephacetrile reaches thebone in therapeutically adequate concentra-tions (Table I).The method used is based on the micro-biological determination of the concentrationof the antibiotic in the cancellous bone of thehead of the femur, after subtraction of thecephacetrile content of the blood in thecancellous bone.The quantitative blood content of thehomogenized bone substance was calculatedvia the determination of haemin, by a newprocedure which has not yet been published.Table L Cephacetrile concentrations in plasma andin blood-free cancellous bone at the time ofexcision of the femoral headTable IL Cephacetrile concentrations in plasma-water and in bone-water (content in bone calcu-lated on the total water content of the bone)Patient Plasma Blood-free spongiosa(ug/ml) (ug/g) % of plasmaDuring the cephacetrile infusionA.A.F.M.R.B.S.LB.I.K.I.S.L.W.K.K.H.H.H.S.G.2 to 4-5 hB.H.G.M.E.D.M.I.49146-7540-238-836-332-825-725-024-715314-3after end7-84-754-74-011-756-926-062-543172-457-365-232-853-477-94of cephacetrile2-44~2-O8~l-99~O-8723-914-8151668-77-528-620-911522-755-5x = 19-6infusion31 343-842-321-8x = 34-8PatientA.A.F.M.R.B.S.I.B.I.K.LS.L,W.K.K.H.H.H.S.G.Concentrationin plasma-water(|ig/ml)36-8335-0630-15291027-2324-619-2818-7518-5311-4810-73Concentrationin bone-water(ug/ml)40-30*23-9215-95*16-0498110-3919-9214-7110-9711 7924-09*Blood content of the cancellous bone: 5 to 33 jtf/g.•Values not directly comparable, since there wasno steady-state in the plasma.The deep-frozen bone was crushed at-80°C, homogenized with phosphate bufferand the cephacetrile content of the homo-genized bone substance determined by theagar well method (B. subtilis). A standardcurve was produced from a series of cephace-trile-concentration dilutions in antibiotic-freebone homogenate.The concentration of cephacetrile in can-cellous bone tissue (after subtraction of thecephacetrile content of the blood in the bonetissue), was, on average, one-fifth of theconcentration in serum (Table I).The elimination of cephacetrile from thecancellous bone tissue is slower than theelimination from the plasma because after theend of the infusion the concentration in thecancellous bone tissue, in relation to theconcentration in the plasma, is higher thanduring the infusion.To the question whether the cephacetrile isonly distributed in the water of the bone, or isadsorbed, for example to the canceUous bonetissue, we can say that cephacetrile is onlypresent in the water of the bone (see Table II).To summarize, cephacetrile can be detectedin the cancellous bone tissue in therapeuticconcentrations. It is however not adsorbed tothe cancellous bone tissue.H. STUFLESSERN. WALKERDepartment of Orthopaedic Surgery,University of Zurich, B.R.D.H. G. MEYER-BRUNOTW. THEOBALDCIBA-GEIGY,Basle, SwitzerlandCorrespondence 189In vitro activity of cefuroxime againstTreponema pallidumSir,Cefuroxime is a new parenteral broad spec-trum cephalosporin antibiotic, active against avariety of Gram-positive and Gram-negativeorganisms (O'Callaghan, Sykes, Griffiths &Thornton, 1976).A preliminary study was carried out toassess the in vitro activity of cefuroximeagainst Treponema pallidum by the immobiliz-ation test. Cerfuroxime was compared withpenicillin G, whose activity is already known(Galla, Pagnes & Ferrari, 1965) and two othercephalosporins, cefazolin and cephacetrile.The virulent Nichols strain of Treponemapallidum was cultivated by the intratesticularinfection of 6 months old New Zealand whiterabbits (Collart, Franceschini & Durel,1971). The rabbits were killed 8 days after theinfection and their testicles were removedaseptically and minced.The spirochetes were suspended in Dela-cretatz medium by gentle shaking (Dela-cretatz, 1953) and incubated with serialdilutions of the drugs at 37°C in N, (95 %) andCO, (5 %) atmosphere.The overnight cultures were checked for themotility of the spirochetes in the controlsuspensions; the anti-treponemic activity ofthe drugs was determined as the MinimumConcentration Immobilizing 100% of themicroorganisms (MlmQ.The data shown in Table I confirm theactivity of penicillin G (Galla, Pagnes &Ferrari, 1965). Cefuroxime also showed a highlevel of activity—greater than cefazolin andcephacetrile.Table L—Minimum immobilizing concentrationof p-Iactam antibiotics against Treponema pallidum,Nichols strainAntibiotic MImC Gig/ml)Penicillin GCefuroximeCefazolinCephacetrile0-00160-01250-255-0LUIGI XERRIPIERO ORSOLINIBiology Department, Research Division,Laboratori Glaxo S.p.A.-Duncan FarmaceuticiS.p.A.,Verona, ItalyReferencesCollart, P., Franceschini, P. & Durel, P. Experi-mental rabbit syphilis. British Journal ofVenereal Diseases 47: 389-400 (1971).Delacretatz, J. Etude d'un nouveau milieu dcsurvie pour les treponimes piles, utilisable parle test d'immobilisation (reaction de Nelson).Annales Dermatologie Syphiligraphie 80: 501(1953).Galla, F., Pagnes, P. & Ferrari, M. Antilueticactivity of Cephaloridine. Chemotherapia 10:24-30 (1965).O'Callaghan, C. H., Sykes, R. B., Griffiths, A. &Thornton, J. E. Cefuroxime, a new cephalo-sporin antibiotic: activity in vitro. Anti-microbial Agents and Chemotherapy 9: 511-9(1976).The effect of antibiotics andacetohydroxamic acid on bacteria]hydrolysis of ureaSir,Ammonia generated by intestinal bacteria andabsorbed into the circulation is implicated inthe genesis of the coma of hepatic failure(Schenker, Breen & Hoyumpa, 1974). Thebeneficial effects of antibiotics given tocorrect ammonia intoxication are generallyattributed to their bactericidal action butBelding & Kern (1963) found that oxytetra-cycline inhibited jack bean urease, and for thisreason suggested that it should be used intreatment. However, bacterial and plantureases are not identical (Hase & Kobashi,1967) and may differ in their sensitivities toantibiotics.To determine whether some benefit may beobtained from antibiotic therapy as a result ofanti-urease activity in addition to antibacterialactivity we have compared the action of fiveantibiotics, and a potent urease inhibitor,acetohydroxamic acid on a bacterial urease.Urease was prepared from Proteus ndrabilisgrown on blood agar base (Oxoid CM271)containing 2% urea. The bacteria wereharvested in 0-1 M-sodium phosphate bufferpH 7-2 containing 0-37 g/1 disodium EDTA,centrifuged at 4°C and resuspended in buffer.Cells were disrupted by ultrasonication,recentrifuged, and the supernatent put throughan 0-45 urn millipore filter. Samples weretested for sterility and potency and stored at-20°C.The antibiotics tested were neomycinsulphate, kanamycin sulphate, gentamicinsulphate, oxytetracycline and chlorampheni-col sodium succinate. Solutions of antibiotics

Microbiological assessment of the concentration of cephacetrile in plasma and cancellous bone of femoral heads

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