In Vitro Activities of Moxalactam and Cefotaxime Against Aerobic Gram-Negative Bacilli

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 90, p /0/ /06$0.00/0 Vol. 7, No. 6 In Vitro Activities of nd Aginst Aerobic Grm-Negtive Bcilli J. H. JORGENSEN,* S. A. CRAWFORD, AND G. A. ALEXANDER Deprtment of Pthology, The University of Texs Helth Science Center t Sn Antonio, Sn Antonio, Texs 7 The in vitro ctivities of two new bet-lctm ntibiotics, moxlctm disodium (LY 7935) nd cefotxime (HR-756), were compred with cefoxitin, cefmndole, cefuroxime, cephlothin, nd, in some instnces, crbenicillin, gentmicin, nd mikcin ginst erobic grm-negtive bcilli. Test isoltes included normlly cephlosporin-resistnt members of the Enterobctericee nd Pseudomons spp. nd vriety of nonfernenttive or oxidse-positive bcteri. Both moxlctm nd cefotxime demonstrted impressive in vitro ctivities ginst both groups of microorgnisms. The two new drugs were clerly more ctive thn ny of the other bet-lctm ntibiotics ginst species of Escherichi, Citrobcter, Enterobcter, Klebsiell, Proteus, Providenci, Pseudomons, nd Serrti. An dditive or synergistic effect could lso be demonstrted with the mjority of Pseudomons nd Serrti isoltes when either moxlctm or cefotxime ws combined with mikcin. disodium (LY 7935) nd cefotxime (HR-756) re two new semisynthetic bet-lctm ntibiotics. is structurlly unique mong bet-lctm compounds in tht n oxygen molecule hs been substituted for sulfur in the cephem nucleus (). Thus, the compound is properly termed -ox-bet-lctm ntibiotic., on the other hnd, is highly bet-lctmse-resistnt semisynthetic cephlosporin (3). Initil reports (, -6) indicte tht both compounds possess n extremely brod spectrum, which includes erobic grm-positive cocci, Enterobctericee, Pseudomons eruginos, Hemophilus influenze, nd certin nerobes. The present study compres the ctivities of both moxlctm nd cefotxime with other currently vilble ntibiotics ginst normlly cephlosporin-resistnt members of the Enterobctericee, Pseudomondcee, nd vriety of glucose nonfermenttive or oxidse-positive fermenttive bcilli. MATERIALS AND METHODS Antibiotics. disodium, cefmndole, nd cephlothin were funished by IJlly Reserch Lbortories, cefotxime ws provided by Hoechst- Roussel Phrmceuticls, nd cefoxitin ws supplied by Merck Shrp & Dohme. ws obtined from Roerig, Division of Pfizer Inc., cefuroxime cme from Glxo Lbortories, gentmicin ws from Schering Corp., nd mikcin ws provided by Bristol Lbortories. All ntibiotics were supplied s dry powders which were used to prepre ntibiotic stock solutions. Test orgnisms. Bcteril test strins represented clinicl isoltes from the Microbil Pthology Lbortories of the Bexr County Hospitl District nd the Audie Murphy Veterns Administrtion Hospitl. Enterobctericee orgnisms were identified by the API Profile Recognition System (Anlytb Products, Inc.) nd dditionl conventionl methods when required. Nonenteric bcteri were identified by the methods nd medi described by Wever (7). Antibiotic susceptibility tests. Agr dilution susceptibility tests were performed by the World Helth Orgniztion interntionl collbortive study method () with Mueller-Hinton gr (Difco Lbortories) nd n inoculum of 0' microorgnisms pplied with Steers replictor. After h of incubtion t 35 C, miniml inhibitory concentrtions (MICs) were defined s the lest concentrtion of ntimicrobil gents which prevented visible growth or llowed growth of no more thn three colonies. Synergy determintions. The bility of moxlctm or cefotxime to ct synergisticlly with mikcin ws determined by gr dilution checkerbord isobologrms (). Synergy ws defined s fourfold decrese in the MICs of both of the ntimicrobil gents when tested in combintion. An dditive effect resulted when t lest twofold decrese in the MICs occurred s result of the combintion. RESULTS Tble shows the results of susceptibility testing of normlly cephlosporin-resistnt species of the Enterobctericee. nd cefotxime showed mrked in vitro ctivity ginst nine isoltes of Proteus morgnii (MICs _ 0.06 nd,ug/ml, respectively). ws the next most ctive gent, followed by 937

2 93 JORGENSEN, CRAWFORD, AND ALEXANDER TABLE. Comnprtive ctivities of six bet-lctm ntibiotics ginst selected Enterobctericee Orgnisn (no. of isoltes) Antibiotic MJC50 MIC90 MIC rnge (pg/mi) (Ag/ml) (pg/mi) Proteus morgnii (9) P. rettgeri (7) Citrobcter freundii (0) Enterobcter erogenes (0) E. cloce (5) Serrti mrcescens () C(ephlothin 6 ANTIMICROB. AGENTS CHEMOTHER. 6 MIC50 nd MlC9o, MICs t which 50 nd 90% of the orgnisms were inhibited, respectively cefoxitin nd cefuroxime. Similr results were observed with seven isoltes of Proteus rettgeri. All isoltes were inhibited by,ug or less of moxlctm or cefotxime per ml. ws gin the next most ctive of the remining drugs. nd cefuroxime were less ctive, lthough 50% of the isoltes were inhibited by drug concentrtions chievble in serum. nd cefotxime were the most ctive gents tested ginst 0 isoltes of Citrobcter freundii (MICs ' Ag/ml). nd cefuroxime were the next most ctive gents, followed by cefoxitin nd cephlothin. nd cefotxime were essentilly equivlent in ctivity ginst Enterobcter erogenes nd Enterobcter cloce (MICs '.,g/ ml). nd cefuroxime were the next most ctive ginst Enterobcter spp., wheres cefoxitin nd cephlothin filed to demonstrte inhibition of these isoltes. nd cefotxime were the most ctive gents tested ginst isoltes of gentmicin-susceptible Serrti mrcescens, which were not effectively inhibited by the remining bet-lctm drugs. Results of testing selected gentmicin-resistnt Enterobctericee re shown in Tble. Eleven isoltes of Escherichi coli were inhibited by ytg of either moxlctm or cefotxiime per ml. The remining bet-lctm ntibiotics nd mikcin demonstrted rel-

3 TABLE. Comprtive ctivities of newer bet-lctm ntibiotics nd minoglycosides ginst gentmicinresistnt Enterobctericee Orgnism MICSO MICoG MIC rnge (no. of isoltes) Antibiotic (ug/mi) (pg/ml) (pg/ml) Escherichi coli () Gentmicin - Amiikcin - Klebsiell pneumonie () Gentmicin 6- Amikcin - Serrti mrcescens () Gentmicin - Amikcin -6 See Tble, footnote. TABLE 3. Comprtive ctivities of seven ntibiotics ginst Pseudomons spp. Orgnism.nii.cMIC50 MIC.O MIC rnge (no. of isoltes) Antibotic (pg/mli) pg/ml) (ug/ml) Pseudomons eruginos (53) Crbenicilhin 6-56 Gentmicin - Amikcin - P. mltophili () - 6- CrbeniciUlin P. putid (0) Cefuroxine CrbeniciUin 5 >5 56->5 P. putrefciens () See Tble, footnote.

4 90 JORGENSEN, CRAWFORD, AND ALEXAI tively good ction ginst these isoltes. However, four of these isoltes were found to be mikcin resistnt. Fourteen gentmicin-resistnt isoltes of Klebsiell pneumonie were inhibited by,ug or less of either moxlctm or cefotxime per ml. The remining bet-lctm compounds nd mikcin showed moderte inhibition of these isoltes. nd cefotxi;me were equivlent to ech other by being the most ctive compounds tested ginst multiply resistnt isoltes of S. mrcescens. All Serrti isoltes were mikcin susceptible but were not inhibited by ny of the other betlctm ntibiotics. Three gentmicin-resistnt Providenci sturtii nd one C. freundii isolte (not shown in Tble ) were susceptible to,ug TABLE. ANTIMICROB. AGENTS CHEMOTHER. or less of either moxlctm or cefotxime per ml Ṫble 3 shows results of testing species of Pseudomons ginst these sme compounds plus crbenicillin. Both moxlctm nd cefotxime demonstrted in vitro inhibition of P. eruginos, in contrst to the other cephlosporin or cephmycin clss of ntibiotics, which filed to show inhibition. proved slightly superior to moxlctm ginst Pseudomons mltophili, Pseudomons putid, nd Pseudomons putrefciens, none of which ws effectively inhibited by the other bet-lctm drugs. Tble lists results obtined when other commonly isolted glucose-nonfermenttive grm- Comprtive ctivities ofseven bet-lctm ntibiotics ginst frequently isolted nonfermenttive orgnisms Orgnism Antibiotic MIC50 MIC MIC rnge (no. of isoltes) (jag/ml) (jg/mi) (jg/ml) Acinetobcter nitrtus () A. lwoffi (5) Commons terrigen (5) Achromobcter xylosoxidns () Morxell spp. () See Tble, footnote > >

5 VOL. 7, 90 negtive bcilli were exmined. Cefotxiime ws slightly superior to moxlctm ginst the Acinetobcter spp., wheres moxlctm demonstrted greter ctivity thn did cefotxime ginst Commons terrigen nd Achromobcter xylosoxidns. The Morxell spp. were exquisitely susceptible to ll of the drugs tested. When glucose-fermenttive, oxidse-positive grm-negtive bcilli were tested (Tble 5), ll isoltes were uniformly susceptible to the new compounds nd the currently vilble ntibiotics. Exceptions were observed in the reltive insusceptibility of Aeromons hydrophil to cephlothin nd crbenicilhin nd the reltive resistnce of the Vibrio spp. to crbenicillin. Tble 6 summrizes susceptibility testing of vriety of less commonly isolted miscellneous nonenteric grm-negtive bcilli. Susceptibility to moxlctm nd cefotxime vried somewht mong these species. Both drugs were ineffective ginst Pseudomons fluorescens nd Flvobcterium sp. (group Ilb). showed greter inhibition of Pseudomons diminut, Pseudomons stutzeri, Pseudomons cepci, nd CDC Ve-, wheres moxlctm ws more ctive ginst Alcligenes odorns, Bordetell bronchiseptic, nd CDC IVC- isoltes. Checkerbord tests for synergy were performed with moxlctm nd cefotxime plus mikcin ginst gentmicin-resistnt Serrti isoltes. Synergy ws demonstrted Aeromons hydrophil () Vibrio spp. () ACTIVITIES OF MOXALACTAM AND CEFOTAXIME 9 ginst of isoltes with cefotxime plus mikcin nd ginst 5 of with moxlctm nd mikcin. When gr dilution checkerbord tests for synergy were performed with isoltes of P. eruginos (including 6 gentmicin-resistnt strins), synergy ws observed with of isoltes with moxlctm plus mikcin, nd n dditive effect ws demonstrted with 7 of the remining 0 isoltes. The combintion of cefotxime plus mikcin ws synergistic ginst 5 of isoltes of P. eruginos, wheres n dditive effect occurred with 7 of the 3 remining strins. DISCUSSION In this study, both moxlctm nd cefotxime showed mrked in vitro ctivity ginst mny cephlosporin-resistnt grm-negtive bcilli, including Pseudomons spp. Currently vilble "newer" cephlosporin or cephmycin ntibiotics, such s cefmndole, cefoxitin, nd cefuroxime, re not uniformly ctive ginst cephlothin-resistnt Enterobctericee nd generlly re inctive ginst pseudomonds (, 5). Thus, cefotxime ppers to be the forerunner of "third genertion" of cephlosporins with extreme grm-negtive bet-lctmse resistnce nd therefore unprecedented ctivity ginst mny erobic grm-negtive bcilli (,, 6). Although moxlctm contins modified cephem nucleus, it is not properly clssified s TABLE 5. Comprtive ctivities ofseven bet-lctm ntibiotics ginst oxidse-positive fermenttive bcilli Org (no. of isoltes) Antibiotic MIC 50 MIC,0" MIC rnge (pg/ml) (jg/mi) (jg/mi) Psteurell spp. (5) See Tble, footnote. Crbeniillin >

6 9 JORGENSEN, CRAWFORD, AND ALEXANDER Q6) *_; r-.. c) * - IO -S i.. 0 i C.,.9g X d O *l I 0Z d.. Is~ eq _-I oc S Ie N~o P- w xv V- A A I A'^^o3 A AI A A Aj A 7 00 c q si " ee A : A A~ A e CO 00~~ ~ ~ cli~ ~ ~ ~ -V e qo~c Lo ANTImICROB. AGENTS CHEMOTHER. cephlosporin, but rther s new -ox-betlctm ntibiotic. In our study, both of these new compounds showed striking in vitro ctivity ginst the Enterobctericee nd good ctivity ginst P. eruginos. nd cefotxime were shown to hve similr ctivities ginst most of the orgnisms included in this study. However, severl interesting differences occurred in which one of the two gents ppered mrkedly more ctive thn the other. seemed superior ginst P. mltophili, P. putid, P. diminut, Acinetobcter Iwoffi, nd P. fluorescens. Moslctm ppered somewht more ctive ginst A. xylosoxidns, C. terrigen, A. odorns, B. bronchiseptic, nd CDC IVC-. It is noteworthy tht both moxlctm nd cefotxime were comprble to or more ctive thn crbenicillin ginst pseudomonds nd other nonfermenttive orgni. The ction of these new compounds ginst isoltes of multiply resistnt S. mrcescens ws prticulrly encourging. The bility of both ntibiotics to ct synergisticlly with mikcin ginst the mjority of Serrti isoltes nd to produce t lest n dditive effect ginst most P. eruginos isoltes further mplifies the potentil usefulness of these new bet-lctm ntibiotics. ACKNOWLEDGMENIS This study ws supported in prt by grnts from Hoechst- Roussel Phrmceuticls nd Lilly Reserch Lbortories. LITERATURE CITED. Brz, M., F. P. Tlly, N. V. Jcobus, nd. L Gorbch In vitro ctivity of LY7935. Antimicrob. Agents Chemother. 6:7-9.. Ericsoon, H. M., nd J. C. Sherris. 97. Antibiotic sensitivity testing. Report of n interntionl collbortive study. Act Pthol. Microbiol. Scnd. Sect. B Suppl Fu, K. P., nd H. C. Neu. 97. Bet-lctmse stbility of HR 756, novel cephlosporin, compred to tht of cefuroxime nd cefoxitin. Antimicrob. Agents Chemother. :-6.. Neu, H. C., N. Aswpokee, P. Aswpokee, nd K. P. Fu HR 756, new cephlosporin ctive ginst grm-positive nd grm-negtive erobic nd nerobic bcteri. Antimicrob. Agents Chemother. 5: Sosn, J. P., P. R. Murry, nd G. Medoff. 97. Comprison of the in vitro ctivities of HR 756 with cephlothin, cefoxitin, nd cefmndole. Antimicrob. Agents Chemother. : Trger, G. M., G. W. White, V. M. Zimelis, nd A. Pnwlker LY-7935: novel bet-lctm ntibiotic with unusul ntibcteril ctivity. Antimicrob. Agents Chemother. 6: Wever, R. 97. Grm-negtive orgnisms: n pproch to identifiction. Center for Disese Control, Atlnt, G.. Weinstein, R. J., L, S. Young, nd W. I Hewitt Comprison of methods for _ng in vitro ntibiotic synergism ginst Pseudomons nd Serrti. J. Lb. Clin. Med. 6:536.