Susceptibility of Anaerobic Bacteria to 23 Antimicrobial

Transcription

1 ArTiMIctoIBAL AGoNT8 AND CHumOrHzRAPY, Oct. 1976, p Copyright Americn Society for Microbiology Vol. 10, No. 4 Printed in U.S.A. Susceptibility of Anerobic to 23 Antimicrobil Agents VERA L. SUTTER* AND SYDNEY M. FINEGOLD Reserch nd Medicl Services, Veterns Administrtion Wdsworth Hospitl Center, Los Angeles, Cliforni 90073,* nd Deprtment ofmedicine, UCLA School ofmedicine, Los Angeles, Cliforni Received for publiction 23 June 1976 The ntimicrobil susceptibility of 492 nerobic bcteri, the mjority of which were. recent clinicl isoltes, ws determined by the gr dilution technique. Penicillin G ws ctive ginst most of the tested t 32 U or less/ ml, but only 72% ofbcteroides frgilis were susceptible t this level nd 9% required 256 U or more/ml. Ampicillin ws effective ginst most of the except B. frgilis t 16 ug or less/ml. Amoxicillin ws ctive ginst only 31% of B. frgilis, 76% of other Bcteroides species, nd 67% of Fusobcterium species t 8,ug/ml. Two new penicillins, mezlocillin nd zlocillin, were similr to mpicillin in their ctivity. Crbenicillin nd ticrcillin inhibited ll but few t 128,ug or less/ml. BLP 1654 ws somewht more ctive thn penicillin G ginst B. frgilis but hd similr ctivity ginst other nerobes. Cephlothin ws inctive ginst B. frgilis, nd only 65% of other Bcteroides species were inhibited by 32 ug or less/ml. It ws effective ginst ll other nerobes t tht level. Cefmndole showed somewht greter ctivity thn cephlothin ginst B. frgilis but generlly less ctivity ginst grm-positive orgnisms. Cefzflur (SKF 59962) ws comprble to cephlothin ginst B. firgilis. Cefoxitin ws distinctly more ctive thn cephlothin ginst B. frgilis. These ltter two gents were less ctive thn cephlothin ginst the grm-positive nerobes. Chlormphenicol remins ctive ginst nerobic bcteri t 16,ug or less/ml, with rre exceptions. Thimphenicol ws similr to chlormphenicol in its ctivity. Clindmycin ws very ctive ginst most ofthe nerobes t 8,ug or less/ml. Erythromycin nd josmycin were lso tested, with josmycin showing greter ctivity ginst B. frgilis thn either erythromycin or clindmycin. A new oligoscchride, everninomicin B, ws less ctive thn clindmycin ginst B. frgilis but more ctive ginst clostridi nd some of the other tested. Most of the groups of bcteri tested demonstrted trend towrd resistnce to tetrcycline. Doxycyline nd minocycline were somewht more ctive thn ws tetrcycline. Metronidzole ws ctive ginst the mjority of the nerobes tested; resistnce ws demonstrted by some of the grm-positive cocci nd grm-positive, non-sporeforming bcilli. It hs been generlly ccepted by investigtors nd clinicins knowledgeble in the dignosis nd therpy of nerobic infections tht rpid, routine susceptibility testing of individul isoltes of nerobic bcteri is imprcticl. Anerobic infections re frequently polymicrobic nd cultures require reltively long periods of time for growth nd isoltion, so tht timely results of susceptibility tests re not fesible. It hs been suggested tht centers with the cpbility for testing on survey bsis do so periodiclly to monitor chnging ptterns of resistnce to commonly recommended gents nd to determine the possible effectiveness of newer gents. The purpose of the present study ws to ssy the in vitro effect of severl drugs currently in 736 use for therpy of nerobic infections nd to determine the ctivity of severl newer gents ginst nerobic bcteri recently isolted from clinicl mteril. MATERIALS AND METHODS l. A totl of 492 of nerobic bcteri ws used throughout the study. All but few were isolted from vriety of clinicl specimens received by the Wdsworth Anerobic Bcteriology Reserch Lbortory from ptients on specil studies nd from ptients seen in consulttion by the Infectious Disese Section during the period of September 1972 to June Exceptions were 21 of Bcteroides melninogeni, 5 of which were reference nd 16 of which were norml orl or fecl isoltes. Tble 1 gives the specific iden-

2 VOL. 10, 1976 ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES 737 TABLE 1. Identitv of bcteril tested tested in Orgnism studies Orgnism Prt I Prt II Totl i It Microerophilic nd n- Bcteroides frgilis 42 subsp. distsonis 8 subsp. frgilis 18 subsp. ovtus 1 subsp. thetiotomicron 9 subsp. vulgtus 4 Other 2 Bcteroides melninogen- 60 i subsp. scchrolyti 21 subsp. intermedius 29 subsp. melninogeni 10 Other 0 Other Bcteroides nd Se- 21 lenomons B. cpillosus 0 B. clostridiiformis 0 subsp. clostridiiformis" B. clostridiiformis 0 subsp. girnsb B. corrodens 2 B. orlis 4 B. pneumosintes 2 B. putredinis 1 B. ruminicol subsp. 0 ruminicol B. ruminicol subsp. 1 brevis B. splnchnic 1 Bcteroides group I 0 Bcteroides group PS 0 Bcteroides sp. 10 Selenomons sp. 0 Fusobcterium nucletum 8 Other Fusobcterium 12 F. gonidiformns 2 F. mortiferum 2 F. nviforme 1 F. necrophorum 1 F. russii 1 Fusobcterium sp. 5 Peptococ nd Gff y 17 P. scchrolyti 2 P. mgnus 4 P. prevotii 6 P. scchrolyti 0 P. vribilis 4 Peptococ sp. 1 Gffky nerobius 0 Peptostreptococ 15 P. nerobius 9 P. micros " 5 Peptostreptococ sp erobic Streptococ I12 30 S. constelltus 2 3 S. intermedius I12 21 S. morbillorum 4 8 Grm-negtive cocci 1 3 Acidminococ fer- I11 71 mentns Veillonell lclescens 1 22 V. prvul 6 35 Eubcterium 2 12 E. erofciens 2 2 E. contortum I IL51 72 E. Ientum E. limosum 3 3 E. moniliforme 2 2 Eubcterium sp. Archni propionic Propionibcterium 1 1 P. cnes P. vidum 0 2 Propionibcterium sp Actinomyces 3 5 A. isrelii 1 2 A. neslundii 1 1 A. viscosus Actinomyces sp. 3 4 Bifidobcterium B. dolescentis vr. B 0 1 B. infntis 6 6 Bifidobcterium sp. 8 8 Lctobcillus L. cidophilus 1 1 L. ctenforme to 18 L. fermentum 4 16 L. minutis 2 4 L. plntrum 0 2 Lctobcillus sp. 1 2 Clostridiumperfringens 0 1 Other Clostridium 0 1 C. bifermentns 1 6 C. butyricum 2 59 C. difficile C. glycolicum 6 10 C. innocuum 8 14 C. prperfringens 2 2 C. plgrum 4 8 C. putrificum 0 1 C. rmosum 1 1 C. sphenoides L4 29 C sporogenes 9 18 C. tertium 4 9 Clostridium sp. 1 2 tested in tested in studies Prt I Prt II Totl It hs recently been proposed tht orgnisms recognized s subspecies of B. frgilis be reinstted to species rnk (7). Strins hving phenotypic chrcteristics similr to these hve recently been found to hve spores nd to be geneticlly similr to Clostridium. It hs been proposed tht they be considered s C. clostridiiformis (15) or C. clostridiiforme (8). Spores hve not been demonstrted in the in the present study. c A new Bcteroides species described by Werner et l. (48).

3 738 SUTTER AND FINEGOLD ANTIMICROB. AGZNTS CHZMOTHEit. tifiction of the bcteri used in ech prt of the study. These bcteri were identified ccording to the criteri of the Wdsworth Anerobic Bcteriology Mnul (40) nd the Virgini Polytechnic Institute Anerobe Lbortory Mnul (13). It hs recently been proposed tht orgnisms recognized s subspecies of Bcteroides frgilis be given species sttus (7). We re in greement with this, but since little or no difference hs been found in the susceptibility of these orgnisms to the ntimicrobil gents in the present study nd in reports of others (2, 14), we will refer to B. frgilis s group including the five species. The subspecies of B. melninogeni re lso referred to s group, bee no differences were observed in their susceptibility to ntimicrobil gents. Six hd the chrcteristics of Bcteroides group 1 nd eight hd the chrcteristics ofbcteroides group PS. These ltter two groups hve recently been recognized s distinct from other Bcteroides species (L. V. Holdemn, personl communiction). Antimicrobil gents. Lbortory-stndrd powders were kindly supplied s follows: penicillin G, cephlothin, cefmndole lithium, nd erythromycin from Eli Lilly & Co., Indinpolis, Ind.; mpicillin trihydrte nd BLP 1654 from Bristol Lbortories, Syre, N.Y.; crbenicillin from Roerig, New York, N.Y.; moxicillin trihydrte nd ticrcillin sodium from Beechm-Mssengill Phrmceuticls, Bristol, Tenn.; mezlocillin nd zlocillin from Delby Phrmceuticls, Inc., Bloomfield, N.J.; sodium cefoxitin from Merck, Shrp nd Dohme, Rhwy, N.J.; cefzflur (SKF 59962) from Smith, Kline nd French Lbortories, Phildelphi, P.; chlormphenicol from Prke-Dvis & Co., Detroit, Mich.; thimphenicol nd thimphenicol glycinte from Zmbon, S.p.A., Bresso, Milno, Itly; clindmycin from The Upjohn Co., Klmzoo, Mich.; everninomicin B from Schering Corp., Bloomfield, N.J.; josmycin from E. I. Dupont de Nemours & Co., Newrk, Del.; tetrcycline nd doxycycline from Pfizer Lbortories, New York, N.Y.; minocycline from Lederle Lbortories, Perl River, N.Y.; nd metronidzole from G. D. Serle & Co., Chicgo, Ill. Procedures. Antimicrobil susceptibility testing ws performed by the gr dilution technique s previously described (40). Sets of three lked blood gr pltes contining no ntibiotic were inoculted before ech series of ntibiotic-contining pltes nd incubted nerobiclly, in 10% CO2 in ir, nd erobiclly, to serve s growth nd contmintion controls. Dt were deleted if poor or no growth occurred on the nerobic growth control plte or if contmintion ws evident. Throughout the study, the following ntimicrobil gents were included: penicillin G, crbenicillin, BLP 1654, chlormphenicol, clindmycin, tetrcycline, doxycycline, minocycline, nd metronidzole. During the first prt of the study, moxicillin, ticrcillin, cefoxitin, cefzflur, thimphenicol, thimphenicol glycinte, nd everninomicin B were included to determine their possible effectiveness ginst nerobes or for comprison of their ctivity with other drugs. During the second prt of the study, the following gents were included: mpicillin, mezlocillin, zlocillin, cephlothin, cefmndole, erythromycin, nd josmycin. RESULTS AND DISCUSSION Penicillins. The ctivity of penicillin G ginst the nerobes tested is shown in Tble 2. An inhibitory concentrtion of 32 U/ml is considered n cceptble level of susceptibility TABLE 2. Activity ofpenicillin G ginst nerobic bcteri Cumultive % susceptible to indicted concn (U/ml) tested r Bcteroides frgilis Bcteroides melnino geni Other Bcteroides nd Selenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gt ky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 3 67 o Propionibcterium Actinomyces Bifidobcterium 5 20 Lctobcillus Clostridium perfringens 9 33 Other Clostridium Includes ll identified s subspecies of B. frgilis.

4 VOL. 10, 1976 if high prenterl dosge is given. Most of the bcteri were inhibited by this concentrtion or less. However, only 72% of B. frgilis, 82% of Bcteroides species other thn B. frgilis nd B. melninogeni, nd 88% offusobcterium species other thn Fusobcterium nucletum were inhibited by 32 U/ml. Nine percent, or seven ofthe in the B. frgilis group (six B. frgilis nd one Bcteroides vulgtus), 4% or three of other Bcteroides species, nd one Fusobcterium species required 256 U or more/ml for inhibition. The B. frgilis included in this study pper to hve bout the sme susceptibility s those tested in prior study in which hd been isolted from vriety of sources, including humn feces, over period of severl yers (39). There ws no difference in susceptibility of tested in the two prts of the study, with pproximtely equl proportions of the resistnt ppering in ech segment. The present results with B. frgilis nd other nerobes tested re lso similr to those reported by others (2, 14, 16, 21, 34, 43, 51), nd greter resistnce to penicillin does not pper to be emerging. The ctivity of mpicillin ginst the tested in the second prt of the study is shown in Tble 3. With prenterl dosge, levels of t lest 16,ug/ml re chievble. Ampicillin inhibited most of the nerobes tested t concentrtions of 16,ug or less/ml but ws effective ginst only 56% of B. frgilis t this level. The results with B. frgilis re similr to ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES those reported by Kislk (16) nd overll results show higher minimum inhibitory concentrtions (MICs) thn those ileported by Rotilie et l. (32), who used microdilution technique for determintion of susceptibility. Amoxicillin, n orl, brod-spectrum penicillin, chieves serum levels of up to 8,ug/ml (24). The ctivity of this ntibiotic ginst nerobes ws determined during the first prt of the study. Amoxicillin ws ctive ginst mny of the tested (Tble 4), but only 31% of B. frgilis, 76% of other Bcteroides species, nd 67% offusobcterium species were inhibited by 8,ug or less/ml. One strin ech ofpeptostreptococ nerobius nd Streptococ intermedius required 16 ug/ml nd one strin of Clostridium perfringens required 32,ug/ml for inhibition. These studies would indicte tht moxicillin would be less useful in serious nerobic infections thn either penicillin G or mpicillin İn the second prt of the study two new semisynthetic cylureido penicillins, mezlocillin nd zlocillin, were tested. Results re shown in Tbles 5 nd 6. These compounds hve similr in vitro effectiveness ginst the nerobes tested nd, on the bsis of weight, re similr to mpicillin in their ctivity. Phrmcologicl dt on these two compounds re not yet vilble. The susceptibility of nerobes to crbenicillin ws tested throughout the study, nd results re shown in Tble 7. Crbenicillin inhibited ll nerobes tested t level of 128,ug/ TABLE 3. Activity of mpicillin ginst nerobic bcteri Cumultive % susceptible to indicted concn (j,g/ml) tested < Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 1 Propionibcterium 7 29 Bifidobcterium 5 Lctobcillus Clostridium perfringens 1 Other Clostridium Includes ll identified s subspecies of B. frgilis. 739

5 740 SUTTER AND FINEGOLD ANTiMICROB. AGZNTS CHZMOTHER. TABLE 4. Activity of moxicillin ginst nerobic bcteri Cumultive % susceptible to indicted concn (Ag/ml) tested s Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium 7 57 Archni propionic 2 Propionibcterium Actinomyces Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of B. frgilis. TABLE 5. Activity of meziocillin ginst nerobic bcteri Cumultive % susceptible to indicted concn (yg/ml) tested Bcteroides frgilis Bcteroides melni nogeni Other Bcteroides nd Selenomons Fusobcterium nu cletum Other Fusobcterium Peptococ nd Gff ky Peptostreptococ Anerobic nd mi croero Grm-negtive cocci Eubcterium Archni propionic 1 Propionibcterium Bifidobcterium Lctobcillus Clostridium perfrin- 1 gens Other Clostridium Includes ll identified s subspecies of B. frgilis. ml, with the exception of four of B. ers (51) but re pprecibly lower thn those of frgilis, Bcteroides species, Bcteroides Blzevic nd Mtsen (3) nd Tlly et l. (43). corrodens, Bcteroides clostridiiformis Both of the ltter studies utilized prereduced subsp. clostridiiformis, nd Fusobcterium medi contining cysteine in determining susspecies. The MICs of in the present ceptibility; this might ccount for some loss of study re similr to those of our previous stud- crbenicillin ctivity. ies (36) nd to those of Kislk (16), Stneck nd The ctivity of ticrcillin ginst the Wshington (34), nd Zbrnsky nd co-work- tested in the second prt of the study is shown

6 VOL. 10, 1976 ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES 741 TABLE 6. Activity of ziocillin ginst nerobic bcteri Cumultive % susceptible to indicted concn (Ig/ml) tested s Bcteroides frgilis Bcteroides melni nogeni Other Bcteroides nd Selenomons Fusobcterium nu cletum Other Fusobcterium Peptococ nd Gff ky Peptostreptococ Anerobic nd mi croero Grm-negtive cocci Eubcterium Archni propionic 1 Propionibcterium 7 29 Bifidobcterium 5 80 Lctobcillus Clostridium perfrin- 1 gens Other Clostridium Includes ll identified s subspecies of B. frgilis. TABLE 7. Activity of crbenicillin ginst nerobic bcteri Cumultive % susceptible to indicted concn (yg/ml) tested Bcteroides figilis Bcteroides melni nogeni Other Bcteroides nd Selenomons Fusobcterium nu cletum Other Fusobcterium Peptococ nd Gff ky Peptostreptococ Anerobic nd mi croero Grm-negtive cocci Eubcterium Archni propionic 3 67 Propionibcterium Actinomyces Bifidobcterium Lctobcillus Clostridium perfrin- 9 gens Other Clostridium Includes ll identified s subspecies of B. frgilis. in Tble 8. With high prenterl dosge sched- effective ginst ll tested t 128,tg or ules, blood levels of ticrcillin re similr to less/ml, with the exception of two of B. those of crbenicillin (26). The in vitro ctivity frgilis nd one strin ech of Fusobcterium ginst nerobes is lso quite similr. It ws species nd Fusobcterium gonidiformns.

7 742 SUTTER AND FINEGOLD ANTIMICROB. AGENTS CHEMOTHER. Tble 9 indictes the ctivity of BLP 1654 in Tble 10. All of B. frgilis were reginst the nerobic bcteri tested through- sistnt to cephlothin, requiring t lest 64,ug/ out the study. Orgnisms with MICs of 32,ug or ml for inhibition. Only 65% of other Bcteroides less/ml re considered susceptible to this gent species were inhibited by 32,g/ml. Previous (4). Unfortuntely, bee of its nephrotoxic- studies indicted 6 to 11% ofb. frgilis nd ll ity, further evlution of BLP 1654 hs been of other Bcteroides species to be indiscontinued. hibited by this concentrtion (36, 42). All other Cephlosporins nd similr drugs. The sus- groups tested in the present study were inceptibility of the nerobic bcteri from the hibited by 32,ug or less/ml. Most of the grmsecond prt of the study to cephlothin is shown positive nerobes were inhibited by 8 ug or TABLE 8. Activity of ticrcillin ginst nerobic bcteri Cumultive % susceptible to indicted concn (.tg/ml) tested so Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 2 50 Propionibcterium 4 75 Actinomyces Lctobcillus Clostridium perfringens 8 88 Other Clostridium Includes ll identified s subspecies of B. frgilis TABLE 9. Activity ofblp 1654 ginst nerobic bcteri Cumultive % susceptible to indicted concn (pg/ml) tested Bcteroides frgilis Bcteroides melninogeni c.u Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 3 67 Propionibcterium Actinomyces Bifldobcterium 5 Lctobcillus Clostridium perfringens 9 22 Other Clostridium Includes ll identified s subspecies of B. frgilis.

8 VOL. 10, 1976 ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES 743 TABLE 10. Activity of cephlothin ginst nerobic bcteri Cumultive % susceptible to indicted concn (,&g/ml) tested < Bcteroides frgilis Bcteroides melni nogeni Other Bcteroides nd Selenomons Fusobcterium nu cletum Other Fusobcterium 4 50 Peptococ nd Gff ky Peptostreptococ Anerobic nd mi croero Grm-negtive cocci Eubcterium Archni propionic 1 Propionibcterium 8 88 Bifidobcterium Lctobcillus 8 13 Clostridium perfrin- 1 gens Other Clostridium Includes ll identified s subspecies of B. frgilis. less/ml. These dt re in greement with those of our erlier study, except tht resistnt clostridi hve not been found s yet. The ctivity of cefmndole (7-D-mndelmido-3- [1-methyl-lH-tetrzol-5-ylthiomethyl]-3- cephem-4-crboxylic cid) ws compred with tht of cephlothin. Cefmndole is new cephlosporin which hs been shown to hve brod spectrum of ctivity ginst fculttive bcteri (5, 22, 25). It hs been shown to be resistnt to penicillinse nd cephlosporinses derived from fculttive bcteri (25, 49). The results of the studies on the ctivity of cefmndole re shown in Tble 11. Since cefmndole is resistnt to /8-lctmses, the of B. frgilis tested were more resistnt to this gent thn would be expected, with only 9% of the susceptible to 32 ug/ml. B. frgilis (3- lctmses hve been shown to be different from those produced by Enterobctericee (29). It is possible tht cefmndole is not resistnt to the cephlosporinse produced by these. Our results with B. frgilis re in disgreement with those recently published by Ernst et l. (12), who found tht 57% of their were inhibited by 32 ug of cefmndole per ml. This discrepncy could be due to n inoculum effect, since our inoculum is t lest 10-fold greter thn tht used by Ernst nd coworkers, or it could be due to crryover of lrger mount of cephlosporinse with the inoculum. The studies of Olsson nd co-workers (29) showed tht the mount of f-lctmse produced by their of B. frgilis ws medium dependent, nd it is possible tht greter mounts of the enzyme re produced in the thioglycolte medium used in our studies. Further investigtion is necessry to determine the significnce of this phenomenon. Cefmndole ws more ctive ginst B. melninogeni nd other Bcteroides species thn ws cephlothin, hd similr ctivity ginst Fusobcterium species, nd ws less ctive ginst the grm-positive nerobes. Prior studies with cefzolin indicted tht it my be slightly more ctive thn cefmndole ginst B. frgilis, the nerobic cocci, nd clostridi (36). The ctivities of cefzflur (7-trifluoromethylthiocetmido [1- methyl - 1H-tetrzol-5- ylthiomethyll-3-cephem-4-crboxylic cid) nd sodium cefoxitin were compred. Cefoxitin is cephmycin, clss of compounds closely relted to the cephlosporins. Results re shown in Tbles 12 nd 13. Cefzflur ws less ctive thn cefoxitin ginst B. frgilis nd other grm-negtive nerobes, ws similr in ctivity ginst grm-positive, non-sporeforming nerobes, nd ws somewht more ctive ginst Clostridium species other thn C. perfringens. Phrmcologicl studies with nimls indicte tht serum levels with cefzflur re similr to those obtined with cephlothin

9 744 SUTTER AND FINEGOLD ANTiMICItOB. AGZNTS CHZMOTHZR. TABLE 11. Activity of cefmndole ginst nerobic bcteri Cumultive % susceptible to indicted concn (,ug/ml) tested s Bcteroides frgilis Bcteroides melni nogeni Other Bcteroides nd Selenomons Fusobcterium nu cletum Other Fusobcterium 4 75 Peptococ nd Gff ky Peptostreptococ Anerobic nd mi croero Grm-negtive cocci Eubcterium Archni propionic 1 Propionibcterium 8 13 Bifidobcterium Lctobcillus Clostridium perfrin- 1 gens Other Clostridium Includes ll identified s subspecies of B. frgilis. TABLE 12. Activity of cefzflur ginst nerobic bcteri Cumultive % susceptible to indicted concn (,ug/ml) tested Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum 8 75 Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci 7 86 Eubcterium Archni propionic 2 Propionibcterium 4 75 Actinomyces Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of B. frgilis. (1); therefore, orgnisms with MICs of 64 Ag or the groups of bcteri pper to be more resistmore/ml would be considered resistnt. Results nt thn those reported in previous study with cefoxitin ginst the nerobes indicte (36). At tht time, ll B. frgilis were tht the mjority of re inhibited t n inhibited by 32 ug/ml, wheres only 85% of chievble level of 32,ug/ml. However, some of recent isoltes re susceptible to tht level.

10 VOL. 10, 1976 ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES 745 Nonetheless, cefoxitin is distinctly more ctive Clostridium species pper slightly more susthn ny of the cephlosporins ginst B. fr- ceptible thn those reported by Tlly et l. (42). gilis. Other Fusobcterium species, grm-posi- Chlormphenicol. The ctivity of chlormtive cocci, nd grm-positive, non-sporeforming phenicol ginst the nerobes tested is shown bcilli lso re demonstrting higher inhibitory in Tble 14. A level of 16 ug/ml is redily end points. The B. frgilis in the cur- chievble, nd ll but two of the bcteri were rent study pper to be less susceptible to cefox- inhibited t this concentrtion. Only one strin itin thn those reported by others (6, 28, 42), in the B. frgilis group (B. frgilis subsp. thebut the reminder of nerobes other thn tiotomicron or Bcteroides thetiotomicron) TABLE 13. Activity of sodium cefoxitin ginst nerobic bcteri Cumultive % susceptible to indicted concn (pg/ml) tested s Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 2 Propionibcterium 4 75 Actinomyces Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of B. frgilis. TABLE 14. Activity of chlormphenicol ginst nerobic bcteri Cumultive % susceptible to indicted concn (pg/ml) tested < Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Seleno mons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microerophilic streptococci Grm-negtive cocci Eubcterium Archni propionic Propionibcterium Actinomyces Bifidobcterium Lctobcillus Clostridium perfringens 9 22 Other Clostridium Includes ll identified s subspecies of B. frgilis.

11 746 SUTTER AND FINEGOLD required 32,ug/ml for inhibition, nd one strin of B. clostridiiformis subsp. clostrid4iformis ws inhibited by 128 yg/ml. These results re similr to previous reports from this lbortory nd to those of others (2, 16, 18, 21, 32, 33, 39, 41, 46, 51). Thimphenicol, n nlogue of chlormphenicol, with substitution of the p-nitro group by methylsulfonyl moiety, nd its prenterl form, thimphenicol glycinte, were tested during the first prt of this study. These compounds produce serum levels equivlent to those of chlormphenicol nd hve been found to produce less serious side effects thn does chlormphenicol (46). Results obtined with thimphenicol re given in Tble 15. Thimphenicol glycinte ws equivlent to thimphenicol in ctivity. Thimphenicol ws similr in ctivity to chlormphenicol, with most of the tested inhibited by 16 ug or less/ml. The orgnisms tht required 32,ug or more/ml for inhibition were one strin ech of Bcteroides species, B. corrodens, Lctobcillus plntrum, nd Clostridium difficile. Mcrolides nd similr drugs. Clindmycin ws very ctive ginst most of the nerobes t 8,Mg or less/ml (Tble 16). All B. frgilis were inhibited t this level. Strins tht required 16,Mg or more/ml for inhibition were three of the Bcteroides species, nine of the Peptococ species, Lctobcillus ctenforme, nd four of the Clostridium species. For most of the groups of nerobes tested, results re in greement with previously published studies (2, 17, 18, 21, 32-34, 39, 41, 47, 50, ANTiMICROB. AGENTS CHZMOTHZR. 51). With regrd to resistnce mong the Peptococ, it ws not observed by Werner nd B6hm (47) but ws observed by Mrtin et l. (21) nd in our own erlier studies (18). This my be n importnt considertion in nerobic pleuropulmonry infections nd in certin other nerobic infections where clindmycin my be recommended when penicillin cnnot be used. Resistnce mong Clostridium species other thn C. perfringens hs been noted previously (34, 41, 50). However, despite the widespred use of this compound over the pst few yers, resistnce does not pper to be emerging mong nerobes previously susceptible to it. The ctivity of erythromycin ginst the nerobes tested in the second prt of the study is indicted in Tble 17. These results show tht the B. frgilis, nd the nerobic nd microero, showed more resistnce to erythromycin, wheres the fusobcteri nd Clostridium species were more susceptible thn used in the first prt of the study. These results were the subject of previous publiction (37). These disprities were not observed with clindmycin in the two prts of the study. Erythromycin ws much less ctive thn clindmycin ginst B. frgilis, the fusobcteri, nd the grm-negtive cocci. It showed greter ctivity ginst the nerobic streptococci nd clostridi nd hd similr ctivity ginst the reminder of the tested. Josmycin, mcrolide structurlly similr to erythromycin nd with similr in vitro ctivity ginst fculttive bcteri, does not induce TABLz 15. Activity of thimphenicol ginst nerobic bcteri Cumultive % susceptible to indicted concn (,tg/ml) tested < Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Seleno mons Fusobcterium nucletum 8 Other Fusobcterium Peptococ nd Gfftky Peptostreptococ Anerobic nd microerophilic streptococci Grm-negtive cocci Eubcterium Archni propionic 2 50 Propionibcterium Actinomyces Lctobcillus Clostridium perfringens 8 Other Clostridium Includes ll identified s subspecies of B. frgilis.

12 VOL. 10, 1976 ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES 747 TABLz 16. Activity of clindmycin ginst nerobic bcteri Cumultive % susceptible to indicted concn (ug/ml) tested Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 3 33 Propionibcterium Actinomyces Bifidobcterium 5 80 Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of B. frgilis. TABLE 17. Activity of erythromycin ginst nerobic bcteri Cumultive % susceptible to indicted concn (jag/ml) tested co Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero- 4 Grm-negtive cocci Eubcterium 9 44 Archni propionic 1 Propionibcterium 8 88 Bifidobcterium 5 60 Lctobcillus Clostridium perfringens 1 Other Clostridium Includes ll identified s subspecies of B. frgilis. mcrolide resistnce mong stphylococci (30). ctive thn clindmycin ginst the clostridi It hs been shown to be ctive ginst B. fr- but ws less ctive thn clindmycin ginst gilis nd other nerobic bcteri (17, 20, 27, the fusobcteri. It ppers to be s ctive s 35). The susceptibility of the nerobes from rosmicin ginst B. frgilis (37) nd other the second prt of the study is given in Tble nerobes. However, direct comprison with 18. On weight bsis, josmycin ws more the sme ws not mde. ctive thn erythromycin or clindmycin A new oligoscchride, everninomicin B, ws ginst B. frgilis nd showed ctivity similr tested nd the results re shown in Tble 19. to tht of erythromycin with the reminder of Phrmcologicl dt re not yet vilble, but the nerobes. It, like erythromycin, ws more on weight bsis everninomicin is less ctive

13 748 SUTTER AND FINEGOLD ANTiMICROB. AGENTS CHZMOTHZR. TABLE 18. Activity ofjosmycin ginst nerobic bcteri Cumultive 9 susceptible to indicted concn (,tg/ml) tested S Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gfthy Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 1 Propionibcterium 8 38 Bifidobcterium 5 Lctobcillus Clostridium perfringens 1 Other Clostridium Includes ll identified s subspecies of B. frgilis. TABLE 19. Activity of everninomicin B ginst nerobic bcteri Cumultive % susceptible to indicted concn (Ag/ml) tested O Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 2 50 Propionibcterium 4 25 Actinomyces Lctobcillus 7 86 Clostridium perfringens Other Clostridium Includes ll identified s subspecies of B. frgilis. thn clindmycin ginst B. frgilis nd other grm-negtive nerobes nd more ctive ginst the clostridi, including resistnt to clindmycin. It ws lso more ctive thn ws clindmycin ginst grm-positive, non-sporeforming bcteri, with the exception of the few. of Archni, Propionibcterium, nd Actinomyces tested. Tetrcyclines. The ctivities of tetrcycline, doxycycline, nd minocycline were determined throughout the study. Results re shown in Tbles 20 through 22. Only 42% of in the B. frgilis group remin susceptible to tetrcycline t 4,ug or less/ml nd 46% t 8,ug or less/ ml. Other groups of nerobes lso exhibited less suceptibility to tetrcycline thn in prior reports (16, 33, 38). The current results re similr to other recently published dt (2, 9, 21, 32, 41, 51). Doxycycline remins more ctive thn tetrcycline ginst nerobes but is

14 VOL. 10, 1976 ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES 749 TABLE 20. Activity of tetrcycline ginst nerobic bcteri Cumultive % susceptible to indicted concn (gg/ml) tested Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Seleno mons Fusohcterium nucletum Other Fusobcterium Peptococ nd Gfftky Peptostreptococ Anerobic nd microerophilic streptococci Grm-negtive cocci Eubcterium Archni propionic 3 67 Propionibcterium Actinomyces Bifidobcterium 5 60 Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of B. frgilis. TABLE 21. Activity of doxycycline ginst nerobic bcteri Cumultive % susceptible to indicted concn (,ug/ml) tested s Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Seleno mons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gffky Peptostreptococ Anerobic nd microerophilic streptococci Grm-negtive cocci Eubcterium Archni propionic 3 67 Propionibcterium Actinomyces Bilidobcterium Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of Bcteroides frgilis. slightly less ctive thn minocycline ginst species, three Streptococ intermedius, two the sme, except for C. perfringens. Eubcterium species, two Archni propion- Metronidzole. The susceptibility of the n- ic, eight Propionibcterium cnes, two Propierobes to metronidzole is shown in Tble 23. onibcterium vidum, eight Actinomyces spe- With the exception of the grm-positive, non- cies, one Actinomyces isrelii, one Actinomyces sporeforming bcilli, the mjority of viscosus, nd one ech of Bifidobcterium spewere inhibited by 16,ug or less/ml. cies, Bifidobcterium dolescentis vr. B, nd requiring MICs of 32,.g or more/ml were two Bifidobcterium infntis. These results gener ofbcteroides pneumosintes, one Pepto- lly gree with those in previous publictions coc scchrolyti, one Peptostreptococ (11, 19, 23, 31, 34, 41, 44, 45). We did not observe

15 750 SUTTER AND FINEGOLD TABLz 22. Activity of minocycline ginst nerobic bcteri Cumultive % susceptible to indicted concn (,tg/ml) tested : Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Selenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gflky Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 3 33 Propionibcterium Actinomyces Bifidobcterium Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of.b. frgilis. ANTiMICROB. AGZNTS CHZMOTHZR. TABLE 23. Activity of metronidzole ginst nerobic bcteri Cumultive % susceptible to indicted concn (jsg/ml) tested s Bcteroides frgilis Bcteroides melninogeni Other Bcteroides nd Se lenomons Fusobcterium nucletum Other Fusobcterium Peptococ nd Gfthy Peptostreptococ Anerobic nd microero Grm-negtive cocci Eubcterium Archni propionic 3 33 Propionibcterium Actinomyces Bifidobcterium Lctobcillus Clostridium perfringens Other Clostridium Includes ll identified s subspecies of B. frgilis. resistnt of B. frgilis, Fusobcterium non-sporeforming bcilli. However, the mjorspecies, or Clostridium species, s ws reported ity of nerobic bcteri most frequently enby Chow et l. (10). countered in infections remin susceptible to Although ll of the in the current chievble levels of metronidzole. study were defined s nerobes bee on initil isoltion they grew poorly or not t ll in ACKNOWLEDGMENTS the presence of ir, some becme more ero- We grtefully cknowledge the contribution of Godfrey tolernt through subsequent in vitro cultiv- K. M. Hrding for his studies on identifiction of subspecies tion. For the most prt, these were the of the B. melninogeni. We thnk Lubn Afzl showing the gretest resistnce to metronid- Kureshi nd Y. Y. Kwok for their excellent technicl ssistnce nd Edwrd 0. Wrburton nd others t the Biomedizole. They belonged in the genus Streptococ cl Engineering nd Computer Center, Sepulved VA Hosnd in the vrious gener of grm-positive, pitl, for their excellent ssistnce in compiling the dt.

16 VOL. 10, 1976 These studies were supported by grnts from Beechm- Mssengill Phrmceuticls, Bristol, Tenn., Bristol Lbortories, Syre, N.Y., Delby Phrmceuticls, Inc., Bloomfield, N.J., E. I. Dupont de Nemours nd Co., Newrk, Del., Lederle Lbortories, Perl River, N.Y., Eli Lilly nd Co., Indinpolis, Ind., Pfizer Lbortories, New York, N.Y., Schering Corp., Bloomfield, N.J., G. D. Serle nd Co., Chicgo, Ill., Smith, Kline nd French Lbortories, Phildelphi, P., nd Zmbon, S.p.A., Bresso, Milno, Itly. LITERATURE CITED 1. Actor, P., J. V. Uri, J. R. Gurini, I. Zjc, L. Phillips, C. S. Schs, R. M. De Mrinis, J. R. E. Hoover, nd J. A. Weisbch A new prenterl cephlosporin. SK&F 59962: in vitro nd in vivo ntibcteril ctivity nd serum levels in experimentl nimls. J. Antibiot. 28: Blzevic, D. J Antibiotic susceptibility of the subspecies of Bcteroides frgilis. Antimicrob. Agents Chemother. 9: Blzevic, D. J., nd J. M. Mtsen Susceptibility of nerobic bcteri to crbenicillin. Antimicrob. Agents Chemother. 5: Bodey, G. P., V. Rodriguez, N. Horikoshi, nd M. Vldivieso New ntibiotics of potentil importnce for immunosuppressed ptients. Trnsplnt. Proc. 5(Suppl.): Bodey, G. P., nd S. Wever In vitro studies of cefmndole. Antimicrob. Agents Chemother. 9: Brumfitt, W., J. Kosmides, J. M. T. Hmilton-Miller, nd J. N. G. Gilchrist Cefoxitin nd cephlothin: ntimicrobil ctivity, humn phrmcokinetics, nd toxicology. Antimicrob. Agents Chemother. 6: Cto, E. P., nd J. L. Johnson Reinsttement of species rnk for Bcteroides frgilis, B. ovtus, B. distsonis, B. thetiotomicron, nd B. vulgtus: designtion of neotype for Bcteroides frgilis (Veillon nd Zuber) Cstellni nd Chlmers nd Bcteroides thetiotomicron (Distso) Cstellni nd Chlmers. Int. J. Syst. Bcteriol. 26: Cto, E. P., nd C. W. Slmon Trnsfer ofbcteroides clostridiiformis subsp. clostridiiformis (Burri nd Ankersmit) Holdemn nd Moore nd Bcteroides clostridiiformis subsp. girns (Prevot) Holdemn nd Moore to the genus Clostridium s Clostridium clostridiiforme (Burri nd Ankersmit) comb. nov.: emendtion of description nd designtion of neotype strin. Int. J. Syst. Bcteriol. 26: Chow, A. W., V. Ptten, nd L. B. Guze Comprtive susceptibility of nerobic bcteri to minocycline, doxycycline, nd tetrcycline. Antimicrob. Agents Chemother. 7: Chow, A. W., V. Ptten, nd L. B. Guze Susceptibility of nerobic bcteri to metronidzole: reltive resistnce of non-spore-forming grm-positive bcilli. J. Infect. Dis. 131: Dornbusch, K., nd C. E. Nord In vitro effect of metronidzole nd tinidzole on nerobic bcteri. Med. Microbiol. Immunol. 160: Ernst, E. C., S. Berger, M. Brz, N. V. Jcobus, nd F. P. Tlly Activity of cefmndole nd other cephlosporins ginst erobic nd nerobic bcteri. Antimicrob. Agents Chemother. 9: Holdemn, L. V., nd W. E. C. Moore (ed) Anerobe lbortory mnul. Virgini Polytechnic Institute nd Stte University, Blcksburg. 14. Jones, R. N., nd P. C. Fuchs Identifiction nd ntimicrobil susceptibility of 250 Bcteroides frgilis subspecies tested by broth microdilution methods. Antimicrob. Agents Chemother. 9: ANTIMICROBIAL SUSCEPTIBILITY OF ANAEROBES Kneuchi, C., K. Wtnbe, A. Terd, Y. Benno, nd T. Mitsuok Txonomic study of Bcteroides clostridiiformis subsp. clostridiiformis (Burri nd Ankersmit) Holdemn nd Moore nd of relted orgnisms: proposl of Clostridium clostridiiformis (Burri nd Ankersmit) comb. nov. nd Clostridium symbiosum (Stevens) comb. nov. Int. J. Syst. Bcteriol. 26: Kislk, J. W The susceptibility of Bcteroides frgilis to 24 ntibotics. J. Infect. Dis. 125: Koski, N., J. Igri, nd T. Oguri Susceptibility of recently isolted pthogens to josmycin, erythromycin nd lincomycin. Chemotherpy (Tokyo) 17: Kwok, Y. Y., F. P. Tlly, V. L. Sutter, nd S. M. Finegold Disk susceptibility testing of slowgrowing nerobic bcteri. Antimicrob. Agents Chemother. 7: Lerner, P. I Susceptibility of pthogenic ctinomycetes to ntimicrobil compounds. Antimicrob. Agents Chemother. 5: Long, S. S., S. Mueller, nd R. M. Swenson In vitro susceptibilities of nerobic bcteri to josmycin. Antimicrob. Agents Chemother. 9: Mrtin, W. J., M. Grdner, nd J. A. Wshington II In vitro ntimicrobil susceptibility of nerobic bcteri isolted from clinicl specimens. Antimicrob. Agents Chemother. 1: Meyers, B. R., B. Leng, nd S. Z. Hirshmn Cefmndole: ntimicrobil ctivity in vitro of new cephlosoporin. Antimicrob. Agents Chemother. 8: Nstro, L. J., nd S. M. Finegold Bctericidl ctivity of five ntimicrobil gents ginst Bcteroides frgilis. J. Infect. Dis. 126: Neu, H. C Antimicrobil ctivity nd humn phrmcology of moxicillin. J. Infect. Dis. 129(Suppl.):S123-S Neu, H. C Cefmndole, cephlosporin ntibiotic with n unusully wide spectrum of ctivity. Antimicrob. Agents Chemother. 6: Neu, H. C., nd G. J. Grvey Comprtive in vitro ctivity nd clinicl phrmcology of ticrcillin nd crbenicillin. Antimicrob. Agents Chemother. 8: Ninomiy, K., K. Wtnbe, K. Ueno, S. Suzuki, I. Mochizuki, Y. Simizu, T. Isogi, nd T. Nisiur Susceptibility of nerobic bcteri to SF 837. Chemotherpy (Tokyo) 22: Norrby, R., J. E. Brorson, nd S. Seeberg Comprtive study of the in vitro ntibcteril ctivity of cefoxitin, cefuroxime, nd cephloridine. Antimicrob. Agents Chemother. 9: Olsson, B., C. E. Nord, nd T. Wdstrom Formtion of bet-lctmse in Bcteroides frgilis: cell bound nd extrcellulr ctivity. Antimicrob. Agents Chemother. 9: Osono, T., nd H. Umezw Josmycin, new mcrolide ntibiotic of resistnce non-inducing type, p In S. Mitsuhshi (ed.), Drug ction nd drug resistnce in bcteri. University Prk Press, Bltimore. 31. Reynolds, A. V., J. M. T. Hmilton-Miller, nd W. Brumfitt A comprison of the in vitro ctivity of metronidzole, tinidzole, nd nimorzole ginst grm-negtive nerobic bcteri. J. Clin. Pthol. 28: Rotilie, C. A., R. J. Fss, R. B. Prior, nd R. L. Perkins Microdilution technique for ntimicrobil susceptibility testing of nerobic bcteri. Antimicrob. Agents Chemother. 7: Spico, F. L., Y. Y. Kwok, V. L. Sutter, nd S. M. Finegold Stndrdized ntimicrobil disc susceptibility testing of nerobic bcteri: in vitro sus-

17 752 SUTTER AND FINEGOLD ceptibility of Clostridium perfringens to nine ntibiotics. Antimicrob. Agents Chemother. 2: Stneck, J. L., nd J. A. Wshington II Antimicrobil susceptibilities 6f nerobic bcteri: recent clinicl isoltes. Antimicrob. Agents Chemother. 6: Strusbugh, L. J., J. A. Dilworth, J. M. Gwltney, Jr., nd M. A. Snde In vitro susceptibility studies with josmycin nd erythromycin. Antimicrob. Agents Chemother. 9: Sutter, V. L., nd S. M. Finegold Susceptibility of nerobic bcteri to crbenicillin, cefoxitin nd relted drugs. J. Infect. Dis. 131: Sutter, V. L., nd S. M. Finegold Rosmicin: in vitro ctivity ginst nerobes nd comprison with erythromycin. Antimicrob. Agents Chemother. 9: Sutter, V. L., Y. Y. Kwok, nd S. M. Finegold Stndrdized ntimicrobil disc susceptibility testing of nerobic bcteri. I. Susceptibility of Bcteroides frgilis to tetrcycline. Appl. Microbiol. 23: Sutter, V. L., Y. Y. Kwok, nd S. M. Finegold Susceptibility ofbcteroides frgilis to six ntibiotics determined by stndrdized ntimicrobil disc susceptibility testing. Antimicrob. Agents Chemother. 3: Sutter, V. L., V. L. Vrgo, nd S. M. Finegold Wdsworth nerobic bcteriology mnul, 2nd ed. University of Cliforni, Los Angeles Extension Division, Los Angeles. 41. Tlly, F. P., A. Y. Armfield, V. R. Dowell, Jr., Y. Y. Kwok, V. L. Sutter, nd S. M. Finegold Susceptibility of Clostridium rmosum to ntimicrobil gents. Antimicrob. Agents Chemother. 5: Tlly, F. P., N. V. Jcobus, J. G. Brtlett, nd S. L. Gorbch Susceptibility of nerobes to cefoxitin nd other cephlosporins. Antimicrob. Agents Chemother. 7: ANTIMICROB. AGZNTS CHZMOTHZR. 43. Tlly, F. P., N. V. Jcobus, J. G. Brtlett, nd S. L. Gorbch In vitro ctivity of penicillins ginst nerobes. Antimicrob. Agents Chemother. 7: Tlly, F. P., V. L. Sutter, nd S. M. Finegold Metronidzole versus nerobes. In vitro dt nd initil clinicl observtions. Clif. Med. 117: Ueno, K., K. Ninomiy, nd S. Suzuki Antibcteril ctivity of metronidzole ginst nerobic bcteri. Chemotherpy (Tokyo) 19: Vn Beers, D., E. Schoutens, M. P. Vnderlinden, nd E. Yourssowsky Comprtive in vitro ctivity of chlormphenicol nd thimphenicol on common erobic nd nerobic Grm-negtive bcilli (Slmonell nd Shigell excluded). Chemotherpy (Bsel) 21: Werner, H., nd G. Bohm Susceptibility of nonsporing nerobes of the gener Bcteroides, Fusobcterium, Spherophorus, Peptococ nd Peptostreptococ to clindmycin. Zentrlbl. Bkteriol. Prsitenkd. Infektionskr. Hyg. Abt. 1 Orig. Reihe A 229: Werner, H., G. Rintelen, nd H. Kunstek-Sntos A new butyric cid-producing Bcteroides species: B. splnchni n. sp. Zentrlbl. Bkteriol. Prsitenkd. Infektionskr. Hyg. Abt. 1 Orig. Reihe A 231: Wick, W. E., nd D. A. Preston Biologicl properties of three 3-heterocyclic-thiomethyl cephlosporin ntibiotics. Antimicrob. Agents Chemother. 1: Wilkins, T. D., nd T. Thiel Resistnce of some species of Clostridium to clindmycin. Antimicrob. Agents Chemother. 3: Zbrnsky, R. J., J. A. Johnston, nd K. J. Huser Bcteriosttic nd bctericidl ctivities of vrious ntibiotics ginst Bcteroides frgilis. Antimicrob. Agents Chemother. 3: