Role of Vancomycin as a Component of Oral Nonabsorbable Antibiotics for Microbial Suppression in Leukemic Patients

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mr. 1979, p /79/ /06$02.00/0 Vol. 15, No. 3 Role of Vncomycin s Component of Orl Nonbsorbble Antibiotics for Microbil Suppression in Leukemic Ptients JOHN F. BENDER,* STEPHEN C. SCHIMPFF, VIOLA MAE YOUNG, CLARENCE L. FORTNER, MARY D. BROUILLET, LILLIAN J. LOVE, AND PETER H. WIERNIK Bltimore Cncer Reserch Center, Ntionl Cncer Institute t the University of Mrylnd Hospitl, Bltimore, Mrylnd Received for publiction 28 September 1978 A totl of 38 dult ptients with cute leukemi who were undergoing remission induction chemotherpy in regulr ptient rooms were rndomly llocted to one of two orl nonbsorbble ntibiotic regimens for infection prophylxis (gentmicin, vncomycin, nd nysttin [GVN] or gentmicin nd nysttin [GN]) to evlute whether vncomycin ws necessry component. The ptient popultion in both groups were comprble. Tolernce to GVN ws less thn GN but complince ws pproximtely equl (>85% in both groups). Ptients receiving vncomycin demonstrted greter overll limentry trct microbil suppression; however, cquisition of potentil pthogens ws pproximtely equl in both groups. The incidence of bcteremi, s well s the overll incidence of infection s relted to the number of dys t vrious grnulocyte levels, ws lso pproximtely equl in both groups. Group D Streptococcus species were poorly suppressed by GN compred with GVN, lthough no ptient developed n infection with these orgnisms. Coloniztion by newly cquired grm-negtive bcilli ws significntly less in the GN group (GN, 3 coloniztions; GVN, 13 coloniztions; P < 0.01). It is concluded tht vncomycin my be sfely eliminted from the GVN regimen provided microbiologicl dt is monitored to detect resistnt orgnisms. Infection is the most common cuse of morbidity in ptients with cute leukemi during gent in the combintion for suppression of ero- might be expected to be stisfctory s the only periods of disese or drug-induced grnulocytopeni (7). Mny infections re cused by the substntil cpbility of suppressing the grmbic bcteri. Vncomycin is believed to hve ptient's own oro-intestinl flor during these positive nerobic limentry trct flor, but periods of severe grnulocytopeni (14). Orl infection with nerobes is uncommon in the nonbsorbble ntibiotics such s the combintion gentmicin, vncomycin, nd nysttin bic florl suppression my not be necessry. In grnulocytopenic stte, suggesting tht nero- (GVN) hve been evluted for their bility to ddition, evidence from niml studies conducted in the Netherlnds suggests tht the suppress the limentry trct microbil flor nd thereby reduce the potentil for microbil presence of nerobic orgnisms in the limentry trct imprts protection to the host ginst invsion (3, 5, 6, 8, 10, 12, 15, 18). Although there is not unnimity of results mong the vrious coloniztion by newly cquired orgnisms, such evlutions, it hs been our opinion tht the s grm-negtive bcilli (16, 17). Therefore, weight of evidence fvors microbil flor suppression during remission induction therpy for tretment with gentmicin nd nysttin (GN) prospective, rndomized tril of GVN versus dults with cute leukemi who experience prolonged grnulocytopeni nd ssocited mucosl sion of vncomycin would improve ptient tol- ws undertken to determine whether the omis- dmge of the limentry trct (Schimpff, in ernce, dequtely suppress limentry trct Infections Complicting the Abnorml Host, in erobic microbil flor, mintin degree of press). coloniztion resistnce ginst cquired orgnisms, nd imprt equivlent protection ginst The GVN combintion is poorly tolerted by most ptients in lrge prt becuse of the poor infection. tste of orl vncomycin. Vncomycin ws included in the originl formultion becuse of its MATERIALS AND METHODS grm-positive spectrum. Gentmicin lso hs Ptient popultions. Adult ptients bout to receive remission induction chemotherpy for cute substntil grm-positive spectrum in ddition to its intended grm-negtive coverge nd nonlymphocytic leukemi, cute lymphocytic leuke- 455

2 456 BENDER ET AL. mi, chronic myelocytic leukemi in blst crisis, nd certin mlignnt lymphoms were rndomly llocted to receive either GVN or GN. Informed consent ws obtined before rndomiztion. On-study time. On-study time ws defined s beginning with ntibiotic institution nd continuing until remission, deth, or 5-week period hd elpsed. Bsic infection prophylxis. Ptients were instructed in progrm of personl hygiene, including the use of hexchlorophene or povidone-iodine swbbing of xill, groin, nd perineum three times per dy, dentl hygiene following dentl prophylxis, use of electric shvers, nd voidnce of occlusive ntiperspirnts [12, 13; J. Murillo, S. C. Schimpff, nd M. D. Brouillet, Cncer (Phildelphi), in press]. A low-microbil-content (cooked food) diet ws utilized, nd live flowers or plnts were excluded from ptient cre res. Visitors nd stff utilized n ntiseptic hnd-clensing fom (12). Orl nonbsorbble ntibiotics. The GVN regimen s utilized t this center since 1970 consists of gentmicin (200 mg; Schering Lbortories) prepred in cherry syrup, vncomycin (500 mg; Eli Lilly & Co.) prepred in sterile wter, nysttin suspension (106 U; Lederle Lbortories) nd nysttin tblets (4 x 10' U; Lederle Lbortories) dministered every 4 h round the clock (12). Ptients were sked to swish ech orl ntibiotic for period of 1 min before swllowing. In ddition, povidone-iodine mouthwsh (The Purdue Frederick Co.) ws dministered every 4 h (timed to come between the regulrly scheduled doses of the orl ntibiotics). These ptients were visited by n infection control nurse nd phrmcist three times week for the entire 5-week study period to stress complince, determine ctul ntibiotic ingestion, nd ssess tolernce. Tolernce (pltbility nd incidence of nuse nd vomiting) ws determined by interviewing the ptients utilizing questionnire contining 10 stndrdized questions directed t eliciting n unemotionl esment of the pltbility of GVN or GN. Complince (the ctul ingestion of ech prescribed dose) ws determined by reviewing computerized drug dministrtion records. Complince ws clculted by totling ech dose of ll orl ntibiotics ctully ingested by the ptient nd dividing by the totl doses ordered (six doses per dy) for ech week. Microbiologicl studies: cultures. All ptients hd cultures of their nose, gums, xill, nd rectum tken t the time of rndomiztion (which usully coincided with dmission) nd twice weekly therefter (14). In ddition to the routine surveillnce cultures, nerobic stool cultures were obtined t dmission nd weekly therfter. Micrqbiologicl identifiction s to genus nd species of ll morphologiclly distinct isoltes ws performed. Antibiotic susceptibility tests (Kirby-Buer [1] disk technique nd microtiter miniml inhibitory concentrtion [9]) were performed on ll isoltes from normlly sterile body fluids, nd disk susceptibility ws performed on selected isoltes from surveillnce cultures. Bse-line orgnisms were those isolted from surveillnce cultures which were obtined before the institution of orl ntibiotics. Acquired orgnisms were considered to be those ANTIMICROB. AGENTS CHEMOTHER. which were isolted from surveillnce cultures nd which were not present in the ptient's bse-line flor (14). An cquired orgnism ws considered trnsient if it ws isolted from only one culture, but it ws considered colonizing if it ws present in cultures from one or more sites on successive surveillnce cultures. Colony quntittion from the rectum ws determined by using the brod microbiologicl designtions of no growth, 1+, 2+, 3+, nd 4+ growth s determined by seril strek plte technique. This quntittion ws then compred with percent ptient complince to the ntibiotic regimens. Infections. (i) Infection identifiction nd documenttion. Dignostic evlution of possibly infected ptients included, t minimum, (i) two seprte blood cultures, (ii) urinlysis nd culture, (iii) surveillnce cultures, nd (iv) chest X rys. Virl cultures, serology, nd invsive procedures, such s trnstrchel spirtion or brushing for pulmonry infiltrtes or biopsies nd cultures of liver, bone mrrow, nd skin, were performed when indicted nd fesible. (ii) Clssifiction of infection. Bsed on clinicl course nd microbiologicl dt, infections were clssified s one of the following: microbiologiclly documented (site nd pthogen defined with nd without bcteremi) or cliniclly documented (site defined but not pthogen). Equivocl infections were disregrded for purposes of this evlution (11). Suspected infectious episodes were mnged initilly with empiric use of ticrcillin nd n minoglycoside. RESULTS Ptient popultion. A totl of 42 ptients were rndomized to receive either GVN (20 ptients) or GN (22 ptients). Two ptients rndomized to the GVN rm of the study were not included in the results. One died of refrctory dvnced cute lymphocytic leukemi within the first week, nd the other ptient, despite prior informed consent, refused the orl ntibiotics, s did two ptients rndomized to receive GN. This resulted in 18 nd 20 evluble ptients who were receiving GVN nd GN, respectively (Tble 1). Tolernce nd complince. Overll, GN ws substntilly more tolerble thn GVN (i.e., it cused less nuse nd vomiting). Vncomycin ws the most objectionble component of the regimen nd ws most likely to precipitte severe nuse nd vomiting. Complince diminished to its lowest level during the dministrtion of chemotherpy (<33% of prescribed doses for tht dy). Septic nd emotionlly depressed ptients complied minimlly (<50% on ny prticulr dy). Cytosine rbinoside ltered tste senstions in most ptients nd thereby interfered with tolernce until the 7-dy infusion of the drug ws completed. Despite poor tolernce, medin complince

3 VOL. 15, 1979 ROLE OF VANCOMYCIN IN SUPPRESSION OF LEUKEMIA 457 for the overll 5-week study period ws more thn 85% for both regimens. Orgnism cquisition. The cquisition of potentil pthogens ws low nd pproximtely equl in both groups. Ptients tking GVN cquired men of 1.66 orgnisms (medin, 1; rnge, 0 to 5) compred with men of 1.55 (medin, 1; rnge, 0 to 6) for the ptients tking GN. Of the totl orgnisms cquired in the GVN group, 11 were trnsient nd 21 were colonizing. In the GN group, 19 were trnsient nd 18 were colonizing. However, the GVN ptients becme colonized with more grm-negtive bcilli thn did the GN group (13 versus 3; P < 0.01); i.e., most grm-negtive bcilli cquired by the GN ptients were trnsient nd did not colonize the limentry trct, wheres grm-negtive bcilli cquired by the GVN ptients were often ble to colonize. (Tble 2). TABLE 1. Ptient chrcteristics No. of ptients receiving the following regi- Dignosis men: GVN GNb Acute nonlymphocytic leukemi Acute lymphocytic leukemi 3 5 Chronic myelocytic leukemi 2 0 (blst crisis) Mlignnt lymphom 1 1 Totl rndomized Exclusions' 2 2 Totl evluted Gentmicin (200 mg), vncomycin (500 mg), nd nysttin (5 x 10' U) were given orlly every 4 h during induction b chemotherpy. Gentmicin (200 mg) nd nysttin (5 x 106 U) were given orlly every 4 h during induction chemotherpy. 'See text. Orgnism TABLE 2. The rte of cquisition of orgnisms ws pproximtely equl. (Fig. 1). There were differences, however, in the types of orgnisms cquired in the two regimens. Group D Streptococcus species, usully first noted in the orl cvity, were commonly isolted in the GN group nd were lmost lwys colonizing; these occurred only spordiclly in the GVN group nd were rrely colonizing. Microbil suppression. Tble 3 compres overll complince with rectl culture semiquntittion of erobic flor. When complince exceeded 85%, microbil suppression of rectl flor with GVN ws better thn tht with GN. The presence of vncomycin (mong ptients with good complince) contributed significntly to erobic flor suppression, especilly group D Streptococcus species, which were usully minoglycoside resistnt. Ptients in both rms of the study consistently demonstrted lrge numbers of yest in their surveillnce cultures despite ingestion of 5 x 106 U of nysttin every 4 h. Yests which were present in the bse-line cultures or which were cquired were persistent for the reminder of the 5-week period. 3.0 (0 z ew0.5 D o-o GVN 0-0o GN 3 WEEKS ON STUDY FIG. 1. Cumultive cquisition of orgnisms. Acquired orgnisms No. of orgnisms in the following groups: GVN Trnsient Colonizing Trnsient Colonizing Gums Rectum Gums Rectum Gums Rectum Gums Rectum Group D Streptococcus spe cies Grm-negtive bcilli Yests Miscellneous Acquired orgnisms re defined s those which were isolted from surveillnce cultures nd which were not present in the bse-line flor of the ptients. Of these, trnsient represents those orgnisms ppering in single culture, wheres colonizing represents those orgnisms which, once cquired, ppered in ll subsequent cultures. GN 5

4 458 BENDER ET AL. Week TABLE 3. ANTIMICROB. AGENTS CHEMOTHER. It could not be determined whether the omission of vncomycin in the GN group mde mjor difference compred with the GVN group s to the preservtion of grm-positive nerobic flor. Although mny ptients in the GN group hd norml numbers nd types of nerobes in rectl cultures, some ptients in the GVN group did lso. Suppression of nerobic flor in both groups my hve been prtilly relted to the use of systemic ntibiotics, such s ticrcillin. Ptients receiving GN who chieved sterile rectl cultures consistently demonstrted tht group D Streptococcus species were the first orgnisms to repper. Ptienits receiving GVN hd Escherichi coli, Proteus species, nd Pseudomons species reppering s the first orgnisms on surveillnce fter no-growth rectl cultures. Except for yests, very few ptients in either rm of the study hd single orgnism constituting persistent growth. In most cses, three to five orgnisms were responsible for persistent growth, indicting n overll lck of microbil suppression rther thn selective process or microbil resistnce. Gentmicin-resistnt orgnisms. Gentmicin-resistnt orgnisms were cquired by the two groups eqully (GVN, 4 orgnisms; GN, 4 orgnisms). All eight gentmicin-resistnt orgnisms were Psuedomons eruginos. Resistnce ppers to hve emerged in one ptient, s suggested by chnging susceptibility over time with the sme serotype, but the other seven P. eruginos were resistnt when first cquired (Tble 4). Infection. The overll incidence of infection ws pproximtely equl in both groups (Fig. 2). There were 16 documented infections (13 microbiologiclly, 3 cliniclly) nd 14 documented infections (7 microbiologiclly, 7 cliniclly) mong Percent complince versus semiquntittion of rectl cultures % Complince" Highest quntittionc No. of species isolted' GVN GN GVN GN GVN GN 1 98 (12)e 93 (15) 4+f 4+f 4f 4f 2 93 (9) 95 (14) (9) 95 (17) (11) 90(12) (8) 96 (10) All vlues re expressed s medins. b Percent complince ws computed by dividing the totl weekly doses ingested by the totl weekly doses ordered. Percent complince ws clculted only for those ptients who were in-ptients during prticulr week. c The vlue given represents the medin of the highest quntittions (O to 4+) found in ll specimens collected from ll ptients during the week in question. d The vlue given represents the medin of the totl number of species isolted from ech individul culture collected during the week in question. 'Numbers in prentheses re numbers of ptients prticipting. f Represent bse-line cultures before institution of orl nonbsorbble ntibiotics. TABLE 4. Gentmicin resistnce of erobic grm-negtive bcilli in surveillnce cultures during period of study Ptient Orgnism bse- Orgnism c- Resistnce emerged Resistnce present rbgsiuetm cued Infection hd ssoline quired during therpy when cquired seqtionfec cited bcteremi GVN A - + +"b + B C _ +c D GN.E F _+ + + G H The only gentmicin-resistnt orgnisms isolted were P. eruginos. b This serotype 1 P. eruginos ws initilly susceptible (miniml inhibitory concentrtion, 1.5,g/ml), but lter resistnt (miniml inhibitory concentrtion, 6 jg/ml). c Present in blood cultures t the time of first ppernce in surveillnce cultures.

5 VOL. 15, 1979 ptients receiving GVN nd GN, respectively. Tble 5 is summry of orgnisms cusing infection. Six ptients receiving GVN (33%) nd six receiving GN (30%) completed their 5 weeks of study without hving ny infections. Of the seven bcteremis in the GVN group, three originted from sites not ffected by orl ntibiotic ingestion (e.g., skin, contminted blood products, finger stick), s did two of seven in the GN group (e.g., skin, bone mrrow). One GVN ptient developed bcteremi with gentmicin-resistnt P. eruginos strin (miniiml inhibitory concentrtion, 12,ug/ml). Two other infections (rectl lesion, rm lesion) were cused by P. eruginos of borderline sensitivity (miniml inhibitory concentrtion, 6 jig/ml for both). There were no other infections cused by gentmicin-resistnt grm-negtive bcilli. However, two ptients in the GN group becme colonized nd developed bcteremis D 14 CD 13 z < V- 8 w7 z 6 O 5 4 w z 3 LE7 ui1 le L ROLE OF VANCOMYCIN IN SUPPRESSION OF LEUKEMIA 459 TOTAL INFECTIONS E BACTEREMIAS z GVN GN GVN GN GVN GN GVN GN >1,000 Z GRANULOCYTE COUNT/mm3 FIG. 2. Incidence of infection t vrious grnulocyte levels. TABLE 5. Infections occurring during study period No. of ptients receiving the following regi- Infection men: GVN GN Microbiologiclly documented' Grm-negtive bcilli 8 (4)b 2 (2) Stphylococcus ureus 2 (1) 1 (1) Diptheroidsc 0 2 (2) Miscellneous 3 (2) 2 (2) Cliniclly documented' 3 7 See text b for definitions. Numbers in prentheses re numbers of ptients with ssocited bcteremi. ' Susceptible only to vncomycin nd rifmpin. with n unusul diphtheroid which ws gentmicin resistnt (nd vncomycin susceptible). DISCUSSION The use of orl nonbsorbble ntibiotics s mens of infection prevention mong grnulocytopenic leukemi ptients not treted in lminr irflow rooms or their equivlent is controversil (3, 5, 6, 8, 10, 12, 15, 18). Although mny trils hve shown efficcy (3, 5, 8, 10), others hve not (17, 18). Nevertheless, we believe tht the weight of evidence fvors this pproch for ptients who will hve prolonged, profound grnulocytopeni, nd we hve therefore plced ll dult cute nonlymphocytic leukemi nd cute lymphpcytic leukemi ptients on GVN during remission induction since mid Such n pproch is not without its disdvntges, including the high cost, poor ptient tolernce, nd cquisition of gentmicin-resistnt orgnisms (4). The current study ws designed with the intention of overcoming, ech of these disdvntges to some degree. Elimintion of vncomycin reduces the cost by 20%, removes the most objectionble tsting of the three gents, nd my llow greter persistence of nerobic flor in the colon (2). The ltter effect my preserve coloniztion- resistnce (17), with the result tht orgnisms cquired my be less ble to colonize, thus reducing the potentil for invsion. However, elimintion of vncomycin lso removes the gent to which the group D Streptococcus species re susceptible. In this study, the elimintion of vncomycin ws found to improve tolernce (i.e., less nuse nd vomiting), lthough complince (the number of prescribed doses ctully ingested) ws the sme due to intensive reinforcement by the stff. Both regimens, when ingested, suppressed rectl flor. GVN produced more totl suppression of erobic gstrointestinl orgnisms, but the bility of the ptients to comply with this regimen ws more difficult becuse of the presence of vncomycin. Yest suppression by both regimens ws poor. Although mny more ptients receiving GN continued to grow group D Streptococcus species from rectl surveillnce cultures thn did ptients receiving GVN, the quntittion level ws not gret, nd no ptient becme infected with these orgnisms. P. eruginos ws cquired by four GVN ptients, with subsequent infection in only one. The semiquntittion levels for the P. eruginos in the GN group were generlly less thn those observed in the GVN group, gin suggesting the possibility tht some coloniztion resistnce hd been preserved. Acquired orgnism coloniztion (s distinct from trnsient occurrence) ws slightly but not

6 460 BENDER ET AL. significntly less in the GN-treted group (GVN, 21 coloniztions; GN, 18 coloniztions) but for grm-negtive bcilli the GN regimen ws superior (GVN, 13 coloniztions; GN, 3 coloniztions; P < 0.01). This suggests tht coloniztion resistnce for grm-negtive bcilli my hve been mintined to some degree by not dministering vncomycin. However, two ptients not receiving vncomycin did develop infection with n unusully resistnt diphtheroid. We recognize the diversity of opinion regrding the use of orl nonbsorbble ntibiotics outside of the setting of the protected environment. Undoubtedly, these gents hve mjor potentil disdvntges. In the bsence of protected environments, such regimens, if utilized t ll, should be crefully monitored. Monitoring should include close observtion of complince, s rpid regrowth of potentilly pthogenic erobic grm-negtive bcilli will ensue shortly fter these gents re discontinued (12). Microbiologicl monitoring is n dditionl necessity to check on complince nd to scertin whether resistnt orgnisms hve been cquired nd re colonizing the ptient. Evidence of noncomplince requires further efforts by the stff, nd detection of resistnt pthogens requires dditions nd ltertions to the orl regimen. It hs been our belief tht the dt vilble in the literture support the use of orl nonbsorbble ntibiotics in the setting of profound, persistnt grnulocytopeni ccompnied by mucosl dmge to the limentry trct. The disdvntges noted bove might be overcome by ttempts to mintin coloniztion resistnce (16). The current study ws step in tht direction. The use of GN is probbly cliniclly equivlent to GVI4 when utilized outside the isoltion setting, but it certinly does not negte ll of the disdvntges noted. Clinicl nd microbiologicl monitoring continues to be essentil, nd further efforts re needed to develop more tolerble regimens which reduce the erobic grmnegtive flor while perserving the nerobic coloniztion-resisting flor of the limentry trct. ANTIMICROB. AGENTS CHEMOTHER. ACKNOWLEDGMENTS We grtefully cknowledge the ssistnce of Mrgret Potts for typing the mnuscript, Normn Friedmn nd Michel Hrgdon in the Bltimore Cncer Reserch Center Microbiology Lbortory, Donn Purvis nd the stff of Hzelton Lbortories, Vienn, V., nd the nursing nd phrmcy stff for their invluble help nd ssistnce. LITERATURE CITED 1. Buer, A. W., W. M. M. Kirby, J. C. Sherris, nd M. Turck Antibiotic susceptibility testing by stndrdized single disk method. Am. J. Clin. Pthol. 45: Bodey, G. P Orl ntibiotic prophylxis in protected environment units: Effect of nonbsorbble nd bsorbble ntibiotics on the fecl flor. Antimicrob. Agents Chemother. 1: Bodey, G. P., nd V. Rodriguez Infections in cncer ptients on protected environment-prophylctic ntibiotic progrm. Am. J. Med. 59: Hhn, D. M., S. C. Schimpff, C. L Fortner, A. C. Smyth, V. M. Young, nd P. H. Wiernik Infection in cute leukemi ptients receiving orl nonbsorbble ntibiotics. Antimicrob. Agents Chemother. 13: Keting, M. J., nd D. G. Pennington Prophylxis ginst septicemi in cute leukemi: the use of frmycetin. Med. J. Aust. 2: Levi, J. A., P. C. Vincent, F. Jennis, D. E. Lind, nd F. W. Gunz Prophylctic orl ntibiotics in the mngement of cute leukemi. Med. J. Aust. 1: Levine, A. S., S. C. Schimpff, R. G. Grw, Jr., nd R. C. Young Hemtologic mlignncies nd other mrrow filure sttes: progress in the mngement of complicting infections. Semin. Hemtol. 2: Levine, A. S., S. E. Siegel, A. D. Schreiber, J. Huser, H. Preisler, I. M. Goldstein, F. Seidler, R. Simon, S. Perry, J. E. Bennett, nd E. S. Henderson Protected environments nd prophylctic ntibiotics. A prospective controlled study of their utility in the therpy of cute leukemi. N. Engl. J. Med. 288: McLowry, J. D., M. J. Jqu, nd S. T. Selepk Detiled methodology nd implementtion of semiutomted seril dilution microtechnique for ntimicrobil susceptibility testing. Appl. Microbiol. 20: Preisler, H. D., I. M. Goldstein, nd E. S. Henderson Gstrointestinl "steriliztion" in the tretment of ptients with cute leukemi. Cncer (Phildelphi) 26: Schimpff, S. C Therpy of infection in ptients with grnulocytopeni. Med. Clin. North Am. 61: Schimpff, S. C., W. H. Greene, V. M. Young, C. L Fortner, L Jepsen, N. Cusck, J. B. Block, nd P. H. Wiernik Infection prevention in cute nonlymphocytic leukemi. Lminr ir flow room reverse isoltion with orl nonbsorbble ntibiotic prophylxis. Ann. Intern. Med. 82: Schimpff, S. C., D. M. Hhn, M. D. Broullet, V. M. Young, C. L Fortner, nd P. H. Wiernlk Infection prevention in cute leukemi: comprison of bsic infection prevention techniques with stndrd room reverse isoltion or with reverse isoltion plus dded ir filtrtion. Leuk. Res. 2: Schimpff, S. C., V. M. Young, W. H. Greene, G. D. Vermeulen, M. R. Moody, nd P. H. Wiernik Origin of infection in cute nonlymphocytic leukemi. Significnce of hospitl cquisition of potentil pthogens. Ann. Intern. Med. 77: Storring, R. A., T. J. McElwin, B. Jmeson, E. Wiltshw, A. S. D. Spiers, nd H. Gy Orl nonbsorbble ntibiotics prevent infection in cute non-lymphocytic leukemi. Lncet ii: vnder Wij, D., nd J. M. Berghuis-deVries Selective elimintion of Enterobctericee species from the digestive trct in mice nd monkeys. J. Hyg. 72: vnder Wij, D., J. M. Berghulis-deVries, J. E. C. Lekkerkerk, nd vnder Wees Coloniztion resistnce of the digestive trct in conventionl nd ntibiotic treted mice. J. Hyg. 69: Ytes, J. M., nd J. F. Hollnd A controlled study of isoltion nd endogenous microbil suppression in cute myelocytic leukemi ptients. Cncer (Phildelphi) 32: