Granulocytopenic Cancer Patients

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, JUIY 1986, P /86/ $02.00/0 Copyright 1986, Americn Society for Microbiology Vol. 30, No. 1 Rndomized Comprison between Two Ceftzidime-Contining Regimens nd Cephlothin-Gentmicin-Crbenicillin in Febrile Grnulocytopenic Cncer Ptients BARNETT S. KRAMER,t* REUBEN RAMPHAL, AND KENNETH H. RAND Divisions of Medicl Oncology nd Infectious Diseses, University of Florid College of Medicine, Ginesville, Florid Received 12 September 1985/Accepted 17 April 1986 Becuse the results of our published tril [R. Rmphl, B. S. Krmer, K. H. Rnd, R. S. Weiner, nd J. W. Shnds, Jr., J. Antimicrob. Chemother. 12(Suppl. A):81-88, 1983] of ceftzidime versus cephlothin, gentmicin, nd crbenicillin (KGC) reveled prepondernce of grm-positive superinfections, including those cused by clostridi, in ptients treted with ceftzidime, we dded vncomycin to the ceftzidime regimen t study entry 49 nd continued with 2:1 rndomized comprison of ceftzidime-vncomycin (CV) versus KGC. Criteri for study entry were fever (temperture,.38.50c on one occsion or -38C on two occsions 6 h prt) nd grnulocytopeni (<500/mm3 or filing count nticipted to be <500/mm3). Ninety-five entries (79 ptients) were evluble. The numbers of initil clinicl responses for ceftzidime-, KGC-, nd CV-treted ptients were 9 of 21 (43%), 21 of 37 (57%), nd 21 of 37 (57%), respectively; differences were not significnt. The deth rte ws lower with CV (2 of 37 ptients) thn with KGC (10 of 37 ptients) (P < 0.05 by two-tiled nlysis) or with ceftzidime lone (7 of 21 ptients) (P < 0.025). Deth from presumed infections occurred in 9 of 37 KGC-treted ptients versus 1 of 37 CV-treted ptients (P < 0.025). Superinfections occurred in five ceftzidime-treted ptients (24%) versus 7 KGC-treted ptients (19%) but not in CV-treted ptients (CV versus KGC, P < 0.05; CV versus ceftzidime, P < 0.01). CV ppers to be superior to KGC or ceftzidime lone in the mngement of febrile grnulocytopenic cncer ptients. The immedite institution of n empiric brod-spectrum ntimicrobil regimen in febrile cncer ptients with cytotoxic therpy-induced grnulocytopeni hs become ccepted prctice over the lst decde (10, 11). Nevertheless, the optiml ntibiotic regimen hs not been defined, nd the use of vriety of complex two- nd three-drug regimens is commonplce (1, 3-5, 7, 8, 13-15). Some of the three-drug regimes involve up to 13 drug dministrtions per dy, compounding costs nd the potentil for mediction errors nd sometimes requiring delys to llow for the dministrtion of other medictions or blood products. The idel empiric regimen would therefore be single ntibiotic with efficcy t lest equl to tht of more complex regimens nd with low incidence of superinfections nd toxicity, mitigting the need for subsequent dditions of drugs nd redjustments. With these considertions in mind, we initited rndomized comprison of ceftzidime versus cephlothin, gentmicin, nd crbenicillin (KGC) in the initil empiric mngement of febrile grnulocytopenic cncer ptients. Ceftzidime hs excellent ctivity ginst grm-negtive bcilli, the most frequent serious pthogens in grnulocytopenic ptients. It hs modest ctivity ginst grm-positive orgnisms. There hd been t tht time no significnt reports of in vitro development of resistnce or of problem with serious superinfections cliniclly. An nlysis of our tril fter the first 48 study entries reveled comprble initil response rtes between the two tretment progrms; however, s previously reported, there ws n lrming super- * Corresponding uthor. t Present ddress: Ntionl Cncer Institute, NCI-Nvy Medicl Oncology Brnch, Nvl Hospitl, Bethesd, MD infection rte with grm-positive orgnisms in the ceftzidime-treted ptients (9). Becuse of this problem, improved grm-positive coverge ws felt necessry. Idelly, the dditionl drug should not hve significnt effects on gut flor. Vncomycin ws therefore chosen becuse of its excellent grm-positive coverge, including its effectiveness ginst Stphylococcus epidermidis, which hs been emerging in some centers s mjor pthogen, nd becuse it hs little or no biliry excretion (2). A rndomized comprison of ceftzidime plus vncomycin (CV) versus KGC with 2:1 imblnce in fvor of CV ws then begun. We now report the results of the entire study (101 study entries). MATERIALS AND METHODS Ptient entry nd mngement. Study entry criteri were s follows: (i) underlying neoplstic disese; (ii).18 yers old; (iii) grnulocytopeni, s defined by n bsolute neutrophil-plus-bnd count of <500/mm3 or <1,000/mm3 nd flling rpidly; (iv) fever, s defined by n orl temperture of.380c on two occsions 6 h prt or.38.50c on one occsion not ssocited with blood product trnsfusions. Ptients were excluded if they hd received ntibiotics in the preceding 96 h or hd known llergy to penicillin or to ny of the study drugs. All ptients gve written informed consent. Since grnulocytopeni could be nticipted in mny ptients, informed consent ws obtined prior to the onset of fever whenever possible. Neither the ptient nor the person obtining informed consent ws wre of the tretment ssignment t the time consent ws obtined. The initil evlution t study included the following: (i) two blood cultures; (ii) cultures of ny site cliniclly sus-

2 VOL. 30, 1986 EMPIRIC THERAPY FOR GRANULOCYTOPENIA AND FEVER 65 TABLE 1. Unevluble ptients AntibioticUnderlyingNo. of grnulocytes/ Initil infection Out- Superinfection Reson for exclusion regimen disese mm3 come Ceftzidime Lymphom 0 E. coli Died None Moribund t study entry; KCG dded 5 h lter Ceftzidime Leukemi 0 P. eruginos Lived C. tertium nd S. Tobrmycin dded on dy epidermidis 2 Ceftzidime Leukemi 1,188 None Lived None Not grnulocytopenic KGC Lymphom 1,044 None Lived None Not grnulocytopenic C/V Leukemi 500 None Died Pulmonry Switched to KCG on dy 3 spergillosis fter responding on dy 1 to CV-hd whels felt 2 to vncomycin C/V Leukemi 42 None Lived None Switched to KGC fter itching subsequent to first CV dose Added becuse of n inccurte lbortory report of susceptibility. The ptient ws febrile nd hd sterile blood culture t this time. pected of being infected; (iii) chest roentgenogrm; (iv) urinlysis; nd (v) serum electrolyte, blood ure nitrogen, cretinine, nd liver function tests. The first 48 study entries were rndomly ssigned to receive either ceftzidime lone (2 g intrvenously every 8 h) or cephlothin (3 g intrvenously every 6 h), gentmicin (1.5 mg/kg intrvenously every 8 h), nd crbenicillin (500 mg/kg per dy) (mximum, 36 g/dy) (KGC) in six dily divided doses. From study entry 49 through 101, there ws 2:1 rndomiztion to receive either ceftzidime s described bove plus vncomycin (500 mg intrvenously every 6 h) or KGC. The ntibiotics in ny individul ptient were chnged only if cultures reveled orgnisms resistnt to the ssigned regimen. The ntibiotics were continued until the grnulocyte count ws >500/mm3 on two successive dys nd the temperture ws <38 C for t lest 24 h. Amphotericin B ws dded empiriclly (0.5 to 0.7 mg/kg per dy) on dy 8 if the ptient ws febrile nd grnulocytopenic without documented source of fever. It ws dded fter dy 8 if febrile, persistently grnulocytopenic ptients subsequently redeveloped fever. Since the empiric ddition of mphotericin B cme no erlier thn dy 8, it did not in ny wy ffect the determintion of the initil clinicl response. Serum gentmicin levels were monitored, nd doses were djusted to chieve pek serum level of 4 to 8 mg/liter nd trough serum level of <2 mg/liter. Chest roentgenogrms were obtined weekly fter study entry or more frequently if pulmonry symptoms or signs evolved. Two sets of blood cultures were obtined once dily if ptients continued to be febrile. Bcteril isoltes were tested for susceptibility to ceftzidime by microtiter nd tube broth dilutions. Definitions of response ctegories. A fvorble clinicl response ws defined s ptient becoming febrile (temperture, <380C) within 96 h of the initition of ntibiotics nd remining febrile for t lest 48 h. A fvorble bcteriologicl response ws defined s the termintion of documented bcteremi on repet cultures regrdless of the febrile response. There were no instnces of microbiologiclly documented soft tissue infections which were not ccompnied by bcteremi. Since cultures of cellulitis re insensitive in our experience, we relied on blood culture results for the determintion of bcteriologicl response. A new fever ws one which occurred fter fvorble clinicl response. A superinfection ws considered to be documented infection by new orgnism while the ptient ws receiving therpy. Deths were ctegorized s being due to initil infections (whether cliniclly or microbiologiclly defined), superinfections, or other cuses (e.g., cerebrl hemorrhge, myocrdil infrction). Sttisticl nlysis. All comprisons of outcome by tretment group were done by two-tiled chi-squre nlysis. All comprisons of mens were done by the student t tests (nd by the Wilcoxon rnk sum test for ptient ge comprisons). Sttisticl significnce did not chnge whether ll ptients entered were nlyzed or the six unevluble ptients were excluded. There ws no sttisticl difference between the 23 entries ssigned to KGC in the first phse, of the study nd the 14 entries ssigned to KGC in the second phse of the study with regrd to initil grnulocyte count, durtion of grnulocytopeni, clinicl response, or deth. For n nlysis of the intensity of chemotherpy of the three tretments, one of us, medicl oncologist (B.S.K.), mde the ssignments retrospectively. In generl, the designtion of intensive therpy ws reserved for ptients undergoing induction or consolidtion therpy for cute leukemi nd occsionl ptients with solid tumors who underwent high-dose therpy, which usully results in grnulocytopeni for more thn 2 weeks. RESULTS There were totl of 101 study entries (85 ptients) from Jnury 1982 through September Ninety-five entries (79 ptients) were considered evluble. Three ptients in the ceftzidime group were considered unevluble: one ws ineligible becuse grnulocytopeni ws not chieved; nother ws moribund t study entry, nd the treting physicin decided to dd KGC 5 h fter study entry; nd tobrmycin ws dded on dy 2 of the study in the third, despite good clinicl nd bcteriologicl response, becuse of n erroneous susceptibility report. One KGC entry ws ineligi-

3 66 KRAMER ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 2. Ptient chrcteristics (evluble ptients) Prmeter Ceftzidime KGC CV (n = 21) (n = 37) (n = 37) No. of mles/femles 10/11 15/22 19/18 Medin ge (rnge) 43 (21-88) 56 (20-77) 35 (18-66) Men ge Dignosisb (no. of ptients) Acute leukemi Solid tumor Intensive chemotherpy (no of ptients) Medin grnulocytes/mm3 t 34 (0-435) 6 (0-888) 20 (0-1,000) study entry (rnge) Men grnulocytes/mm3 82 t t t 324 t study entry t SD No. of dys grnulocytopenic Medin (rnge) 12 (2-38) 10 (1-38) 15 (2-39) Men No differences between groups re sttisticlly significnt, except where noted. b CV versus KGC, P < 0.05; others, P not significnt. ble becuse grnulocytopeni did not occur. Two CV entries were unevluble: both were switched to KGC fter the ptients hd cutneous rections to the vncomycin infusion erly in the course of therpy. These six unevluble ptients nd outcomes re listed in Tble 1. The chrcteristics of the remining 95 entries re listed in Tble 2. There were no sttisticlly significnt differences mong the three tretments with regrd to sex, ge, intensity of chemotherpy, initil grnulocyte count, or durtion of grnulocytopeni t <500/mm3. It should be noted tht the medin durtion of grnulocytopeni in ech group ws reltively long, 12, 10, nd 15 dys. There ws n imblnce in the distribution of the tretments by dignosis, since the CV group hd significntly higher proportion of cute TABLE 3. Therpeutic responses Prmeter Ceftzi- KC dime (n 7) (n = 21) n=3) (n=-37) n=37 No. (%) of clinicl responses 9 (43) 21 (57) 21 (57) No. (%) with bcteriologicl 4/5 (80) 4/5 (80) 4/4 (100) cure of bcteremis Durtion of fever in responders (dys) Medin (rnge) 1 (1-4) 2 (1-4) 2 (1-4) Men No. (%) of ptients with new 7 (78) 12 (57) 15 (71) fevers during therpy Superinfections No. (%) of ptientsb 5 (24) 7 (19)c 0 No. of different orgnisms No. of dethsd cused by: Infections Superinfections Other No. of ptients receiving 8/9 11/14 20/23 mphotericin B/no. of ptients eligible Differences not significnt. b CV versus ceftzidime, P < 0.01; CV versus KGC, P < 0.05; ceftzidime versus KGC, P not significnt. c One KGC ptient developed new pulmonry infiltrte with recurrence of fever fter n initil clinicl response, but there ws no microbiologicl documenttion of the etiology. d CV versus ceftzidime, P < 0.025; CV versus KGC, P < 0.05; ceftzidime versus KGC, P not significnt. leukemi ptients thn did the KGC group: 33 of 37 versus 25 of 37 (P < 0.05). There were no significnt differences between the KGC ptients in the first versus the second prts of the study with regrd to sex, ge, dignosis, proportion undergoing intensive chemotherpy, men nd medin grnulocyte counts t study entry, durtion of grnulocytopeni, or outcome. Therpeutic responses nd outcomes re shown in Tble 3 for the three groups. Although the initil clinicl response rte in the ceftzidime group ws 43%, compred with 57% in ech of the other two groups, this difference ws not sttisticlly significnt. Similrly, the bcteriologicl response rtes mong the three groups were nerly identicl. The initil orgnisms responsible for documented bcteremis nd their outcomes re listed in Tble 4. The sole bcteriologicl filure in the ceftzidime group ws in ptient with overwhelming Escherichi coli sepsis in the setting of mssive gstrointestinl ulcertion resulting from high-dose 5-fluorourcil. The sole bcteriologicl filure in the KGC group ws n episode of Pseudomons eruginos sepsis. There were no filures in the CV group. The durtion TABLE 4. Outcome of microbiologiclly documented bcteremis Drug nd no. Orgnism Outof ptients come Ceftzidime 2 E. coli Died 18 P. eruginos Cured 23 C. subterminle Cured 28 E. coli Cured 33 Klebsiell sp. Cured KCG 7 P. eruginos Cured 11 Enterococcus sp. Cured 14 P. eruginos Cured 17 P. eruginos Died 63 P. eruginos Cured CV 53 S. ureus Cured 71 S. ureus Cured 85 S. ureus Cured 99 S. ureus Cured

4 VOL. 30, 1986 EMPIRIC THERAPY FOR GRANULOCYTOPENIA AND FEVER 67 TABLE 5. Outcome of microbiologiclly documented superinfections Drug nd no. Superinfecting orgnism(s) Dy of Outcome of ptients superinfectionoucm Ceftzidime 1 C. septicum 10 Died 3 Enterococcus sp. 14 Died (noninfectious cuse) 18 C. perfringens nd Enterococcus sp. 5 nd 7 Died 45 C. tertium nd Citrobcter sp. 17 nd 17 Died 47 C. septicum nd Enterococcus sp. 11 nd 11 Died KCG 7 E. coli 9 Lived 11 P. eruginos 20 Died 27 Cndid lbicns 19 Died 32 C. lbicns 8 Lived 34 P. cepci 1, B. frgilis, nd P. cepci 2 18, 27, nd 32 Lived 36 P. eruginos 10 Died CV None None of fevers in responding ptients ws quite similr in ech group. The recurrence rtes of fever in the ceftzidime, KGC, nd CV groups were 78, 57, nd 71%, respectively (P not significnt). Sttisticlly significnt differences, however, emerged for the nlysis of deth rte by tretment ssignment (Tble 3). Of 21 ptients treted with ceftzidime, 7 died, compred with 10 of 37 KGC-treted ptients nd only 2 of 37 CVtreted ptients (CV versus ceftzidime, P < 0.025; CV versus KGC, P < 0.05; ceftzidime versus KGC, P not significnt). One deth in ech of the three groups ws considered to hve noninfectious cuse. Deth due to presumed infections occurred in totl of 6 of 21 ceftzidime-treted ptients, 9 of 37 KGC-treted ptients, nd 1 of 37 CV-treted ptients (KGC versus CV, P < 0.025; ceftzidime versus CV, P < 0.05; KGC versus ceftzidime, P not significnt). Of these, there were 4 deths due to documented superinfections in the ceftzidime group, 3 in the KGC group, nd none in the CV group. There were lso significnt differences mong the groups with regrd to documented superinfections. Of 21 ptients who received ceftzidime, 5 (24%) developed superinfections (eight orgnisms), compred with 7 of 37 (19%) ptients who received GKC (eight orgnisms) nd none of 37 ptients who received CV (CV versus ceftzidime, P < 0.01; CV versus KGC, P < 0.05; ceftzidime versus KGC, P not significnt). As previously reported, there ws striking difference in the profiles of superinfecting orgnisms between the ceftzidime nd KGC regimens (Tble 5). Seven of eight superinfections occurring in ptients receiving ceftzidime were cused by grm-positive orgnisms, compred with prepondernce of grm-negtive orgnisms (five of eight superinfections) in those receiving KGC. There were two episodes of cndidemi in the KGC group, one of them ftl. The outcomes of ll microbiologiclly documented superinfections re shown in Tble 5. Autopsies were performed on 5 of the 19 evluble ptients who died. One of the five, who hd been given ceftzidime, ws determined to hve noninfectious cuse of deth from progressive Hodgkin's disese nd crdic tmponde. The remining four hd utopsy-proven infectious cuses of deth, s follows: Clostridium sepsis, Clostridium sepsis with orgnisms in multiple orgns, pulmonry spergillosis, nd overwhelming E. coli sepsis in the setting of bloody dirrhe cused by chemotherpy-induced bowel mucositis. Since potentil bis in nlyzing deths mong the groups would be n imblnce in the frequency of initition of mphotericin B therpy on dy 8 in febrile neutropenic ptients, s stipulted in the study protocol, we took this into ccount. Indeed, some of the primry physicins were reluctnt to dd mphotericin B in febrile neutropenic ptient who ppered to be stble. Of nine ptients who qulified for the ddition of mphotericin B while receiving ceftzidime, eight ctully received it. This compres with 11 of 14 ptients receiving KGC nd 20 of 23 ptients receiving CV. None of these differences pproched sttisticl significnce (Tble 3). No cses of renl filure occurred, nd no deths were ttributed to ny of the ntibiotics used. Rshes or pruritis occurred in one ceftzidime-treted ptient, two KGCtreted ptients nd four CV-treted ptients. Two cses of fluid overlod occurred, both in the KGC group. DISCUSSION A vriety of empiric brod-spectrum ntimicrobil regimens hve been used nd compred in the initil mngement of febrile neutropenic cncer ptients, but none hs demonstrted cler superiority (1, 3-5, 7, 8, 13-15). A possible reson is tht minor chnges in spectrum cnnot be expected to yield mjor differences in response rtes, s long s most of the commonly infecting orgnisms in the ptient popultion re within the spectrum of the regimen chosen. Indeed, the initil clinicl response rtes in our own study were similr in the single, double, nd triple ntibiotic regimens. Admittedly, the, error (chnce of missing reltively smll initil response rte differences) ws lrge. Bsed on two-sided nlysis with n x error (chnce of declring difference between two regimens exists when, in fct, none exists) of 0.05, the chnce of detecting n improvement in the response from 45% with ceftzidime to 65% with KGC ws only bout 40% (I error, 0.6). Likewise, the P error ws lso bout 0.6 in the bility to detect n improvement in the response from 55% with KGC to 75% with CV. Lrge differences in efficcy nd outcome between groups did not emerge until lter in the tretment course of these ptients, t which time there were differences in

5 68 KRAMER ET AL. superinfection nd deth rtes. Hence, regimen which hs the sme initil response rte my ultimtely prove superior to nother if there re fewer superinfections or deths. One might rgue tht it would be dvntgeous to strt with single brod-spectrum ntibiotic such s ceftzidime nd mke djustments in coverge s becomes necessry lter in the tretment course. Indeed, recent preliminry report by Pizzo et l. showed tht ceftzidime my be s effective s KGC in the initil mngement of febrile grnulocytopenic cncer ptients (P. Pizzo, M. Thler, J. Hiemenz, D. Cotton, J. ithorn, J. Commers, J. Gress, D. Mrshll, D. Longo, nd M. Browne, Progrm Abstr. 24th Intersci. Conf. Antimicrob. Chemother., bstr. no. 380, 1984). However, tht report ws for younger popultion (medin ge, 25) thn our own, with shorter durtion of grnulocytopeni (medin, 8.5 dys). Adjustments in ntibcteril coverge were often necessry fter the first 72 h of therpy. Moreover, one cnnot ccurtely predict in ny given episode precisely when superinfection will emerge. In fct, one of our ptients receiving ceftzidime developed superinfection with Clostridium perfringens on dy 5 of therpy. Seril surveillnce cultures re generlly of no benefit in predicting infective orgnisms (6). Our initil hope ws to find single-gent regimen which would mtch the effectiveness of the brod-spectrum coverge of cephlosporin, n minoglycoside, nd n ntipseudomonl penicillin. Becuse of surprisingly high rte of superinfection with grm-positive orgnisms, including nerobes, we felt tht the combintion of ceftzidime nd vncomycin would cover the "holes." After the initition of our study, there ws report of the emergence of resistnt orgnisms in ptients treted with ceftzidime (12). However, these were primrily P. eruginos in ptients with cystic fibrosis. We were subsequently impressed by the complete bsence of documented superinfections with the two-drug combintion. This ppers to trnslte into lower mortlity rte thn for either stndrd KGC tretment or ceftzidime tretmnent. Nevertheless, severl conclusions re probbly wrrnted. (i) Ceftzidime, KGC, nd CV hd comprble initil response rtes when used s initil empiric htimicrobil therpy in dult febrile grnulocytopenic cncer ptients. (ii) Ceftzidime lone ws ssocited with high superinfection rte with grm-positive orgnisms, nd KGC ws ssocited with predominntly grm-negtive superinfections. This stnds in contrst to CV, with which no superinfections were documented. (iii) CV ws ssocited with fewer deths thn ws ceftzidime lone or KGC nd ppers to be the superior regimen in febrile grnulocytopenic cncer ptients. Of course, s newer individul ntibiotics with even broder spectr become vilble, the sitution must be ressessed. ANTIMICROB. AGENTS CHEMOTHER. ACKNOWLEDGMENT This study ws supported by contribution from Glxo, Inc. LITERATURE CITED 1. Brown, A. E Neutropeni, fever, nd infection. Am. J. Med. 76: Cook, F. V., nd W. E. Frrr, Jr Vncomycin revisited. Ann. Intern. Med. 88: DeJongh, C. A., J. C. Wde, S. C. Schimpff, K. A. Newmn, R. S. Finley, P. C. Slvtore, M. R. Moody, H. C. Stndiford, C. L. Fortner, nd P. H. Wiernik Empiric ntibiotic therpy for suspected infection in grnulocytopenic cncer ptients. Am. J. Med. 73: Klstersky, J Therpy of bcteril infections in cncer ptients, p In J. Verhoef, P. K. Peterson, nd P. G. Quie, (ed.), Infections in the immunocompromised host-pthogenesis, prevention, nd therpy. Elsevier Biomedicl Press, Amsterdm. 5. Klstersky, J Tretment of severe infections in ptients with cncer. Arch. Intern. Med. 142: Krmer, B. S., P. A. Pizzo, K. Robichud, F. Witebsky, nd R. Wesley Role of microbiologic surveillnce nd clinicl evlution in the mngement of cncer ptients with fever nd grnulocytopeni. Am. J. Med. 72: Love, L. L., S. C. Schimpff, C. A. Schiffer, nd P. H. Wiernik Improved prognosis for grnulocytopenic ptients with grm negtive bcteremi. Am. J. Med. 68: Pizzo, P. A., K. J. Robechud, F. A. Gili, nd F. A. Witebsky Empiric ntibiotic nd ntifungl therpy for cncer ptients with prolonged fever nd grnulocytopeni. Am. J. Med. 72: Rmphl, R., B. S. Krmer, K. H. Rnd, R. S. Weiner, nd J. W. Shnds, Jr Erly results of comprtive tril of ceftzidime versus cephlothin, crbenicillin, nd gentmicin in the tretment of febrile grnulocytopenic ptients. J. Antimicrob. Chemother. 12(Suppl. A): Schimpff, S. C., nd J. Aisner Empiric ntibiotic therpy. Cncer Tret. Rep. 62: Schimpff, S. C., W. Stterlee, V. M. Young, nd A. Serpick Empiric therpy with crbenicillin nd gentmicin for febrile ptients with cncer nd grnulocytopeni. N. Engl. J. Med. 284: Scully, B. E., nd H. C. Neu Clinicl efficcy of ceftzidime: tretment of serious infection due to multiresistnt Pseudomons nd other grm-negtive bcteri. Arch. Intern. Med. 144: Singer, C., M. H. Kpln, nd D. Armstrong Bcteremi nd fungemi complicting neoplstic disese: study of 364 cses. Am. J. Med. 62: Wde, J. C., S. C. Schimpff, K. A. Newmn, C. L. Fortner, H. C. Stndiford, nd P. H. Wiernik Pipercillin or ticrcillin plus mikcin. Am. J. Med. 71: Winston, D. J., W. G. Ho, L. S. Young, W. L. Hewitt, nd R. P. Gle Pipercillin plus mikcin therpy in febrile grnulocytopenic ptients. Arch. Intern. Med. 142: