sulbactam versus cefoperazone plus mezlocillin: empiric therapy for febrile, neutropenic bone marrow transplant patients

Antimicrobial Agents ELSEVIER

International Journal of Antimicrobial Agents 7 (1996) 85-91

Cefoperazonekulbactam versus cefoperazone plus mezlocillin: empiric therapy for febrile, neutropenic bone marrow transplant patients Hillard M. Lazarus* a, Richard J. Creger”, Rasim Gucalpb, Robert M. Fox”, Niculae Ciobanub”, Penelope S. Carlisleb, Brenda W. Coopera, Michael R. JacobsC ‘Deparlment of Medicine, the Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve Vniversity, Cleveland, OH, VSA ‘Department of Pathology, the Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, VSA bAIbert Einstein Cancer Center, Bronx, NY, USA Accepted 14 February 1996

Abstract

We conducted a prospective, randomized trial in 132 patients undergoing bone marrow transplantation comparing cefopcrazone in combination with sulbactam (S), N = 66, vs. cefoperazone plus mezlocillin (CM), N = 66, as empiric antibiotic therapy for fever and neutropenia. Overall duration of neutropenia was 3-55 (median, 13) days. Forty-one patients had positive initial cultures (S = 22 and CM = 19). Twelve of these 41 patients responded to initial study antibacterial agent treatment (S = 6 and CM = 6). Twenty-nine of 41 patients, were withdrawn from study because of clinical deterioration, continued fever, or persistently positive cultures (S = 16 and CM = 13). Of the 90 patients who had culture-negative fever (S = 44 and CM = 46) 44 subjects responded with or without the addition of amphotericin B (S = 21 and CM = 23). Thirty-seven of 90 patients were withdrawn from study due to continued fever or clinical ‘deterioration (S = 17 and CM = 20). Nine patients were withdrawn as a result of rash or diarrhea (S = 6 and CM = 3). We conclude that in patients undergoing bone marrow transplantation, there was no difference in effkacy between cefoperazonekulbactam and the combination of cefoperazone plus mezlocillin in the empiric treatment of the febrile neutropenic patient. Since the majority of initial infections were due to gram positive bacteria, consideration should he given to broadening

initial empiric antibacterial agent therapy with drugs that possess potent activity against these organisms. Yeywordr: Bone marrow t.ransplant; Cefoperazone; Sulbactam; Mezlocillin; Neutropenia;

1. IntrodnetIon Antibacterial agents must be administered promptly in the febrile, neutropenic cancer patient to reduce infectious morbidity and mortality [ 1,2]. Such therapy must be empiric, i.e. initiated prior to determining the causal pathogen(s). ‘Success’, or resolution of suspected or documented infection, can be achieved using antibiotics in optimal dosage that are appropriate for the organisms

l Corresponding author, Ikpartment of Medicine, University Hospitals of Cleveland, 11100Euclid Avenue, Cleveland, OH 44106, USA.Tel.:+l2168443629;Fax:+12168445979or+12168447406. ’ Current address: St. Vincent Hospital and Medical Center, New York, NY 1001l-8397, USA.

092~857906/$32.00 0 1996 Elsevier Science B.V. All rights reserved PII 0924-8579(96)00300-7

Gram positive bacteria

that are most likely to be the causative agents. Empiric antibacterial regimens generally are broad-spectrum and may include, among others: /I-lactam antibiotics combined with an aminoglycoside; a combination of two & lactam antibiotics; or single agent or ‘monotherapy’ with a third-generation cephalosporin; or any of the above regimens combined with an anti-staphylococcal drug such as vancomycin [3-lo]. These therapies not only differ in antimicrobial efficacy but also possess different toxicity profiles, which can be considerable. Although many studies have been published evaluating the use of antibacterials as empiric therapy in immunosuppressed patients, few studies enrolling large numbers of bone marrow transplant patients have been published

DOI.

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H.M. Lazarus et al. /International Journal of Antimicrobial Agents 7 (19%)

Aerobic gram positive and gram negative bacteria are the most common pathogens responsible for infections which occur during the first 30 days after bone marrow transplantation [ 111. Unfortunately, an increasing number of these pathogens may have acquired resistance to several of the frequently used antibacterials. Of particular importance is the increasing incidence of /3-lactamase-producing bacteria as the cause of serious infection arising in immunocompromised patients. These enzymes hydrolyze the cyclic amide bond of the penicillin nucleus, producing inactive penicilloates. Moreover, certain &lactamases can hydrolyze the dihydrothiazine ring of cephalosporins converting these agents to unstable, antibacterially inactive products [ 121. To circumvent the activity of many /3-lactamase enzymes, a host of &lactamase inhibitors, including clavulanic acid, tazobactam, and sulbactam, have been combined with specific, enzyme susceptible antibiotics to expand their spectrum of antibacterial activity [13]. Cefoperazone is a third-generation cephalosporin that possesses in vitro activity against many of the bacterial pathogens associated with infections in the neutropenic patient. Recently, the addition of sulbactam to cefoperazone has expanded this drug’s spectrum of antibacterial activity to include anaerobes and many /3-lactamase-producing strains of aerobic gram negative bacteria [14-161. The enhanced spectrum of antibacterial activity of the combination drug, cefoperazonel sulbactam, strongly suggests potential utility as monotherapy in the empiric treatment of the febrile neutropenic. Thus, to assess the clinical utility of this combination, we undertook a prospective, randomized trial comparing cefoperazone/sulbactam to the combination of cefoperazone and mezlocillin as initial empiric therapy for the febrile, neutropenic patient undergoing bone marrow transplantation. 2. Patient selection and methods From September 1989 to December 1992 consecutive patients undergoing bone marrow transplantation at the University Hospitals of Cleveland, Ireland Cancer Center, Case Western Reserve University, Cleveland, OH, and the Montefiore Hospital, Albert Einstein College of Medicine, Bronx, NY, were evaluated for entry into this study. Eligible patients received high-dose cytotoxic therapy followed by infusion of hematopoietic stem cells, e.g. allogeneic or autologous bone marrow, or peripheral blood progenitor cells [ 17-261. Patients were enrolled when they developed neutropenia (absolute granulocyte count < lOOO/~l)and fever (one temperature of 38.5”C or greater, or two temperatures of 38°C or greater within a 24-h period). All patients gave written informed consent and the protocol was approved by the Institutional Review Board for Human Investigation at both institutions.

8.5-91

Patients were excluded from participation if they had a known type I allergy to penicillin or cephalosporins, were expected to expire within 24 h of initiating antibiotic treatment, or had hepatic impairment defined as an increase of greater than 6 times the upper limit of normal for SGOT (AST), SGPT (ALT) or serum bilirubin. Patients who had evidence of any hepatic or severe renal dysfunction (defined as an actual or calculated creatinine clearance less than 15 ml/mm) also were excluded [27]. Patients could not receive any antibacterial therapy within 2 weeks prior to enrollment and could not receive any antibiotics other than study medications within the initial 72 h antibacterial treatment period with the exception of antiviral drugs, topical antifungal agents, or trimethoprim-sulfamethoxazole, the latter administered only as prophylaxis against Pneumocystis carinii pneumonia. Patients were not eligible to re-enter this study during a subsequent bone marrow transplantation procedure. All patients were treated in single hospital rooms that received high efficiency particulate air (HEPA) tiltration, and were served low pathogen diets. All patients were cared for using indwelling, multi-lumen central venous catheters, and routine care of these catheters included daily inspection of the exit site with complete dressing changes at least three times per week by nurses trained in the care of these catheters 128,291.Parenteral alimentation and irradiated (3000 cGy) blood component support were used when clinically indicated. All pztients received intravenous acyclovir prophylaxis 750 mg/m2 per day in divided dose. Patients received trimethoprim-sulfamethoxazole 1 double strength tablet by mouth, twice per day prior to beginning chemotherapy along with either topical oral nystatin 3 million units 4-6 times per day or clotrimazole troches by the oral route 5 times per day until recovery of neutrophils to >5OO/pl occurred. Patients allergic to sulfonamides received pentamidine 300 mg by inhalation. When the study criteria were met, patients were evaluated by physical examination and chest X-ray along with microbiologic cultures of the blood from central venous catheter and peripheral venous sites, urine, and if available, sputum. Other suspected sites of infection, if present, also were cultured. Patients then were randomized on the basis of a computer-generated randomization code to receive either: (1) cefoperazone (Pfizer Pharmaceuticals, Roerig Division, New York), 2 g every 12 h intravenous, and mezlocillin (Miles Inc., Pharmaceutical Division, West Haven, CT), 4 g every 6 h intravenous, or (2) cefoperazone/sulbactam (Pfizer) at a dose consisting of 2 g cefoperazone and 1 g of sulbactam intravenous every 12 h. Study antibacterials were reconstituted with sterile water for injection, diluted in 100 ml 5% dextrose/water and infused intravenously over 30 min. All patients received phytonadione 10 mg intravenously on the first study day, and treatment was

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HM. Lazarus et al. /International Journal of Anhukrobial Agents 7 (1996) 85-91

repeated every 5 days thereafter while they received the study drug. On the third day and again on the final day of antibiotic therapy, patients underwent repeat evaluation including an extensive physical examination, microbiologic cultures of blood, urine, and other appropriate sites, and a chest X-ray. If patients remained febrile, blood cultures were obtained at least every 24 h along with a chest X-ray every third day. Blood cultures, if initially positive, were repeated every 24-48 h until negative. The following laboratory studies were carried out prior to initiating antibacterial therapy and were repeated at least twice per week until completion of therapy or upon withdrawal from study: complete blood count with differential, Iplatelet count, serum creatinine, total and direct serum bilirubin, SGGT (ALT), SGPT (AST), serum alkaline phosphatase, prothrombin and partial thromboplastin times, and serum electrolytes. All patients who received at least one dose of study drug were considered evaluable for toxicity, whereas patients were required to have received antibacterial drug therapy for at least 72 h to be evaluable for antibiotic efficacy. Patients could be removed from study for persistent fever, hypotension (systolic blood pressure less than 80 mmHg), persistently positive initial cultures, or, in the opinion of the treating physician, any significant clinical deterioration. 2.1. In vitro microbiologic testing

All pathogens isolated were tested for susceptibility to cefoperazone, mezlocillin and cefoperazone/sulbactam by disk diffusion. Organism suspensions at a density equivalent to a 0.5 MacFarland standard (1.5 x lo8 CFU/ml) were plated onto 15 cm diameter MuellerHinton agar plates according to standard procedure, disks applied to plates and incubated overnight at 35°C. Zone diameters were measured and interpreted as follows: cefoperazone and cefoperazone/sulbactamsusceptible, 121 mm; resistant, I 15 mm; mezlocillinsusceptible, r 21 mm; resistant, I 17 mm. Clinical efficacy was defined as follows. 1. Completed course: Patient became afebrile and completed course of study antibacterials without the need for the addition of other agents such as an empiric course of amphotericin B. 2. Completed course with amphotericin B: Patient completed course of study antibacterials and became afebrile with the addition of an empiric course of amphotericin B. 3. Failure: Patient wa,s was withdrawn from the study as a result of continued fever, clinical deterioration, adverse effects, addition of another antibiotic excluding amphotericin B or any combination of these.

2.2. Statistics Statistical assessments were performed dent’s t-test and Chi-square analysis.

using Stu-

3. Results 3.1. Patient characteristics The clinical characteristics and diagnoses of the 132 study patients are given in Table 1. Chemotherapeutic treatment regimens used in study subjects included those previously published [ 17-261. Of the 132 febrile, neutropenic patients, 66 patients were treated using cefoperazone plus mezlocillin, and 66 patients were assigned to the cefoperazone/sulbactam group. Patient characteristics did not differ between the 2 groups, including the assignment to study drugs (Table 1). The period for neutrophils < SOO/jJranged from 3 to 35 days (median: 14 days) in the cefoperazone plus mezlocillin group, and ranged from 4 to 55 days (median: 13 days) in the cefoperazone/sulbactam group. The duration of administration of the study antibacterial drugs ranged from 1 to 25 (median: 10) days in the cefoperazone plus mezlocilin group, and from 1 to 31 (median: 10) days in the cefoperazone/sulbactam group. 3.2. Infections coincident with first fever Forty-one patients experienced documented infections (a total of 47 separate organisms) based on initial

Table 1 Patient characteristics in both antibacterial agent treatment groups Characteristic

Cefoperazone + mezlocillin

Cefoperazone/ sulbactam

No. patients Diagnoses lymphoma leukemia breast cancer colon cancer brain cancer ovarian cancer othera Median age (range) Gender: male/female Duration neutrophils < 5OO/jblb Duration study antibacterials b AutologousMlogeneic transplant

66

66

I7 I4 I4 6 3 3 9 41 (19-64) years 33133 I4 (3-35) days

I3 I6 I9 3 4 4 7 41 (19-63) years 26MO I3 (4-55) days

IO (l-25) days

IO (I-31) days

65/l

5818

OLungcancer, sarcoma, malignant melanoma, severe aplastic anemia, multiple myeloma, testicular cancer. bMedian (range).

88

H.M. Lazarus et al. /International

Journal of Antimicrobial

microbiologic cultures co-incident with the first temperature elevation; six patients experienced polymicrobial infections (Table 2). The source of the isolates and the presumed sites of infection included bloodstream (N = 35) and urinary tract (N = 6). Since all blood cultures were obtained at the first occurence of temperature elevation during the neutropenic period, any positive blood culture was deemed to represent an infection. The majority of bacterial infections were due to gram positive organisms. Thirty-nine of the 47 isolates (83%) involved gram positive bacteria (15 in the cefoperazonelsulbactam group, and 24 in the cefoperazone + mezlocillin group). Viridans group streptococci were the most commonly isolated bacteria (N = 23). Gram negative organisms occured as the first infection in only 7 patients. Five of the episodes occured in the cefoperazone + mezlocillin group and 2 were in the cefoperazonekulbactam group.

Agents 7 (19%)

85-91

Table 3 Clinical responses for patients who had positive initial urine and blood cultures as well as culture-negative patients Patient characteristic

Cefoperazone + mezlocillin N=6Y

Cefoperazone/ sulbactam N=66

Total N= 131a

Culture-positive Eradication Persistently positive culture Failure Completed course Completed course plus amphotericin B

I9 I8 I

22 I8 4

41 36 5

I3 2 4

I6 3 3

29 5 7

468 IO I3

44 I2 9

9Oa 22 22

3

6

9

3.3. Response to study antibacterial drugs

Culture-negative Completed course Completed course with amphotericin B Withdrawn due to toxicity Failure

20

I7

37

3.3.1. Culture-positive

%oes not include one early death due to gastrointestinal bleeding.

infections

Thirty-six of 41 culture positive patients cleared their infection (eradication) while receiving study drug (18 of 19 cefoperazone/mezlocillin patients and 18 of 22 cefoperazone/sulbactam patients) (Table 3). Five subjects, 3 individuals treated with cefoperazonekulbactam and 2 patients treated with cefoperazone + mezlocillin, became afebrile and culture-negative completing their course of antibacterials without further modification in antibiotic therapy. Seven additional bacteremic patients cleared their infection but required the addition of amphotericin B for the empiric treatment of persistent fever Table 2 Documented infections for initial isolates Infecting organisma

Cefoperazone + mezlocillin No. infections

Viridans streptococcus group I I (11) Enterococcus

sp.

Group B streptococcus Corynebacterium sp. Coagulase-negative staphylococcus

12 (II)

I (0) 1 (1)

2 69 I (1)

0 2 (2)

2 (1) 6 (3)

I (1)

Klebsiella pneumonioe Enterobacter cloacae Bacih sp. Psefidomonas jhorescens

0

Condida krwei E. coli

I (0) 2 (2)

Total

Cefoperazone/ sulbactam No. Infections

2 0

0

(2)

I (1) 0

1 (0)

21 (18)

0

1 (0) 26 (18)

Number of sensitive organisms given in parentheses. ‘6 patients experienced polymicrobial infection.

(N = 3 cefoperazonekulbactam

and N = 4 cefoperazone + mezlocillin). These patients completed the course of antibacterial agent therapy without further modifications. Five patients demonstrated persistently positive cultures after the initiation of their assigned antibiotic regimen. Three of these patients had organisms resistant to the study antibacterials on initial culture and sensitivity testing: coagulase-negative staphylococcus (N = 2) and Enterococcus sp. (N = 1). The other two patents had organisms susceptible to study antibiotics in vitro, but continued to have persistently positive cultures: E. co/i (urine) and Streptococcus mitis (blood). Twenty-nine of the 41 patients with positive cultures were removed from study for persistent fever, hypotension or clinical deterioration (N = 13 cefoperazone + mezlocillin and N = 16 cefoperazonekulbactam). Two of 6 subjects with urinary sepsis became culture-negative while receiving the study antibacterial agent regimen but had persistent fever; they became afebrile with the empiric addition of amphotericin B. The remaining 4 of 6 patients were withdrawn due to clinical deterioration or persistent fever. 3.3.2. Suspected (culture-negative) infections Of the 90 patients whose cultures were negative, 22

(N = 12 cefoperazoneksulbactam; N = 10 cefoperazone + mezlocillin) completed the assigned course of study antibiotics without the need for modification of

H.M. Lazarus et al. /International Journal of Antimicrobial Agents 7 (19%) 85-91

antibiotic therapy or the addition of antifungal agents (Table 3). Twenty-two of these 90 patients required the addition of amphotericin B in empiric fashion (N = 9 cefoperazone/sulbactam; N = 13 cefoperazone + mezlocillin) to complete the course of therapy. Thirty-seven (N = 17 cefoperazone/sulbactam; N = 20 cefoperazone + mezlocillin) pat:ients who had culture-negative, febrile, neutropenia were removed from study because of persistent fever, hypotension or clinical deterioration. Nine additional subjects (N = 6 cefoperazone/sulbactam; N = 3 cefoperazone + mezlocillin) were withdrawn from study due to drug-related toxicities (see below). One patient expired on the third day of treatment due to severe, refractory thrombocytopenia and a massive gastrointestinal bleed believed to be unrelated to study drug administration, and was considered inevaluable for antibacterial efficacy. 3.4. Superinfections Superinfections, shown in Table 4, were more common in patients who received cefoperazone + mezlocillin (17 of 65 patients, 26%) than in patients who received cefoperazone/sulbactam (9 of 66 patients, 14%) (P = 0.209). The most common superinfections included fungal infections, e.g. oropharyngeal, intestinal or esophageal candidiasis (N = lo), or Aspergillus sp. pneumonia (N = 3). C’lostridium difficile toxin colitis

Table 4 Superinfections noted during antibacterial therapy Organism

Infection

Cefopemzone + mezlocillin N=65

Cefoperazonekdbactam N=66

Staphylococcus aureus Xanthomonas

Cellulitis Bacteremia

1 0

0

Coagulase-negative staphylococcus

Bacteremia

I

1

E. coli

Bacteremia I and urinary tract Bacteremia 1 Pneumonia 1

0

Bacteremia

0

1

3 I

0 0

candida sp. candiak sp.

Pneumonia Gastroenteritis Pharyngitis Esophag-

1 3

4

Clostridium difJicile

Colitis

4

1

I

maltophilia

Klebsiella pneumoniae PseudomoMs aerugitwsa

Viridans streptoCocGusgroup Aspergillus sp. Candida sp.

(toxin) Total

. . 1t1:i

17 (26%)

0 0

I

9 (14%)

89

was demonstrated in the stool in 5 patients, 4 in the cefoperazone + mezlocillin group (P = 0.380). No patient expired as a result of a superinfection. 3.5. Drug-related toxicities Toxicities directly attributable to or likely the result of the use of study antibacterial agents were uncommon, mild, and reversible; nine patients, however, were removed from study because of adverse events. Fortynine patients developed a rash, usually maculo-papular in consistency (N = 27 cefoperazone/sulbactam; N = 22 cefoperazone + mezlocillin). Eight patients with rash were withdrawn early from study, 4 due to extensive rash and 4 due to rash and persistent unexplained fever. Six of these patients were treated using cefoperazone/ sulbactam, while 2 received cefoperazone + mezlocillin. Transient watery diarrhea was noted in 41 patients (N = 22 cefoperazone/sulbactam; N = 19 cefoperazone + mezlocillin); one patient had severe diarrhea and was removed from study. Transient elevation in serum hepatic enzymes was observed in 18 patients (N = 8 cefoperazonelsulbactam; N = 10 cefoperazone + mezlocillin). The high dose chemotherapy could not be excluded as the cause of the diarrhea or elevation in serum tests of liver function. 4. Discussion We prospectively evaluated the efficacy and safety of the antibacterial agent fixed drug combination, cefoperazone/sulbactam in severely immunosuppressed, febrile bone marrow transplant patients. This agent was anticipated to provide adequate antibacterial activity against the common gram negative and gram positive bacteria most likely to infect patients undergoing bone marrow transplantation [2,6,30-341. It was hoped that such a combination would exhibit less toxicity and require less frequent dose administration compared with other antibacterial agent combinations frequently used in the treatment of febrile neutropenic bone marrow transplant patients, factors which could result in marked financial savings. In the present study, cefoperazone/sulbactam and the combination of cefoperazone + mezlocillin demonstrated equal efficacy in critically ill patients who had either culture-documented or culture-negative febrile, neutropenic episodes. Gram positive bacteria were the most frequently isolated pathogens in our study patient population, accounting for 39 of 47 isolates. Viridans group streptococci were cultured from 23 of the 47 cultures. These data likely can be explained by the use of multilumen central venous catheters in all patients and the intensive chemotherapeutic regimens that caused extensive mucositis, both leading to subsequent bacteremias [6,28,35,36]. Bacteremia caused by the viridans

90

H.M. Luzorus et 01./International Journal of Antimicrobial Agents 7 (19%) 85-91

group streptococci is increasing in neutropenic febrile patients [31,32]. Furthermore, septicemia caused by gram positive organisms has become a concern due to the marked toxic effects of these organisms [31,32]. In 90 patients (N = 46 cefoperazone + mezlocillin and N = 44 cefoperazone/sulbactam) the cultures of all specimens obtained at the initial febrile episode were negative. Twenty-two patients became afebrile, completed the course of antibacterial agent therapy, and did not require the use of additional antibiotics such as antifungals. An additional 22 patients continued to receive the study medications but required amphotericin B before resolution of the febrile, neutropenic episode. Sixty-six patients (29 with positive cultures and 37 with negative cultures) were removed from the study for persistent fever, continued hypotension, or clinical deterioration. All patients were switched to an assortment of antibiotic regimens based on a decision of the supervising physician, all completed their transplant course, and were discharged from the hospital. Although bacterial superinfections were less common in the sulbactam group (9 of 66, 14%) compared with 17 of 65 (26%) in the cefoperazone + mezlocillin group, these data were not of statistical significance. Similarly, Clostridium difficile toxin colitis was more common in the cefoperazone + mezlocillin group (4 vs. l), but was not of statistical significance. We did not observe hypoprothrombinemia, commonly described in patients treated with cephalosporins containing an N-methylthioltetrazole size chain [37]. Patients in this study received vitamin K prophylaxis while receiving study antibiotics, which prevented the interference with vitamin K-dependent clotting factor synthesis [37]. Adverse effects associated with the administration of study antibiotics were generally mild and transient. Rash, diarrhea, and abnormalities in serum tests of liver function were common, with 108 occurences in the combined population (sulbactam N = 58; cefoperazone + mezlocillin N = 51). Although only nine patients were withdrawn from study at the time they developed a’rash, it is difticult to attribute their rash entirely to study antibacterial agents, since all patients had received high-dose cytotoxic chemotherapeutic agents, and most were given other drugs such as trimethoprim-sulfamethoxazole, all of which can be associated with rash. Similarly, diarrhea and abnormalities in serum tests of liver function possibly due to the study drugs could have resulted from other causes. Diarrhea previously has been reported to occur frequently in association with cefoperazone therapy, but the prevalence was lower than reported in other series [5]. No patients developed life-threatening dermatologic, gastrointestinal, hepatic, or fatal toxicity while receiving the cefoperazone-containing regimens. The antimicrobial combination of cefoperazone/sulbactam has been used effectively by a number of in-

vestigators in the treatment of the febrile, neutropenic hematologic malignancy patient [ 14- 161. Our study, however, is a prospective, randomized trial and is one of the largest reported to date for patients undergoing bone marrow transplantation. We demonstrated that both antibacterial regimens, e.g. cefoperazone/sulbactam, and cefoperazone + mezlocillin, appeared safe and equivalent for initial empiric treatment of the febrile, neutropenic bone marrow transplant patient. Since the majority of initial infections at the two study centers were due to gram positive bacteria, consideration should be given to broadening initial empiric antibacterial agent therapy with drugs that possess potent activity against these pathogens [38]. Acknowledgments The authors thank Michael D. Reed, PharmD. for manuscript review and useful suggestions. This work was supported, in part, by grants P3OCA43703 and CA 21115 from the National Cancer Institute, the National Institutes of Health, and the United States Public Health Service. References 111The Working Committee, Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis, 1990;161:381-401. 121Wingard JR. Advances in the management of infectious complications after bone bone marrow transplant. Bone Marrow Transplant, 1990;6:371-383. 131 Jones P, Bodey GP, Rolston K, Fainstein V, Riccardi S. Cefoperazone plus mezlocillin for empiric therapy of febrile cancer patients. Am J Med, 1988;85:3-8. 141 Klastersky J. Cefoperazone in the treatment of infections in cancer patients. Am J Med, 1988;85:9-16. PI Winston DJ, Ho WG, Bruckner DA, Gale RP, Champlin RE. Controlled trials of double &lactam therapy with cefoperazone plus piperacillin in febrile granulocytopenic patients. Am J bled, 1988;85:21-30. if51 Rubin M, Hawthorn JW, Marshall D et al. Gram-positive infections and the use of vancomycin in 550 episodes of fever and neutropenia. Ann Intern Med, 1988;108:30-35. 171 Winston DJ, Winston G, Ho et al. Beta-lactam antibiotic therapy in febrile granulocytopenic patients: a randomized trial comparing cefoperazone plus piperacillin, ceftazidime plus piperacillin, and imipenem alone. Ann Intern Med, 1991;I 15: 849-859.

ISI EORTC Clinical Trials Group. Vancomycin added to empirical combination antibiotic therapy for fever in granulocytopenic cancer patients. J Infect Dis, 1991;163:951-958. 191 Wimperis JZ, Baglin TP, Marcus RE, Warren RE. An assessment of the efficacy of antimicrobial prophylaxis in bone marrow autografts. Bone Marrow Transplant, 1991;8:363-367. HOI DePauw BE, Deresinski SC, Feld R et al. Ceftazidime compared with pipericillin and tobramycin for empiric treatment of fever in neutropenic patrients with cancer. Ann Intern Med. 1994; 120:834-844. 1111 Momin F, Chandrasekar PH. Antimicrobial prophylaxis in

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bone marrow transplantation. Ann Intern Med. 1995;123: 205-215. [I21 Neu HC. Contribution of &lactamases to bacterial resistance and mechanisms to inhibit 8-lactamases. Am J Med, 1985; 79(suppl 5B):2-12. [13] Payne DJ, Cramp R, Winstanley DJ, Knowles DJ. Comparative activities of clavulanic acid, sulbactam, and taxobactam against clinically important &lactamases. Antimicrob Agents Chemother, 1994,38:767-774. [I41 Bodey GP, Elting LS, Narro J, Keller C, O’Brien S, Estey E, Benjamin R. An open trial of cefoperaxone plus sulbactam for the treatment of fever in cancer patients. J Antimicrob Chemother, 1993;32:141-152. [15] Misawa S, Tsuda S, Taniwaki M et al. A combined consecutive therapy with fosfomycin and sulbactam/cefoperazone for bacterial infections associated with hematological diseases. Jpn J Antibiot, 1995;48:514-521. [la] Kawai Y, Ueda T, Iwasaki H, Nakamura T. Clinical evaluation of sulbactam/cefoperaxone for infections during the chemotherapy of hematologic malignancy. Jpn J Antibiot, 1994;47: 1196-1201. [17] Lazarus HM, Gray R, Ciobanu N, Winter J, Weiner RS. A phase I trial of high-dose melphalan, high-dose etoposide, and autologous bone marrow re-infusion in solid tumors: an Eastern Cooperative Oncology (Group (ECOG) study. Bone Marrow Transplant, 1994;14:443-448. [IS] Lazarus HM, Spitxer TR, Creger RJ. Phase I trial of high-dose etoposide, high-dose cisplatin, and re-infusion of autologous bone marrow for lung cancer. Am J Clin Oncol, 1990;13: 107-l 12. [I91 Spitxer TR, Lazarus HM, Creger RJ, Berger NA. High dose melphalan, misonidaxole, and autologous bone marrow transplantation of the treatment of metastatic colorectal carcinoma-a phase I study. Am J Clin Oncol, 1989;12:145-151. [20] Lazarus HM, Crilley P, Ciobanu N et al. High-dose carmustine, etoposide, and cisplatin, and autologous bone marrow transplantation for relapsed and refractory lymphoma. J Clin Oncol, 1992;10:1682-1689. [21] Antman K, Ayash L, Elias A et al. A phase II study of high dose cyclophosphamide, thiolepa, and carboplatin with autologous marrow support in women with measureable advanced breast cancer responding to standard-dose therapy. J Chn Oncol, 1992;10:102-110. [22] Fields KK, Elfenbein GJ, Lazarus HM et al. Maximum tolerated doses of ifosfamide, carboplatin, and etoposide given over six days followed by autologous stem cell rescue: toxicity profile. J Clin Oncol, 1995;13:323-332. [23] Nichols CR, Andersen J, Lazarus HM et al. High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol. J Clin Oncol, 1992;10:558-563. [24] Tutschka PJ, Copelan EA, Klein JP. Bone marrow transplanta-

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