Transplantation (2006) 37, 373–379 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt

ORIGINAL ARTICLE /tazobactam vs ceftazidime in the treatment of neutropenic in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial

C Harter1, B Schulze1, H Goldschmidt1, A Benner2, HK Geiss3, T Hoppe-Tichy4,ADHo1 and G Egerer1

1Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 2Central Unit Biostatistics, German Cancer Research Center, Heidelberg, Germany; 3Institute of Hygiene, University of Heidelberg, Heidelberg, Germany and 4Pharmacology Department, University of Heidelberg, Heidelberg, Germany

Piperacillin/tazobactam was compared with ceftazidime Introduction for the empirical treatment of febrile in patients with acute leukemia or following autologous Infectious complications are the main cause of death in peripheral blood stem cell transplantation. Owing to hematological patients undergoing aggressive chemother- inclusion criteria, it was possible for the same patient to be apy or high-dose (HDCT) and autologous randomized several times. A total of 219 individual peripheral blood stem cell transplantation (PBSCT). Early patients were admitted to a prospective randomized commencement of empirical therapy can reduce clinical study: 24 patients were included twice. Patients the associated morbidity and mortality.1,2 Controlled (23.5%) remained afebrile. Patients who developed febrile studies have shown that no differences are demonstrable neutropenia were randomized to receive intravenous with regard to response to therapy when the results of ceftazidime (n ¼ 74 patients, group I) or piperacillin/ combined antibiotic therapy are compared with those of tazobactam (n ¼ 87 patients, group II). Response to first- single-agent therapy.3,4 line antibiotic treatment was seen in 55% (group I) and Ceftazidime, a third-generation , has been 53% (group II). After the addition of vancomycin, a examined in a number of studies as single-agent therapy5 further 19% (group I) and 24% (group II) of the patients and combined therapy.6 became afebrile. Causes of fever were: microbiologically Ceftazidime displays very good efficacy against Gram- documented in 36 and 34 patients of group I and negative bacteria including but, II; Clostridium difficile in eight and 12 patients of group I like most cephalosporin , only limited activity and II, and fever of unknown origin in 30 and 41 patients against Gram-positive bacteria. of group I and II. One patient died in each group. Single- Piperacillin – a synthetic broad-spectrum penicillin – in agent therapy with piperacillin/tazobactam is as effective combination with the potent b-lactamase inhibitor tazo- as ceftazidime in the treatment of neutropenic fever and is bactam has been available for the empirical initial therapy well tolerated. Direct and indirect costs of both treatment of febrile neutropenic patients since 1993. Piperacillin/ regimes are equivalent. tazobactam was chosen for the comparative single-agent Bone Marrow Transplantation (2006) 37, 373–379. arm of this study because of its broad antimicrobial doi:10.1038/sj.bmt.1705256; published online 9 January spectrum – which includes P. aeruginosa – and its excellent 2006 efficacy against Gram-positive pathogens including Strepto- Keywords: treatment; neutropenic fever; high-dose chemo- cocci. In vitro studies in which piperacillin/tazobactam was therapy; antibiotics; monotherapy tested against 365 bacteremic isolates of neutropenic patients showed efficacy comparable to that of ceftazidime with regard to Gram-negative bacteria and superior to that of ceftazidime with regard to Gram-positive bacteria.7 In the EORTC 9 study, piperacillin/tazobactam com- bined with amikacin was tested as empirical therapy in febrile neutropenic patients. The combination proved to be successful in comparison to ceftazidime plus amikacin, Correspondence: Dr G Egerer, Department of Internal Medicine V, achieving defervescence in a shorter period of time.8 Kelsey University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, et al.9 performed a noncomparative study with piperacillin/ Germany. E-mail: [email protected] tazobactam plus gentamicin in 44 febrile neutropenic Received 5 August 2005; revised 7 November 2005; accepted 11 patients with hematological malignancies in which 67% November 2005; published online 9 January 2006 of the patients responded to the combination therapy. Neutropenic fever in patients with acute leukemia or following stem cell transplantation C Harter et al 374 We report here on the first randomized study to examine total of 588 patients evaluable for response to therapy piperacillin/tazobactam as single-agent therapy in com- during an accrual period of 3 years. The study was closed in parison to ceftazidime for febrile neutropenic patients November 2003 after 3.5 years accrual, after it became with acute leukemia or following HDCT and PBSCT. obvious that the required number of 588 patients would not The purpose of the randomized, prospective study was be achieved within a reasonable amount of time. At that to compare the equivalence, safety, efficacy and tolerability time a total of 243 evaluable patients were included into the of piperacillin/tazobactam with those of ceftazidime as study. empirical antibiotic therapy. Treatment regimes Patients and methods In keeping with the randomization list, the patients were randomized either in group I (single-agent therapy with ceftazidime 3 2 g every 8 h) or group II (single-agent The study was performed at the Department of Internal  therapy with piperacillin/tazobactam 3 4.5 g every 8 h). Medicine V of the University of Heidelberg.  Patients were examined daily by the physician and the first evaluation of the therapy was performed 72 h after the Patient-selection criteria start of antibiotic therapy. The initial treatment was Patients recruited to the study were either suffering from retained in the event of defervescence (freedom from fever acute leukemia or had undergone HDCT and PBSCT. A for 5 days or 41.0/nl). If the fever did not count of o0.5/nl was required at the start of subside and/or the clinical symptoms deteriorated, supple- treatment (at the latest 24 h after admission to the study). mentary treatment with vancomycin was given (2  1g Patients with fever 438.5 or 4381C on two occasions daily every 12 h). A further evaluation was carried out within 12 h were admitted. The fever was required not to be 48–72 h later. If the fever persisted, the initial treatment was associated with the underlying disease, transfusion of blood replaced by /cilastin (4  0.5 g daily). Systemic products or administration of cytokines. The existence of amphotericin-B treatment (0.7–1 mg/kg body weight) was an allergy to any of the study preparations was regarded as instituted if radiology revealed pulmonary infiltration. An an exclusion criterion. In addition, patients with severe antibiogram was obtained and the therapy modified impairment of liver function or HIV disease, and dialysis- accordingly in the event of microbiologically documented dependent patients were excluded. It was decided to allow infection (MDI). to include the same patient several times during a series of neutropenic episodes, assuming that subsequent neutrope- nic episodes correspond to independent observations. Examinations at the start of the study Patients received oral anti-infection prophylaxis with After a clinical examination, at least two separate venous either trimethoprim-sulfometoxazol or ciprofloxacin, and blood cultures (aerobic/anaerobic) were drawn within 30– antimycotic prophylaxis with amphotericin-B suspension 60 min, and an additional from a central or fluconazole. venous catheter in patients with a central venous access. Clean catch urine cultures were taken whenever a urinary tract infection was suspected. Thoracic organs were Ethics X-rayed in two projections. Further imaging proce- The study protocol was approved by the ethics committee dures (HR-CT, X-ray of the paranasal sinuses, upper responsible and conducted in compliance with the Declara- abdominal sonography) were performed at intervals in the tion of Helsinki and the guidelines of Good Clinical event of clinical symptoms. Additional diagnostic tests were Practice. All patients gave written informed consent to undertaken only in cases of persisting clinical symptoms participate in the study. (e.g. stool cultures including tests for Clostridium difficile enterotoxin A and B, wound swabs, and needle aspirates Randomization procedure from abscess, etc.). Randomization was performed by the team of pharmacists providing a 24-h service, by means of a randomization list with which patients were assigned randomly to the two Definition of infectious events arms with equal probability. Owing to the inclusion Definition of infectious events was based on the Consensus criteria, it was possible for the same patient to be Conference of the Immune-compromised Host Society.10 randomized several times. Randomization numbers were assigned to the patients in ascending order. Treatment Fever of unknown origin group I received single-agent therapy with ceftazidime (2 g Newly occurring fever 438.5 or 438.01C lasting 1 h or every 8 h as a short-term infusion over 30 min; in cases twice within 12 h with no clinical or microbiological of impaired kidney function the dose was reduced in infection findings to indicate the direction. accordance with the manufacturer’s data sheet). Treatment group II received single-agent therapy with piperacillin/ tazobactam (4.5 g every 8 h as a short-term infusion over Clinicallydocumented infection 30 min; in cases of impaired kidney function the dose was Clinically documented infection (CDI) was defined as fever reduced in accordance with the manufacturer’s data sheet). in association with a diagnostically clearly localized finding, According to the study protocol it was planned to include a for example, pneumonia.

Bone Marrow Transplantation Neutropenic fever in patients with acute leukemia or following stem cell transplantation C Harter et al 375 MDI with or without bacteremia Therapy failure. Therapy was considered to have failed if A MDI was regarded as present if, in addition to a localized extension, modification or replacement of the initial focus of infection, a clinically relevant pathogen could be therapy with another antimicrobial therapy failed to elicit isolated from blood cultures or other relevant sample sites. an initial response in the absence of a secondary infection. At least two positive blood cultures from separate samples were required for coagulase-negative Staphylococci and Deaths. All patients who died during the study therapy Corynebacterium spp. to be judged as relevant, while a or within 7 days after the end of therapy were counted single isolate was regarded as contamination. In the case of as deaths within the study. The possibility of a causal pulmonary infiltrates, detection of a relevant pathogen association with the infection under treatment or with from blood cultures or bronchoalveolar lavage was any toxicity from the antimicrobial substances employed regarded as reliable, while throat swabs and sputum were was to be investigated. considered relevant only if obligate pathogens were isolated in direct temporal association with the occurrence of Toxicity pulmonary infiltrates. A single positive test for C. difficile Nephrotoxicity and hepatotoxicity, which were defined as enterotoxin A and B fulfilled the diagnostic criteria for an increase in serum creatinine, transaminases, bilirubin or antibiotic-associated diarrhea, while other possible entero- alkaline phosphatase by at least twice the upper normal pathogenic bacteria had to be isolated in at least two limit, were studied by means of laboratory analysis. Side consecutive fecal specimens. effects were entered in the case report forms and an association with the study drugs was assessed as definite, Duration of treatment probable, possible, improbable or definitely nonexistent. Length of treatment depended on duration and severity of the granulocytopenia as the leading risk factor for the Statistics severity and course of infectious complications following The primary task of the study was to test noninferiority of chemotherapy and PBSCT. The first time point for treatment group II (single-agent therapy with piperacillin/ assessing clinical results of treatment was set in both tazobactam) compared to treatment group I (single-agent treatment groups at 72 h after the start of therapy. The therapy with ceftazidime) with respect to therapeutic initial therapy was continued for at least 5 days (or until the response. Thus, if p and p are the response rates of the granulocytes increased to 41.0/nl) if the treatment was I II two treatments, the goal is to test the null hypothesis of successful. If no improvement was achieved with the initial inferiority, p p –d , against the one-sided alternative therapy, treatment was escalated after 72 h (3 full days of IIo I 0 hypothesis of noninferiority, p Xp –d , for a prespecified therapy). In line with the time course of the initial therapy, II I 0 noninferiority margin d 40. In this study, a noninferiority subsequent treatment was also assessed after 48–72 h and 0 margin d ¼ 10% was chosen. A score test according to continued depending on the status of the granulocytopenia. 0 Chan11 was used. In addition, an exact test for differences An observation period of 7 days was required after the end between response probabilities was performed using of the antimicrobial treatment to be able to detect recurrent Pearson’s w2 test statistic. A Type-I error value of a ¼ 0.05 or secondary infection. The follow-up observation could was chosen for all tests. also be carried out within the framework of outpatient or All statistical computations were performed using the GP supervision. software package StatXact, version 6 (Cytel Software Corporation, Cambridge, MA, USA). Definition of therapeutic response The result of treatment was assessed (a) within 72 h after the start of antimicrobial therapy (initial response), (b) on Results completion of the study therapy (definitive response) and (c) at the end of the study. Characteristics of the studypopulation Two hundred and forty-three patients (219 individuals) Successful treatment without modification. Normalization who had undergone PBSCT or were suffering from an of body temperature to below 381C and elimination of all acute leukemia were recruited to this study from February clinical symptoms of infection and of any documented 2000 to November 2003. Antibiotic prophylaxis was given pathogens by the initial therapy with piperacillin/tazobac- with either ciprofloxacin (2 Â 500 mg per day) or trimetho- tam or ceftazidime and no new signs of infection within 1 prim-sulfomethoxazol (2 Â 160/800 mg per day). Of the week after the end of the antimicrobial therapy. 243 patients, 57 (23.5%) did not develop fever in the neutropenic phase. Twenty-five patients (10.3%) were not Successful treatment after modification. Elimination of all evaluable because the antibiotic treatment was commenced clinical symptoms of infection and of the infective agent prior randomization to the treatment arms. Thus, 74 after appropriate modification of the therapy or renewed patients who received ceftazidime (group I) and 87 patients fever of unknown origin (FUO) after 72 h following who received piperacillin/tazobactam (group II) were an initial response, and extension of the initial therapy suitable for evaluation. Patients’ characteristics are shown with this substance, which is directed against a different in Table 1. No differences existed between the two spectrum of infective agents than the initial therapy, and treatment groups with regard to any of the characteristics. stable defervescence after such modification. The majority of patients in both groups was suffering from

Bone Marrow Transplantation Neutropenic fever in patients with acute leukemia or following stem cell transplantation C Harter et al 376 Table 1 Patient characteristics Table 2 Causes of fever

Group I Group II Group I Group II (n ¼ 74) (n ¼ 87) (n ¼ 74) (n ¼ 87)

Acute leukemia 7 9 FUO 30 (41%) 41 (47%) HDCT+PBSCT 67 78 CDI 8 (10%) 12 (14%) MM 43 49 Of these CDI+MDI 3 8 NHL 15 21 MDI 36 (49%) 34 (39%) Solid tumors 5 5 Hodgkin’s disease 2 2 AL amyloidosis 1 1 MPS 1 1 Table 3 Blood culture isolates/response to first-line treatment in Age (years) MDI Median (range) 57 (21–70) 53 (19–71) Group I Group II Sex Female 26 (35%) 25 (29%) Gram positive 32 38 Corynebacteria sp. 0 2 Male 48 (65%) 62 (71%) Enterococcus faecium 30 Enterococcus sp. 1 1 Duration of neutropenia (days) Staphylococci Median (range) 9 (1–36) 9 (1–29) Coagulase-neg. 24 27 Propioni bacteria 1 0 Fever (days) Staphylococcus aureus 01 Streptococcus sp. 0 3 Median (range) 3 (1–26) 3 (1–20) Purulent Streptococci 34 Response to first-line therapy 17/31 (55%) 22/37 (59%) Duration of the antibiotic therapy Gram negative 13 13 (Days; median (range)) 8 (1–29) 8 (2–23) Campylobacter 01 Escherichia coli 811 Fusobacterium sp. 1 0 Klebsiella pneumoniae 10 multiple myeloma and had undergone PBSCT (n ¼ 43 in Proteus mirabilis 10 group I and n ¼ 49 in group II). Pseudomonas aeruginosa 21 In addition, seven patients in group I and nine patients in Response to first-line therapy 7/13 (54%) 4/13 (31%) group II who were suffering from acute leukemia were admitted to the study. Fifteen patients in group I and 21 patients in group II exhibited NHL. Patients who had One patient of group I and one patient of group II died, the undergone PBSCT because of solid tumors, Hodgkin’s latter from Pseudomonas sepsis 2 days after the start of the disease or AL amyloidosis and myeloproliferative disease antibiotic therapy, the former from pneumonia 10 days formed a small subgroup of the study population. after the start of the antibiotic therapy. The median duration of the neutropenia was 9 days (range 1–36 days) in group I and likewise 9 days (range 1– 29 days) in group II. The number of days with fever and the Results and response rates to first- and second-line length of the antibiotic therapy did not differ considerably treatment in the two groups. Fifty-seven of the 243 patients (23.5%) did not develop fever in the neutropenic phase. These patients were given antibiotic prophylaxis consisting either of ciprofloxacin Causes of fever (n ¼ 11) or of trimethoprim-sulfomethoxazol (n ¼ 46). No cause of the fever was found in 30 patients in group I These patients did not differ from those who developed and 41 patients in group II (Table 2); the fever was fever in regard to age, diagnosis and duration of the classified as ‘FUO’. neutropenia. Isolated bacteremias occurred in 36 patients (49%) of Forty-one of 74 patients (55%) in group I and 46 of 87 group I and in 34 patients (39%) of group II. Mainly patients (53%) in group II responded to the first-line Gram-positive pathogens were demonstrated in both treatment ceftazidime or piperacillin-tazobactam. Non- groups (group I 32 Gram-positive agents, group II 38 inferiority of group II could not be shown (P ¼ 0.17). The Gram-positive agents). Gram-negative pathogens were one-sided 95% confidence bound for the difference in found in 13 patients in group I and in 13 patients of group responses was 15.5%. In addition, no statistically signifi- II. Pathogens isolated from blood cultures are shown in cant difference was demonstrable between the two treat- Table 3. Mixed cultures were isolated from the blood ment groups (P ¼ 0.75) concerning inferiority. Extension of culture of nine patients in group I and 17 patients of group the primary therapy with vancomycin occurred with equal II, respectively. A CDI was present in eight patients of frequency in both groups (n ¼ 33 group I, n ¼ 41 group II). group I and in 12 patients of group II. A pathogen was also An additional 14 patients of group I (19%) and 21 patients demonstrated in the blood culture of three vs eight of these of group II (24%) became afebrile after the addition of patients with CDI. vancomycin (Table 4). After extension with vancomycin the Two patients of group I and three patients of group II response rate in group II was noninferior to the response developed pseudomembranous during the study. rate in group I (P ¼ 0.04; the one-sided upper confidence

Bone Marrow Transplantation Neutropenic fever in patients with acute leukemia or following stem cell transplantation C Harter et al 377 Table 4 Response to therapy treatment with ceftazidime. Only those patients were recruited to the study who had either undergone HDCT Group I Group II (n ¼ 74) (n ¼ 87) and PBSCT or who were suffering from an acute leukemia. In 1998, a randomized study comparing piperacillin/ Response to the first-line therapy 41 (55%) 46 (53%) tazobactam single-agent therapy with ceftazidime in Response after extension with Vancomycin 14 (19%) 21 (24%) combination with amikacin in neutropenic cancer patients Response after further modification 18 (25%) 19 (22%) 16 Deaths 1 (1%) 1 (1%) was published by Hess et al. Response rates to the single- agent treatments in our patients were comparable in both groups (group I 55 vs 53% group II). Supplementation with vancomycin was done with equal frequency in both groups. Table 5 Response to therapy in relation to the cause of fever When the glycopeptide antibiotic was added to the regimen of patients who were still febrile after 72 h, a further 14 Group I Group II (n ¼ 74) (n ¼ 87) patients of group I and 21 patients of group II became afebrile. Thus, the results are comparable to other data FUO 17/30 (57%) 24/41 (59%) from the literature17,18 and to our own data in previously CDI 3/8 3/12 published papers.19,20 Of these CDI+MDI 2/3 1/8 MDI 25/44 (57%) 24/50 (48%) Antibiotic therapy was discontinued when the patients Gram positive 18/31 20/37 displayed a body temperature below 381C on 5 consecutive Gram negative 7/13 4/13 days, even if they were still neutropenic. In other studies, treatment was not discontinued until after 10 afebrile days, or antibiotic treatment was continued until the granulocyte count increased to values above 0.5/nl. The strategy of bound for pI–pII was now 9%). Further modifications to discontinuing antibiotic therapy after just 5 afebrile days treatment were required in 18 patients of group I (25%) helps to minimize selection out of fungi, and also and in 19 patients of group II (22%). contributes to cost-saving. When response to therapy is viewed in relation to the Our results are comparable to those from a study by the cause of the fever (Table 5), no difference between EORTC comparing piperacillin/tazobactam plus amikacin treatment groups can be seen even with respect to the with ceftazidime plus amikacin as empirical therapy in gram-positive pathogens. Response with regard to Gram- neutropenic patients.8 The reason for the high response negative tended to be better in the group treated rates in Hess’s study16 is that he used different definitions of with ceftazidime than in group II: Seven of 13 patients with therapeutic success from ours. In our study and as well as in Gram-negative pathogens in group I became afebrile in the EORTC study, every modification of the initial response to single-agent therapy with ceftazidime, com- therapeutic regime was classified as a failure. In the study pared to only four of 13 in group II (Table 3). However, by Hess, vancomycin therapy became an additional this difference was not statistically significant (P ¼ 0.43). constituent part of the study medication after 48 h in line with predetermined criteria, and it was this that resulted in the high response rates of 82%. The main end point of this Discussion study was the success due to modification. The generally high success rate of single-agent therapy The concept of empirical antibiotic therapy was developed may, to a certain extent, be the consequence of micro- more than 30 years ago. In 1962, Curtin and Marshall biological changes, for example, the occurrence of Gram- realized that, ‘in some patients, therapy must be instituted positive pathogens, which are associated with much lower before the bacteriological data are available’.12 morbidity and mortality.21 Several combined treatments – for the greater part Bacteremias occurred in 49% of the febrile episodes in broad-spectrum b-lactames plus aminoglycoside – have group I and in 39% of those in group II. This rate is higher been tested in the last 20 years. Single-agent treatments than that in the IATCG-EORTC studies 8 and 9,22 in were employed as broad-spectrum b-lactames, such as which the rate of bacteremias was 22%. The difference can ceftazidime and imipenem became available. Pizzo et al.13 possibly be explained by the fact that the majority of our published the first large-scale randomized study involving patients had been fitted with a central venous catheter and single-agent therapy. They compared ceftazidime single- by antibiotic prophylactic strategies with a higher efficiency agent therapy with the combination of carbenicillin, against Gram-negative bacteria. In the EORTC study 1, cephalotin and gentamicin. The treatments proved to be which ran from 1973–1978, the ratio of Gram-negative to equally effective, with failure rates of only 5 and 4%, Gram-positive bacteremias was 71–29%. A reversal of respectively. Many subsequent studies in which a single- these figures has been observed over the last few decades, so agent treatment was compared with a combined treatment that Gram-positive pathogens are now the predominant failed to show any significant difference in the success rates. infective agents. Our results, with rates of 30% Gram- In most cases, the single agent employed was ceftazidime or negative bacteremias in group I and 26% in group II, agree imipenem. Data on and as single- with those in the IATCG-EORTC studies 8 and 9, which agent therapy have also been published.4,14,15 We compared showed rates of 31 and 33%, respectively. piperacillin/tazobactam with its broad antibacterial activity CDIs occurred in eight patients of group I and in 12 and the inhibitor for b-lactamases with single-agent patients of group II. Although 94% were suffering from

Bone Marrow Transplantation Neutropenic fever in patients with acute leukemia or following stem cell transplantation C Harter et al 378 an underlying hematological disease, the low rate of References systemic invasive mycosis is not surprising because the number of patients with acute leukemia was small. 1 Schimpff S, Satterlee W, Young VM, Serpick A. Empiric Systemic antimycotic treatment was started in only four therapy with carbenicillin and gentamycin for febrile patients with cancer granulocytopenia. New Engl J Med 1971; 284: patients. 1061–1065. Additional therapy with vancomycin was given in 45% 2 Schimpff SC. Overview of empirical antibiotic therapy for the of the febrile events in group I and in 47% of those in febrile neutropenic patients. Rev Infect Dis 1985; 7 (Suppl 4): group II. These figures agree with those of a study in 734–740. which meropenem was compared with ceftazidime plus 3 Leyland MJ, Bayston KF, Cohen J, Warren R, Newland AC, amikacin.14 Bint AJ et al. A comparative study of imipenem versus The trend towards low mortality secondary to infections piperacillin plus gentamycin in the initial management of has been documented worldwide. At the Jule Bordet febrile neutropenic patients with hematological malignancies. Institute, a decrease of mortality during febrile neutropenia J Antimicrob Ag Chemother 1992; 30: 843–854. from 24 to 12% was observed in patients admitted to 4 Sanders JW, Powe NR, Moore RD. Ceftazidime monotherapy the consecutive IATCG EORTC studies in the course of for empiric treatment of febrile neutropenic patients: a meta- 22,23 analysis. J Infect Dis 1991; 164: 907–916. the last 20 years. The latest IATCG-EORTC studies 5 De Pauw B, Williams K, De Neeff J, Bothof T, de Witte T, 7, 9 and 11 show a total mortality of between 5 and 12%, Holdrinet RS et al. Randomized prospective study of with the infection-related mortality lying between 1 and ceftazidime versus ceftazidime plus flucloxacillin in the 3%.8,14,24 The infection-related mortality in our study – empirical treatment of febrile episodes in severely neutropenic 1.25% – is extremely low. patients. Antimicrob Ag Chemother 1985; 28: 824–828. Toxic effects and side effects caused by the study 6 Egerer G, Goldschmidt H, Streich N, Ehrhard I, Sonntag HG, treatments were mild and included skin rashes and Haas R et al. Ceftazidime in combination with glycopeptide diarrhea. Anand et al.25 stated that third-generation antibiotic is an effective first-line therapy for patients cephalosporin use is correlated with the development of undergoing high-dose therapy with autologous peripheral Support Care Cancer C. difficile associated diarrhoea; ceftazidime was highly blood stem cell support. 1999; 7: 336–342. significantly associated (Po0.01) with more cases than 7 EORTC International Antimicrobial Therapy Cooperative expected by usage alone vs ticarcillin/clavulanate. Com- Group. In vitro activity of piperacillin/tazobactam against pared to the literature the incidence of C. difficile diarrhoea 365 aerobic bacteria isolated from blood in granulocytopenic was low in our trial. Also, no difference in the incidence cancer patients. 18th International Conference of Chemo- of C. difficile diarrhoea (ceftazidime group: two patients therapy, Program and Abstract 380, 1993. (3%), piperacillin/tazobactam group: three patients (3%)) 8 Cometta A, Zinner S, De Bock R, Calandra T, Gaya H, was observed. In our study, only patients with diarrhoea Klastersky J et al., for the International Antimicrobial underwent an investigation for C. difficile toxin. Low Therapy Cooperative Group of the European Organisation for Research and Treatment of Cancer. Piperacillin/tazobactam duration of hospitalization (o3 weeks) and only investiga- tion for the toxin may explain the low rate of C. difficile plus amikacin versus ceftazidime plus amikacin as an empiric therapy for fever in granulocytopenic patients with cancer. positivity in our study. Although an increasing incidence of Antimicrob Agents Chemother 1995; 39: 445–552. antimicrobial resistance among both Gram-positive and 9 Kelsey SM, Weinhardt B, Procock CE, Shaw E, Newland AC. Gram-negative pathogens isolated from patients with Piperacillin/Tazobactam plus gentamycin as empirical therapy neutropenia is described in the literature,26 we failed to for febrile neutropenic patients with haematological malig- observe this trend in our department. nancies. J Chemotherapy 1992; 4: 281–285. The results of this study show that piperacillin/tazobac- 10 Pizzo PA, Armstrong D, Bodey GP, DePauw BE, Feld R, tam and ceftazidime are of equal value in the treatment Glauser M et al., Immune-compromized Host Society Panel. of neutropenic fever in patients following high-dose The design, analysis, and reporting of clinical trials on the chemotherapy and autologous peripheral blood stem-cell empirical antibiotic management of the neutropenic patient: transplantation or in patients with acute leukemia. Mean- report of a consensus panel for the Immunocompromised Host Society. J Infect Dis 1990; 161: 397–401. while, direct costs are equal for both antibiotic agents. 11 Chan I. Exact tests of equivalence and efficacy with a non-zero Indirect costs concerning infusion material and working lower bound for comparative studies. Statist Med 1998; 17: time for treatment (three times/day) are the same for both 1403–1413. treatment regimes. These therapeutic guidelines with 12 Curtin JA, Marshall BD. Use of Antibiotics in cancer und restricted use of glycopeptides27 and early discontinuation leukemia. J Chronic Disease 1962; 15: 713–718. of intravenous empirical antibiotic therapy after 5 afebrile 13 Pizzo P, Hathorn JW, Hiemenz J, Browne M, Commers J, days contribute significantly to the reduction of costs and Cotton D et al. A randomized trial comparing ceftazidime toxic side effects, counter the development of resistance and alone with combination antibiotic therapy in cancer patients minimize the positive selection of fungi. with fever and neutropenia. New Engl J Med 1986; 315: 552–558. 14 Cometta A, Calandra T, Gaya H, Zinner SH, de Bock R, Del Favero A et al., for the International Antimicrobial Therapy Acknowledgements Cooperative Group of the European Organisation for Research and Treatment of Cancer and the Gruppo Italiano This study was supported by Wyeth Pharma GmbH, Muenster. Malattie Ematologiche Maligne dell’Adulto Infection Pro- The authors thank Ms Ulla Scheidler for her expert secretarial gram. Monotherapy with meropenem versus combination help. therapy with ceftazidime plus amikacin as empiric therapy

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