Meropenem versus ceftazidime as empirical monotherapy in febrile neutropenia of paediatric patients with cancer

Gudrun Fleischhacka,*, Claudia Hartmanna, Arne Simona, Beate Wulffb, Werner Haversb, Guenter Markleinc, Carola Hasana and Udo Bodea

a Department of Paediatric Haematology/Oncology, Children's Medical Hospital, University of Bonn, Adenauerallee 119, D-53113 Bonn; b Department of Paediatric Haematology/Oncology, University of Essen, Hufelandstrasse 55, D-45122 Essen; c Institute of Medical Microbiology and Immunology, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This trial assessed the efficacy and safety of meropenem versus ceftazidime as empirical monotherapy for febrile neutropenia in paediatric cancer patients. In a prospective randomized study, 172 evaluable febrile episodes in the meropenem arm and 170 episodes in the ceftazidime arm were analysed for the clinical and microbiological response dependent on the kind of infection. About half the episodes were classified as fever of unknown origin (FUO) and the remainder as microbiologically or clinically documented infections. The most frequently documented infections in both arms were bacteraemias (22.1 versus 26.5%), predominantly caused by Gram-positive organisms (57.9 versus 71.1%). The success rate of the initial monotherapy differed significantly between the two arms and was 55.8% in the meropenem and 40.0% in the ceftazidime arm (P = 0.003). In addition, a significantly longer duration of fever and of antimicrobial therapy was observed in the ceftazidime arm than in the meropenem arm (median 5 versus 4 days, P = 0.022, and 7 versus 6 days, P = 0.009, respectively). With respect to the kind of infection, differences between the two arms were significant only in episodes classified as FUO but not in documented infections. In both arms, side effects were minimal. Despite the greater response rate for meropenem in FUO, the fact that ceftazidime has been proven to be as effective as meropenem in documented infections in the present study suggests that both drugs are useful as empirical monotherapy in febrile paediatric cancer patients.


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Life-threatening complications due to bacterial infections have been reported in c. 5–10% of febrile episodes in children with cancer.1,2 To prevent these, broad-spectrum antibiotic therapy is started empirically in these patients at the onset of fever. The combination of ß-lactam antibiotics plus an aminoglycoside or a glycopeptide was long considered the ‘gold standard’ of empirical antibiotic therapy in febrile neutropenic patients.1,36 The effectiveness of these regimens was documented in many studies reporting synergic bactericidal activity against a broad spectrum of Gram-positive and -negative bacteria and a low incidence of emerging bacterial resistance. However, the disadvantages of this combination treatment, i.e. (i) the need for drug monitoring of antibiotics with a low therapeutic index (e.g. aminoglycosides or vancomycin), (ii) high antimicrobial costs and (iii) resource intensity involved in preparation and application, coupled with the development of antimicrobial agents with a broader spectrum of antibacterial activity, led to a change in this practice during the past decade. Thus, recent studies have evaluated carbapenems and third- or fourth-generation cephalosporins as initial monotherapy in febrile neutropenic cancer patients.5,713 Most of these studies focused on adult patients and showed no significant advantage of any specific regimen.5,7,14,15 Trials evaluating empirical monotherapy in febrile neutropenic children are rare and in most instances of low predictive validity because of the small number of treatment episodes.1619 Following years of dominance of antimicrobial combinations with cephalosporin or penicillin derivatives with a glycopeptide or an aminoglycoside, meropenem and ceftazidime were chosen in the present study for initial monotherapy of febrile episodes in neutropenic paediatric cancer patients. The aim of this prospective randomized study was to evaluate and to compare the efficacy and safety of meropenem and ceftazidime as empirical monotherapy and as part of a sequential regimen.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient eligibility

This study included all febrile and neutropenic patients who had been treated with conventional or high-dose chemotherapy for a primary, refractory or relapsed solid tumour or for a haematological malignancy at the Departments of Paediatric Haematology/Oncology of the University Hospitals of Bonn and Essen, Germany, between January 1998 and April 2000. Eligible were all consecutive patients (i) with fever defined as an elevation to 38.5°C over at least a 4 h period or a single temperature elevation above 39°C, (ii) with neutropenia defined as an absolute neutrophil count (ANC) of <0.5 x 109/L at admission or >0.5 x 109/L expected to fall within the next 24–48 h to <0.5 x 109/L and (iii) with a presumptive infection (i.e. exclusion of febrile episodes likely to be due to neoplastic disease or to drug or blood product administration). Patients who had repeated febrile neutropenic episodes during consecutive cytostatic treatment periods could be entered more than once. Patients were excluded from this study if they had received any iv or oral antibiotic medication other than antimicrobial prophylaxis during the 48 h preceding admission, if they had a history of allergy or other incompatibility to one of the study drugs or if they were suffering from hepatic or renal failure [World Health Organization (WHO) toxicity scale > 3].20

Study design

The study was a prospective, open, randomized, two-centre comparative trial with two parallel study arms. Patients were assigned at random to either meropenem or ceftazidime as initial monotherapy of a sequential antibiotic regimen. Allocation was based on the sequential drawing of sealed envelopes, which had been centrally prepared beforehand in balanced blocks of four groups. To minimize imbalances between the two treatment arms, three stratification variables were used: the centre (stratum 1), the intensity of chemotherapy [stratum 2, conventional and high-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT)] and the age of patients who had received conventional-dose chemotherapy (stratum 3, >=3 months to <6 years, >=6 years to <12 years, >=12 years).

Antimicrobial regimen

Either meropenem [60 mg/kg/day in three single doses (SDs), SD <= 1.0 g, AstraZeneca GmbH Wedel & Gruenenthal GmbH Stolberg, Germany] or ceftazidime (100 mg/kg/day in 3 SDs, SD <= 2.0 g, Glaxo Wellcome GmbH, Bad Oldesloe, Germany) was administered as initial monotherapy of the sequential regimen (Table IGo). In the case of non-response 48 h after initiation of therapy, teicoplanin (Hoechst AG, Frankfurt am Main, Germany) was added to the ceftazidime arm. In view of the broader spectrum of activity expected against Gram-positive organisms in the meropenem arm, teicoplanin was added only in cases of documented infection with Gram-positive organisms. If fever and other signs of infection still persisted after 96 h of therapy, the medication was changed in both arms to meropenem in combination with teicoplanin and an antifungal drug (fluconazole, Pfizer GmbH Karlsruhe, Germany; itraconazole, Janssen-Cilag GmbH Neuss & Glaxo Wellcome GmbH; amphotericin B, Squibb-von Heyden GmbH Munich, Germany; liposomal amphotericin B, NeXstar Pharmaceuticals Ltd, Blackrock, N. Ireland). In cases of clinically suspected or culture-proven local infections caused by herpes simplex virus (HSV), additional therapy with aciclovir was allowed. Modification of antimicrobial therapy was permitted at the discretion of the attendant clinician if study treatment failed and in microbiologically documented infections, depending on the results of antimicrobial susceptibility tests. The individual reasons for modification had to be documented in the clinical record and checked by the principal investigator. Antibiotics were administered intravenously to all patients for at least 24 h after the cessation of fever and for a minimum of 72 h. In culture-proven cases of bacteraemia, antibiotics were given for a minimum of 7 days. The study treatment was stopped irrespective of the recovery of the ANC and of a persistently high level of the C reactive protein (CRP) at the discretion of the clinicians responsible.


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Table I. Sequential antimicrobial regimen

 
Investigations

Pre-treatment evaluation included clinical and medical histories, a physical examination and routine laboratory tests (complete blood cell count, electrolytes, renal and hepatic values, CRP). During the febrile episode, blood cell counts (BCCs) were taken daily and biochemical tests were performed at least twice a week. Blood cultures were drawn from all lumens of an indwelling central venous catheter or from a peripheral vein before the initiation of antibiotic therapy, every other day while fever and other signs of infection persisted, and until initially positive culture results became negative. Specimens of urine, faeces, throat swabs and other appropriate sources were cultured initially and before any escalation or modification of the antimicrobial therapy. Chest radiography and abdominal sonography were performed at the time of admission if indicated clinically or at least 4 days after admission in case of persistent fever.

Classification of febrile episodes

Febrile episodes were classified according to the kind of infection as (i) fever of unknown origin (FUO), (ii) microbiologically documented infection or (iii) clinically documented infection, and according to the suspected source or site of infection (unknown, bacteraemia, fungaemia, viraemia, lower airway infection, upper airway infection, gastrointestinal tract infection, urogenital tract infection, soft tissue infection). FUO was defined as both the absence of any clinical or radiological signs of infection other than fever and no isolation of any causative organism. The diagnosis of microbiologically documented infections was based on both the isolation of causative agents from urine, faeces, throat, bronchoalveolar lavage, CSF or wound, and fever accompanied by clinical symptoms adopted from the case definitions of the Centers for Disease Control (CDC) surveillance system for nosocomial infections.21 Bacteraemia or fungaemia was defined as fever with positive blood cultures for bacteria or fungi and with/without septic symptoms or signs of localized infection. In bacteraemia caused by coagulase-negative staphylococci (CNS) or Micrococcus spp. at least two independent positive blood cultures were stipulated. Viral infection was defined as fever both with typical exanthema [e.g. varizella-zoster virus (VZV) viraemia] or signs of an airway or gastrointestinal infection and with culture-proven virus detection.21 Fever arising from a clinically evident source of infection, including radiological findings, without detection of any pathogen, was classified as clinically documented infection. The detection of common skin contaminants and mucosal colonization with no clinical symptoms was not classified as documented infection.

Bacterial isolates were identified and tested according to standard identification techniques and antibiotic susceptibility tests.22 A bacterium was considered resistant if the disc diffusion method yielded an MIC of >=16 mg/L of meropenem, >=32 mg/L of ceftazidime or >=32 mg/L of teicoplanin.22

Evaluation of response and toxicity

The response to the antimicrobial treatment was defined irrespective of the course of the ANC and the CRP. Success was classified (i) in FUO if fever resolved with no requirement for further antimicrobial therapy for at least 7 days following completion of the treatment or (ii) in clinically and microbiologically documented infections if cessation of fever, the resolution of clinical signs and the eradication of causative microorganisms with no recurrence of infection for at least 1 week after the end of the antimicrobial therapy were observed. Patients were evaluated 48 h from the beginning of steps 1 and 2 (in step 2 in the meropenem arm irrespective of whether or not teicoplanin was added) and after 96 h of antimicrobial therapy in step 3. They were considered successfully treated if they survived with no modification of study medication. The overall evaluation was performed 7 days after the completion of treatment. All patients who died of a non-infectious cause during the febrile episode were considered ‘not evaluable’.

The treatment was considered a failure if (i) fever (>38.5°C) persisted for longer than 48 h in steps 1 and 2 (in step 2 in the meropenem arm irrespective of whether or not teicoplanin was added) and longer than 96 h in step 3 or with modified therapy, (ii) the patient died of a cause related to the primary infection within the first 48 h (steps 1 and 2) to 96 h (step 3) of the treatment, (iii) the patient showed clinical deterioration with or without persistence of the primary isolated microorganism or detection of a new bacterial pathogen other than the primary one. In cases of failure, a successful response to modified antimicrobial therapy, any surgical intervention and the course of bone marrow recovery (i.e. an increase of ANC to >0.5 x 109/L 24 h before or simultaneously with the cessation of fever) were documented.

All febrile episodes were included in the assessment of the haematological and non-haematological toxicity of study drugs, which was evaluated for all episodes according to the WHO grading system for side effects of cytostatic treatment.20

Statistical analysis

For all eligible patients an intent-to-treat analysis was performed. A second analysis of response was carried out for all evaluable patients after exclusion of patients with treatment changed without adequate reason (assessed as failure in the intent-to-treat analysis) and of patients with allergic reactions to the study antibiotics (assessed as success in the intent-to-treat analysis).

Data were evaluated using descriptive statistical methods (median, ranges, frequencies and percentages). The Mann– Whitney U-test was used for comparison of independent continuous variables, Pearson's {chi}2 test (asymptotic) for comparison of categorical data and Fisher's exact test for small numbers. In case of dichotomous variables the binomial distribution was tested using the normal approximation. Multivariate analysis was performed to evaluate prognostic factors for response to monotherapy. In all statistical tests, values of P <= 0.05 (two-tailed) were considered significant. For assessment of the statistical significance of the differences between the two treatment arms, confidence intervals (CIs) were also constructed. Statistical calculations were done with the SPSS software package (Statistical Program for Social Science, version 9.0.1, Chicago, IL, USA).

Based on previously published studies of febrile neutropenic patients, the success rate anticipated for ceftazidime monotherapy was 45%. It was hypothesized that meropenem monotherapy might increase the success rate to 60%. For a study to detect such a difference of 15% at the two-sided level of significance of 0.05 with 80% power, 173 evaluable episodes per treatment arm were required. The final number of evaluable episodes was 170 and 172 in the ceftazidime and the meropenem arm, respectively. Therefore, the power of the difference between the two arms was calculated on the number of eligible episodes and the estimated success rates at a significance of 0.05.23

Ethics

The study was conducted in accordance with the updated Declaration of Helsinki and was approved by the local ethics committee of the University of Bonn. Before enrolment in the study, the patients' parents and/or the patients themselves were informed of the investigational character of the study and their informed written consent was given.


    Results
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 Abstract
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 Materials and methods
 Results
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Patient characteristics

During the study period a total of 375 febrile episodes were documented in 169 paediatric cancer patients. Thirty-one episodes were not eligible for the following reasons: non-neutropenic episodes (n = 22), non-febrile episodes with clinically documented localized infections (n = 3), non-neoplastic disorder (n = 1), fever related to cytostatic treatment or to malignancy (n = 4) or incomplete documentation (n = 1). In addition, two eligible patients in the meropenem arm were not evaluable for efficacy because they died of their underlying diseases during the febrile episode. Thus, 342 episodes (91.2% of the randomized cases) in 164 children and adolescents were included in the intent-to-treat analysis of efficacy. Randomized patients were well balanced in the two study arms with respect to the stratification categories such as location, chemotherapy intensity and age. Nor were there any significant differences between the two arms in the underlying disease, the stage of disease, the use of central venous catheters, oral antimicrobial prophylaxis or administration of granulocyte colony-stimulating factor (G-CSF) (Table IIGo). In addition, there was no significant difference in the degree of chemotherapy-induced mucositis, although the frequency of mucositis scale III or IV was higher in the ceftazidime group (38/170 versus 22/172) than in the meropenem group (P = 0.098).


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Table II.  Characteristics of eligible febrile episodes
 
The pre-treatment BCCs showed no significant differences between the two treatment arms in the absolute counts of neutrophils (both arms: median ANC 0.1 x 109/L, P = 0.578), lymphocytes (median ALC: 0.3 x 109/L in the meropenem arm, 0.2 x 109/L in the ceftazidime arm, P = 0.085) and monocytes (both arms: median AMC 0.1 x 109/L, P = 0.462). In both groups (meropenem versus ceftazidime), most patients showed pre-treatment CRP values <= 50 mg/L (57.6% versus 67.1%). Besides the different degree of neutropenia, the different intensity of chemotherapy (i.e. myelosuppressive to myeloablative) also accounted for the widely varying duration of neutropenia (ANC <0.5 x 109/L) in the individual patient (meropenem arm: median 4 days, range 0–19 days, ceftazidime arm: median 5 days, range 0–35 days, P = 0.225).

Infections

In terms of the classification of the febrile episodes, there were no significant differences between the two groups. In both arms, about half the episodes were classified as FUO (meropenem arm: 82/172 episodes, 47.7%; ceftazidime arm: 77/170 episodes, 45.3%, P = 0.751). Ninety (70 and 20 episodes) of 172 episodes (40.7% and 11.6%) in the meropenem arm and 93 (73 and 20) of 170 episodes (42.9% and 11.8%) in the ceftazidime arm were microbiologically or clinically documented infections (P = 0.867 and P = 1.000). In the vast majority of microbiologically documented infections, bacterial pathogens were the causative agents: in 62 of 70 episodes (88.6%) in the meropenem arm and in 67 of 73 episodes (91.8%) in the ceftazidime arm. Viral infections were detected in eight and five episodes, respectively, and were associated with an airway infection [respiratory syncytial virus (RSV) in three and four episodes, respectively], a gastrointestinal infection (HSV in a single episode in each arm and rotavirus in two episodes in the meropenem arm) and VZV viraemia in two episodes in the meropenem arm. Bacteraemia was responsible for fever in 38 of 172 episodes (22.1%) in the meropenem arm and in 45 of 170 episodes (26.5%) in the ceftazidime arm (P = 0.445). In both arms, bacteraemia with a single isolate was caused predominantly by Gram-positive organisms, accounting for 22 episodes (57.9% of all bacteraemic episodes) and 32 episodes (71.1%), respectively. The vast majority of the causative organisms in Gram-positive bacteraemia were coagulase-negative staphylococci (CNS) and Streptococcus mitis, isolated in 31 (14 meropenem arm, 17 ceftazidime arm) and 10 (two meropenem arm, eight ceftazidime arm) episodes, respectively. Rarely isolated were Bacillus spp. (n = 1), Corynebacterium spp. (n = 3), Enterococcus spp. (n = 6), Micrococcus spp. (n = 3), Staphylococcus aureus (n = 3) and other Streptococcus spp. (n = 2). Gram-negative and fungal organisms, respectively, were classified as causative microorganisms in 30 (15 in each arm) and three (one meropenem arm, two ceftazidime arm) cases of mono- or polymicrobial bacteraemia/fungaemia. The most frequent pathogen in Gram-negative bacteraemia was Escherichia coli (12 meropenem arm, seven ceftazidime arm) followed by Klebsiella pneumoniae (two meropenem arm, three ceftazidime arm) and Acinetobacter spp. (one meropenem arm, two ceftazidime arm). Other Gram- negative bacteria (Bacteroides fragilis, Campylobacter jejuni, Enterobacter cloacae, Fusobacterium nucleatum, Kluyvera cryocrescens, Pseudomonas aeruginosa) were detected once. Candida albicans, Candida guilliermondii and Aspergillus fumigatus were isolated in the blood cultures of patients with fungaemia as mono- or polymicrobial infection. Urinary tract infections were caused predominantly by Gram- negative bacteria, i.e. E. coli (seven episodes) and Klebsiella spp. (three episodes). In only eight of 14 episodes of deep airway infection was a putative causative organism identified: Haemophilus influenzae (n = 4), P. aeruginosa (n = 1), Mycoplasma pneumoniae (n = 1), RSV (n = 1) and Chlamydia trachomatis (n = 1). Six episodes of deep airway infections were exclusively clinically and radiographically documented. In two cases pulmonary aspergillosis was strongly suspected. In 11 of 29 episodes classified as gastrointestinal tract infections bacteria were isolated: in nine instances toxin B-producing Clostridium difficile (n = 5 in the meropenem arm, n = 4 in the ceftazidime arm) and twice Salmonella typhimurium (n = 1 in each arm). Eight of nine microbiologically documented soft tissue infections were caused by Gram-positive agents: CNS (n = 4), S. aureus (n = 2), Corynebacterium sp. (n = 1). The initial clinical and microbiological evaluation revealed a second infectious site in 10 (5.8%) episodes of the meropenem arm and in 14 (8.2%) episodes of the ceftazidime arm (P = 0.541). These were mostly observed in bacteraemic episodes (in 6/10 and 8/14 episodes, respectively) and were suspected to be the primary focus of infection in these patients. The majority of second infectious sites were the gastrointestinal tract (6/10 and 4/14 episodes) and the airways (3/10 and 5/14 episodes).

Before antibiotic treatment, an ANC of <=0.1 x 109/L in 55 of 84 episodes (65.5%), an absolute lymphocyte count (ALC) of <=0.1 x 109/L in 44 of 84 episodes (52.4%), an absolute monocyte count (AMC) of <=0.1 x 109/L in 67 of 84 episodes (79.8%) and a CRP value of >50 mg/L in 35 of 84 episodes (41.6%) were observed in infections classified as bacteraemia/fungaemia, with no significant differences between the two arms. Compared with non-bacteraemic/ non-fungaemic episodes there were significant differences for both ANC (P = 0.001) and ALC (P = 0.003) but not for AMC (P = 0.091) and CRP (P = 0.345). Correspondingly, the duration of neutropenia (ANC <0.5 x 109/L) was significantly longer in bacteraemic/fungaemic episodes (median: 4 versus 7 days, P = 0.000).

Response

In the intent-to-treat analysis, the overall success rates of both treatment arms were comparable (both 99.4%) (Table IIIGo). In two patients the treatment failed irrespective of escalation or modification of therapy. One patient died within 12 h of ceftazidime therapy without modification due to fulminant septic shock caused by polybacterial bacteraemia with severe mucositis and perforative appendicitis. In this patient the causative organisms were E. coli (susceptible in vitro to ceftazidime) and S. mitis (susceptibility to ceftazidime was not tested). In a second patient treated in the meropenem arm (escalation to step 3 plus aciclovir because of a VZV superinfection) cessation of fever was not achieved until day 25 after corticosteroid interaction. In this case an autoimmune process and drug fever were possible reasons.


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Table III.  Intent-to-treat analysis of outcome of all eligible episodes (n = 342 episodes)
 
Response to initial monotherapy (intent-to-treat analysis).
The success rate of initial monotherapy differed significantly between the two treatment groups with 96/172 (55.8%) in the meropenem arm and 68/170 (40.0%) in the ceftazidime arm (P = 0.003, CI 0.053–0.263, at significance of 0.05, power 0.83). Regarding the type of infection, the success rates in both arms were higher in episodes classified as FUO than in documented infections (63/82, 76.8% versus 33/90, 36.7% in the meropenem arm, P = 0.000, CI 0.266–0.546; 40/77, 51.9% versus 28/93, 30.1% in the ceftazidime arm, P = 0.004, CI 0.073–0.363). Comparison of the two treatment arms showed that the success rate differed significantly only in FUO episodes and not in documented infections. In addition, there were no significant differences between the two arms regarding the different types, sites and sources of documented infection (Table IIIGo).

The overall response rates to initial monotherapy dependent on the underlying disease were not significantly different in patients with haematological malignancies and in those with solid tumours (44.4 versus 54.6%, P = 0.071, CI –0.009–0.213). Regarding the treatment arm and all febrile episodes, a significant difference (50.0 versus 66.7%, P = 0.026, CI 0.016–0.318) in the meropenem arm and no significant difference (38.7 versus 42.4%, P = 0.383, CI –0.118–0.192) in the ceftazidime arm were observed between these subgroups. Regarding only documented infections, the overall response rates were not significantly different in patients with haematological malignancies or in those with solid tumours (31.1 versus 39.2%, P = 0.294, CI –0.074–0.236); in part there were also no differences in each regimen (meropenem arm, 33.8 versus 45.5%, P = 0.325, CI –0.120–0.354; ceftazidime arm 28.1 versus 34.4%, P = 0.536, CI –0.141–0.269).

Regarding only FUO episodes, the different response rates of the two treatment arms were not attributed to differences in the ANC at admission and to the duration of neutropenia (ANC <0.5 x 109/L) between the regimens (P = 0.894 and P = 0.360). In both arms, in contrast to the failures, the responders to initial monotherapy showed a significantly shorter duration of neutropenia (in both arms: 3 versus 5 days, P = 0.006 and P = 0.008).

Response to an escalation of, or to modified, therapy.
In all episodes failing to respond to monotherapy, the success rates of escalation therapy, modified therapy, bone marrow recovery and surgical intervention were analysed. Escalation of therapy by the addition of teicoplanin in step 2 (in the meropenem arm 12 patients without a documented Gram-positive infection were not given teicoplanin, and monotherapy was continued according to the conditions of the sequential regimen, and inconsistent with the study strategy 10 patients with FUO received teicoplanin at the discretion of the treating physician) and by a change to teicoplanin, meropenem and antifungals in step 3 was successful in 43 of 76 (56.6%) treated episodes in the meropenem arm and in 69 of 101 (68.3%) episodes in the ceftazidime arm. This difference in success rate was not statistically significant (P = 0.092, CI –0.025–0.260). The reasons prompting the escalation therapy according to step 2 or 3 were persistent fever (24 episodes in the meropenem arm versus 41 episodes in the ceftazidime arm), documentation of a resistant organism (13 and 16 episodes, respectively), progression of the primary infection (three and seven episodes, respectively) and the occurrence of a secondary infection (three and five episodes, respectively). Overall, the sequential regimen failed in 33 of 172 episodes (19.2%) in the meropenem arm and in 33 of 170 episodes (19.4%) in the ceftazidime arm (P = 0.958, CI –0.082–0.086). In part, these episodes were successfully resolved by modifying antimicrobial therapy and by surgical intervention (i.e. by removing an infected central venous catheter, n = 7, or another infectious focus, n = 1) (Table IIIGo), with no differences in success rates between the two treatment arms. The main reason for modification of the study medication in both arms was clinical deterioration with a documented infectious site such as deep airway infection or haemorrhagic enterocolitis, with or without a pathogen showing antimicrobial resistance. Twelve of these episodes (five in the meropenem arm, seven in the ceftazidime arm) were secondary infections. The antibiotics most frequently used for modified therapy were metronidazole (seven times in both arms), aminoglycosides (three and four times in the meropenem and the ceftazidime arm, respectively), ß- lactams other than ceftazidime or meropenem (four and three times, respectively) and macrolides (four and seven times, respectively). In 12 of 172 episodes (7.0%) in the meropenem arm and in 11 of the 170 episodes (6.5%) in the ceftazidime arm failing to respond to study treatment, bone marrow recovery (i.e. an increase in ANC to >0.5 x 109/L) led to permanent cessation of fever (P = 0.852, CI –0.058–0.068).

Analysis of efficacy in evaluable patients.
From the analysis of efficacy in all evaluable episodes, 17 patients whose treatment was changed without adequate reason (10 in the meropenem arm and seven in the ceftazidime arm) and six patients with allergic reactions to the study antibiotics (three patients in each arm) were excluded (Table IVGo). Thus, 159 and 160 episodes were assessable for efficacy. In comparison with the intent-to-treat analysis, similar success rates were observed with the initial monotherapy (59.7 versus 40.6%) as well as with escalation of therapy according to steps 2 and 3. There were also no differences in success rates of monotherapy in documented infections (36.0 versus 31.0%) in contrast to the rates in FUO episodes which differed significantly (90.0 versus 52.1%, P = 0.000).


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Table IV.  Analysis of efficacy in all evaluable episodes (n = 319 episodes)
 
Response and antimicrobial susceptibility.
In patients with bacteraemia, the results of antimicrobial susceptibility testing and clinical response to monotherapy with meropenem or ceftazidime or to the addition of teicoplanin were documented. In vitro susceptibility to meropenem and ceftazidime was seen in 100 and 95.8% of the Gram-negative organisms tested, respectively, and was 100% with both agents for the most common Gram-negative organisms such as E. coli and K. pneumoniae. Nevertheless, the clinical response in cases of Gram-negative bacteraemia was markedly lower with success rates of 9/16 (56.2%) in the meropenem arm and 8/17 (47.1%) in the ceftazidime arm (P = 0.870).

Not all Gram-positive bacteria were tested for their susceptibility to meropenem (23/59, 39.0%) or to ceftazidime (7/59, 11.9%). However, 58 of 59 Gram-positive isolates were tested for their susceptibility to oxacillin and showed resistance in 21 isolates (n = 9 in the meropenem arm, n = 12 in the ceftazidime arm), implying resistance to meropenem or ceftazidime in these cases too. The clinical success rate was lower in the ceftazidime arm (6/33, 18.2%) than in the meropenem arm (12/26, 46.2%) but not significantly different (P = 0.082, CI –0.048–0.512). In general, third-generation cephalosporins such as ceftazidime are less active than the carbapenems against Gram-positive cocci.24 The in vitro susceptibility of all Gram-positive isolates to teicoplanin was tested, with only one resistant isolate of Enterococcus faecium being detected. The addition of teicoplanin led to the eradication of Gram-positive organisms in 25 of 40 (62.5%) bacteraemic episodes. For the most common Gram-positive organisms, e.g. CNS and S. mitis, the susceptibility rate to teicoplanin was 100% with clinical success rates of 19/25 (76.0%) and 1/5 (20.0%), respectively.

Time-to-event analysis of all eligible episodes.
The duration of fever, antimicrobial therapy and hospitalization was significantly longer in the ceftazidime arm than in the meropenem arm (Table VGo). Regarding the different types of infection, i.e. FUO and documented infections, the differences for all parameters were significant only when comparing episodes classified as FUO. All parameters depended also on the initial ANC (<= or >0.1 x 109/L) and the duration of neutropenia (>10 or <=10 days ANC <=0.5 x 109/L). Application of the Mann–Whitney U test revealed a significantly prolonged duration of all parameters in episodes with an initial ANC <=0.1 x 109/L (duration of fever, P = 0.003, CI 0.002–0.004; duration of antimicrobial therapy, P = 0.004, CI 0.003–0.005; duration of hospitalization, P = 0.002, CI 0.001–0.003) and in episodes with long-term neutropenia (>10 days ANC <=0.5 x 109/L, P = 0.000 for all three parameters). Comparison of the two treatment arms depending on initial ANC (> or <=0.1 x 109/L) revealed significant differences in these parameters only in the meropenem arm (P = 0.038, P = 0.021, P = 0.026, respectively) but not in the ceftazidime arm (P = 0.075, P = 0.146, P = 0.101). In contrast, long-term neutropenia (>10 days ANC <=0.5 x 109/L) was associated in both arms with a longer duration of all parameters (P = 0.000).


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Table V.  Time-to-event analysis of all eligible episodes (n = 342)a
 
Relapses of febrile episodes.
Relapses within 7 days of the end of therapy were analysed in all febrile episodes irrespective of the response to the unmodified or modified antimicrobial therapy. Ten relapses were observed in the meropenem arm, and five in the ceftazidime arm (P = 0.203). In both arms the relapses were observed in median within 4 days (range: 2–6 days) of the end of therapy and mostly with an ANC of <=0.1 x 109/L (7/10 in the meropenem arm, 4/5 in the ceftazidime arm). These episodes were classified as FUO (7/10 and 2/5 episodes, respectively), septicaemic episodes (one fungaemia caused by C. albicans in the meropenem arm and two cases of Gram-positive bacteraemia caused by S. mitis and E. faecium in the ceftazidime arm) and as localized infections (2/10 and 1/5 episodes, respectively).

Toxicity

Excluding the patient who died, 341 episodes were evaluable for toxic side effects. Overall, the rate of adverse events did not differ (seven events in 172 episodes in the meropenem arm and nine events in 169 episodes in the ceftazidime arm, P = 0.592). In the meropenem arm, two cases of transient elevation of the transaminases (WHO scale II), one of persistent fever probably attributable to meropenem or teicoplanin, and two of allergic reaction believed to be related to teicoplanin were reported. In the ceftazidime arm, four patients developed exanthema, probably attributable to ceftazidime in three patients and to teicoplanin in one patient. In addition, hypokalaemia was reported in two patients, and a transient elevation of serum lipase and creatinine, both related to amphotericin B, in one patient. In two patients in the meropenem arm and in one in the ceftazidime arm a vancomycin/ teicoplanin-resistant E. faecium (VRE) colonization of the intestine was observed within 3 weeks of the end of antimicrobial therapy. All these patients were treated more than once with teicoplanin in multiple febrile episodes. C. difficile toxin-positive enterocolitis as a secondary infection was not considered to be a side effect but a complication of severe chemotherapy-induced mucositis. There was no evidence of a study drug-related neurotoxicity. Allergic side effects led to modification and to cessation of any antimicrobial therapy in three patients.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Several investigators have evaluated the use of broadspectrum antibiotics such as third- or fourth-generation cephalosporins or carbapenems as empirical monotherapy for febrile and neutropenic episodes. The reported success rates range from 48 to 82% for meropenem or imipenem5,7,911,16,2427 and from 38 to 66% for ceftazidime or cefepime.5,811,13,18,19,24,26 In our study the response rates to meropenem and ceftazidime as empirical monotherapies were in the lower range of those reported previously and were inferior to the success rates documented in trials using combination therapies of imipenem or ceftazidime with an aminoglycoside or a glycopeptide.2,5,7,18,19 Possible explanations for the differences in success rates between the individual studies using the same drug as initial monotherapy are the limited number of patients enrolled in several of the trials and the differences between the study groups with respect to age (adults, children or both), underlying malignant disease (haematological, non-haematological malignancies or both), disease stage (newly diag- nosed cancer patients, relapsed patients or both) and intensity of chemotherapy (less myelotoxic or myeloablative therapy associated with a different non-haematological toxicity). Some of these study or patient characteristics might affect the response rates and hamper comparison of results across studies. According to the multivariate analysis in our study, which was based on all patients and their response at 48 h of monotherapy, statistically significant, prognostically unfavourable factors were male gender, severe mucositis, PBSCT, long-term neutropenia, severe lymphocytopenia and monocytopenia at admission, and ceftazidime as initial therapy (Table VIGo). However, the age, location, underlying disease, stage of disease, neutrophil count and CRP at admission were not confirmed as factors of prognostic importance. Although the overall success rate of ceftazidime as initial monotherapy was lower than that of meropenem in our study, this difference was not necessarily the result only of the extended antibacterial activity of meropenem (especially against Gram-positive bacteria) but might also have been due to differences in study characteristics. The multivariate analysis showed that the type (documented infection) and the site of infection (bacteraemia/fungaemia) were also poor prognostic variables of response to monotherapy (Table VIGo). Therefore, the higher—but not significantly different—frequencies of bacteraemic episodes and episodes with severe mucositis, severe lymphocytopenia at admission and long-term neutropenia in the ceftazidime arm might also account for the different outcomes. Nevertheless, meropenem was more successful than ceftazidime as monotherapy in the subgroup of episodes classified as FUO. The success rates of both arms in documented infections were lower than those in FUO and comparable with those reported from previous trials.79,18 Although no randomized trial5,711,24 has detected significant differences in success rates between carbapenems and ceftazidime in documented infections, observed success rates have generally been found to be slightly higher with the carbapenems.


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Table VI.  Multivariate analysis of prognostic factors for successful response to monotherapy at 48 h of all eligible episodes (n = 342)
 
Irrespective of the study arm, monotherapy with meropenem or ceftazidime was safe for paediatric cancer patients and prevented early death from infection (i.e. during the first 48–72 h of treatment) in nearly all patients. The only early death observed was due to polybacterial septic shock and occurred in the ceftazidime arm. All other patients who failed to respond to monotherapy responded to early escalation or modification of the antimicrobial therapy, surgical intervention or bone marrow recovery. The addition of teicoplanin in step 2 of the sequential regimen increased the rate of successfully treated febrile episodes in documented Gram-positive infections (to 71.0% in the meropenem arm and 53.7% in the ceftazidime arm). Although the difference between the two treatment arms was not significant, the higher response rate in the meropenem arm suggests a possible additive activity of meropenem and teicoplanin against Gram-positive organisms. As concluded in previous studies, teicoplanin is a suitable option for second-line therapy in cases of persistent fever in FUO or in documented infections caused by susceptible Gram-positive organisms in children.8,9,15,27 Considering the risk of resistance development or selection, the empirical use of glycopeptides should be avoided except in febrile neutropenic patients presenting with signs of an infected central indwelling catheter, a lower respiratory tract infection or severe mucositis, who are at high risk of Grampositive infection.2729

Since there was no switch to ceftazidime in the meropenem arm in step 3 of our study design and therefore a possible bias towards meropenem, the efficacy of step 3 did not differ significantly in the two study arms. Most patients requiring escalation (like step 3) or modification of therapy had documented infections like bacteraemia or pneumonia and long-term neutropenia (ANC <0.5 x 109/L for >10 days).

Owing to the extensive use of central venous catheters in our paediatric study population (in >85% of patients in both arms), the pathogens most frequently isolated in documented infections were Gram-positive organisms, predominantly CNS; this is in accordance with the findings of other authors.1,16,30 In bacteraemic episodes caused by CNS the response to monotherapy either with ceftazidime or with meropenem was poor and modified antibacterial therapy or the addition of teicoplanin was required for successful treatment. Only in three cases of CNS-positive bacteraemia was removal of the central venous access device necessary for cessation of fever. After CNS, the second most frequently isolated Gram-positive bacterium was S. mitis. As reported in previous studies, the majority of patients with viridans streptococcal bacteraemia in the present study were suffering from haematological malignancies (7/10), had severe chemotherapy-induced oropharyngeal mucositis (WHO scale III or IV, 5/10) or were females (7/10).31,32 High-dose cytarabine, also suggested to be a risk factor for viridans streptococcal bloodstream infections, was administered to only two of 10 patients.32 In the present trial, all isolates of S. mitis tested were susceptible to meropenem in vitro. No isolate was tested for its susceptibility to ceftazidime. However, a previous trial documented in vitro susceptibility of all viridans streptococcus strains to meropenem but a high resistance of these isolates to ceftazidime (>80%).33 The number of bacteraemic episodes caused by viridans streptococci in this study was too small to compare the clinical efficacy of meropenem and ceftazidime for this subgroup of infections and to give any recommendation for their empirical use in patients at high risk for these kinds of infection. Regarding the cases of Gram-negative bacteraemia, both the in vitro susceptibility of strains and the clinical response rates to meropenem and ceftazidime were comparable.

As expected, the observed toxicity was low in both arms with that probably attributable to meropenem or ceftazidime occurring in <3% of episodes, a figure comparable with previous studies.7,8 Neurological side effects such as vomiting, headache or seizures were not observed in either arm, even in the 29 febrile episodes of patients with cerebral malignancies.

In conclusion, empirical monotherapy with meropenem or ceftazidime provides a safe and well tolerated option for the treatment of febrile neutropenic episodes in paediatric cancer patients. Regarding the limitations of our study design as a non-blinded study and the possible bias through switching to meropenem after 96 h of treatment in all non-responders and through the repeated enrolment of the same patient, the results are equivalent in both study arms. Although meropenem was slightly more effective in the treatment of FUO episodes, the similar efficacy of the two drugs in documented infections suggests that both agents are useful as empirical monotherapy in febrile paediatric cancer patients.


    Acknowledgments
 
Appreciation is expressed to AstraZeneca GmbH Wedel & Gruenenthal GmbH Stolberg, and to Glaxo Wellcome GmbH & Co., Bad Oldesloe, Germany, for financial support.


    Notes
 
* Corresponding author. Tel: +31;49-228-287-3254; Fax: +31;49-228-287-3301; E-mail: fleischh{at}mailer.meb.uni-bonn.de Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Received 2 November 2001; returned 16 January 2001; revised 28 February 2001; accepted 12 March 2001