Ceftazidime Compared with Piperacillin and Tobramycin for the Empiric Treatment of Fever in Neutropenic Patients with Cancer: A Multicenter Randomized Trial

The rapid, empiric institution of broad-spectrum antibacterial therapy for the febrile, neutropenic patient has had a profound effect in reducing the mortality from gram-negative infection to approximately 10% [1, 2]. All the evidence accumulated during the 1970s indicated that adequate therapy could only be achieved by administering antibiotics in combinations, leading to the widespread practice of using either a -lactam with an aminoglycoside [3, 4] or two -lactams [5, 6]. Concerns about the toxicity associated with combination therapy encouraged several investigators to assess the feasibility of using certain broad-spectrum -lactams as single agents for empiric therapy in febrile neutropenic patients [7-9]. Among the drugs investigated, ceftazidime has emerged as a candidate for effective monotherapy [9-11]. However, previous studies have had several shortcomings, including inadequate statistical power [12-16], the inclusion of a large number of patients at relatively low risk for major infection [17], and the limited number of patients with gram-negative sepsis [18, 19]. Therefore, the issue of monotherapy remained controversial and a definitive study with sufficient patients was warranted. When evaluating empiric therapy in this setting, the criteria for assessment have a major effect on the outcome [20]. Regardless of the method of assessment, the principal goal of empiric antibacterial therapy is to ensure that the patient survives both the infection and the neutropenic episode. Consequently, we used the criteria proposed by Pizzo and colleagues [17], in which the outcome of treatment is only scored as a failure if the patient dies of infection. Importantly, this method of assessment takes account of the initial infective event as well as any event that might subsequently develop during the same neutropenic episode. We also wished to reflect the common clinical practice of adjusting therapy whenever it is proved or perceived to be inadequate. Therefore, the protocol allowed modification of the empiric regimen by addition or substitution, but the reasons for altering therapy had to be reported in the case report form. By so doing, we were then able to subdivide the category of success with modification as defined by Pizzo and colleagues [17] and discriminate between true failures, such as persistence of the initial pathogen, and changes in therapy made simply because the clinician lacked confidence in the regimen without any objective sign of clinical deterioration caused by a bacterial infection. Several alternatives were available for the comparative arm, but the combination of piperacillin and tobramycin was established as the standard empiric therapy for the febrile, neutropenic adult patient in most centers. We therefore selected this combination to compare its efficacy and toxicity with that of ceftazidime alone as empiric therapy for fever in the neutropenic patient, particularly focusing on infections caused by gram-negative bacteria. Methods The study was designed as a multicenter, nonblinded, randomized, parallel-group comparison of ceftazidime and a combination of piperacillin and tobramycin for the empiric management of fever defined as a single axillary temperature of 38.5 C or at least two readings of more than 38 C taken 2 hours apart (Figure 1). Patients with cancer who were older than 12 years were included provided that intensive chemotherapy induced neutropenia with granulocyte counts of less than 500 cells/mm3 within 3 days of starting antibiotic treatment. Those who received only palliative therapy for their malignant disease were not eligible. Patients were excluded if they were allergic to any of the trial antibiotics, if their serum creatinine exceeded 265 mol/L (3 mg/dL), or if they had received previous parenteral antibiotic therapy during the same neutropenic episode. Any prophylactic antibacterial agents were to be withdrawn at the onset of fever with the exception of tuberculostatics and sulfamethoxazole-trimethoprim when administered twice weekly for the prevention of Pneumocystis carinii infection [21]. As is common practice in such trials [22], patients could re-enter the protocol for multiple, separate episodes of neutropenia provided that each episode was followed by an interval of at least one week with granulocyte counts in excess of 1000/mm3 and the patient also satisfied all inclusion criteria. The protocol was approved by the ethical committees of the participating institutions. Figure 1. Flow diagram of the study. Randomization Procedure After giving informed consent, patients were assigned to one of six strata. They were first stratified according to underlying disease, namely leukemia and bone marrow transplants or solid tumor and lymphoma, following which, they were stratified according to the infection at presentation, skin or soft-tissue infection likely to be caused by gram-positive bacteria (for example exit-site infections related to venous access devices), anaerobic infection associated with the alimentary tract, or other infectious complications. The last group comprised the principal group of patients who were to be treated with either ceftazidime alone or a combination of piperacillin and tobramycin, whereas patients with skin and soft-tissue infections and those with anaerobic infections were to receive vancomycin and metronidazole, respectively, in addition to these core regimens. We do not report results obtained for episodes treated with these additional antibiotics because the data were not germane to the primary objective of the study and only a limited number of patients were involved. Treatment Allocation After having been placed in one of the three strata, patients were sequentially and randomly assigned to receive one of the regimens by means of opening sealed envelopes that contained the treatment allocation that had been generated centrally for each participating institution in blocks of eight to ensure balance. All drugs were given intravenously: ceftazidime as a 20- to 30-minute infusion of 2 g every 8 h; piperacillin by slow injection of 16 to 18 g/d in 4 to 6 divided doses, except in Finland and Sweden, where the regulatory authorities recommended not exceeding 12 g daily. Tobramycin was given at an initial dose of 1.7 to 2 mg per kilogram body weight every 8 h. Serum concentrations of tobramycin were to be determined at least once during the first 3 days of therapy to certify that adequate trough and peak levels were achieved. Dosages were reduced accordingly for patients with impaired renal function. Treatment was discontinued once the granulocyte count had risen to greater than 500/mm3 and all signs and symptoms of infection had resolved for at least 2 days or after at least 5 consecutive days if neutropenia persisted provided that the patient had been free of all signs or symptoms of infection during this time. All patients who were still neutropenic when antibiotic treatment was stopped remained under observation for the occurrence of relapses or new fevers until neutropenia had resolved. Therapy was started immediately after a comprehensive clinical examination and collection of specimens for microbiological investigation [12]. Ten millilitres of blood was obtained for culture from two separate veins; another 10 mL was taken via the central venous catheter when present. Appropriate cultures were also obtained from other local sites of infection when present. Isolates were identified using standard techniques. Patients were examined daily and biochemical and hematologic profiles were done once and three times weekly, respectively. Blood was cultured after 48 to 72 hours of treatment, before any change in antibiotic therapy, and only when indicated thereafter. Chest radiographs were done weekly in persistently febrile patients, and invasive diagnostic procedures, such as bronchoalveolar lavage, were done on a case-by-case basis according to local practice. Appropriate investigations were repeated whenever changes in therapy were deemed necessary. Modification of Initial Therapy Changes in therapy were recommended when a primary pathogen appeared to be resistant or if a presumably causative pathogen persisted after at least 48 hours of therapy. In addition, continued deterioration or progression of the presenting infection, evidence of a nonbacterial infection, or a serious adverse event were considered reasons to modify therapy. The choice of the agent for modification was to be directed by the in vitro susceptibility when available, although vancomycin was recommended for infections involving gram-positive cocci and amphotericin B was the drug of choice in patients with either evidence of fungal infection or unexplained fever persisting for 6 days during neutropenia. Acyclovir was to be given to treat infections caused by herpes simplex virus and varicella zoster. Finally, erythromycin and sulfamethoxazole-trimethoprim were the treatment of choice for patients with pulmonary infiltrates suggestive of infection with Legionella species and P. carinii, respectively. Definitions of Infections and Infectious Death Primary infection was classified as microbiologically proven when cultures yielded organisms from a site of infection or bacteremia was detected; as clinically documented when a putative site of infection such as pulmonary infiltrate or cellulitis was identified without confirmation by culture; and as unexplained fever when no site was identified and microbiological evaluation failed to yield any potential pathogen within the first 72 hours after inclusion in the study. Bacteremia was defined as the occurrence of at least one positive blood culture of any organism with the exception of coagulase-negative staphylococci and skin coryneforms, for which two identical positive cultures were necessary. Defervescence was defined as a return of the temperature to below 37.5 C for at least 2 days. A recurrent fever was one that develop