Reply to J.H. Joshi.

We welcome the comments by Joshi and appreciate his interest in our work. Joshi comments that most of the difficulties in treating neutropenic febrile episodes are encountered when profound granulocytopenia (neutrophil count 100/ L) persists for the duration of antimicrobial therapy, and that only in this setting, and in particular when a bacteremia caused by a Gram-negative agent is involved, should comparative efficacy between two different empiric antibiotic regimens be determined. As in the majority of published randomized trials that have supported the role of antibiotic monotherapy toward a synergistic combination in febrile neutropenia, in our study the response rate of the subgroup of patients with persistent profound neutropenia for the duration of antibiotic therapy was not considered the major end point. However, according to the Infectious Diseases Society of America, the National Comprehensive Cancer Network, and the European Conference on Infections in Leukemia guidelines, the population enrolled in our study should be classified at the highest risk for infection, and in need of the prompt institution of intravenous broad-spectrum empiric antibiotic therapy. In fact, in our study, 85% of patients were profoundly neutropenic (neutrophil count 100/ L) at the onset of fever, the median duration of profound neutropenia was 9 days, and the mean duration of chemotherapy induced neutropenia was 20 days. Moreover, the majority of the patients were affected by acute leukemia. The role of the duration of neutropenia as a prognostic factor for response to antibacterial treatment is controversial. In the recently published fourth European Conference on Infections in Leukemia “European Guideline for Empirical Therapy for Febrile Neutropenic Patients in the Era of Growing Resistance,” profound and persistent aplasia was included among the risk factors for a complicated clinical course. On the other hand, the duration of neutropenia is not considered an important risk factor by the Multinational Association for Supportive Care in Cancer Risk Index that considered underlying disease (such as acute leukemia) as a risk factor. Moreover, in our study the multivariable analysis did not confirm the duration of neutropenia as a predictive factor that could influence the failure of empiric therapy, and the same results were found in our previous prospective randomized trial that compared piperacillin/tazobactam with or without amikacin in the empiric treatment of febrile neutropenia. Conversely, the underlying disease (acute leukemia) represented an independent risk factor for failure in both studies. More recently, because the new epidemiologic setting (emergence of Gram-negatives and diffusion of multidrug resistance such as extended-spectrum -lactamase [ESBL] production and glycopeptides resistance), the appropriate initial antibiotic therapy containing at least one antibiotic active against the involved microorganism(s) was crucial for a favorable outcome. Several studies have also shown that in patients with cancer, failure to address Gram-negative pathogens, particularly ESBL producers, significantly and independently impairs outcomes and prolongs hospitalization despite neutropenia. In this scenario, in our opinion, the tigecycline combination, more than exerting a synergistic activity, is able to improve the likelihood that the empiric treatment may initially address the possible involved multidrug resistant pathogens, which is the main aim of an empiric antibiotic strategy. For all the above-mentioned reasons, we believe that the results of our study should be considered adequate to support the final authors’ statements. However, even if the study was not powered to document an effect of the tigecycline combination in the subset of patients with persistent profound neutropenia, we have reassessed the study data to evaluate the comparative efficacy of the two regimens in this subgroup of patients. Also in this case, as shown in Table 1, the combination regimen showed to be significantly superior to monotherapy, albeit with an overall lower success rate with respect to the overall population, as expected.