Assessing the Theoretical Efficacy of Combination Therapy Against Gram-Negative Infections in Neutropenic Pediatric Cancer Patients: Insights from the Statistical Analysis of Survey Data
Elio Castagnola,
Francesca Bagnasco,
Alessio Mesini,
Philipp K. A. Agyeman,
Roland A. Ammann,
Marta Arrabito,
Fabianne Carlesse,
Maria Rosaria D’Amico,
Giovanna Giagnuolo,
Gabrielle M. Haeusler,
Evgeny A. Idelevich,
Christa Koenig,
Thomas Lehrnbecher,
Marie Luckowitsch,
Mariaclaudia Meli,
Giuseppe Menna,
Giovanna Russo,
Maria Elena Santolaya de Pablo,
Arne Simon,
Galina Solopova,
Lillian Sung,
Annalisa Tondo,
Andreas H. Groll
Affiliations
Elio Castagnola
Infectious Diseases Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
Francesca Bagnasco
Epidemiology and Biostatistics Unit, Scientific Directorate, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
Alessio Mesini
Infectious Diseases Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
Philipp K. A. Agyeman
Division of Pediatric Infectious Disease, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
Roland A. Ammann
StatConsult Ammann, 3400 Burgdorf, Switzerland
Marta Arrabito
Hematology-Oncology Unit, AOU Policlinico “G. Rodolico-San Marco”, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
Fabianne Carlesse
Pediatric Department, Federal University of Sao Paulo, Sao Paulo 04023-062, Brazil
Maria Rosaria D’Amico
Unità Operativa di Trapianto di Cellule Staminali Emopoietiche e Terapie Cellulari, Azienda Ospedaliera di Rilievo Nazionale, Santobono-Pausilipon, 80123 Naples, Italy
Giovanna Giagnuolo
Unità Operativa di Ematologia, Azienda Ospedaliera di Rilievo Nazionale, Santobono-Pausilipon, 80123 Naples, Italy
Gabrielle M. Haeusler
National Center for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
Evgeny A. Idelevich
Friedrich Loeffler Institute of Medical Microbiology, University Medicine Greifswald, 17475 Greifswald, Germany
Christa Koenig
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
Thomas Lehrnbecher
Department of Pediatrics, Division of Hematology, Oncology and Hemostaseology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
Marie Luckowitsch
Department of Pediatrics, Division of Hematology, Oncology and Hemostaseology, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
Mariaclaudia Meli
Hematology-Oncology Unit, AOU Policlinico “G. Rodolico-San Marco”, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
Giuseppe Menna
Unità Operativa di Ematologia, Azienda Ospedaliera di Rilievo Nazionale, Santobono-Pausilipon, 80123 Naples, Italy
Giovanna Russo
Hematology-Oncology Unit, AOU Policlinico “G. Rodolico-San Marco”, Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
Maria Elena Santolaya de Pablo
Department of Infectious Diseases Hospital Dt. Luis Calvo Mackenna, Faculty of Medicine, Universitad de Chile, Santiago 7500539, Chile
Arne Simon
Klinik fur Paediatrische Onkologie und Hematologie, Universitaetklinikum des Saarlandes Homburg, 6642 Homburg, Germany
Galina Solopova
Department of Infection Control, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow 117997, Russia
Lillian Sung
Pediatric Oncology Supportive Care, Division Hematology/Oncology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Infectious Diseases Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children’s Hospital, 48149 Muenster, Germany
Background: Empirical antibacterial therapy for febrile neutropenia reduces mortality due to Gram-negative blood stream infections (BSIs). Pediatric guidelines recommend monotherapy with an antipseudomonal beta-lactam or a carbapenem and to add a second anti-Gram-negative agent in selected situations. We evaluated the changes in the proportions of resistance of beta-lactam monotherapies vs. their combination with amikacin, and the possible impact on ICU admission or death. Results: 797 BSIs due to Gram-negative bacteria in 685 patients were included. Combination therapies with amikacin had a lower percentage of isolates resistant to one or to both drugs compared with the respective monotherapy. The highest OR for ICU admission was observed when both drugs of the combination of meropenem–amikacin were resistant. Mortality was significantly associated with relapse or the progression of the underlying malignancy, and resistance to both drugs of the combinations of cefepime–amikacin or meropenem–amikacin. Methods: This study was based on data collected for a large multinational study, in which the susceptibility of Gram-negative bloodstream isolates was categorized following either EUCAST or CLSI according to local laboratory standards. An escalation antibiogram was generated for each selected drug. For resistant bacteria, the conditional susceptibility probability on resistance was calculated. Conclusions: In pediatric cancer patients with Gram-negative BSIs, the proportion of the resistant organism correlates with ICU admission or death, which may be reduced by combination therapy. In patients with suspected or confirmed Gram-negative BSIs that are not-improving or deteriorating under monotherapy, escalation to meropenem may represent the best option. Amikacin should be preferred when combination therapy is considered with ciprofloxacin as an alternative in the case of impaired renal function.
