Impact of β-lactam + Aminoglycoside Combination Regimen As Empirical Therapy For the Treatment of Bacteraemia Due to Gram-Negative Bacilli in Neutropenic Haematological Patients In An Era Of Antimicrobial Resistance (AMINOLACTAM Study)
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 9, Issue 4
Abstract
Background: Current guidelines for the management of patients with febrile neutropenia don't recommend the use of empirical combination antibiotic therapy. The addition of an aminoglycoside to the recommended broad-spectrum ß-lactam could be beneficial because of the pharmacological properties of these drugs, and because it broadens the antibacterial spectrum. However, the risk-benefit of adding an aminoglycoside to the ß-lactam is far from clear, especially considering adverse events and the current situation of widespread antimicrobial resistance. We hypothesize that combination therapy may be more effective than monotherapy in this scenario; therefore, we aim to compare the effectiveness of these two strategies for the treatment of bacteraemia due to Gram-negative bacilli (GNB) in neutropenic haematological patients. Methods: Multinational, multicentre, retrospective, observational cohort study. Adult haematological patients with neutropenia and GNB bacteraemia receiving adequate empirical ß-lactam monotherapy, or combination therapy with a ß-lactam + aminoglycoside (January 2010 - June 2017), will be analysed. The primary endpoint will be 30-day case-fatality rate. Secondary endpoints will be 7- and 14-day case-fatality rates, nephrotoxicity, persistent bacteraemia, relapse of bacteraemia, infection by resistant bacteria, and intensive care unit admission. Discussion: Early and appropriate empirical antibiotic therapy is the cornerstone in the treatment of patients with severe infections. In patients with impaired immunity such as those with haematological diseases and neutropenia, the role of the antibiotic in the course of infection is even more crucial. Prescribing the optimal antibiotic therapy for neutropenic patients with bacteraemia due to GNB is a daily challenge for clinicians, and the impact of monotherapy with a broad-spectrum ß-lactam versus combination therapy with a broad-spectrum ß-lactam + an aminoglycoside on clinical and microbiological outcomes remains a controversial issue. A meta-analysis published in 2013, found that ß-lactam monotherapy performed better than ß-lactam-aminoglycoside combination therapy for the treatment of bacteraemia in patients with febrile neutropenia with regard to mortality, fungal super-infections, and nephrotoxicity. However, this meta-analysis was performed with data from studies performed between 1983 and 2012, when the burden of bacterial resistance was increasing but had not yet reached the levels we are facing at the moment. Patients with haematological malignancies, and especially those with severe neutropenia, are prone to infections with high associated morbidity and mortality. Specifically, they are at high risk of Gram-negative bacteraemia due to chemotherapy-induced gastrointestinal mucositis and prolonged periods of neutropenia. Owing to the impact of infection on clinical outcomes, antibiotic therapy is usually initiated empirically upon suspicion of infection before the causative pathogen/s or their susceptibilities are identified. Historically, initial empirical antibiotic therapy for febrile neutropenia consisted in combination therapy including double ß-lactam regimens and, afterwards, aminoglycoside-ß-lactam combinations [1,2]. Pharmacological properties of aminoglycosides include fast and concentration-dependent killing of bacteria, with a post-antibiotic effect and a potential synergistic effect [3]. Moreover, addition of an aminoglycoside broadens the antibacterial spectrum, which in an era of increasing antimicrobial resistance may reduce the risk of prescribing inadequate empirical treatment and, at the same time, may provide protection against the development of bacterial resistance. However, despite these potential advantages, the use of aminoglycosides remains controversial because of their adverse events, mainly nephrotoxicity. In this regard, clinical trials and meta-analyses have failed to demonstrate a beneficial effect of ß-lactam + aminoglycoside combination therapy over ß-lactam monotherapy on survival in patients with febrile neutropenia. In this patient population, the 2011 Infectious Diseases Society of America (IDSA) guidelines recommend the use of an antipseudomonal ß-lactam in monotherapy [4]. However, multidrug-resistant Gram-negative bacilli (MDRGNB), and particularly carbapenem-resistant strains, are spreading quickly and severely compromise patients' outcomes [5-9]. Currently, the guidelines of the European Conference on Infections in Leukaemia (ECIL) recommend applying an escalation or de-escalation strategy according to the individual risk of infection due to resistant organisms of each patient [10]. Thus, it is still a matter of debate whether monotherapy with a broad- spectrum ß-lactam may be sufficient in the empirical approach of high-risk haematological patients with febrile neutropenia in the current era of widespread antimicrobial resistance. It is also unclear whether the risk-benefit balance of combination is positive, especially regarding toxicity, considering that haematological patients are likely to be administered frequent repeated cycles of potentially nephrotoxic antibiotics and other drugs that may favour the development of kidney disease.
Authors and Affiliations
Ulldemolins M, Gudiol C, Pomares H, Akova M, Puerta Alcalde P, Herrera F, Martm Davila P, Albasanz Puig A, Royo Cebrecos C, Mercadal S, Ayaz MC, Cardozo C, Torres D, Fortun J, Bergas A, Laporte J, Garcia Vidal, Mancho N, Carratala J
Keywords
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- EP ID EP587899
- DOI 10.26717/BJSTR.2018.09.001836
- Views 175
- Downloads 0
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