Rectal colonization is a recognized predictive factor for CR-KpBSI occurrence (13–14). Patients with hematological malignancies colonized with CR-K.pneumoniae, mostly AML patients, are at high risk of developing BSI (4, 8, 10). In this population, the reported CR-KpBSI mortality rate is dramatic (1–10), mainly in acute leukaemia patients (7–8). AML, intensive chemotherapy and severe and/or prolonged neutropenia were associated with CR-KPBSI-related death (7–8), and septic shock and acute respiratory failure resulted predictors of mortality (7).
This study focuses on KPC-KpBSI-related mortality in high-risk patients with hematological malignancies. The prompt identification of KPC-K.pneumoniae carriers, and the preemptive antibiotic strategy applied to all the carriers -KPC-K.pneumoniae active therapy for the empiric treatment of febrile neutropenia- was associated with the drop of KPC-KpBSI-related mortality from 50%, observed between March 2012-December 2013, to 6% recorded 3 years later, between January 2017-October 2018. To our knowledge, this is the lowest rate reported so far.
KPC-K.pneumoniae colonized patients who developed BSI in the two periods had comparable high risk factors for KPC-KpBSI-related death: the majority had acute leukaemia, mainly AML, and had received intensive chemotherapy developing profound and prolonged neutropenia, KPC-KpBSI presented with shock in a similar proportion of patients, but KPC-KpBSI mortality rate was significantly higher in Period 1. Initial treatment with active antibiotics is crucial for survival to CR-KpBSI (7–8, 11–12), and the 78% of patients who died from KPC-KpBSI in Period 1 had received inactive initial antibiotic treatment.
KPC-KpBSI treatment based on culture results presents a high risk of delaying or never receiving appropriate therapy (1, 5). In hematological neutropenic KPC-Kpneumoniae carriers at high risk of KPC-KpBSI (8–10), the initial appropriate treatment can be ensured by the preemptive administration of active therapy at any febrile episode. This preemptive approach was fully applied in Period 2, and all the KPC-KpBSI patients received initial active therapy and KPC-KpBSI-related mortality dropped to 6%, as had already been observed applying the same strategy on a small population of HSCT carriers (9). The multivariate analysis confirmed that only the initial active antibiotic treatment was independently associated with survival and, differently from other reports (7–8), AML and shock were not predictors of mortality.
The role of initial active treatment in hematological patients with CR-KpBSI is critical. We previously reported the 90% of mortality in patients not receiving initial active treatment (8); another study observed inappropriate initial treatment in the 78% of non-survivors, associated with 21-day mortality and significant predictor of mortality (7). In the present study the overall KPC-KpBSI mortality rate in KPC-Kpneumoniae carriers not receiving initial active treatment was 88%, but reduced to 13% in those initially treated with at least one active antibiotic, and even to 9% with initial active combinations. The combination of active drugs had already been associated with a lower mortality rate (5) and independently associated with survival (7), and as a matter of fact in Period 2 all but one KPC-KpBSI patients received an active combination as initial treatment.
The 61% of KPC-KpBSI observed in Period 1 were breakthrough and the outcome was fatal in the 72% of cases. In Period 2, the preemptive administration of active antibiotics at the onset of febrile neutropenia could have prevented breakthrough KPC-KpBSI development, avoiding the overgrowth of the colonizing KPC-K.pneumoniae under inactive antibiotics and the subsequent blood-stream diffusion through the damaged mucosa, strongly contributing to the mortality reduction.
In high prevalence areas, active surveillance of the gastrointestinal tract is critical to avoid KPC-K.pneumoniae nosocomial diffusion (8–10, 14), particularly in hematological wards where several conditions favor KPC-K.pneumoniae spread (8). In our experience we focused on the search and prompt detection of KPC-K.pneumoniae carriers, with the purpose of identifying the patients at the highest risk to develop KPC-KpBSI who would mostly benefit from the preemptive active strategy, obtaining a targeted initial treatment for KPC-KpBSI. In patients with hematological malignancies we strongly recommend the careful screening for KPC-K.pneumoniae rectal colonization, that represented the cornerstone of the preemptive strategy we customarily applied in Period 2: all KPC-KpBSI analyzed in the two study Periods developed in patients known as KPC-K.pneumoniae carriers but, in Period 2 all KPC-KpBSI were initially treated with active therapy. It is to be noted that in 25% of KPC-KpBSI developed in Period 2, the increased frequency of rectal screening avoided the delay in the active initial treatment due to unrecognized new carriers.
Finally, the reduction in the probability of death from KPC-KpBSI led us to be less concerned about the occurrence of fatal KPC-KpBSI in prosecuting and scheduling intensive chemotherapeutic and/or HSCT programs in those patients identified as KPC-K.pneumoniae carriers.
Some considerations are needed. The preemptive strategy certainly increases the use of active drugs, and consequently a de-escalation of empirical active treatments should be carried out if KPC-K.pneumonia infection is not confirmed. Nephrotoxicity, especially in hematological patients receiving many other toxic drugs -chemotherapeutics, immunosuppressants, antifungals- may represent a limitation in colistin use (19); furthermore the emergence of resistance (15, 19–20) observed in 26% of our KPC-K.pneumonia blood isolates, makes colistin role uncertain. Ceftazidime-avibactam was widely used against KPC-K.pneumonia infections with lower toxicity than colistin or aminoglycosides (19–24–25, 27); it proved active against all our KPC-K.pneumoniae blood isolates but resistance reported during (29) and independently (30) from previous ceftazidime-avibactam exposure, is troubling. New combinations with β-lactamase inhibitors, including carbapenem/β-lactamase inhibitor combinations (26), could represent therapeutic alternatives also in the setting of hematological patients.
The monocentric design and the low number of patients included represent a limitation to the present report, and prospective larger studies are needed to confirm and generalize the results. Good-quality prospective randomized studies on CRE infections management are still needed, also in neutropenic haematological patients, and therefore our strategy -search of carriers and preemptive active treatment- obtained a noteworthy and promising reduction of KPC-KpBSI-related mortality in this population.
In conclusion, in high-risk haematological patients colonized with KPC-K.pneumoniae, the preemptive use of antibiotics active against KPC-K.pneumoniae as empiric treatment of febrile neutropenia resulted in a drop to 6% of KPC-KpBSI mortality rate, reduction of breakthrough KPC-KpBSI and probability of death for KPC-KpBSI, including AML patients.