Carbapenemase-producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological malignancies or aplastic anaemia: Analysis of 50 cases

Accepted Manuscript Title: Carbapenemase-producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological malignancies or aplastic anaemia: analysis of 50 cases Author: Polydoros Tofas Anna Skiada Maria Angelopoulou Nikolaos Sipsas Ioanna Pavlopoulou Sofia Tsaousi Maria Pagoni Maria Kotsopoulou Stavroula Perlorentzou Anastasia Antoniadou Maria Pirounaki Athanasios Skoutelis George L. Daikos PII: DOI: Reference:

S0924-8579(16)00049-2 http://dx.doi.org/doi:10.1016/j.ijantimicag.2016.01.011 ANTAGE 4753

To appear in:

International

Received date: Revised date: Accepted date:

20-10-2015 20-1-2016 25-1-2016

Journal

of

Antimicrobial

Agents

Please cite this article as: Tofas P, Skiada A, Angelopoulou M, Sipsas N, Pavlopoulou I, Tsaousi S, Pagoni M, Kotsopoulou M, Perlorentzou S, Antoniadou A, Pirounaki M, Skoutelis A, Daikos GL, Carbapenemase-producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological malignancies or aplastic anaemia: analysis of 50 cases, International Journal of Antimicrobial Agents (2016), http://dx.doi.org/10.1016/j.ijantimicag.2016.01.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Highlights  Neutropenic patients with carbapenemase-producing Klebsiella pneumoniae bacteraemia have a high mortality (50%).

death.

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 Combination therapy may lower the risk of mortality.

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 Persistent neutropenia and septic shock were independent predictors of

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Carbapenemase-producing Klebsiella pneumoniae bloodstream infections in neutropenic patients with haematological

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malignancies or aplastic anaemia: analysis of 50 cases

Polydoros Tofas a, Anna Skiada a, Maria Angelopoulou b, Nikolaos Sipsas c, Ioanna

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Pavlopoulou a, Sofia Tsaousi d, Maria Pagoni e, Maria Kotsopoulou f, Stavroula

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Perlorentzou f, Anastasia Antoniadou g, Maria Pirounaki h, Athanasios Skoutelis d,

a

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George L. Daikos a,*

First Department of Medicine, National and Kapodistrian University of Athens,

b

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Athens, Greece

Department of Hematology, National and Kapodistrian University of Athens,

Department of Pathophysiology, National and Kapodistrian University of Athens,

d e f g

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Athens, Greece

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c

d

Athens, Greece

Fifth Department of Medicine, Evangelismos Hospital, Athens, Greece Department of Hematology, Evangelismos Hospital, Athens, Greece Department of Hematology, Metaxa Hospital, Piraeus, Greece Fourth Department of Medicine, National and Kapodistrian University of Athens,

Athens, Greece h

Department of Medicine, Hippokrateion Hospital, Athens, Greece

ARTICLE INFO Article history: Received 20 October 2015 2 Page 2 of 22

Accepted 25 January 2016

Keywords:

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Carbapenemase Klebsiella

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Neutropenia

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Infection

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* Corresponding author. Tel.: +30 210 745 6843; fax: +30 213 206 1795.

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E-mail address: [email protected] (G.L. Daikos).

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ABSTRACT Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) are currently among the most important nosocomial pathogens in many geographic regions. A retrospective

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study was conducted between 2010 and 2014 in four hospitals located in a highprevalence area (Athens, Greece) to describe the clinical features, treatment and

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outcomes of neutropenic patients with haematological diseases complicated with

CP-Kp bloodstream infections. A total of 50 patients were identified, including 48 with

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haematological malignancies and 2 with aplastic anaemia. All patients had

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neutropenia (<500 cells/mm3), of whom 40 had <100 neutrophils/mm3. The probable source of bacteraemia was identified in 9 patients; in the remaining 41 patients the

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bacteraemia was considered primary. For definitive treatment, 30 patients received combination therapy (two or more active drugs), 10 received monotherapy (one

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active drug) and 4 received therapy with no active drug; the remaining 6 patients

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died within 48 h after the onset of bacteraemia. The 14-day all-cause mortality rate was 50%, 38% and 33% for those who received one, two or three active drugs

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respectively. In the Cox proportional hazards model, unresolved neutropenia [hazard ratio (HR) = 19.28, 95% confidence interval (CI) 2.31–160.69; P = 0.006], septic shock (HR = 3.04, 95% CI 1.06–8.78; P = 0.04) and treatment with one active drug (HR for monotherapy versus combination therapy = 3.95, 95% CI 1.23–12.65; P = 0.02) were independent predictors of death, whilst combination therapy was associated with lower mortality. These findings may assist physicians in making treatment decisions for neutropenic patients with CP-Kp infections.

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1. Introduction Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) has been established as an important nosocomial pathogen in many geographic areas [1]. Whilst CP-Kp can affect any

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patient with significant healthcare exposure in an endemic setting, they mainly cause

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serious infections in critically ill patients. These infections are associated with increased morbidity and mortality, particularly in patients with severe underlying diseases and co-

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morbidities [1]. Recent reports have shown that expansion of these organisms into immunosuppressed patients represents a challenging problem in terms of outcome and

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management [2–5]. The dearth of effective treatment against CP-Kp infections, in conjunction with prolonged neutropenia and other immunological defects observed in

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patients with haematological malignancies, may make the outcome even worse.

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Although a few studies have examined the burden of CP-Kp infections in

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immunosuppressed patients [2–5], there is a paucity of clinical data and limited

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information on the treatment of CP-Kp infections in neutropenic patients. In this study we have attempted an analysis of mortality-associated factors in 50 neutropenic patients with haematological diseases complicated with CP-Kp bloodstream infection (BSI). Emphasis was given to the role of antimicrobial treatment.

2. Materials and methods 2.1. Setting This study was conducted between January 2010 and May 2014 in the haematology units of four tertiary care hospitals located in Athens, Greece.

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2.2. Study design This was a retrospective study that included consecutive patients with CP-Kp BSIs.

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Enrolled subjects had (i) at least one blood culture positive for CP-Kp; (ii) clinical findings consistent with systemic inflammatory response syndrome and (iii)

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neutropenia (<500 cells/mm3). Only the first BSI episode was considered. Patients

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with polymicrobial bacteraemia were included in the study only if they had received antibiotics active in vitro against the co-infecting organism. Pertinent information was

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extracted from the medical records in a pre-designed form. Co-morbidities were classified using the Charlson score [6]. The study was approved by the institutional

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2.3. Microbiology

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review board of each participating hospital.

Species identification and susceptibility testing were performed using automated

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systems VITEK® 2 (bioMérieux, Marcy-l’Étoile, France) or Wider I (Francisco Soria Melguizo, S.A., Madrid, Spain) with MicroScan® panels (Dade Behring, West Sacramento, CA). Organisms were considered resistant to carbapenems and colistin according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (>8 g/mL for imipenem and meropenem, >4 g/mL for doripenem and >2 g/mL for colistin) [7]. For tigecycline, the US Food and Drug Administration (FDA) interpretive criteria were used [8]. bla gene content and carbapenemase production were determined as described previously [9].

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2.4. Definitions Patients with haematological malignancies [acute myelogenous leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) or non-

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Hodgkin’s lymphoma (NHL)] receiving induction-phase chemotherapy or treated for relapsed or refractory disease as well as patients with aplastic anaemia, multiple

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myeloma (MM) or myelodysplastic syndrome (MDS) were considered to have active

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disease. Neutropenia was considered unresolved if it was present until Day 14 after

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the onset of bacteraemia, or until death if this occurred before Day 14.

Onset of bacteraemia was defined as the date of collection of the first blood culture

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that yielded the CP-Kp strain. The severity of BSI was distinguished as sepsis, severe sepsis or septic shock [10]. Antimicrobial treatment with agents that had no in

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vitro activity against the infecting organism or that were administered for <48 h was

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considered inadequate. Treatment administered before the susceptibility testing results were available was characterised as empirical, whereas treatment given after

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the results were available (usually 48–72 h after the index culture) was defined as definitive. Treatment regimens were classified as monotherapy (treatment with one in vitro active agent) or combination therapy (treatment with two or more in vitro active agents).

2.5. Statistical analysis Data were analysed using IBM SPSS Statistics for Windows v.20.0 (IBM Corp., Armonk, NY). The outcome measured was all-cause mortality within 14 days after the onset of bacteraemia. Univariate analysis was performed to identify factors related to mortality. The 2 test was used for categorical variables and the Student’s 7 Page 7 of 22

t-test (for normally distributed variables) or the Mann-Whitney U-test (for nonnormally distributed variables) for continuous variables. A Cox proportional hazards model was used to identify factors independently associated with mortality. Sets of

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variables that had P  0.1 in the univariate analysis or a potential effect on mortality were entered into the model and their contribution was assessed using the likelihood

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ratio test. All tests were two tailed and a P-value of <0.05 was considered significant.

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3. Results 3.1. Patients

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Fifty patients with CP-Kp BSI and neutropenia were identified (31 male and 19 female). Mean patient age was 54 years (median, 58 years; range, 18–76 years). All

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episodes of CP-Kp BSI were hospital-acquired. The median duration of

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hospitalisation before the onset of bacteraemia was 22 days [interquartile range (IQR), 16–54 days]. Thirty-four patients had AML (68%), six had ALL (12%), one had

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CLL (2%), five had NHL (10%), one had MDS (2%), one had MM (2%) and two had aplastic anaemia (4%). At the onset of bacteraemia, all patients had neutropenia (<500 cells/mm3), of whom 40 had <100 neutrophils/mm3. The median duration of neutropenia before the onset of bacteraemia was 10.5 days (range, 1–384 days; IQR, 6–18 days). The median duration after the onset of bacteraemia was 7 days (range, 1–22 days; IQR, 4–13 days). Forty-six patients had active disease at the onset of bacteraemia and four were in complete remission. The mean Karnofsky index was 80 (range, 20–100) and the mean Charlson score was 2 (range, 0–6). The probable source of infection was identified in 9 patients (central venous catheter in 5, lungs in 2 and the urinary tract in 2); in the remaining 41 patients the bacteraemia 8 Page 8 of 22

was considered primary as no source of infection was identified. Five patients had polymicrobial bacteraemia (three with Enterococcus faecium, one with Pseudomonas aeruginosa and E, faecium, and one with Prevotella spp.). At the

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onset of bacteraemia, 17 patients presented with sepsis, 20 with severe sepsis and

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13 with septic shock.

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3.2. Micro-organisms

Of the 50 CP-Kp isolates, 48 produced KPC enzyme and 2 produced VIM enzyme.

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All CP-Kp were resistant to penicillin/inhibitor combinations, expanded-spectrum cephalosporins and trimethoprim/sulfamethoxazole. Resistance frequencies to

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imipenem and meropenem were 82% and 84%, respectively. The minimum inhibitory concentrations (MICs) of meropenem were ≤2 g/mL in 4 isolates (8%), 4–8 g/mL

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in 4 isolates (8%) and >8 g/mL in 42 isolates (84%). The most active drugs were

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gentamicin, tigecycline and colistin, with 90%, 86% and 74% of the isolates being

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susceptible to these agents, respectively. Three isolates were susceptible to amikacin and one to ciprofloxacin.

3.3. Treatment

Antibiotic therapy was selected at the discretion of the attending physician. For empirical treatment, 33 patients (66%) received at least one active drug within 48 h after the onset of bacteraemia, whilst the remaining 17 patients (34%) received no active drug. For definitive treatment, 40 patients (80%) received at least one active drug; 30 received combination therapy (10 received gentamicin and tigecycline, 7 gentamicin and colistin, 4 colistin and tigecycline, 7 colistin, gentamicin and 9 Page 9 of 22

tigecycline, 1 colistin, gentamicin and doripenem, and 1 colistin, gentamicin and fosfomycin) and 10 received monotherapy (7 received colistin and 3 gentamicin), Four patients received therapy with no active drug and the remaining six patients

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died within 48 h after the onset of bacteraemia, before the susceptibility results were available. The total daily dose of colistin, following an initial loading dose of 9 million

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International Units (IU), was 9 million IU given in two or three divided doses; for

tigecycline the total daily dose was 100 mg for 11 patients, 150 mg for 6 patients and

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200 mg for 4 patients, administered in two divided doses.

Gentamicin was administered at a total daily dose of 5 mg/kg. Dosages were

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adjusted to creatinine clearance when indicated. Infection source control, including line removal in five patients and abscesses drainage in two patients, was performed

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3.4. Outcome

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in a timely manner in all cases.

The 14-day mortality rate was 50% and all deaths were considered as related to CPKp BSI. The highest mortality rate (90%) was observed in patients who received inadequate treatment. The 14-day mortality was 50% (5 of 10 died) in patients who received one active drug, 38% (8 of 21 died) in those who received two active drugs and 33% (3 of 9 died) in those who received three active drugs. The mean time from the onset of bacteraemia to death was 5.6 days (range, 1–14 days). The effects of host-, infection- and treatment-related factors on 14-day mortality were assessed in a univariate analysis (Table 1). Adverse outcome appeared to be more likely in patients with unresolved neutropenia or septic shock. By entering the variables that had P  0.1 in the univariate analysis and those that had a potential effect on 10 Page 10 of 22

mortality in the Cox proportional hazards model, unresolved neutropenia [hazard ratio (HR) = 19.28, 95% confidence interval (CI) 2.31–160.69; P = 0.006], septic shock (HR = 3.04, 95% CI 1.06–8.78; P = 0.04) and treatment with one active drug

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(HR for monotherapy versus combination therapy, 3.95, 95% CI 1.23–12.65; P = 0.02) were independent predictors of death (Table 2; Fig. 1). Eight patients who

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survived the first episode of bacteraemia developed a new episode of CP-Kp BSI

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within 3–12 weeks after the end of treatment of the first episode.

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4. Discussion

Here we present the clinical characteristics, treatment and outcomes of 50

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neutropenic patients with haematological malignancies or aplastic anaemia and CPKp BSI. The patient population examined had several distinct characteristics. At the

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onset of bacteraemia, the vast majority of patients had active haematological

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disease complicated with severe and prolonged neutropenia. Also, the affected

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patients had prolonged hospital stay (median 22 days) before the onset of bacteraemia, and all infection episodes were hospital-acquired.

The mortality rate (50%) observed in the present study was higher than that reported in contemporary studies of carbapenem-susceptible Enterobacteriaceae BSIs in patients with haematological malignancies [5,11,12] and was similar to that reported by others for carbapenem-resistant Enterobacteriaceae BSIs in neutropenic patients [2,5]. Several factors may have contributed to the high mortality rate observed in the study population. The analysis showed that unresolved neutropenia and the presence of septic shock at the onset of bacteraemia were independent predictors of death. In addition to these factors, antibiotic therapy per se might have had a 11 Page 11 of 22

significant impact on outcome; treatment with a single active agent resulted in an unacceptably high mortality rate, whereas combination therapy was associated with

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a lower risk of death.

The efficacy of monotherapy with an aminoglycoside, colistin or tigecycline against

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CP-Kp infections has been questioned by several studies and particularly among patients in septic shock or in those with severe underlying diseases [13–16].

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Moreover, previous studies by Bodey et al. have shown that aminoglycosides and polymyxins, when administered as single agents, are ineffective against Gram-

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negative infections in patients with a neutrophil count <100 cells/mm3 [17,18]. Unlike

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monotherapy, combination therapy was more effective and was associated with a lower mortality rate (36.7%). The latter effect was more apparent and emerged as an

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independent predictor of survival after adjusting for septic shock and unresolved

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neutropenia. In previous studies, the lowest mortality rates among patients infected with CP-Kp have been achieved with combination schemes containing a

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carbapenem when the meropenem MIC of the infecting organism was 8 g/mL [14,16]. In the present study, only one patient received such treatment despite the fact that 8 of 40 patients could have received the potential benefit of carbapenemcontaining combinations as a respective number of the infecting organisms had MICs in this range.

Another treatment-related factor that could have affected outcome is the time to initiation of effective antimicrobial treatment. It has been widely accepted, after the studies by Schimpff et al. [19], that immediate initiation of empirical antimicrobial treatment in the management of fever reduces mortality rates in neutropenic patients 12 Page 12 of 22

with Gram-negative bacteraemia. In the present study, 17 of 50 patients received empirical antimicrobial therapy not covering the infecting organism; delayed initiation of active treatment, however, did not affect the association between CP-Kp BSI and

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mortality. A plausible explanation for this could be the inadequate power of the study to detect such an association or the operation of another mechanism related to

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suboptimal efficacy of the available antimicrobial agents against CP-Kp infections.

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While CP-Kp emerges as a life-threatening pathogen among haematological

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patients, it is critical to develop diagnostic and therapeutic strategies to ensure timely and effective treatment against infections caused by such organisms. The European

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Conference on Infections in Leukemia recommends a de-escalation approach for the management of fever in neutropenic patients [20]. For patients with known

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colonisation or previous infection due to carbapenemase-producers and at centres in

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which the prevalence of carbapenemase-producing organisms is high, empirical therapy should include a combination of two agents, one of which has a high

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probability of activity against the infecting organism guided by the local epidemiology of antimicrobial resistance. If cultures are negative or reveal a susceptible organism, de-escalation to standard therapy should be performed.

The present study has several caveats, namely the retrospective design and the relatively small sample size. Although these limitations do not permit to draw firm conclusions, the findings presented here may assist physicians in making treatment decisions for neutropenic patients with CP-Kp infections until large-scale controlled trials define the optimal antibiotic schemes for this group of patients.

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In conclusion, these findings indicate that CP-Kp BSIs among neutropenic patients with haematological diseases are associated with increased mortality. Unresolved neutropenia and septic shock at the onset of bacteraemia are independent predictors

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of death, whilst combination therapy may lower the risk of mortality.

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Funding: This work was partially supported by the EU-project AIDA [grant Health-

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F3-2011-278348].

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Competing interests: None declared.

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Boards of the participating hospitals.

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Ethical approval: Ethical approval was received from the Institutional Review

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evolving crisis of global dimensions. Clin Microbiol Rev 2012;25:682–707.

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[2] Satlin MJ, Calfee DP, Chen L, Fauntleroy KA, Wilson SJ, Jenkins SG, et al. Emergence of carbapenem-resistant Enterobacteriaceae as causes of

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bloodstream infections in patients with hematologic malignancies. Leuk Lymphoma 2013;54:799–806.

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[3] Satlin MJ, Jenkins SG, Walsh TJ. The global challenge of carbapenemresistant Enterobacteriaceae in transplant recipients and patients with

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hematologic malignancies. Clin Infect Dis 2014;58:1274–83. [4] Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, et

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al. Infections by carbapenem-resistant Klebsiella pneumoniae in SCT

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recipients: a nationwide retrospective survey from Italy. Bone Marrow

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Transplant 2014;50:282–8.

[5] Andria N, Henig O, Kotler O, Domchenko A, Oren I, Zuckerman T, et al. Mortality burden related to infection with carbapenem-resistant Gram-negative bacteria among haematological cancer patients: a retrospective cohort study. J Antimicrob Chemother 2015;70:3146–53.

[6] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:379–83. [7] European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 3.1, 2013.

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http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_ta bles/Breakpoint_table_v_3.1.pdf [accessed 11 February 2016]. [8] US Food and Drug Administration. Highlights of prescribing information:

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[accessed 11 February 2016].

[9] Giakkoupi P, Papagiannitsis CC, Miriagou V, Pappa O, Polemis M,

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Klebsiella pneumoniae in Greece (2009–10). J Antimicrob Chemother 2011;66:1510–3.

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al.

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Klastersky J, Ameye L, Maertens J, Georgala A, Muanza F, Aoun M, et

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al. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents

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2007;30(Suppl 1):S51–9.

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Kang CI, Chung DR, Ko KS, Peck KR, Song JH; Korean Network for

Study of Infectious Diseases. Risk factors for infection and treatment outcome of extended-spectrum -lactamase-producing Escherichia coli and Klebsiella

pneumoniae bacteremia in patients with hematologic malignancy. Ann Hematol 2012;91:115–21.

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Tumbarello M, Viale P, Viscoli C, Trecarichi M, Tumietto F, Marchese

A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55:943–50. 16 Page 16 of 22

[14]

Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M,

Argyropoulou A, et al. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes

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and the role of carbapenems. Antimicrob Agents Chemother 2014;58:2322–8. Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL.

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Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect 2014;20:862–72.

Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe

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DR, Bassetti M, et al. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J

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Antimicrob Chemother 2015;70:2133–43.

Bodey GP, Rodriguez V. Advances in the management of

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Pseudomonas aeruginosa infections in cancer patients. Eur J Cancer

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1973;9:435–41.

Bodey GP, Middleman E, Umsawadi T, Rodriguez V. Infections in

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cancer patients. Results with gentamicin sulfate therapy. Cancer 1972;29:1697–701.

[19]

Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with

carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med 1971;284:1061–5.

[20]

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Fig. 1. Cumulative survival probability by Cox regression in 40 neutropenic patients with carbapenemase-producing Klebsiella pneumoniae bloodstream infection (BSI) according to treatment regimen after adjustment for septic shock, unresolved

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(hazard ratio = 4, 95% confidence interval 1.25–12.9; P = 0.02).

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neutropenia and empirical therapy. —–, combination therapy; – – –, monotherapy

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Table 1 Univariate analysis of factors associated with 14-day mortality for 50 neutropenic patients with carbapenemase-producing Klebsiella pneumoniae bloodstream

Outcome Died (n =

Survived (n =

25)

25)

56.6 ± 12.7

50.52 ± 18.9

Sex 17

Female

8

Charlson co-morbidity index [median

2 (2.5–2)

(IQR)]

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With active disease

Yes No

0.281 0.382

11

2 (2–2)

23

23

2

2

0.758 1.000

0.0001 24

11

1

14

0.009

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Severity of sepsis

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Unresolved neutropenia

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Without active disease

value

14

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Male

Disease status

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Age (years) (mean ± S.D.)

P-

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Variable

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infection (BSI) a

Sepsis

5

12

Severe sepsis

9

11

Septic shock

11

2

Polymicrobial infection

0.637

Yes

2

3

No

23

22

Source of BSI

0.527

Lungs

2

0

Urinary tract

1

1

CVC

2

3

Primary

20

21

Carbapenemase type

0.149 19 Page 19 of 22

VIM

0

2

KPC

25

23

0.370

Inappropriate

10

7

Appropriate

15

18

Definitive therapy a

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Empirical treatment

0.48

5

5

Combination

11

19

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Monotherapy

S.D., standard deviation; IQR, interquartile range; CVC, central venous catheter.

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Patients who received at least one active drug for 48 h (n = 40).

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Table 2 Cox proportional hazards model of factors associated with 14-day mortality in 40 neutropenic patients with carbapenemase-producing Klebsiella pneumoniae

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bloodstream infection a Variable

HR (95% CI)

Septic shock

3.04 (1.06–8.78)

Unresolved neutropenia

19.28 (2.31–160.69) 0.006

Definitive therapy: monotherapy vs. combination

3.95 (1.23–12.65)

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0.02

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Patients who received at least one active drug for 48 h.

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0.04

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HR, hazard ratio; CI, confidence interval.

P-value

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