Venditti

New Insight on Epidemiology and Management of Bacterial Bloodstream Infection in Patients with Hematological Malignancies

Sara Lo Menzo*, Giulia la Martire*, Giancarlo Ceccarelli and Mario Venditti

Department of Public Health and Infectious Diseases. University of Rome “Sapienza”, Rome (Italy)
* These authors contributed equally to this paper 

Corresponding author: Mario Venditti MD, Ph.D. Department of Public Health and Infectious Diseases, University of Rome “Sapienza”, Viale del Policlinico 155, (00161) Rome, Italy. Tel. +39-06-49970313, Fax +39-06-49972625. E-mail: mario.venditti@uniroma1.it
.

Published: July 01, 2015,
Received: April 28, 2015
Accepted: June 08, 2015
Mediterr J Hematol Infect Dis 2015, 7(1): e2015044, DOI 10.4084/MJHID.2015.044
This article is available on PDF format at:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

Bloodstream infections (BSI) are a significant cause of morbidity and mortality in onco-hematologic patients. The Gram-negative bacteria were the main responsible for the febrile neutropenia in the sixties; their impact declined due to the use of fluoroquinolone prophylaxis.  This situation was followed by the gradual emergence of Gram-positive bacteria also following the increased use of intravascular devices and the introduction of new chemotherapeutic strategies. In the last decade, the Gram-negative etiology is raising again because of the emergence of resistant strains that make questionable the usefulness of current strategies for prophylaxis and empirical treatment. Gram-negative BSI attributable mortality is relevant, and the appropriate empirical treatment significantly improves the prognosis; on the other hand the adequate delayed treatment of Gram-positive BSI does not seem to have a high impact on survival. The clinician has to be aware of the epidemiology of his institution and colonizations of his patients to choose the most appropriate empiric therapy. In a setting of high endemicity of multidrug-resistant infections also the choice of targeted therapy can be a challenge, often requiring strategies based on off-label prescriptions and low grade evidence.
In this review, we summarize the current evidence for the best targeted therapies for difficult to treat bacteria BSIs and future perspectives in this topic. We also provide a flow chart for a rational approach to the empirical treatment of febrile neutropenia in a multidrug resistant, high prevalence setting.


Emerging Bacterial Infection in Hematological Neutropenic Patients

Although in the last decades noteworthy improvements have been achieved in the management of hematologic cancer patients, infections persist as leading cause of morbidity and mortality  particularly during the cytotoxic  neutropenia, defined as a neutrophil count < 500/mmc.[1,2] Respiratory tract infections occur very often, followed by bloodstream infections (BSI), urinary tract infections, skin/skin structure infections and oro-pharynx/gastrointestinal tract infections.[2] In this paper, we shall focus only on BSI.
These infections, mostly caused by bacteria, range from 11 to 38% mortality in neutropenic patients,[3,4] with an unknown origin in most cases (oropharyngeal and gastrointestinal tract are assumed as probable sources). As shown in figure 1, the etiology of BSI has changed through the years. Since 1960, the importance of Gram-negative bacilli in BSI began to be clearly recognized and in the following two decades these organisms represented the most frequent etiological agents. During the nineties, Gram-positive bacteria and emerged as a leading cause of BSI. This increased prevalence has been analyzed by several authors,[5-7] factors such as the large use of central venous catheters (CVC), fluoroquinolones (FQ) and antifungal prophylaxis, gut decolonization strategies, use of high cytarabine doses, use of protonic pump inhibitors have been highlighted as possible causative factors. In the last few years, many papers report a turnaround in BSI etiology, with an increasing role of gram negative bacteria,[2,5,8] becoming the first cause of BSI in some settings.[7]

Figure 1 Figure 1. Time trend of bacterial etiology in neutropenic patients BSI

Moreover, the widespread of antimicrobial resistance, especially among Gram-negative bacilli as extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae or carbapenem resistant Gram- negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa), makes the correct setting of empirical therapy becoming a challenge, since alternative regimes are very few and often present some management issues.[1]
The aim of this paper is to review the current BSI epidemiology among neutropenic onco-hematologic patients, as well as to highlight the most important clinical features and therapeutic management issues. 

Gram-positive BSI in Hematologic Cancer Patients

Gram-positive bacteria BSIs in neutropenic patients became a major concern during the nineties because of their growing prevalence. The emergence of staphylococcal infections in relation to the increased use of CVC and FQ prophylaxis led to a significant reduction in the proportion of Gram-negative bacteria.[5] A large prospective multicenter study by Cordonnier et al[6] established the Gram-positive risk index based on four major factors represented by the use of high cytarabine doses, proton pump inhibitors, decolonization strategies with colimycin without aminoglycosides and the presence of chills at the onset of fever.
Other authors also outlined the importance of high-grade mucositis and toxic enterocolitis in the development of streptococcal and enterococcal bacteremia during neutropenia.[9-10] Nowadays Gram-positive bacteria still reaches 50% of BSI in neutropenic patients,[8-7] being coagulase negative staphylococci (CoNS) the most frequent, followed by streptococci, S. aureus, enterococci, and occasionally Corynebacterium spp or other rare Gram-positive bacteria.


Coagulase Negative Staphylococci (CoNS)

CoNS normally colonize mammalian skin and mucosa. In the past, they were almost universally considered as blood cultures contaminants. S. epidermidis has been recognized as the single most frequently isolated species from BSI. S. haemoliticus, S. lugdunensis, S. saprophiticus, S. capitis, S. auricularis have been isolated less frequently. In general they have a low grade virulence with a poor propensity to invade; however they have a peculiar ability to form a biofilm on biomaterials[11]  and often carry resistance genes.
CoNS are a major cause of BSI in neutropenic patients reaching 25% (5-60%) of all cases.[8] As previously outlined, their incidence in this population seem to be related to the use of FQ prophylaxis. Gudiol et al. observed a significant reduction of Gram-positive BSI since FQ prophylaxis was abandoned in their center. A significant part of CoNS’s bacteremias seems to be related to mucosal more than commensal skin bacteria.[12-13] This could explain their important role in neutropenic patients in which mucosal disruption is very frequent due to the cytotoxic treatment.
Even if they are the first BSI etiologic agent in neutropenic patients, their clinical relevance is questionable. Their attributable mortality is low,[14] as for immune-competent patients in the absence of specific risk factors (such as prosthetic heart valves, joints, and other prosthetic materials).
CoNS blood isolates are usually methicillin resistant, achieving an 80% rate in the last reports[15] except S. lugdunensis or S. capitis that are almost always susceptible to oxacillin.[16]
Concerning glycopeptides, growing resistance to teicoplanin has been observed,[15] in particular in S. haemoliticus where it can reach 20% of clinical isolates.[14] On the other hand, resistance to vancomycin is still very low, except for S. schlefferi.[16] More recently an alarming emergence of linezolid resistant S. epidermidis has been described in Greece.[17] Resistance to linezolid has been associated with higher virulence and higher attributable mortality compared to linezolid susceptible staphylococci[18] but they have not been described yet among neutropenic patients. Resistance to daptomycin is still anecdotic.[19]


Staphylococcus aureus

S. aureus is a common cause of both hospital and community acquired BSIs[11] and it handles 6% (0-20%) of BSIs in onco-hematologic patients.[8] The clinical management of S. aureus BSI (SAB) changes in case of complicated or uncomplicated presentation,[20] in terms of duration of treatment, indication to perform an echocardiogram and metastatic foci research.
Surprisingly, compared to non neutropenic patients, S. aureus BSI during neutropenia seems to be associated with lower attributable mortality and low incidence of metastatic events or endocarditis (Table 1).[21] Two explanations have been proposed for this phenomenon. Firstly, in neutropenia even few cells of S. aureus could be able to gain access to bloodstream trough altered mucosal and skin barrier and evade phagocytosis; thus  an altered bacterial clearance could be responsible for positive blood cultures even with very low inoculum bacteremia. On the other hand, the absence of severe sepsis and septic shock could be related to the inability of these patients to produce the highly orchestrated inflammatory response (that include neutrophils and macrophages).[21]

table1 Table 1. Severity of SAB in neutropenic and non neutropenic patients

Methicillin resistance among S. aureus isolates reported in Europe in 2013 was 18% with percentages ranging from 0 to 64% depending on the country.[22] Neutropenic patients are at high risk to become MRSA carriers. In fact the use of FQ, recommended as prophylaxis in all cases of prolonged neutropenia,[1] can represent an important risk factor for the emergence of MRSA.[23]
Vancomycin resistance is a marginal problem but high vancomycin MIC (between 1 and 2 mg/L), is associated with risk of failure.[24] Interestingly vancomycin MIC >1 mg/L seem to be independently associated with the worst outcome also in methicillin susceptible S. aureus (MSSA) infected patients.[25]
Linezolid resistant S. aureus are still rarely isolated, but several reports in the last few years[26,27] highlight this emerging problem that is not yet described in neutropenic population. Daptomycin resistance is also very rare and described mainly in case reports.
Because of low attributable morbidity and mortality of methicillin resistant strains, empirical treatment with glycopeptides is not required in neutropenic patients as demonstrated in two recent meta-analysis, where it was outlined that a appropriate delayed treatment had no impact on prognosis.[28-29]
Considering the high rate of gastrointestinal origin of staphylococcal BSI and the management problems in onco-hematologic population (piastrinopenia, chemotherapies needing a central line) the indication for the removal of CVC has to be considered for each single case. However the ascertained S. aureus etiology of a catheter related BSI  is an absolute indication for the removal of the catheter.[30]
The antibiogram guided therapy for MRSA has to take into account that a vancomycin MIC >1 mg/L could lead to a failure when treated with vancomycin. Daptomycin should be preferred in these cases unless in the presence of pneumonia. The possible use of clindamycin, cotrimoxazole and aminoglicosides needs to be evaluated in each case, due to the variable susceptibility of these antibiotics in MRSA.
The use of newer drugs need further evaluations but should be considered for cases difficult to treat. In Table 2 are reported the newest anti-staphylococcal drugs that are already or will be soon available.

Table 2 Table 2. New or soon available drugs for MDR bacteria and their characteristics 

Enterococci

Enterococci reach only 5% (0-38%) of BSIs (E-BSI) in neutropenic patients, while the higher rates are observed in  hematopoietic stem cell transplantation (HSCT) recipients, in particular in the first 10 days after transplantation.[8] Mikulska and collaborators[10] identified risk factors associated with E-BSI in this category of patients: donors other than HLA identical, pharyngeal enterococcal colonization, high grade mucositis, Karnofsky score <50, previous use of third generation cephalosporines.
E. faecalis and E. faecium are the most frequent isolated species, but E. faecalis/E. faecium ratio of isolation has changed during the last 20 years. It was approximately 10:1 in the eighties[31] and it is almost 20:1 in more recent reports;[10,32] this is probably due to E. faecium resistance profile.
The clinical significance of their isolation (poor clinical condition marker versus “true infection maker”) should be established in each cause of BSI during neutropenia.
Enterococci intrinsic virulence is low but they are intrinsically resistant to aminoglicosides, cotrimoxazole (in vivo), cephalosporines.[11]  Ampicillin resistance is very prevalent for E. faecium and rare for E. faecalis. High level aminoglycosides resistance is very prevalent for both E. faecalis and E. faecium. Resistance to vancomycin is mainly present in E. faecium. The most frequent genes being Van A and Van B that codify for modified cell wall proteins. In Van B strains teicoplanin is active but not in Van A strains. Vancomycin resistance is more frequent in Eastern Europe, UK and USA.[22] Factors associated with vancomycin resistant enterococci BSI (VRE-BSI) among E-BSI are the recent use of vancomycin or glucocorticosteroids or severity of illness.[33] In HSCT recipients, previous VRE colonization and Graft versus Host Disease (GVHD) were also associated with VRE-BSI.[34]
VRE seem to a have a peculiar clinical behavior compared to VSE (Vancomycin Susceptible Enterococci). Diaz Granados and collaborators performed a meta-analysis including 1614 E-BSI cases, and highlighted an increased mortality in VRE-BSI, compared to VSE-BSI (OR 2.51).[35] The authors could not conclude if this observation was an effect of a delay of appropriate therapy or of an increased virulence of VRE (that are E. faecium in most cases).
Empirical treatment for E-BSI is not recommended. No benefit was observed even in HSCT recipients colonized with VRE receiving empirical linezolid.[36]
Even if randomized controlled trials comparing linezolid and daptomycin in VRE-BSI are lacking, the available evidence suggests a superiority of linezolid in terms of mortality and treatment failure.[37-38] This observation has also been highlighted in neutropenic patients.[39]
.

Viridans Streptococci

Viridans streptococci are an important part of the normal microbial flora. They are indigenous to the upper respiratory tract, the female genital tract, and all regions of the gastrointestinal tract but are most prevalent in the oral cavity.[11] They normally have a low virulence and tendency to invade. However not surprisingly they are an important cause (5%) of BSI in neutropenic patients.[8]
In the previously mentioned paper, Cordonnier established a score of risk for the development of viridians streptococcal BSI in neutropenic patients. This score included the use of high dose cytarabine during induction therapy, oral colimycin without aminoglycosides as decontamination, prophylaxis with antifungal drugs and the presence of diarrhea.[6] Oral mucositis appeared associated with this infection only in univariate analysis. Another possible association has been seen with periodontitis at the time of the onset of neutropenia.[40]
Viridans streptococci BSIs (VS-BSI) during neutropenia carry substantial morbidity and mortality. Attributable mortality is ranging from 6 to 12%.[11] Severe cases, presenting ARDS or shock or both were associated with allogenic bone marrow transplantation, presence of severe oral mucositis (grade 3 or 4) and high dose therapy with cyclophosphamide reaching 11% of the streptococcal bacteremias in Marron et al series.[41] Since the end of the eighties, reduced susceptibility (MIC > 0.12mg/L) and resistance to penicillin (> 0.25 mg/L) have been described in viridians streptococci,[41-43] including those isolated in onco-hematologic patients.[11] Poor susceptibility of streptococci to ceftazidime[41] should suggest not using this agent as an empirical treatment of febrile neutropenia in institutions, and should preclude its use in patients at high risk of streptococcal BSI.[41]

Corynebacterium spp. and other Rare Gram-Positive Etiologies

“Other Gram-positive” etiologies reach 6% (0-21%) of BSI in neutropenic patients.[8] They include Corynebacteria (usually represented by multidrug resistant (MDR) isolates with a spectrum of antibiotic resistances similar to that of MRSA,[9] beta haemolytic streptococci and several organisms that colonize the skin such as Aerococcus spp., Bacillus spp., Micrococcus spp. and S. pneumonia are also relevant. Organisms, such as Listeria monocytogenes, Rhodococcus equi, and vancomycin-resistant bacteria, such as Lactobacillus spp., Leuconostoc spp. and Pediococcus, are occasionally encountered (Figure 2).[44,45] Both linezolid and daptomycin demonstrated good in vitro activity against all Gram-positive isolates in cancer patients.[44]

Figure 2 Figure 2. Spectrum of gram + bacteremias in patients with cancer (1082 patients) Modified by Rolston[44]

Gram-negative BSI in Hematologic Cancer Patients

We already mentioned in the introduction the turnaround in BSI etiology in neutropenic patients. In a recent Italian multicenter study,[7] Gram-negative bacteria were the most frequent isolates in patients with hematologic malignancy. Infections caused by these microorganisms have been identified as an independent predictor of death in patients with malignancies and bloodstream infection: BSI alone reach 12%-42% of mortality.[46,47]  
The distribution of Gram-negative bacilli from BSI remained stable over time but the emergence of multi drug resistant (non susceptible to more than 1 agent in 3 or more antimicrobial categories, MDR), extremely drug resistant (non susceptible to more than 1 agent in all but 2 or less antimicrobial categories, XDR)  and pandrug resistant (non susceptible to all antimicrobial active agents, PDR) isolates represent today the main challenge in managing of Gram-negative BSI.[48]

Escherichia coli

Due to its ability to colonize the human gastrointestinal tract, E. coli is the most common bacterial species found in human fecal flora. Thus, it is not surprising that it also represents the more frequent cause of Gram-negative BSI in neutropenic patients, reaching almost one quarter of all isolates.[8,44,49,50] In this patient population, the morbidity and mortality due to E. coli BSI might be due to several factors, including antibiotic resistance,  FQ resistance and ESBL production, which are the most represented, can be present in almost one third of all isolates and both are favoured by the widespread use of FQ prophylaxis.[5,51-54]
Since inadequate initial antimicrobial therapy has been associated with poorer outcomes, in recent years carbapenems have been employed increasingly as agents of choice against ESBL E. coli and for the empirical treatment of BSI in neutropenic patients.[50,55] However, the concomitant emergence of carbapenems resistance GNB and the observation that carbapenem restriction might be associated with lower rates of carbapenem-resistances have led researchers to consider carbapenem-spearing antibiotic strategies.[56]
Among the potential alternative therapies explored, the role of piperacillin-tazobactam, has been reassessed: in fact patients treated with this combination and those treated with carbapenem against β-lactam-β-lactamase inhibitor BLBLI susceptible E. coli presented a similar therapeutic outcome.[51,57
Therefore, considered these assumptions, in a setting of high ESBL prevalence, a possible antimicrobial stewardship program could be based on simply model of de-escalation strategy. Indeed, in case of proven susceptibility, the change of treatment from carbapenem to piperacillin/tazobactam could be safe and prevent the risk of carbapenemase induction.
Otherwise in epidemiologic settings characterized by a high prevalence of infection due to piperacillin-tazobactam resistant E. coli, empirical therapy with a combination piperacillin-tazobactam and tigecyclin could be another suitable option.[58]


Klebsiella pneumoniae

K. pneumoniae is the primary species of genus Klebsiella associated with illness in human beings. It is found in the gastrointestinal tract and is frequently involved in health-care and intensive care unit (ICU) associated infections.[59] Infections with K. pneumoniae are usually hospital-acquired, sustained by MDR strains and occur primarily in patients with impaired host defenses.
As described for E. coli, K. pneumoniae is often represented by FQ and third generation cephalosporin resistant strains; thus it shares with E. coli all the therapeutic challenges deriving from these types of resistance. Moreover, several mechanisms have been identified as responsible for carbapenem resistance among Enterobacteriaceae: Ambler class A beta-lactamases are enzymes that can be either plasmid encoded (blaKPC and, less frequent, blaIMI-2, blaGES) or chromosomally encoded (blaNMC, blaSME, blaIMI-1, blaSFC-1). The class B metallo-β-lactamases includes (MBLs) Verona integron-encoded metallo-β-lactamase (blaVIM), blaIMP, and the New Delhi metallo-β-lactamase (blaNDM). BlaOXA-48 carbapenemases belong to Ambler class D. Finally resistance to carbapenems can also be caused by hyperexpression of AmpC gene or to decreased permeability of the outer membrane because of porin loss in combination with the expression of AmpC enzymes or ESBLs.[60,61]
From an epidemiological point of view, K. pneumoniae represents the third leading cause of GNB BSI in neutropenic patients population reaching almost 12.5% in a recent Italian multicenter study.[7] Since 2008 an increasing number of reports described the spread of carbapenem resistant strains mainly in the Mediterranean and Southern European countries with a rapid spread in Israel and Greece.[62] The spread of carbapenem resistant Enterobacteriaceae (CRE) has dramatically increased also in Italy rising from 15.2% in 2010 to 34.3% in 2013.[7,63,64]
The high incidence of these MDR strains in immune-compromised populations was confirmed by recent multicenter studies reporting that a KPC producing K. pneumonia (KPC-Kp) rectal colonization was common in onco-hematological patients. In this cohort the colonization was followed by an infection in 39.2% cases of allogeneic Stem Cell Transplantation Recipients (allo-SCT)[65] and 45% of cases of neutropenic patients.[66] Observed mortality rate attributable to KPC-Kp BSI was of 57.6% in adult inpatients,[64] while it was of 64.4% in allo-STC recipients.[65] Therefore considering these aspects, it is crucial to recognize the KPC-Kp carriers and consider this information in febrile neutropenic patients at risk of BSI.
Although empirical treatments against KPC-Kp are not recommended by current IDSA-ECIL guidelines, due to their potential toxicity and off label usage (Figure 3), we believe that these therapies are justified in this setting, according to the evidence of the literature. The different scenarios potentially met by the clinician are analyzed in the figure 3, which provides a diagnostic and therapeutic algorithm that might be useful in this setting. In any case, it is essential to stress that neutropenic patients should be routinely screened on rectal swab cultures to identify patients with KPC-Kp gut colonization.

Figure 3 Figure 3. Flow chart for empirical and targeted treatment of febrile neutropenic patients at risk of ESBL and or KPC producing  Enterobacteriace (Colistin: 9 M loading dose, 4,5 M q 12h; Rifampicin: 600 mg q 24h; Gentamicin: 5-7 mg/kg; Doripenem: 500 mg q 8h, extended  infusion; Meropenem : 1-2 gr q 6-8h, extended infusion; Ertapenem 1 gr q 24h; Tigecycline: 200 mg loading dose, 100 mg q 12h; *in clinical center with blood isolate meropenem MIC≥16 consider gentamycin instead of carbapenem).[95-105]

Awaiting new drugs showed in Table 2 potentially active against KPC-Kp, at the moment colistin represents the back-bone of therapeutic regimes against KPC-KP;[64,67-70] its use is possible in the case of infections due to both colistin susceptible and resistant strains, as showed in figure 3.
Synergistic activity have been reported with therapeutic strategies combining colistin with rifampicin[71] and ertapenem with meropenem +/-colistin.[72] This last strategy, so called “double carbapenem” therapy, could be employed in cases of severe infection not responsive to previous treatment. The activity of combination is justified from in vivo studies[73-74] that seems to corroborate in vitro experiments performed by Bulik et al., who recently postulated that the enhanced efficacy of this therapy against KPC-Kp may be related to the KPC enzyme's preferential affinity for ertapenem.[75]
Finally, it is worth to remember that rectal swab surveillance is recommended as a component of infection prevention programs and of antimicrobial stewardship that can reduce the rate of CRE infections, including BSI.   


Pseudomonas aeruginosa and other non Fermentative Gram Negative Bacilli (NFGNB)

P. aeruginosa is an ubiquitary Gram-negative invasive pathogen, responsible for severe infections in immune-compromised hosts. Since 1960 P. aeruginosa BSI has been highlighted as an important and frequent cause of morbidity and mortality in neutropenic patients. With the introduction of FQ prophylaxis P. aeruginosa prevalence progressively declined, but nevertheless it is still responsible for 18% to 27% of BSI in this population[2,5,7] with a mortality rate of 40%.[76]
However, at the moment the benefit of FQ prophylaxis, despite its historical value, is a matter of concern for its association with the emergence of antibiotic resistance, especially in those countries where MDR and XDR strains reached 50% of isolates.[63] Furthermore the problem of the emergence of MDR strains is related to the clinical outcome. In fact, an increased invasive capacity of MDR P. aeruginosa was evidenced by the observation that the patients colonized with MDR strains are at higher risk of BSI compared to those with a no-MDR colonization.[77]
Concerning therapeutic resources, first line recommended therapy of ECIL and IDSA guidelines for the management of fever in neutropenic patients ensure coverage for susceptible  P. aeruginosa. The addition of aminoglycosides could be effective in cases of severe sepsis or septic shock.
Regimes based on colistin, in association with rifampicin +/- antipseudomonal carbapenem, have been suggested to treat MDR/XDR strains due to their possible synergistic effect.[78,79] Among soon available drugs, ceftolozane-tazobactam, seems to be the most promising in the treatment of such infections.[80]
NFGNB only account for less than 3% of BSI in neutropenic patients. In this group, Stenotrophomonas maltophilia and Acinetobacter baumannii are the most represented bacteria (see Table 3).

Table 3 Table 3. Spectrum of gram negative infection in neutropenic patients and principal type of resistance.

Ecthyma gangrenosum (EG) is a well-recognized cutaneous infection classically associated with S. maltophilia and P. aeruginosa bacteremia. EG usually occurs in patients who are critically ill and immunocompromised; it is almost always a sign of pseudomonal or stenotrophomonal sepsis.[81,82] Intrinsic resistance profile of S. maltophilia is a therapeutic hitch worthy of consideration: trimethroprim-sulfametoxazole is the drug of choice, but also levofloxacine and moxifloxacine were usually active.[83,84] Moreover recently i.v. minocycline demonstrated an exellent in vitro activity.[85
Acinetobacter spp BSI accounts for only 1% of neutropenic patients. Therapies versus A. baumannii are based on carbapenem or aminoglycosides when the strains are susceptible to these drugs and colistin, eventually in association with rifampicin and ortigecyclin, ampicillin-sulbactam or carbapenem, when the stains are XDR.[86-91]
In conclusion, the current epidemiology of BSI in onco-hematologic patients is characterized by the emergence of MDR pathogens. This observation has several implications both in the institution of empirical and targeted treatment and in the need of containment strategies. We proposed here some possible regimens for empirical and focused treatment based on current evidence to help the clinician who is going to treat febrile neutropenia in the MDR bugs era. We believe that every effort has to be made for the containment of the spread of these pathogens. For this purpose, shared antibiotic stewardship strategies need to be implemented. Concepts like antibiotic de-escalation, availability of the antibiograms, isolation of the colonized patients, and careful limitation of carbapenem use are cornerstones of resistance containment both in neutropenic and non-neutropenic patients.
Some special considerations should be made on neutropenic patients. First of all, FQ prophylaxis has been highlighted as one of the most important causative factors for the emergence of ESBL enterobateriaceae and MRSA. Therefore, its use need probably to be systematically re-evaluated at least in selected epidemiological settings (i.e. in relation to FQ resistance prevalence among E. coli isolates). Secondly, around 70% of fevers in neutropenia are classified as fever of unknown origin (FUO)[92] in which antibiotic therapy could be unneeded. Expert opinion[93]  and recent evidence[94] support early discontinuation of antibiotic therapy in FUOs. Finally, approaches to reduce the antibiotic exposure with the adoption of short antibiotic treatments for specific infections should be evaluated. As an example, a five days course of daptomycin for CoNS BSIs promptly responding to CVC removal might prove efficacious.
The knowledge of the general and local epidemiology and resistance profiles are of a paramount importance in the correct management of febrile neutropenia. Frequent, up to dated, reports about trends in etiology and emerging resistances need to be implemented. 
.

References

  1. Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M e ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th european conference on infections in leukemia. Haematologica. 2013, Vol. 98, 1826-35. http://dx.doi.org/10.3324/haematol.2013.091025  PMid:24323983  PMCid:PMC3856957 .  
  2. Nesher L, Rolston KV. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection. 2014; 42, 5-13. http://dx.doi.org/10.1007/s15010-013-0525-9  PMid:23975584  .    
  3. Klastersky J, Ameye L, Maertens J, Georgala A, Muanza F, Aoun M, Ferrant A, Rapoport B, Rolston K, Paesmans M. Bacteraemia in febrile neutropenic cancer patients. Int J Antimicrob Agents. 2007; 30 S, 51-9. .  
  4. Gaytán-Martínez J1, Mateos-García E, Sánchez-Cortés E, González-Llaven J, Casanova-Cardiel LJ, Fuentes-Allen JL. Microbiological findings in febrile neutropenia. Arch Med Res. 2000; 31, 388-92.  PMid:11068081 .      
  5. Gudiol C1, Bodro M, Simonetti A, Tubau F, González-Barca E, Cisnal M, Domingo-Domenech E, Jiménez L, Carratalà J. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect. 2012; 19, 474-9. PMid:22524597   .  
  6. Cordonnier C1, Buzyn A, Leverger G, Herbrecht R, Hunault M, Leclercq R, Bastuji-Garin S e Onco-Hématologie., Club de Réflexion sur les Infections en. Epidemiology and Risk Factors for Gram-Positive Coccal Infections in Neutropenia: Toward a More Targeted Antibiotic Strategy. Clin Infect dis. 2003; 36, 149-58. http://dx.doi.org/10.1086/345435 PMid:12522746    .      
  7. Trecarichi EM, Pagano L, Candoni A, Pastore D, Cattaneo C, Fanci R, Nosari A, Caira M, Spadea A, Busca A, Vianelli N, Tumbarello M. Current epidemiology and antimicrobial resistance data for bacterial bloodstream infections in patients with hematologic malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect. 2014; pii: S1198-743X(14)00108-6.   .    
  8. Mikulska M, Viscoli C, Orasch C, Livermore DM, Averbuch D, Cordonnier C, Akova M e Fourth European Conference on Infections in Leukemia Group (ECIL-4), a joint venture of EBMT, EORTC, ICHS, ELN and ESGICH/ESCMID. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect. 2013; 68, 321-31. http://dx.doi.org/10.1016/j.jinf.2013.12.006 PMid:24370562   .        
  9. Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis. 1999; 29, 490-4. http://dx.doi.org/10.1086/598620 PMid:10530434  .    
  10. Mikulska M, Del Bono V, Prinapori R, Boni L, Raiola AM, Gualandi F, Van Lint MT, Dominietto A, Lamparelli T, Cappellano P, Bacigalupo A, Viscoli C. Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2010; 6, 505-12. http://dx.doi.org/10.1111/j.1399-3062.2010.00544.x PMid:20636482 .    
  11. Mandell G L, Bennett J E, Dolin R.Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 7th ed. Philadelphia : Churcill Livingstone Elsevier, 2010.
  12. Costa SF, Barone AA, Miceli MH, van der Heijden IM, Soares RE, Levin AS, Anaissie EJ. Colonization and molecular epidemiology of coagulase-negative Staphylococcal bacteremia in cancer patients: a pilot study. Am J Infect Control. 2006; 34, 36-40. http://dx.doi.org/10.1016/j.ajic.2005.10.007 PMid:16443091 .     
  13. Costa SF, Miceli MH, Anaissie EJ. Mucosa or skin as source of coagulase-negative staphylococcal bacteraemia? Lancet Infect Dis. 2004; 4, 278-86. http://dx.doi.org/10.1016/S1473-3099(04)01003-5   
  14. Falcone M, Micozzi A, Pompeo ME, Baiocchi P, Fabi F, Penni A, Martino P, Venditti M. Methicillin-resistant staphylococcal bacteremia in patients with hematologic malignancies: clinical and microbiological retrospective comparative analysis of S. haemolyticus, S. epidermidis and S. aureus. J Chemother. 2004; 16, 540-8. http://dx.doi.org/10.1179/joc.2004.16.6.540 PMid:15700845  .    
  15. Mendes RE, Hogan PA, Streit JM, Jones RN, Flamm RK. Zyvox® Annual Appraisal of Potency and Spectrum (ZAAPS) program: report of linezolid activity over 9 years (2004-12). J Antimicrob Chemother. 2014; 69, 1582-8. http://dx.doi.org/10.1093/jac/dkt541 PMid:24468866 .     
  16. Stuart JI, John MA, Milburn S, Diagre D, Wilson B, Hussain Z. Susceptibility patterns of coagulase-negative staphylococci to several newer antimicrobial agents in comparison with vancomycin and oxacillin. Int J Antimicrob Agents. 2011; 37, 248-52. http://dx.doi.org/10.1016/j.ijantimicag.2010.11.020 PMid:21295951  .     
  17. Karavasilis V, Zarkotou O, Panopoulou M, Kachrimanidou M, Themeli-Digalaki K, Stylianakis A, Gennimata V, Ntokou E, Stathopoulos C, Tsakris A, Pournaras S e Resistance., Greek Study Group on Staphylococcal Linezolid. Wide dissemination of linezolid-resistant Staphylococcus epidermidis in Greece is associated with a linezolid-dependent ST22 clone. J Antimicrob Chemother. 2015, Epub ahead of print.
  18. Russo A, Campanile F, Falcone M, Tascini C, Bassetti M, Goldoni P, Trancassini M, Della Siega P, Menichetti F, Stefani S, Venditti M. Linezolid-resistant staphylococcal bacteraemia: A multicentre case-case-control study in Italy. Int J Antimicrob Agents. 2015; 45, 255-61. http://dx.doi.org/10.1016/j.ijantimicag.2014.12.008 PMid:25600893 .     
  19. Sader HS, Farrell DJ, Flamm RK, Jones RN. Daptomycin activity tested against 164457 bacterial isolates from hospitalised patients: summary of 8 years of a Worldwide Surveillance Programme (2005-2012). Int J Antimicrob Agents. 2014; 43, 465-9. http://dx.doi.org/10.1016/j.ijantimicag.2014.01.018 PMid:24636430    .  
  20. Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, Kirby A, Tilley R, Török ME, Walker S, Wertheim HF, Wilson P, Llewelyn MJ e Group., UK Clinical Infection Research. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis. 2011; 11, 208-22. http://dx.doi.org/10.1016/S1473-3099(10)70285-1   .  
  21. Venditti M, Falcone M, Micozzi A, Carfagna P, Taglietti F, Serra PF, Martino P. Staphylococcus aureus bacteremia in patients with hematologic malignancies: a retrospective case-control study. Haematologica. 2004; 88, 923-30.  .  
  22. European Antimicrobial Resistance Surveillance Network (EARS-Net). European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2013. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm : ECDC, 2014.
  23. Tacconelli E, De Angelis G, Cataldo MA, Pozzi E, Cauda R. Does antibiotic exposure increase the risk of methicillin-resistant Staphylococcus aureus (MRSA) isolation? A systematic review and meta-analysis. J Antimicrob Chemother. 2008; 61, 26-38. http://dx.doi.org/10.1093/jac/dkm416 PMid:17986491 .      
  24. Soriano A, Marco F, Martínez JA, Pisos E, Almela M, Dimova VP, Alamo D, Ortega M, Lopez J, Mensa J. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008; 46, 193-200. http://dx.doi.org/10.1086/524667 PMid:18171250  .    
  25. Cervera C, Casta-eda X, de la Maria CG, del Rio A, Moreno A, Soy D, Pericas JM, Falces C, Armero Y, Almela M, Ninot S, Pare JC, Mestres CA, Gatell JM, Marco F, Miro JM e Group., Hospital Clinic Endocarditis Study. Effect of vancomycin minimal inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus endocarditis. Clin Infect Dis. 2014; 58, 1668-75. http://dx.doi.org/10.1093/cid/ciu183 PMid:24647021  .    
  26. Sánchez García M, De la Torre MA, Morales G, Peláez B, Tolón MJ, Domingo S, Candel FJ, Andrade R, Arribi A, García N, Martínez Sagasti F, Fereres J, Picazo J. Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA. 2010; 303, 2260-4. http://dx.doi.org/10.1001/jama.2010.757 PMid:20530779  .    
  27. Endimiani A, Blackford M, Dasenbrook EC, Reed MD, Bajaksouszian S, Hujer AM, Rudin SD, Hujer KM, Perreten V, Rice LB, Jacobs MR, Konstan MW, Bonomo RA. Emergence of linezolid-resistant Staphylococcus aureus after prolonged treatment of cystic fibrosis patients in Cleveland, Ohio. Antimicrob Agents Chemother. 2011; 55, 1684-92. http://dx.doi.org/10.1128/AAC.01308-10 PMid:21263048 PMCid:PMC3067150  .  
  28. Paul M, Dickstein Y, Borok S, Vidal L, Leibovici L. Empirical antibiotics targeting Gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2014 Jan 14;1:CD003914. http://dx.doi.org/10.1002/14651858.cd003914.pub3  .  
  29. Vardakas KZ, Samonis G, Chrysanthopoulou SA, Bliziotis IA, Falagas ME. Role of glycopeptides as part of initial empirical treatment of febrile neutropenic patients: a meta-analysis of randomised controlled trials. Lancet Infect Dis. 2005; 5, 431-9. http://dx.doi.org/10.1016/S1473-3099(05)70164-X  .  
  30. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, Raad II, Rijnders BJ, Sherertz RJ, Warren DK. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009; 49, 1-45. http://dx.doi.org/10.1086/599376 PMid:19489710 PMCid:PMC4039170  .  
  31. Venditti M, Tarasi A, Visco Comandini U, Gentile G, Girmenia C, Micozzi A, Martino P. Enterococcal septicemia in patients with hematological malignancies. Eur J Clin Microbiol Infect Dis. 1993; 12, 241-7. http://dx.doi.org/10.1007/BF01967253 PMid:8513811 .    
  32. Todeschini G, Tecchio C, Borghero C, D'Emilio A, Pegoraro E, de Lalla F, Benedetti P, Spolaore P, Pellizzer G. Association between Enterococcus bacteraemia and death in neutropenic patients with haematological malignancies. J Infect. 2006; 53, 266-73. http://dx.doi.org/10.1016/j.jinf.2005.11.012 PMid:16388852  .    
  33. Vergis EN, Hayden MK, Chow JW, Snydman DR, Zervos MJ, Linden PK, Wagener MM, Schmitt B, Muder RR. Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. a prospective multicenter study. Ann Intern Med. 2001; 135, 484-92. http://dx.doi.org/10.7326/0003-4819-135-7-200110020-00007 PMid:11578151  .    
  34. Vydra J, Shanley RM, George I, Ustun C, Smith AR, Weisdorf DJ, Young JA. Enterococcal bacteremia is associated with increased risk of mortality in recipients of allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012; 55, 764-70. http://dx.doi.org/10.1093/cid/cis550 PMid:22693346 PMCid:PMC3657510  .  
  35. DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis. 2005; 41, 327-33. http://dx.doi.org/10.1086/430909 PMid:16007529   .   
  36. Lisboa LF, Miranda BG, Vieira MB, Dulley FL, Fonseca GG, Guimarães T, Levin AS, Shikanai-Yasuda MA, Costa SF. Empiric use of linezolid in febrile hematology and hematopoietic stem cell transplantation patients colonized with vancomycin-resistant Enterococcus spp. Int J Infect Dis. 2015; 33, 171-76. http://dx.doi.org/10.1016/j.ijid.2015.02.001 PMid:25660090 .     
  37. Balli EP, Venetis CA, Miyakis S. Systematic review and meta-analysis of linezolid versus daptomycin for treatment of vancomycin-resistant enterococcal bacteremia. Antimicrob Agents Chemother. 2014; 58, 734-9. http://dx.doi.org/10.1128/AAC.01289-13 PMid:24247127 PMCid:PMC3910884  .  
  38. Chuang YC, Wang JT, Lin HY, Chang SC. Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. BMC Infect Dis. 2014; 14, 687. http://dx.doi.org/10.1186/s12879-014-0687-9 PMid:25495779 PMCid:PMC4269951  .  
  39. McKinnell JA, Patel M, Shirley RM, Kunz DF, Moser SA, Baddley JW. Observational study of the epidemiology and outcomes of vancomycin-resistant Enterococcus bacteraemia treated with newer antimicrobial agents. Epidemiol Infect. 2011; 139, 1342-50. http://dx.doi.org/10.1017/S0950268810002475 PMid:21073764 PMCid:PMC3879115  .  
  40. Raber-Durlacher JE, Laheij AM, Epstein JB, Epstein M, Geerligs GM, Wolffe GN, Blijlevens NM, Donnelly JP. Periodontal status and bacteremia with oral viridans streptococci and coagulase negative staphylococci in allogeneic hematopoietic stem cell transplantation recipients: a prospective observational study. Support Care Cancer. 2013; 21, 1621-7. http://dx.doi.org/10.1007/s00520-012-1706-2 PMid:23288398  .    
  41. Marron A, Carratalà J, González-Barca E, Fernández-Sevilla A, Alcaide F, Gudiol F. Serious complications of bacteremia caused by Viridans streptococci in neutropenic patients with cancer. Clin Infect Dis. 2000; 31, 1126-30. http://dx.doi.org/10.1086/317460 PMid:11073739    .  
  42. Venditti M, Baiocchi P, Santini C, Brandimarte C, Serra P, Gentile G, Girmenia C, Martino P. Antimicrobial susceptibilities of Streptococcus species that cause septicemia in neutropenic patients. Antimicrob Agents Chemother. 1989; 33, 580-2. http://dx.doi.org/10.1128/AAC.33.4.580 PMid:2729950 PMCid:PMC172484  .  
  43. Carratalá J, Alcaide F, Fernández-Sevilla A, Corbella X, Linares J, Gudiol F. Bacteremia due to viridans streptococci that are highly resistant to penicillin: increase among neutropenic patients with cancer. Clin Infect Dis. 1995; 20, 1169-73. http://dx.doi.org/10.1093/clinids/20.5.1169 PMid:7619995 .     
  44. Rolston KV, Kapadia M, Tarrand J, Coyle E, Prince RA. Spectrum of gram-positive bacteraemia and in vitro activities of daptomycin, linezolid and vancomycin against organisms isolated from cancer patients. Int J Antimicrob Agents. 2013; 41, 516-21. http://dx.doi.org/10.1016/j.ijantimicag.2013.01.014 PMid:23481658  .    
  45. Rozdzinski E, Kern W, Schmeiser T, Kurrle E. Corynebacterium jeikeium bacteremia at a tertiary care center. Infection. 1991; 19, 201-4. http://dx.doi.org/10.1007/BF01644945 PMid:1917029  .     
  46. Tumbarello M, Sanguinetti M, Montuori E, Trecarichi EM, Posteraro B, Fiori B, Citton R, D'Inzeo T, Fadda G, Cauda R, Spanu T. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum-beta-lactamase-producing Enterobacteriaceae: importance of inadequate initial antimicrobial treatment. Antimicrob Agents Chemother. 2007; 51, 1987-94. http://dx.doi.org/10.1128/AAC.01509-06 PMid:17387156 PMCid:PMC1891412  .  
  47. Tumbarello M, Spanu T, Caira M, Trecarichi EM, Laurenti L, Montuori E, Fianchi L, Leone F, Fadda G, Cauda R, Pagano L. Factors associated with mortality in bacteremic patients with hematologic malignancies. Diagn Microbiol Infect Dis. 2009; 64, 320-6. http://dx.doi.org/10.1016/j.diagmicrobio.2009.02.008 PMid:19345033  .    
  48. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, Harbarth S, Hindler JF, Kahlmeter G, Olsson-Liljequist B, Paterson DL, Rice LB, Stelling J, Struelens MJ, Vatopoulos A, Weber JT, Monnet DL. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2011; 18, 268-81. http://dx.doi.org/10.1111/j.1469-0691.2011.03570.x PMid:21793988 .     
  49. Cattaneo C, Quaresmini G, Casari S, Capucci MA, Micheletti M, Borlenghi E, Signorini L, Re A, Carosi G, Rossi G. Recent changes in bacterial epidemiology and the emergence of fluoroquinolone-resistant Escherichia coli among patients with haematological malignancies: results of a prospective study on 823 patients at a single institution. J Antimicrob Chemother. 2008; 61, 721-8. http://dx.doi.org/10.1093/jac/dkm514 PMid:18218645 .     
  50. Trecarichi EM, Tumbarello M, Spanu T, Caira M, Fianchi L, Chiusolo P, Fadda G, Leone G, Cauda R, Pagano L. Incidence and clinical impact of extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance in bloodstream infections caused by Escherichia coli in patients with hematological malignancies. J Infect. 2009; 58, 299-307. http://dx.doi.org/10.1016/j.jinf.2009.02.002 PMid:19272650  .    
  51. Kim SH, Kwon JC, Choi SM, Lee DG, Park SH, Choi JH, Yoo JH, Cho BS, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS. Escherichia coli and Klebsiella pneumoniae bacteremia in patients with neutropenic fever: factors associated with extended-spectrum ß-lactamase production and its impact on outcome. Ann Hematol. . 2013; 92, 533-41. http://dx.doi.org/10.1007/s00277-012-1631-y PMid:23161391 .      
  52. EJ, Bow. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis. 2011; 24, 545-53. http://dx.doi.org/10.1097/QCO.0b013e32834cf054 PMid:22001945   .   
  53. Lingaratnam S, Thursky KA, Slavin MA. Fluoroquinolone prophylaxis: a word of caution. Leuk Lymphoma. 2011; 52, 5-6. http://dx.doi.org/10.3109/10428194.2010.527408 PMid:21067448  .    
  54. Kang CI, Chung DR, Ko KS, Peck KR, Song JH e Diseases., Korean Network for Study of Infectious. Risk factors for infection and treatment outcome of extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae bacteremia in patients with hematologic malignancy. Ann Hematol. 2012; 91, 115-21. http://dx.doi.org/10.1007/s00277-011-1247-7 PMid:21556875 .     
  55. Pitout JD. Infections with extended-spectrum beta-lactamase-producing enterobacteriaceae: changing epidemiology and drug treatment choices. Drugs. 2010; 70, 313-33. http://dx.doi.org/10.2165/11533040-000000000-00000 PMid:20166768  .    
  56. Pakyz AL, Oinonen M, Polk RE. Relationship of carbapenem restriction in 22 university teaching hospitals to carbapenem use and carbapenem-resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2009; 53(5): 1983-6. http://dx.doi.org/10.1128/AAC.01535-08 PMid:19273670 PMCid:PMC2681502  .  
  57. Rodríguez-Ba-o J, Navarro MD, Retamar P, Picón E, Pascual Á e Group, Extended-Spectrum Beta-Lactamases–Red Espa-ola de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria.ß-Lactam/ß-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum ß-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012; 54, 167-74. http://dx.doi.org/10.1093/cid/cir790 PMid:22057701  .    
  58. Bucaneve G, Micozzi A, Picardi M, Ballanti S, Cascavilla N, Salutari P, Specchia G, Fanci R, Luppi M, Cudillo L, Cantaffa R, Milone G, Bocchia M, Martinelli G, Offidani M, Chierichini A, Fabbiano F, Quarta G, Primon V, Martino B, Manna A, Zuffa E, Ferrar.Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia. J Clin Oncol. 2014; 32, 1463-71. http://dx.doi.org/10.1200/JCO.2013.51.6963 PMid:24733807  .    
  59. Girometti N, Lewis RE, Giannella M, Ambretti S, Bartoletti M, Tedeschi S, Tumietto F, Cristini F, Trapani F, Gaibani P, Viale P. Klebsiella pneumoniae bloodstream infection: epidemiology and impact of inappropriate empirical therapy. Medicine (Baltimore). 2014; 93, 298-309. http://dx.doi.org/10.1097/MD.0000000000000111 PMid:25398065  .  
  60. K, Bush. Alarming ß-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr Opin Microbiol. 2010; 13, 558-64. http://dx.doi.org/10.1016/j.mib.2010.09.006 PMid:20920882 .     
  61. García-Fernández A, Villa L, Carta C, Venditti C, Giordano A, Venditti M, Mancini C, Carattoli A. Klebsiella pneumoniae ST258 producing KPC-3 identified in italy carries novel plasmids and OmpK36/OmpK35 porin variants. Antimicrob Agents Chemother. 2012; 56, 2143-5. http://dx.doi.org/10.1128/AAC.05308-11 PMid:22252815 PMCid:PMC3318348  .  
  62. Tsakris A, Kristo I, Poulou A, Markou F, Ikonomidis A, Pournaras S. First occurrence of KPC-2-possessing Klebsiella pneumoniae in a Greek hospital and recommendation for detection with boronic acid disc tests. J Antimicrob Chemother. 2008; 62(6) :1257-60. http://dx.doi.org/10.1093/jac/dkn364 PMid:18772158 .     
  63. European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2013. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net). ECDC, Stockholm 2014
  64. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, Losito AR, Tedeschi S, Cauda R, Bassetti M. 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. http://dx.doi.org/10.1093/cid/cis588 PMid:22752516  .    
  65. Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, Sica S, Severino A, Cudillo L, Ciceri F, Scimè R, Lombardini L, Viscoli C, Rambaldi A, (GITMO), Gruppo Italiano Trapianto Midollo Osseo e GITMO., Gruppo Italiano Trapianto Midollo Osseo.Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant. 2015; 50, 282-8. http://dx.doi.org/10.1038/bmt.2014.231 PMid:25310302   .    
  66. Giannella M, Trecarichi EM, De Rosa FG, Del Bono V, Bassetti M, Lewis RE, Losito AR, Corcione S, Saffioti C, Bartoletti M, Maiuro G, Cardellino CS, Tedeschi S, Cauda R, Viscoli C, Viale P, Tumbarello M. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infection among rectal carriers: a prospective observational multicentre study. Clin Microbiol Infect. 2014; 20, 1357-62. http://dx.doi.org/10.1111/1469-0691.12747 PMid:24980276   .    
  67. Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014; 58, 2322-8. http://dx.doi.org/10.1128/AAC.02166-13 PMid:24514083 PMCid:PMC4023796  .  
  68. Qureshi ZA, Paterson DL, Potoski BA, Kilayko MC, Sandovsky G, Sordillo E, Polsky B, Adams-Haduch JM, Doi Y. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012; 56, 2108-13. http://dx.doi.org/10.1128/AAC.06268-11   PMid:22252816 PMCid:PMC3318350  .  
  69. Daikos GL, Markogiannakis A. Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems? Clin Microbiol Infect. 2011; 17, 1135-41. http://dx.doi.org/10.1111/j.1469-0691.2011.03553.x PMid:21635663 .     
  70. Daikos GL, Markogiannakis A, Souli M, Tzouvelekis LS. Bloodstream infections caused by carbapenemase-producing Klebsiella pneumoniae: a clinical perspective. Expert Rev Anti Infect Ther. 2012;10(12): 1393-404. http://dx.doi.org/10.1586/eri.12.138 PMid:23253318  .  
  71. Tascini C, Tagliaferri E, Giani T, Leonildi A, Flammini S, Casini B, Lewis R, Ferranti S, Rossolini GM, Menichetti F. Synergistic activity of colistin plus rifampin against colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013; 57, 3990-3. http://dx.doi.org/10.1128/AAC.00179-13 PMid:23752510 PMCid:PMC3719736  .  
  72. Jernigan MG, Press EG, Nguyen MH, Clancy CJ, Shields RK. The combination of doripenem and colistin is bactericidal and synergistic against colistin-resistant, carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2012; 56, 3395-8. http://dx.doi.org/10.1128/AAC.06364-11 PMid:22430958 PMCid:PMC3370798  .  
  73. Ceccarelli G, Falcone M, Giordano A, Mezzatesta ML, Caio C, Stefani S, Venditti M. Successful ertapenem-doripenem combination treatment of bacteremic ventilator-associated pneumonia due to colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013; 57, 2900-1. http://dx.doi.org/10.1128/AAC.00188-13 PMid:23571536 PMCid:PMC3716145  .  
  74. Oliva A, D'Abramo A, D'Agostino C, Iannetta M, Mascellino MT, Gallinelli C, Mastroianni CM, Vullo V. Synergistic activity and effectiveness of a double-carbapenem regimen in pandrug-resistant Klebsiella pneumoniae bloodstream infections. J Antimicrob Chemother. 2014; 69, epub feb 11. .  
  75. Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011; 55, 3002-4. http://dx.doi.org/10.1128/AAC.01420-10 PMid:21422205 PMCid:PMC3101469  .  
  76. Trecarichi EM, Tumbarello M, Caira M, Candoni A, Cattaneo C, Pastore D, Fanci R, Nosari A, Vianelli N, Busca A, Spadea A, Pagano L. Multidrug resistant Pseudomonas aeruginosa bloodstream infection in adult patients with hematologic malignancies. Haematologica. 2011; 96, 1-3. http://dx.doi.org/10.3324/haematol.2010.036640 PMid:21193424 PMCid:PMC3012771 .  
  77. Pe-a C, Gómez-Zorrilla S, Suarez C, Dominguez MA, Tubau F, Arch O, Oliver A, Pujol M, Ariza J. Extensively drug-resistant Pseudomonas aeruginosa: risk of bloodstream infection in hospitalized patients. Eur J Clin Microbiol Infect Dis. 2012; 31, 2791-7. http://dx.doi.org/10.1007/s10096-012-1629-3 PMid:22552893 .     
  78. Tascini C, Gemignani G, Ferranti S, Tagliaferri E, Leonildi A, Lucarini A, Menichetti F. Microbiological activity and clinical efficacy of a colistin and rifampin combination in multidrug-resistant Pseudomonas aeruginosa infections. J Chemother. 2004; 16(3): 282-7. http://dx.doi.org/10.1179/joc.2004.16.3.282 PMid:15330326 .     
  79. Landman D, Bratu S, Alam M, Quale J. Citywide emergence of Pseudomonas aeruginosa strains with reduced susceptibility to polymyxin B. J Antimicrob Chemother. 2005; 55(6): 954-7. http://dx.doi.org/10.1093/jac/dki153 PMid:15883174 .      
  80. Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). J Infect. 2014; 69(3): 266-77. http://dx.doi.org/10.1016/j.jinf.2014.04.004 PMid:24780763  .    
  81. Demiraslan H, Sevim M, Pala Ç, Durmaz S, Berk V, Kaynar L, Metan G. Risk factors influencing mortality related to Stenotrophomonas maltophilia infection in hematology-oncology patients. Int J Hematol. 2013; 97, 414-20. http://dx.doi.org/10.1007/s12185-013-1296-x PMid:23430671  .    
  82. Micozzi A, Venditti M, Monaco M, Friedrich A, Taglietti F, Santilli S, Martino P. Bacteremia due to Stenotrophomonas maltophilia in patients with hematologic malignancies. Clin Infect Dis. 2000; 31, 705-11. http://dx.doi.org/10.1086/314043 PMid:11017819 .     
  83. Bonfiglio G, Cascone C, Azzarelli C, Cafiso V, Marchetti F, Stefani S. Levofloxacin in vitro activity and time-kill evaluation of Stenotrophomonas maltophilia clinical isolates. J Antimicrob Chemother. 2000; 45, 115-7. http://dx.doi.org/10.1093/jac/45.1.115 PMid:10629022 .     
  84. Venditti M, Monaco M, Micozzi A, Tarasi A, Friedrich A, Martino P. In vitro activity of moxifloxacin against Stenotrophomonas maltophilia blood isolates from patients with hematologic malignancies. Clin Microbiol Infect. . 2001; 7, 37-9. http://dx.doi.org/10.1046/j.1469-0691.2001.00191.x PMid:11284945  .    
  85. Rizek C, Ferraz JR, van der Heijden IM, Giudice M, Mostachio AK, Paez J, Carrilho C, Levin AS, Costa SF. In vitro activity of potential old and new drugs against multidrug-resistant gram-negatives. J Infect Chemother. 2015; 21(2): 114-7. http://dx.doi.org/10.1016/j.jiac.2014.10.009 PMid:25456893  .    
  86. Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev. 2008; 21, 538-82. http://dx.doi.org/10.1128/CMR.00058-07  PMid:18625687 PMCid:PMC2493088  .  
  87. Durante-Mangoni E, Del Franco M, Andini R, Bernardo M, Giannouli M, Zarrilli R. Emergence of colistin resistance without loss of fitness and virulence after prolonged colistin administration in a patient with extensively drug-resistant Acinetobacter baumannii. Diagn Microbiol Infect Dis. 2015, Vol. Epub ahead of print. .  
  88. Tascini C, Menichetti F, Bozza S, Del Favero A, Bistoni F. Evaluation of the activities of two-drug combinations of rifampicin, polymyxin B and ampicillin/sulbactam against Acinetobacter baumannii. J Antimicrob Chemother. 1998; 42, 270-1. http://dx.doi.org/10.1093/jac/42.2.270 PMid:9738852  .      
  89. Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, Bassetti M, Malacarne P, Petrosillo N, Galdieri N, Mocavero P, Corcione A, Viscoli C, Zarrilli R, Gallo C, Utili R. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis. 2013, Vol. 57, 349-58. http://dx.doi.org/10.1093/cid/cit253 PMid:23616495 .     
  90. Metan G, Alp E, Yildiz O, Percin D, Aygen B, Sumerkan B. Clinical experience with tigecycline in the treatment of carbapenem-resistant Acinetobacter infections. J Chemother. 2010; 22(2): 110-4. http://dx.doi.org/10.1179/joc.2010.22.2.110 PMid:20435570  .    
  91. Metan G, Pala Ç, Kaynar L, Cevahir F, Alp E. A nightmare for haematology clinics: extensively drug-resistant (XDR) Acinetobacter baumannnii. Infez Med. 2014; 22, 277-82. PMid:25551842  .    
  92. Nesher L, Rolston KV. The current spectrum of infection in cancer patients with chemotherapy related neutropenia. Infection. 2014; 42(1): 5-13. http://dx.doi.org/10.1007/s15010-013-0525-9 PMid:23975584  .    
  93. Orasch C, Averbuch D, Mikulska M, Cordonnier C, Livermore DM, Gyssens IC, Klyasova G, Engelhard D, Kern W, Viscoli C, Akova M, Marchetti O; 4th European Conference on Infections in Leukemia (ECIL-4); joint venture of Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation (IDWP-EBMT); Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (IDG-EORTC); International Immunocompromised Host Society (ICHS); European Leukemia Net (ELN) and European Study Group on Infections in Immunocompromised Hosts of the European Society for Clinical Microbiology and Infectious Diseases (ESGICH-ESCMID). Discontinuation of empirical antibiotic therapy in neutropenic leukaemia patients with fever of unknown origin is ethical. Clin Microbiol Infect. 2015; 21(3): e25-7.  .  
  94. Korucu B, Inkaya AC, Erbil AA, Okay M, Ascioglu S, Akova M. Early cessation of empirical antibacterial therapy in high-risk febrile neutropenic patients with FUO. 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 25-28 April 2015, Copenhagen, Denmark. P1206.
  95. Retamar P, López-Cerero L, Muniain MA, Pascual Á, Rodríguez-Ba-o J e Group., ESBL-REIPI/GEIH. Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-ß-lactamase-producing Escherichia coli. Antimicrob Agents Chemother. 2013; 57, 3402-4. http://dx.doi.org/10.1128/AAC.00135-13 PMid:23612190 PMCid:PMC3697383  .  
  96. Pagano L, Caira M, Trecarichi EM, Spanu T, Di Blasi R, Sica S, Sanguinetti M, Tumbarello M. Carbapenemase-producing Klebsiella pneumoniae and hematologic malignancies. Emerg Infect Dis. 2014; 20, 1235-6. http://dx.doi.org/10.3201/eid2007.130094  PMid:24960464 PMCid:PMC4073839  .  
  97. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR, Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011; 15, e56-93. http://dx.doi.org/10.1093/cid/cir073 PMid:21258094   .   
  98. Viale P, Tumietto F, Giannella M, Bartoletti M, Tedeschi S, Ambretti S, Cristini F, Gibertoni C, Venturi S, Cavalli M, De Palma A, Puggioli MC, Mosci D, Callea E, Masina R, Moro ML, Lewis RE. Impact of a hospital-wide multifaceted programme for reducing carbapenem-resistant Enterobacteriaceae infections in a large teaching hospital in northern Italy. Clin Microbiol Infect. 2015, Vol. 21, 242-7. http://dx.doi.org/10.1016/j.cmi.2014.10.020 PMid:25658534  .      
  99. Cattaneo C, Antoniazzi F, Casari S, Ravizzola G, Gelmi M, Pagani C, D'Adda M, Morello E, Re A, Borlenghi E, Manca N, Rossi G. P. aeruginosa bloodstream infections among hematological patients: an old or new question? Ann Hematol. 2012; 91, 1299-304. http://dx.doi.org/10.1007/s00277-012-1424-3 PMid:22349723 .     
  100. Lodise TP Jr, Patel N, Kwa A, Graves J, Furuno JP, Graffunder E, Lomaestro B, McGregor JC. Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection. Antimicrob Agents Chemother. 2007; 51, 3510-5. http://dx.doi.org/10.1128/AAC.00338-07 PMid:17646415 PMCid:PMC2043259  .  
  101. Deris ZZ, Yu HH, Davis K, Soon RL, Jacob J, Ku CK, Poudyal A, Bergen PJ, Tsuji BT, Bulitta JB, Forrest A, Paterson DL, Velkov T, Li J, Nation RL. The combination of colistin and doripenem is synergistic against Klebsiella pneumoniae at multiple inocula and suppresses colistin resistance in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrob Agents Chemother. 2012; 56, 5103-12..   http://dx.doi.org/10.1128/AAC.01064-12 PMid:22802247 PMCid:PMC3457376 .  
  102. Sbrana F, Malacarne P, Viaggi B, Costanzo S, Leonetti P, Leonildi A, Casini B, Tascini C, Menichetti F. Carbapenem-sparing antibiotic regimens for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae in intensive care unit. Clin Infect Dis. 2013; 56, 697-700. http://dx.doi.org/10.1093/cid/cis969 PMid:23155147  .    
  103. De Pascale G, Montini L, Pennisi M, Bernini V, Maviglia R, Bello G, Spanu T, Tumbarello M, Antonelli M. High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria. Crit Care. 2014, 5, 10.1186/cc13858. http://dx.doi.org/10.1186/cc13858  .  
  104. Fehér C, Rovira M, Soriano A, Esteve J, Martínez JA, Marco F, Carreras E, Martínez C, Fernández-Avilés F, Suárez-Lledó M, Mensa J. Effect of meropenem administration in extended infusion on the clinical outcome of febrile neutropenia: a retrospective observational study. J Antimicrob Chemother. 2014; 69, 2556-62. http://dx.doi.org/10.1093/jac/dku150 PMid:24855125  .   .   .      
  105. Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, Silveira FP, Forrest A, Nation RL. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011; 55, 3284-94. http://dx.doi.org/10.1128/AAC.01733-10 PMid:21555763 PMCid:PMC3122440    .   

 [TOP

Abstract views:
377

Views:
PDF
256
HTML
3961

Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM


Copyright (c) 2016 Mediterranean Journal of Hematology and Infectious Diseases

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

 

The Mediterranean Journal of Hematology and Infectious Diseases [eISSN 2035-3006] is owned by the U.C.S.C. and it is published by PAGEPress®, Pavia, Italy. All credits and honors to PKP for their OJS.
 
 
© PAGEPress 2008-2017     -     PAGEPress is a registered trademark property of PAGEPress srl, Italy.     -     VAT: IT02125780185