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
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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. 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.
|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
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. A large prospective
multicenter study by Cordonnier et al 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 and often
carry resistance genes.
CoNS are a major cause of BSI in neutropenic patients reaching 25% (5-60%) of all cases. 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, 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 except S. lugdunensis or S. capitis that are almost always susceptible to oxacillin.
Concerning glycopeptides, growing resistance to teicoplanin has been observed, in particular in S. haemoliticus where it can reach 20% of clinical isolates. On the other hand, resistance to vancomycin is still very low, except for S. schlefferi. More recently an alarming emergence of linezolid resistant S. epidermidis has been described in Greece. Resistance to linezolid has been associated with higher virulence and higher attributable mortality compared to linezolid susceptible staphylococci but they have not been described yet among neutropenic patients. Resistance to daptomycin is still anecdotic.
S. aureus is a common cause
of both hospital and community acquired BSIs and it handles 6%
(0-20%) of BSIs in onco-hematologic patients. The clinical
management of S. aureus BSI
(SAB) changes in case of complicated or uncomplicated presentation,
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). 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).
|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. 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, can represent
an important risk factor for the emergence of MRSA.
Vancomycin resistance is a marginal problem but high vancomycin MIC (between 1 and 2 mg/L), is associated with risk of failure. Interestingly vancomycin MIC >1 mg/L seem to be independently associated with the worst outcome also in methicillin susceptible S. aureus (MSSA) infected patients.
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.
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. New or soon available drugs for MDR bacteria and their characteristics|
Corynebacterium spp. and other Rare Gram-Positive Etiologies
|Figure 2. Spectrum of gram + bacteremias in patients with cancer (1082 patients) Modified by Rolston|
Gram-negative BSI in Hematologic Cancer Patients
|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]
Pseudomonas aeruginosa and other non Fermentative Gram Negative Bacilli (NFGNB)
|Table 3. Spectrum of gram negative infection in neutropenic patients and principal type of resistance.|